Cancer

The long term efficacy of combined transcatheter arterial embolization and percutaneous ethanol injection in the treatment of patients with large hepatocellular carcinoma and cirrhosis.

Tanaka K. Nakamura S. Numata K. Kondo M. Morita K. Kitamura T. Saito S. Kiba T. Okazaki H. Sekihara H.
Third Department of Internal Medicine, Yokohama City University School of Medicine, Yokohama, Japan.
BACKGROUND: The long term efficacy of combination therapy with transcatheter arterial embolization (TAE) followed by percutaneous ethanol injection (PEI) was studied in patients with large primary hepatocellular carcinoma (HCC) tumors and cirrhosis. METHODS: The series included 83 patients with large unresectable HCC lesions, the largest of which was greater than 3 cm in largest dimension. Fifty-five had a solitary lesion and 28 had multiple (2 or 3) lesions. All patients were treated with both TAE and PEI and their survival rates were determined. RESULTS: The 3-, 5-, and 7-year calculated survival rates for the patients were be 68%, 35%, and 14%, respectively. The number of lesions (solitary vs. multiple), the stage of cirrhosis (Child's Class A vs. Class B or C), and the size of the largest lesion (3-5 cm in largest dimension compared with > 5 cm) significantly affected the survival rate (P < 0.05 to P < 0.01, log rank test). The 3-, 5-, and 7-year survival rates of the Child's Class A patients who had a 3-5 cm solitary lesion (n = 22) were 100%, 75%, and 27%, respectively. The Cox proportional hazards model showed the stage of cirrhosis and size of the largest lesion to be independently associated with survival. No serious complications occurred during or after treatment. CONCLUSIONS: Combination therapy with TAE and PEI is an effective and safe treatment that may improve the long term survival of patients with cirrhosis associated with large HCC lesions, and survival after this combination therapy may be comparable to that after surgery.

Assessment of the expression of p53, MIB-1 (Ki-67 antigen), and argyrophilic nucleolar organizer regions in carcinoma of the extrahepatic bile duct.

Suto T. Sugai T. Nakamura S. Funato O. Nitta H. Sasaki R. Kanno S. Saito K.
Department of Surgery I, School of Medicine, Iwate Medical University, Morioka, Japan.
BACKGROUND: The authors retrospectively examined the predictive value of p53, MIB-1, and the argyrophilic nucleolar organizer regions (AgNOR) and examined the relationships among them in carcinoma of the extrahepatic bile duct (EHBD). METHODS: Formalin fixed, paraffin embedded specimens from 54 patients with EHBD carcinoma were immunostained with MIB-1 against the Ki-67 nuclear antigen and p53 by the avidin-biotin peroxidase complex method, using the antigen retrieval technique of heating tissue sections in a microwave oven. The AgNOR proteins were localized at the optical level, as shown by a one-step silver staining technique. RESULTS: MIB-1 and AgNOR were closely associated with lymph node metastasis (P < 0.01). The cumulative survival rate for patients with a low MIB-1 labeling index (LI) (< 29%) was significantly better than that for patients with a high MIB-1 LI (> or = 29%) in cases of EHBD carcinoma (P < 0.05), but MIB-1 was not an independent prognostic factor in multivariate analysis. The results indicated that AgNOR and p53 overexpression had no prognostic value. The authors detected p53 in 24 of the 54 EHBD carcinomas (44.4%). There was a significant correlation between MIB-1 and AgNOR (P < 0.01). The authors found that neither MIB-1 nor AgNOR correlated with p53 overexpression. CONCLUSIONS: MIB-1 and AgNOR proved to be useful predictors of lymph node metastasis. The results of this study indicated that MIB-1 and AgNOR might be markers of the progression of EHBD carcinoma.

K-ras mutations in the duodenal fluid of patients with pancreatic carcinoma.

Wilentz RE. Chung CH. Sturm PD. Musler A. Sohn TA. Offerhaus GJ. Yeo CJ. Hruban RH. Slebos RJ.
Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
BACKGROUND: Many patients with carcinoma of the pancreas die because their disease is not detected until late in its course. Methods that detect these cancers earlier will improve patient outcome. Over 80% of pancreatic carcinomas contain mutations in codon 12 of the K-ras gene. Screening duodenal fluid for these mutations may lead to early detection of these cancers and assist in establishing a diagnosis of pancreatic carcinoma. METHODS: Polymerase chain reaction (PCR), with and without restriction enzyme-mediated mutant enrichment, was performed on DNA isolated from duodenal fluid specimens from 61 patients who underwent pancreaticoduodenectomy (Whipple's operation) for either periampullary cancer or a benign condition of the pancreas. Representative sections of pancreas pathology (primary carcinoma, benign tumor, or chronic pancreatitis) from the patients with duodenal fluid specimens containing amplifiable DNA were also analyzed for K-ras mutations. Wild-type and mutant K-ras were detected by hybridization of the PCR products with K-ras codon 12 mutant and wild-type specific probes. RESULTS: Seven of the 61 duodenal fluid specimens contained DNA that did not amplify. Thirteen (24% of the 54 duodenal fluid specimens with amplifiable DNA and 21% of the total of 61 specimens) contained activating point mutations at codon 12 of the K-ras gene. Mutations were detected in 13 of the 51 duodenal fluid specimens from patients with cancer (sensitivity, 25%), whereas mutations were not detected in any of the 9 amplifiable duodenal fluid specimens from patients with benign conditions of the pancreas (specificity, 100%). One duodenal fluid specimen from a patient with adenocarcinoma of the pancreas had two different K-ras mutations. DNA from three of the primary carcinomas did not amplify or was not available. Twenty-nine (69%) of the 42 primary tumors with amplifiable DNA contained K-ras mutations, whereas 3 (30%) of the 10 pancreata with benign conditions harbored mutations. Twenty-two (65%) of 34 ductal adenocarcinomas of the pancreas with amplifiable DNA had K-ras mutations. It is noteworthy that the same mutation was present in both the duodenal fluid and the primary carcinomas of 11 (92%) of the 12 patients who had primary tumors with amplifiable DNA as well as K-ras mutations in their duodenal fluid specimens. CONCLUSIONS: The identification of genetic alterations in cancer-causing genes in duodenal fluid may form the basis for the development of new approaches to the detection of carcinoma of the pancreas. Some pancreata without cancer, however, may also harbor K-ras mutations, potentially limiting the specificity of K-ras-based tests.

Identification of oncofetal fibronectin in patients with advanced epithelial ovarian cancer: detection in ascitic fluid and localization to primary sites and metastatic implants.

Menzin AW. Loret de Mola JR. Bilker WB. Wheeler JE. Rubin SC. Feinberg RF.
Department of Obstetrics and Gynecology, University of Pennsylvania Medical Center, Philadelphia, USA.
BACKGROUND: The mechanisms by which metastatic ovarian cancer adheres to peritoneal surfaces are not well understood. A role for tumor-derived extracellular matrix adhesive molecules such as fibronectin (FN) has been proposed. Because oncofetal fibronectin (onfFN) isoforms function in the adhesion of trophoblasts and have been identified in association with several malignancies, we sought to study onfFN in patients with advanced epithelial ovarian cancer. METHODS: Total FN was identified with the nonspecific anti-FN monoclonal antibody CAF. OnfFN was identified using the specific monoclonal antibodies FDC-6 and X18A4. These antibodies were applied to: 1) ascitic fluid from advanced epithelial ovarian cancer patients and peritoneal fluid from patients without pathologic conditions and 2) tissue sections of primary lesions and metastatic ovarian cancer implants. Comparative histologic specimens included normal ovarian tissue and small bowel implants of endometriosis. RESULTS: When measured by sandwich enzyme-linked immunoadsorbent assay, all peritoneal fluids (32 malignant and 32 benign) contained marked quantities of total (CAF reactive) FN, although malignant ascites had higher concentrations than benign samples (173.2 +/- 36.8 microg/mL vs. 76.4 +/- 31.8 microg/mL; P = 0.001). Malignant ascites also had significantly higher levels of onfFN than benign peritoneal fluid (FDC-6: 3.4 +/- 0.6 vs. 0.9 +/- 0.2 microg/mL; and X18A4: 5.1 +/- 1.3 vs. 1.1 +/- 0.4 microg/mL; P = 0.0001). Immunohistochemical staining of malignant lesions revealed prominent localization of both CAF reactive FN and onfFN to the stroma surrounding epithelial tumor nests. More delicate fibrillar staining within tumor nests also was evident. In contrast, implants of endometriosis revealed strong stromal staining for CAF reactive FN but not for onfFN. CONCLUSIONS: These results demonstrate the presence of onfFN in advanced ovarian malignancies. We speculate that onfFN may participate in tumor-associated peritoneal adhesive interactions.

Cancer among spouses: review of 195 couples.

Walach N. Novikov I. Milievskaya I. Goldzand G. Modan B.
Department of Oncology, Assaf Harofeh Medical Center, Zrifin, Israel.
BACKGROUND: The study of cancer in spouses may play an important role in the assessment of cancer etiology. METHODS: Patterns of occurrence of cancer in 195 couples related by marriage only and treated in a regional hospital are reported. The distribution of tumors by site was compared with national data. RESULTS: Seven sites of cancer were found to be more frequent in married couples than in the general population, in particular carcinoma of the colon (37 observed vs. 19.5 expected in husbands [relative risk (RR) = 1.89 (95% confidence intervals [CI], 1.5-2.4); P < 0.001] and 32 vs. 16.7 in wives [RR = 1.92 (95% CI, 1.4-2.5); P < 0.001]), carcinoma of the prostate (32 vs. 20 in husbands [RR = 1.6 (95% CI, 1.19-2.09); P < 0.01]), and carcinoma of the female breast (84 vs. 55 in wives [RR = 1.53 (95% CI, 1.3-1.8); P < 0.001]). Same site tumors were observed in 13 couples versus 6.21 expected in the general population (RR = 2.09 [95% CI, 1.25-3.26]; P < 0.01). A combination of carcinoma of the prostate and female breast sites was found in 18 couples versus 5.4 expected in the general population (RR = 3.34 [95% CI, 2.19-4.84]; P < 0.001). CONCLUSIONS: The distribution of cancer sites among spouses in those families in which both spouses have developed a cancer differs from that of the general population. These differences may be caused by shared risk factors. Increased awareness can explain only part of the excess.

Effects of cachexia due to cancer on whole body and skeletal muscle protein turnover.

Dworzak F. Ferrari P. Gavazzi C. Maiorana C. Bozzetti F.
Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
BACKGROUND: Data available in the literature regarding whole body protein (WBP) kinetics in patients with cachexia due to cancer are conflicting. Some authors have reported an increase of WBP synthesis and breakdown, whereas others have not found any significant changes; only a few researchers have investigated more compartments simultaneously. The main purpose of this study was to investigate WBP and skeletal muscle protein (SMP) turnover simultaneously in cachectic patients to understand better the mechanisms underlying the general wasting of the host present in cancer cachexia. METHODS: WBP and SMP synthesis and breakdown were studied in malnourished patients with advanced gastric carcinoma and in healthy volunteers. Protein turnover was evaluated in a postabsorptive state, using a model based on a primed constant infusion of L-[(2)H5] phenylalanine and L-[(2)H4]tyrosine, and by determining the isotopic enrichment and concentration in plasma during a plateau phase by gas chromatography and mass spectrometry. RESULTS: Rates of WBP synthesis and breakdown did not differ significantly between the two groups (whole body synthesis [WBS] of 4.35 +/- 0.2 g/kg/day and whole body breakdown [WBB] of 4.77 +/- 0.2 g/kg/day in the control group and WBS of 3.34 +/- 0.7 g/kg/day and WBB of 4.5 +/- 0.4 g/kg/day in the patient group). The skeletal muscle compartment of the patients showed a significantly lower synthesis compared with controls (patients, 9.6 +/- 1.8 nmol/100 mL/minute and control, 25.9 +/- 7.6 nmol/100 mL/minute; P < 0.05), whereas the breakdown was similar in the two groups. Such reduction in SMP synthesis in the gastric carcinoma patients resulted in a more negative net balance. CONCLUSIONS: Conflicting data in the literature may be accounted for by the different selection of patients and controls. Furthermore, WBP kinetics is the result of the metabolism of at least two compartments, the muscle and the nonmuscle compartments (including the tumor), which can change in opposite ways. In patients with cachexia due to cancer, the skeletal compartment appears to be the more compromised, with a significant decrease in SMP synthesis.

Prognostic significance of DNA ploidy in patients with stage II and stage III colon carcinoma: a prospective flow cytometric study.

Lanza G. Gafa R. Santini A. Maestri I. Dubini A. Gilli G. Cavazzini L.
Dipartimento di Medicina Sperimentale e Diagnostica, Universita di Ferrera, Italy.
BACKGROUND: The prognostic value of flow cytometric DNA ploidy in colorectal carcinoma has not been defined clearly. Most previous studies were conducted retrospectively using archival formalin fixed, paraffin embedded tumor samples. Conversely, few data on prospective studies employing fresh or frozen tissue specimens are available. There is general agreement that fresh/frozen material is more reliable than paraffin embedded tissue for DNA ploidy analysis by flow cytometry. METHODS: In the current investigation we evaluated the prognostic significance of nuclear DNA content in a prospective series of 191 patients with curatively resected TNM Stage II (n = 107) or Stage III (n = 84) sporadic colon carcinomas. DNA ploidy status was assessed by flow cytometry utilizing multiple frozen tumor samples. Mean follow-up in surviving patients was 48.5 months (median, 46.9 months; range, 29-77 months). The Cox proportional hazards model was used to adjust for several clinical and pathologic covariates. RESULTS: Of the 191 carcinomas examined, 47 (24.6%) were classified as DNA diploid and 144 (75.4%) as DNA aneuploid. DNA ploidy pattern was significantly related to tumor site (P < 0.0001), histologic type (P = 0.0002), and grade of differentiation (P = 0.009), but not to other clinical and pathologic variables. Patients with DNA diploid tumors showed a better disease free (P = 0.013) and overall survival (P = 0.021) than patients with DNA aneuploid adenocarcinomas. In particular, patients with Stage II DNA diploid tumors (n = 30) had an excellent clinical outcome, with an overall 5-year survival rate of 97%. When patients were analyzed according to the anatomic site of the tumor, a significant relationship between DNA ploidy status and disease free and overall survival was observed in the group of patients with carcinomas of the proximal colon (n = 84) (P = 0.004 and P = 0.002, respectively), but not among patients whose tumors were sited distally to the splenic flexure (n = 107). In multivariate analysis, nuclear DNA content was demonstrated to be an independent prognostic variable for both disease free and overall survival. Furthermore, in the group of patients with tumors of the proximal colon, DNA ploidy pattern was the single most important prognostic factor. CONCLUSIONS: Our results confirm that flow cytometric DNA ploidy status is a significant and independent prognostic factor in patients with colon carcinoma. These findings may have clinical implications for the management of affected patients, especially those with Stage II disease.

Differences in the diagnostic criteria used by Japanese and Western pathologists to diagnose colorectal carcinoma.

Schlemper RJ. Itabashi M. Kato Y. Lewin KJ. Riddell RH. Shimoda T. Sipponen P. Stolte M. Watanabe H.
Department of Gastroenterology, Showa University Fujigaoka Hospital, Yokohama, Japan.
BACKGROUND: In view of the many studies of early stage colorectal carcinoma from Japan, it is essential to know whether the criteria for the histologic diagnosis of colorectal carcinoma are similar in Japan and Western countries. METHODS: Eight expert pathologists from Japan (4), North America (2), and Europe (2) individually reviewed microscope slides of 20 colorectal lesions from Japanese patients who had undergone endoscopic mucosal resection or surgery because early stage carcinoma and/or adenoma was suspected. The pathologists indicated the pathologic findings on which they based each diagnosis. RESULTS: For 11 slides that showed adenoma according to the Western pathologists with low grade dysplasia according to at least half of them, the Japanese diagnosed definite carcinoma with or without adenoma in 4 cases and adenoma in 5, and in 2 cases they were equally divided between a diagnosis of adenoma and carcinoma. For five slides showing adenoma with high grade dysplasia according to the Western pathologists, the Japanese diagnosed definite carcinoma with adenoma in three cases and adenoma in one, and in one case they were equally divided between a diagnosis of adenoma and carcinoma. For one case in which the Western pathologists were equally divided between a diagnosis of carcinoma and adenoma with high grade dysplasia, all the Japanese pathologists diagnosed definite carcinoma with or without adenoma. Three slides showed definite carcinoma with or without adenoma, according to both the Western and the Japanese pathologists. The presence of invasion was the most important diagnostic criterion of colorectal carcinoma for the Western pathologists, whereas for the Japanese the nuclear features and glandular structures were more important. CONCLUSIONS: In Japan, colorectal carcinoma is diagnosed on the basis of nuclear and structural criteria, even in cases considered by Western pathologists to be noninvasive lesions with low grade dysplasia. This diagnostic practice may contribute to the relatively high incidence of early stage colorectal carcinoma reported in Japan as compared with Western countries.

A new prognostic factor for colorectal carcinoma, thymidylate synthase, and its therapeutic significance.

Yamachika T. Nakanishi H. Inada K. Tsukamoto T. Kato T. Fukushima M. Inoue M. Tatematsu M.
Laboratory of Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.
BACKGROUND: Expression of thymidylate synthase (TS) has been studied as a mechanism of drug resistance and a prognostic factor for various cancers. METHODS: The relation between TS expression in surgically resected specimens and patient survival was examined in 86 patients with colorectal carcinoma (58 of whom received adjuvant chemotherapy and 28 who did not) who had been followed for 10 years. Immunohistochemical demonstration of the protein was achieved using an anti-TS polyclonal antibody. RESULTS: In the 58 patients who received chemotherapy, the overall 10-year survival rate was 77.8% for patients with TS positive tumors and 89.4% for patients with TS negative tumors (difference not significant). However, in the 28 patients who did not receive chemotherapy, these figures were only 42.9% and 85.7%, respectively (P < 0.05). Multivariate analysis also revealed TS expression to be a significant variable for predicting postoperative survival (P < 0.05). CONCLUSIONS: TS expression can be used as an independent prognostic factor for patients with colorectal carcinoma. Patients with TS positive tumors have a poorer prognosis than those with TS negative lesions and therefore should receive special consideration with regard to chemotherapy.

Helicobacter pylori and the null genotype of glutathione-S-transferase-mu in patients with gastric adenocarcinoma.

Ng EK. Sung JJ. Ling TK. Ip SM. Lau JY. Chan AC. Liew CT. Chung SC.
Department of Surgery, Prince of Wales Hospital, Shatin, N.T., Hong Kong.
BACKGROUND. Chronic Helicobacter pylori infection now is recognized as an important causative agent for gastric carcinoma. However, only a small minority of infected individuals develop the malignancy, even in areas with a high prevalence of gastric carcinoma. It has been postulated that the absence of glutathione-S-transferase-mu (GST-mu), which impairs detoxification of exogenous carcinogens, might predispose some infected individuals to the development of gastric carcinoma. METHODS. Patients with histologically confirmed adenocarcinoma of the stomach were tested for H. pylori infection and the GST-mu genotype. Prevalence of GST-mu gene deletion was compared with the H. pylori status of the patients. A group of gender- and age-matched control subjects with known H. pylori-related nonulcer dyspepsia also were tested for the GST-mu genotype and compared with patients with H. pylori positive carcinoma. RESULTS. Fifty-one patients with gastric adenocarcinoma were enrolled into the study. Thirty-five were found to have H. pylori in the resected specimens. The null genotype of GST-mu was significantly more common among those patients with H. pylori positive carcinoma compared with the H. pylori negative group (65.7% vs. 31.3%; P < 0.05). Homozygous deletion of GST-mu was significantly higher in the H. pylori positive carcinoma patients than in the H. pylori-infected, nonmalignant control group (65.7% vs. 37.1%; P < 0.05). CONCLUSIONS. The null genotype for GST-mu is found more commonly in gastric carcinoma associated with H. pylori infection. The absence of the GST-mu enzyme may increase the risk of the development of gastric carcinoma in these patients.

Resection of hepatic and pulmonary metastases in patients with colorectal carcinoma.

Ambiru S. Miyazaki M. Ito H. Nakagawa K. Shimizu H. Kato A. Nakamura S. Omoto H. Nakajima N.
The First Department of Surgery, Chiba University School of Medicine, Japan.
BACKGROUND. Surgical resection of hepatic or pulmonary metastases has been accepted as appropriate therapy. However, whether aggressive surgery of both hepatic and pulmonary metastases from colorectal carcinoma is of value has not been verified in detail. METHODS. The authors identified 156 patients who had undergone hepatic resection for colorectal carcinoma metastases. This study reviewed six of these patients who underwent resection of both hepatic and pulmonary metastases from colorectal carcinoma. RESULTS. Five of the patients included four who underwent pulmonary resection for pulmonary metastases after initial hepatic resection for hepatic metastases and one patient who underwent hepatic metastasis resection after initial pulmonary metastasis resection. One additional patient underwent a simultaneous resection of hepatic and pulmonary metastases. The median interval between the 2 resections was 23 months. The median follow-up was 32 months after the second resection. At the time of last follow-up, 4 patients were alive and free of recurrent disease at 6, 7, 38, and 64 months, respectively, after their second resection. The remaining 2 patients died of disease at 17 and 32 months, respectively, after the second surgery. CONCLUSIONS. The results of the current study suggest that hepatic and pulmonary resection can result in long term survival in select patients with hepatic and pulmonary metastases from colorectal carcinoma because surgery remains the only potentially curative treatment.

Clinicopathologic and genetic features of nonfamilial colorectal carcinomas with DNA replication errors.

Senba S. Konishi F. Okamoto T. Kashiwagi H. Kanazawa K. Miyaki M. Konishi M. Tsukamoto T.
Department of Surgery, Jichi Medical School, Tochigi, Japan.
BACKGROUND. DNA replication errors (RERs) are closely associated with hereditary nonpolyposis colorectal carcinoma (HNPCC). Recently, alterations in DNA mismatch repair genes, including hMSH2, hMLH1, and hPMS2, have been implicated in the pathogenesis of HNPCC. Several studies have demonstrated RER in 13-17% of nonfamilial colorectal carcinomas. It is unclear, however, as to whether or not these RER positive nonfamilial colorectal carcinomas are incomplete forms of HNPCC or are caused by incidental alterations of DNA mismatch repair genes. Consequently, the authors studied the characteristics of RER positive nonfamilial colorectal carcinomas, placing particular emphasis on hMSH2 and hMLH1 gene mutations. METHODS. Fresh or frozen samples of 103 nonfamilial colorectal carcinomas were examined for RERs using the polymerase chain reaction (PCR) and specific microsatellite primers. The authors also identified mutations of the hMSH2 and hMLH1 genes in RER positive samples by a PCR single strand conformational polymorphism analysis followed by direct nucleotide sequencing. RESULTS. The incidence of RER was 15.7% (17/103) in nonfamilial colorectal carcinomas, and only 1 case, which was found in the ascending colon, showed a somatic mutation at exon 12 in the hMSH2 gene. Neither germline nor somatic mutations of the hMSH2 or hMLH1 genes could be found in any of the remaining RER positive tumors. RER positive nonfamilial carcinomas tended to be located more frequently in the right colon. There was no increased prevalence in young patients, and the clinicopathologic characteristics of HNPCC were absent in the patients with RER positive nonfamilial colorectal carcinoma. CONCLUSIONS. Based on these findings, the carcinogenesis of RER positive nonfamilial colorectal carcinoma is considered different from that of HNPCC.

Cisplatin, ifosfamide, and prolonged oral etoposide in the treatment of patients with extensive small cell lung carcinoma.

Glisson B. Lee JS. Palmer J. Fossella F. Shin DM. Murphy WK. Perez-Soler R. Hong WK.
The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
BACKGROUND. The combination of cisplatin, ifosfamide, and prolonged oral etoposide (PIE) was studied in patients with extensive small cell lung carcinoma (SCLC) in a Phase I trial followed by a Phase II trial to determine the maximum tolerated dose (MTD), characterize toxicity, and estimate response and median survival rates. METHODS. Thirty-three patients were treated between October 1991 and December 1994. Doses for the initial cohort were cisplatin 20 mg/m2/day, ifosfamide 1500 mg/m2/day with mesna (all given intravenously on Days 1-3), and oral etoposide 50 mg/m2 on Days 4-17. This cycle was repeated every 4 weeks for up to 6 cycles. The MTD was reached for the first 9 patients. For these 9 patients and the next 24 patients, who were entered in the Phase II trial, response and survival were estimated. RESULTS. Dose-limiting toxicity was manifested as Grade 4 neutropenia in 3 of 3 patients (associated with fever in 2 of 3), and Grade 4 thrombocytopenia was encountered in 2 of 3 patients at the second dose level. Of 6 patients treated at the first dose level, 4 achieved targeted myelosuppression (absolute granulocyte count nadir

A phase II study of irinotecan (CPT-11) in patients with advanced squamous cell carcinoma of the cervix.

Irvin WP. Price FV. Bailey H. Gelder M. Rosenbluth R. Durivage HJ. Potkul RK.
Division of Gynecologic Oncology, Loyola University Medical Center, Maywood, Illinois 60153, USA.
BACKGROUND. This study was conducted to determine the efficacy and safety of irinotecan (CPT-11) as second-line therapy in patients with advanced cervical carcinoma. METHODS. Sixteen patients with platinum-resistant squamous cell carcinoma were treated with CPT-11 as second-line therapy. CPT-11 was administered in repeated 6-week cycles comprised of the administration of CPT-11 once weekly for 4 weeks, followed by a 2-week rest. The starting dose of CPT-11 was 125 mg/M2 given intravenously over 90 minutes; subsequent doses were adjusted based on individual patient tolerance. RESULTS. The median age of the patients was 43 years (range, 27-69 years). Three patients had a baseline Eastern Cooperative Oncology Group performance score (PS) of 0, 8 had a PS of 1, and 5 had a PS of 2. All patients had received cisplatin-based chemotherapy and 13 of 16 patients (81.3%) had been treated with prior pelvic/abdominal radiation therapy. Fourteen patients were evaluable for response. There were no objective responses although subjective decreases in symptoms were observed in some patients. Grade 3 to 4 toxicities included diarrhea in three patients, nausea and emesis in one patient, leukopenia in six patients, and neutropenia in five patients. Eighteen of 25 cycles required dose reductions leading to a median dose intensity of only 59.4 mg/M2/week, which was 71% of the planned dose of 83.3 mg/M2/week. CONCLUSIONS. The amount of CPT-11 actually delivered to the patients under the conditions of this pilot study failed to result in an antitumor response. However, the marked subjective improvement of symptoms observed in this study and the significant activity reported by other investigators justify future studies of CPT-11 in patients with cervical carcinoma.

The role of surgery in the treatment of clinically isolated adrenal metastasis.

Kim SH. Brennan MF. Russo P. Burt ME. Coit DG.
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
BACKGROUND. Clinically isolated adrenal metastasis is rare. The role of surgical resection is unknown. The aim of this study was to define clinical and pathologic parameters that might predict long term survival after resection of adrenal metastasis. METHODS. The authors conducted a retrospective review of 37 patients who had undergone adrenalectomy for metastatic disease at the Memorial Sloan-Kettering Cancer Center (MSKCC) between July 1986 and October 1996. Patients who underwent resection of tumors that locally invaded the adrenal gland were excluded from the study, as were all patients with primary adrenal tumors. RESULTS. There were 24 men and 13 women, with a median age of 58 years (range, 42-77 years). Lung carcinoma was the most common primary tumor (n = 17), followed by renal cell carcinoma (n = 9), and colorectal carcinoma (n = 5). The median length of stay at MSKCC was 8 days (range, 3-21 days). There was a 19% incidence of complications (12% major). There was one perioperative death. Five-year survival for the entire group was 24% (median, 21 months). Disease free interval (DFI) of > 6 months and complete resection were the only predictors of improved survival. CONCLUSIONS. Adrenalectomy for clinically solitary, resectable lesions can be performed safely, and prolonged survival can be achieved in such selected patients. Adrenalectomy should be considered for patients with completely resectable disease and a DFI of > 6 months.

A prospective crossover randomized trial of novobiocin and rifampin prophylaxis for the prevention of intravascular catheter infections in cancer patients treated with interleukin-2.

Raad II. Hachem RY. Abi-Said D. Rolston KV. Whimbey E. Buzaid AC. Legha S.
Department of Medical Specialties, the University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
BACKGROUND. The aim of this study was to determine the efficacy of novobiocin and rifampin as oral antibiotic prophylaxis for the prevention of catheter-related infection in melanoma patients treated with interleukin-2 (IL-2) plus interferon-alpha and chemotherapy (biochemotherapy). METHODS. Patients with advanced melanoma who were treated with biochemotherapy at the University of Texas M. D. Anderson Cancer Center were randomized in a crossover study to receive either oral antibiotic prophylaxis consisting of novobiocin and rifampin or observation alone over a 35-day course period. Patients were subsequently "crossed over" to the opposite arm of the study for an additional 35-day period, with each serving as his or her own control. RESULTS. Twenty-six patients were enrolled. Nine patients (35%) failed to tolerate oral antibiotics because of severe nausea and vomiting; 17 patients (65%) were crossed over and considered evaluable. During the control patient courses, 71% of evaluable patients had infectious complications, 41% had a catheter-associated bacteremia, and 53% had a local catheter infection. In contrast, of the patients treated with antibiotic prophylaxis, only 12% had an infectious complication (P = 0.001), 12% had a local catheter infection (P = 0.008), and 6% had catheter-associated bacteremias (P = 0.04). Thirty-six episodes of catheter infections occurred during the 17 control courses, whereas only 3 episodes occurred during antibiotic prophylaxis (P < 0.001). CONCLUSIONS. Although more than one-third of patients receiving IL-2 treatment with biochemotherapy failed to tolerate novobiocin and rifampin, this oral antibiotic regimen was efficacious in preventing the infectious complications, especially those associated with vascular catheters, in this high risk patient population.

Helicobacter pylori and the null genotype of glutathione-S-transferase-mu in patients with gastric adenocarcinoma.

Ng EK. Sung JJ. Ling TK. Ip SM. Lau JY. Chan AC. Liew CT. Chung SC.
Department of Surgery, Prince of Wales Hospital, Shatin, N.T., Hong Kong.
BACKGROUND. Chronic Helicobacter pylori infection now is recognized as an important causative agent for gastric carcinoma. However, only a small minority of infected individuals develop the malignancy, even in areas with a high prevalence of gastric carcinoma. It has been postulated that the absence of glutathione-S-transferase-mu (GST-mu), which impairs detoxification of exogenous carcinogens, might predispose some infected individuals to the development of gastric carcinoma. METHODS. Patients with histologically confirmed adenocarcinoma of the stomach were tested for H. pylori infection and the GST-mu genotype. Prevalence of GST-mu gene deletion was compared with the H. pylori status of the patients. A group of gender- and age-matched control subjects with known H. pylori-related nonulcer dyspepsia also were tested for the GST-mu genotype and compared with patients with H. pylori positive carcinoma. RESULTS. Fifty-one patients with gastric adenocarcinoma were enrolled into the study. Thirty-five were found to have H. pylori in the resected specimens. The null genotype of GST-mu was significantly more common among those patients with H. pylori positive carcinoma compared with the H. pylori negative group (65.7% vs. 31.3%; P < 0.05). Homozygous deletion of GST-mu was significantly higher in the H. pylori positive carcinoma patients than in the H. pylori-infected, nonmalignant control group (65.7% vs. 37.1%; P < 0.05). CONCLUSIONS. The null genotype for GST-mu is found more commonly in gastric carcinoma associated with H. pylori infection. The absence of the GST-mu enzyme may increase the risk of the development of gastric carcinoma in these patients.

Resection of hepatic and pulmonary metastases in patients with colorectal carcinoma.

Ambiru S. Miyazaki M. Ito H. Nakagawa K. Shimizu H. Kato A. Nakamura S. Omoto H. Nakajima N.
The First Department of Surgery, Chiba University School of Medicine, Japan.
BACKGROUND. Surgical resection of hepatic or pulmonary metastases has been accepted as appropriate therapy. However, whether aggressive surgery of both hepatic and pulmonary metastases from colorectal carcinoma is of value has not been verified in detail. METHODS. The authors identified 156 patients who had undergone hepatic resection for colorectal carcinoma metastases. This study reviewed six of these patients who underwent resection of both hepatic and pulmonary metastases from colorectal carcinoma. RESULTS. Five of the patients included four who underwent pulmonary resection for pulmonary metastases after initial hepatic resection for hepatic metastases and one patient who underwent hepatic metastasis resection after initial pulmonary metastasis resection. One additional patient underwent a simultaneous resection of hepatic and pulmonary metastases. The median interval between the 2 resections was 23 months. The median follow-up was 32 months after the second resection. At the time of last follow-up, 4 patients were alive and free of recurrent disease at 6, 7, 38, and 64 months, respectively, after their second resection. The remaining 2 patients died of disease at 17 and 32 months, respectively, after the second surgery. CONCLUSIONS. The results of the current study suggest that hepatic and pulmonary resection can result in long term survival in select patients with hepatic and pulmonary metastases from colorectal carcinoma because surgery remains the only potentially curative treatment.

Clinicopathologic and genetic features of nonfamilial colorectal carcinomas with DNA replication errors.

Senba S. Konishi F. Okamoto T. Kashiwagi H. Kanazawa K. Miyaki M. Konishi M. Tsukamoto T.
Department of Surgery, Jichi Medical School, Tochigi, Japan.
BACKGROUND. DNA replication errors (RERs) are closely associated with hereditary nonpolyposis colorectal carcinoma (HNPCC). Recently, alterations in DNA mismatch repair genes, including hMSH2, hMLH1, and hPMS2, have been implicated in the pathogenesis of HNPCC. Several studies have demonstrated RER in 13-17% of nonfamilial colorectal carcinomas. It is unclear, however, as to whether or not these RER positive nonfamilial colorectal carcinomas are incomplete forms of HNPCC or are caused by incidental alterations of DNA mismatch repair genes. Consequently, the authors studied the characteristics of RER positive nonfamilial colorectal carcinomas, placing particular emphasis on hMSH2 and hMLH1 gene mutations. METHODS. Fresh or frozen samples of 103 nonfamilial colorectal carcinomas were examined for RERs using the polymerase chain reaction (PCR) and specific microsatellite primers. The authors also identified mutations of the hMSH2 and hMLH1 genes in RER positive samples by a PCR single strand conformational polymorphism analysis followed by direct nucleotide sequencing. RESULTS. The incidence of RER was 15.7% (17/103) in nonfamilial colorectal carcinomas, and only 1 case, which was found in the ascending colon, showed a somatic mutation at exon 12 in the hMSH2 gene. Neither germline nor somatic mutations of the hMSH2 or hMLH1 genes could be found in any of the remaining RER positive tumors. RER positive nonfamilial carcinomas tended to be located more frequently in the right colon. There was no increased prevalence in young patients, and the clinicopathologic characteristics of HNPCC were absent in the patients with RER positive nonfamilial colorectal carcinoma. CONCLUSIONS. Based on these findings, the carcinogenesis of RER positive nonfamilial colorectal carcinoma is considered different from that of HNPCC.

Cisplatin, ifosfamide, and prolonged oral etoposide in the treatment of patients with extensive small cell lung carcinoma.

Glisson B. Lee JS. Palmer J. Fossella F. Shin DM. Murphy WK. Perez-Soler R. Hong WK.
The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
BACKGROUND. The combination of cisplatin, ifosfamide, and prolonged oral etoposide (PIE) was studied in patients with extensive small cell lung carcinoma (SCLC) in a Phase I trial followed by a Phase II trial to determine the maximum tolerated dose (MTD), characterize toxicity, and estimate response and median survival rates. METHODS. Thirty-three patients were treated between October 1991 and December 1994. Doses for the initial cohort were cisplatin 20 mg/m2/day, ifosfamide 1500 mg/m2/day with mesna (all given intravenously on Days 1-3), and oral etoposide 50 mg/m2 on Days 4-17. This cycle was repeated every 4 weeks for up to 6 cycles. The MTD was reached for the first 9 patients. For these 9 patients and the next 24 patients, who were entered in the Phase II trial, response and survival were estimated. RESULTS. Dose-limiting toxicity was manifested as Grade 4 neutropenia in 3 of 3 patients (associated with fever in 2 of 3), and Grade 4 thrombocytopenia was encountered in 2 of 3 patients at the second dose level. Of 6 patients treated at the first dose level, 4 achieved targeted myelosuppression (absolute granulocyte count nadir

A phase II study of irinotecan (CPT-11) in patients with advanced squamous cell carcinoma of the cervix.

Irvin WP. Price FV. Bailey H. Gelder M. Rosenbluth R. Durivage HJ. Potkul RK.
Division of Gynecologic Oncology, Loyola University Medical Center, Maywood, Illinois 60153, USA.
BACKGROUND. This study was conducted to determine the efficacy and safety of irinotecan (CPT-11) as second-line therapy in patients with advanced cervical carcinoma. METHODS. Sixteen patients with platinum-resistant squamous cell carcinoma were treated with CPT-11 as second-line therapy. CPT-11 was administered in repeated 6-week cycles comprised of the administration of CPT-11 once weekly for 4 weeks, followed by a 2-week rest. The starting dose of CPT-11 was 125 mg/M2 given intravenously over 90 minutes; subsequent doses were adjusted based on individual patient tolerance. RESULTS. The median age of the patients was 43 years (range, 27-69 years). Three patients had a baseline Eastern Cooperative Oncology Group performance score (PS) of 0, 8 had a PS of 1, and 5 had a PS of 2. All patients had received cisplatin-based chemotherapy and 13 of 16 patients (81.3%) had been treated with prior pelvic/abdominal radiation therapy. Fourteen patients were evaluable for response. There were no objective responses although subjective decreases in symptoms were observed in some patients. Grade 3 to 4 toxicities included diarrhea in three patients, nausea and emesis in one patient, leukopenia in six patients, and neutropenia in five patients. Eighteen of 25 cycles required dose reductions leading to a median dose intensity of only 59.4 mg/M2/week, which was 71% of the planned dose of 83.3 mg/M2/week. CONCLUSIONS. The amount of CPT-11 actually delivered to the patients under the conditions of this pilot study failed to result in an antitumor response. However, the marked subjective improvement of symptoms observed in this study and the significant activity reported by other investigators justify future studies of CPT-11 in patients with cervical carcinoma.

The role of surgery in the treatment of clinically isolated adrenal metastasis.

Kim SH. Brennan MF. Russo P. Burt ME. Coit DG.
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
BACKGROUND. Clinically isolated adrenal metastasis is rare. The role of surgical resection is unknown. The aim of this study was to define clinical and pathologic parameters that might predict long term survival after resection of adrenal metastasis. METHODS. The authors conducted a retrospective review of 37 patients who had undergone adrenalectomy for metastatic disease at the Memorial Sloan-Kettering Cancer Center (MSKCC) between July 1986 and October 1996. Patients who underwent resection of tumors that locally invaded the adrenal gland were excluded from the study, as were all patients with primary adrenal tumors. RESULTS. There were 24 men and 13 women, with a median age of 58 years (range, 42-77 years). Lung carcinoma was the most common primary tumor (n = 17), followed by renal cell carcinoma (n = 9), and colorectal carcinoma (n = 5). The median length of stay at MSKCC was 8 days (range, 3-21 days). There was a 19% incidence of complications (12% major). There was one perioperative death. Five-year survival for the entire group was 24% (median, 21 months). Disease free interval (DFI) of > 6 months and complete resection were the only predictors of improved survival. CONCLUSIONS. Adrenalectomy for clinically solitary, resectable lesions can be performed safely, and prolonged survival can be achieved in such selected patients. Adrenalectomy should be considered for patients with completely resectable disease and a DFI of > 6 months.

A prospective crossover randomized trial of novobiocin and rifampin prophylaxis for the prevention of intravascular catheter infections in cancer patients treated with interleukin-2.

Raad II. Hachem RY. Abi-Said D. Rolston KV. Whimbey E. Buzaid AC. Legha S.
Department of Medical Specialties, the University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
BACKGROUND. The aim of this study was to determine the efficacy of novobiocin and rifampin as oral antibiotic prophylaxis for the prevention of catheter-related infection in melanoma patients treated with interleukin-2 (IL-2) plus interferon-alpha and chemotherapy (biochemotherapy). METHODS. Patients with advanced melanoma who were treated with biochemotherapy at the University of Texas M. D. Anderson Cancer Center were randomized in a crossover study to receive either oral antibiotic prophylaxis consisting of novobiocin and rifampin or observation alone over a 35-day course period. Patients were subsequently "crossed over" to the opposite arm of the study for an additional 35-day period, with each serving as his or her own control. RESULTS. Twenty-six patients were enrolled. Nine patients (35%) failed to tolerate oral antibiotics because of severe nausea and vomiting; 17 patients (65%) were crossed over and considered evaluable. During the control patient courses, 71% of evaluable patients had infectious complications, 41% had a catheter-associated bacteremia, and 53% had a local catheter infection. In contrast, of the patients treated with antibiotic prophylaxis, only 12% had an infectious complication (P = 0.001), 12% had a local catheter infection (P = 0.008), and 6% had catheter-associated bacteremias (P = 0.04). Thirty-six episodes of catheter infections occurred during the 17 control courses, whereas only 3 episodes occurred during antibiotic prophylaxis (P < 0.001). CONCLUSIONS. Although more than one-third of patients receiving IL-2 treatment with biochemotherapy failed to tolerate novobiocin and rifampin, this oral antibiotic regimen was efficacious in preventing the infectious complications, especially those associated with vascular catheters, in this high risk patient population.

Olive oil, other seasoning fats, and the risk of colorectal carcinoma.

Braga C. La Vecchia C. Franceschi S. Negri E. Parpinel M. Decarli A. Giacosa A. Trichopoulos D.
Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
BACKGROUND: An association between fats and colorectal carcinoma has been suggested, but the epidemiologic evidence by type of dietary fat is far less clear. Colorectal carcinoma rates have been relatively low in Mediterranean countries compared with most other Western countries, but the components of the Mediterranean diet responsible for this favorable pattern are unclear. METHODS: The relationship between various added (seasoning) fats and colorectal carcinoma risk was investigated using data from a case-control study conducted between January 1992 and June 1996 in six Italian areas. Cases were 1953 patients with incident, histologically confirmed colorectal carcinoma (1225 of the colon and 728 of the rectum) admitted to the major teaching and general hospitals in the study areas. Controls were 4154 subjects with no history of cancer who were admitted to hospitals in the same catchment areas for acute, nonneoplastic diseases unrelated to the the digestive tract and requiring no long term modifications of diet. Dietary habits were investigated using a validated food frequency questionnaire including 78 items. Lipid intake was estimated by taking into account the content of seasoning lipids in different dishes, the frequency of consumption and portion size of each dish, and individual fat intake patterns. RESULTS: The odds ratios (OR) for successive tertiles of olive oil intake, compared with the lowest one, were 0.87 (95% confidence interval [CI], 0.75-1.01) and 0.83 (95% CI, 0.70-0.99) (chi2trend = 4.49, P = 0.03) when colorectal carcinoma was analyzed as a whole, 0.82 (95% CI, 0.68-0.98) and 0.81 (95% CI, 0.66-0.99) (chi2trend = 4.05, P = 0.04) for colon carcinoma, and 0.96 (95% CI, 0.77-1.19) and 0.88 (95% CI, 0.66-1.12) for rectal carcinoma. For specific seed oils (including sunflower, maize, peanut, and soya), the OR for colorectal carcinoma was 0.91 in the highest tertile of intake, and the corresponding values were 1.01 for mixed seed oils and 0.93 for butter. None of these estimates was significantly different from the unity. Allowance for vegetable intake attenuated the apparent protection from olive oil consumption (OR, 0.94 for colon and 0.97 for rectum for the highest tertile), which still was apparent in younger subjects (OR, 0.82 for colon and 0.69 for rectum). CONCLUSIONS: In this study, seasoning fats did not appear to increase the risk of colorectal carcinoma, and there was little evidence for a differential effect by fat type. If such a differential effect exists, it is minor and could favor olive oil.

Genomic aberrations in early stage human hepatocellular carcinomas.

Nagai H. Ponglikitmongkol M. Fujimoto J. Yamamoto H. Kim YS. Konishi N. Matsubara K.
Institute for Molecular and Cellular Biology, Osaka University, Japan.
BACKGROUND: Primary liver cancer, which most often takes the form of hepatocellular carcinoma (HCC), is among the 10 most common cancers in humans worldwide. In hepatocarcinogenesis, evidence of a multistep process is supported by the marked increase of HCC incidence with age; most HCCs are diagnosed in the second half of life, generally after a long period of chronic liver disease and in frequent association with cirrhosis. This long process may be correlated with the development of multiple genetic lesions, the origin of which currently remain largely unknown. In a previous study, the authors collected data on genomic DNA aberrations in primary HCC by restriction landmark genomic scanning (RLGS), a powerful screening method for the human genome. METHODS: The authors examined the genomic aberrations that occurred in early stage HCCs by means of RLGS of NotI-cleaved and 32P-end-labeled genomic DNA resolved by electrophoresis in a two-dimensional gel. More than 2000 radioactive spots originating from NotI cleavage sites were compared among six small HCC nodules and their normal counterparts. RESULTS: The intensities of five spots were consistently higher in the small HCCs, and the same effect was observed in large HCCs. In addition, the intensities of 22 spots were consistently half those of normal tissue, suggesting the loss of one allele. CONCLUSIONS: The occurrence of certain genomic alterations in early stage HCCs, as reflected by an increase or decrease in spot intensity, seems to reflect early events that occur during HCC development.

A Phase I trial of ifosfamide and paclitaxel with granulocyte-colony stimulating factor in the treatment of patients with refractory solid tumors.

Bunnell CA. Thompson L. Buswell L. Berkowitz R. Muto M. Sheets E. Shulman LN.
Hematology-Oncology Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
BACKGROUND: Ifosfamide and paclitaxel are antineoplastic agents with broad activity and with different mechanisms of action. A Phase I trial was conducted to determine the maximum tolerated dose and associated toxicities of these agents when used in combination. METHODS: Patients with refractory, incurable solid tumors were entered on a 5-step Phase I trial of ifosfamide, given in doses of 2-3 g/m2 intravenous (i.v.) bolus for 3 days with mesna support, and paclitaxel, given in doses of 135-190 g/m2 i.v. by continuous infusion over 24 hours. Paclitaxel was given after the first dose of ifosfamide on Day 1. RESULTS: Twenty-three patients were treated, and the maximum tolerated dose was the highest planned dose level of the trial: ifosfamide, 3 g/m2/day i.v. for 3 days, and paclitaxel, 190 mg/m2 i.v. over 24 hours. Hematologic toxicity was not dose-limiting, and although neutropenia occurred, it was brief (median, 2-4 days) and resulted in hospitalization for neutropenia and fever in only 7 of 111 courses of therapy. For patients treated at the highest dose level, only 1 of 50 courses of therapy resulted in hospitalization for neutropenia and fever. Nonhematologic toxicity also was not severe and no significant neuropathy occurred. Although patients entered into the study were heavily pretreated, responses were observed, particularly in patients with breast or ovarian carcinoma. CONCLUSIONS: Ifosfamide and paclitaxel can be administered safely in the doses used in this study and there are indications of significant antitumor effect. Further studies are necessary to explore the antineoplastic activity of this regimen, particularly for patients with breast and ovarian carcinoma.

The use of epithelial membrane antigen and silver-stained nucleolar organizer regions testing in the differential diagnosis of mesothelioma from benign reactive mesothelioses.

Wolanski KD. Whitaker D. Shilkin KB. Henderson DW.
Western Australian Centre for Pathology & Medical Research, Queen Elizabeth II Medical Centre, Nedlands.
BACKGROUND: The accurate diagnosis of pleural lesions obtained from small closed biopsy is difficult. As yet there is no single reliable test to distinguish between malignant and benign mesothelial tissue. METHODS: Immunostaining of epithelial membrane antigen (EMA) and the quantitation of silver stained nucleolar organizer regions (AgNORs) each were applied to benign and malignant histologic sections of pleural and peritoneal biopsies. The usefulness of these stains was tested both individually and in combination in the diagnosis of epithelial malignant mesothelioma. RESULTS: One hundred and three of the 141 malignant lesions (73%) were immunoreactive for EMA but only 3 of the 73 benign lesions (4%) reacted equivocally, and none positively. The average count of AgNORs/cell in malignant lesions (n = 80) was elevated compared with benign cases (n = 26), but a significant overlap was exhibited in the AgNOR count and this form of analysis was considered to be of little value in distinguishing benign from malignant mesothelial processes. Much less overlap was observed when the average AgNOR area was measured. By using the maximum benign AgNOR area of 0.6677 microm2 as the upper threshold, 51 cases (63.8%) were identified as malignant; the test demonstrated 100% specificity and 63.8% sensitivity. By combining the EMA and AgNOR results, 76 of 80 of the malignant mesothelioma cases (95%) tested positive for at least 1 of the tests with no false-positive results identified. CONCLUSIONS: This study confirms the usefulness of EMA in diagnosing malignant and benign mesothelial lesions, and demonstrates the enhanced diagnostic value of combining EMA immunoreaction with the average area of AgNOR per cell, thereby increasing sensitivity in the diagnosis of epithelial malignant mesothelioma.

Classification of regional lymph node metastasis from gastric carcinoma. German Gastric Cancer Study Group.

Roder JD. Bottcher K. Busch R. Wittekind C. Hermanek P. Siewert JR.
Chirurgische Klinik und Poliklinik, Technische Universitat Munchen, Germany.
BACKGROUND: Classification of lymph node metastasis from gastric carcinoma was based on the localization (International Union Against Cancer/American Joint Committee on Cancer [UICC/AJCC] 1992). The authors analyzed the data of the German Gastric Cancer Study (GGCS) to determine whether the number of involved lymph nodes related to the prognosis independent of their anatomic localization (UICC/AJCC 1997). METHODS: For 477 patients of the GGCS resected for cure (UICC/AJCC R0 resection) who had involved regional lymph nodes and no evidence of distant metastases, the 1992 UICC/AJCC classification was compared with the new UICC/AJCC classification (1997) based on the number of involved lymph nodes (ILN). RESULTS: Two hundred fifty-eight patients (54.1%) had 1-6 ILN, 137 patients (28.7%) had 7-15, and 82 patients (17.2%) had more than 15. When the 1992 and 1997 UICC/AJCC classifications were compared, the prognosis of patients classified as pN1 (n = 187) in the 1992 pN classification was homogeneous, whereas there was a marked lack of homogeneity among the patients classified as pN2 (n = 290). For 103 of 290 patients with 1-6 ILN, the prognosis appeared to be more favorable (5-year survival rate, 45.5%), whereas 137 of 290 patients with 7-15 ILN had an intermediate prognosis (5-year survival rate, 29.7%). Eighty-two of 290 patients had a dismal prognosis, with a 5-year survival rate of 10.4%. There was a highly significant difference in survival (P < 0.0001). Within the groups with 1-6, 7-15, and more than 15 ILN, the localization of ILN did not significantly alter the prognosis. CONCLUSIONS: The UICC/AJCC classification based on the number of involved regional lymph nodes allows for an estimation of prognosis superior to the 1992 classification. In addition, the new classification can now be applied without methodologic problems and seems more reproducible.

Plasma thrombospondin levels in patients with colorectal carcinoma.

Yamashita Y. Kurohiji T. Tuszynski GP. Sakai T. Shirakusa T.
Second Department of Surgery, Fukuoka University School of Medicine, Fukuoka City, Japan.
BACKGROUND: Thrombospondin in a 450-kilodalton glycoprotein, first described as a secretion product of thrombin-stimulated platelets. In a recent study, thrombospondin was discovered not only to accelerate platelet aggregation and to promote construction of the extracellular matrix but also to be involved in the progression of malignant tumors. In another study, plasma thrombospondin was reported to be elevated in patients with colorectal carcinoma with hepatic metastasis. Moreover, venous invasion in colorectal carcinoma is well known to be involved profoundly in organ metastasis. METHODS: Blood samples from patients with colorectal carcinoma were collected preoperatively by venipuncture using ice-chilled tubes, and immediately centrifuged at 4 degrees C. The plasma was aspirated and frozen until the concentration of thrombospondin was measured using a competitive enzyme-linked immunoadsorbent assay. The degree of venous invasion in each case was evaluated pathologically using resected specimens to examine for any correlation with the plasma thrombospondin level. RESULTS: The plasma thrombospondin level was significantly higher in those patients with malignant venous invasion than in those patients with no venous invasion, according to Dukes staging. There was a direct correlation between the plasma thrombospondin level and the degree of venous invasion. CONCLUSIONS: Venous invasion by colorectal carcinoma was found to play an important role in the elevation of the plasma thrombospondin level. Alternatively, a high concentration of thrombospondin may support metastasis and progression of this malignancy.

Efficacy of gemcitabine in the treatment of patients with gallbladder carcinoma: a case report.

Castro MP.
Glens Falls Cancer Center, New York 12801, USA.
BACKGROUND: Advanced carcinoma of the gallbladder typically is unresponsive to chemotherapy, and patients with progressive metastatic disease have a short survival. METHODS: A patient with advanced metastatic carcinoma of the gallbladder causing peritoneal carcinomatosis and hepatic metastases is reported. This patient achieved a dramatic remission with gemcitabine after failing two other chemotherapeutic regimens. RESULTS: Response included reversal of complete small bowel obstruction with resumption of the ability to eat and the disappearance of liver metastases. CONCLUSIONS: Gemcitabine appears to be worthy of organized clinical trials in patients with this notoriously chemotherapy-resistant malignancy.

Involvement of matrix metalloproteinase-2 activity in invasion and metastasis of pancreatic carcinoma.

Koshiba T. Hosotani R. Wada M. Miyamoto Y. Fujimoto K. Lee JU. Doi R. Arii S. Imamura M.
First Department of Surgery, Kyoto University, Sakyo, Japan.
BACKGROUND: Activation of matrix metalloproteinase-2 (MMP-2) has been implicated in the progression, invasion, and metastasis of various cancers, but little information is available with regard to its role in pancreatic carcinoma with poor prognosis. METHODS: Gelatin zymography was used for the detection of latent and activated forms of MMP-2 and MMP-9 in 13 normal pancreatic tissue specimens, 14 chronic pancreatitis tissue specimens, and 33 pancreatic carcinoma tissue specimens. The gelatinase activity was quantified by densitometer, and the 66-kilodalton (kDa)/(66-kDa + 72-kDa) ratio was calculated as the MMP-2 activation ratio. Western blot analysis was performed to confirm the zymographic profile. RESULTS: Latent forms of MMP-2 and MMP-9 were detected in all samples of pancreatic carcinoma, chronic pancreatitis, and normal pancreatic tissue. The expression rate of the MMP-2 activated form in pancreatic carcinoma tissue specimens was 100% (33 of 33) but that of MMP-9 was 21%. The MMP-2 activation ratio in pancreatic carcinoma tissue specimens was significantly higher than that of chronic pancreatitis and normal pancreatic tissue specimens. The MMP-2 activation ratio in pT3 tumors was significantly higher than that in pT1 tumors. The MMP-2 activation ratio also was significantly higher in pancreatic carcinoma specimens with histologically positive regional lymph node metastasis and distant metastasis than those without metastasis. The MMP-2 activation ratio observed in patients who developed postresection recurrence within 6 months was significantly higher than that in patients without recurrence at 6 months. CONCLUSIONS: The results of the current study indicate that MMP-2 activation plays a significant role in tumor invasion and metastasis in pancreatic carcinoma.

Determination of pancreatic ductal carcinoma histogenesis by analysis of mucous quality and K-ras mutation.

Matsubayashi H. Watanabe H. Nishikura K. Ajioka Y. Kijima H. Saito T.
First Department of Pathology, Niigata University School of Medicine, Japan.
BACKGROUND: The authors sought to elucidate the histogenesis of pancreatic ductal carcinoma by correlating K-ras mutation with mucus type in normal epithelium, mucous cell hyperplasia (MCH), and carcinoma. METHODS: Seventy-four solid-type carcinomas (SCs), 23 ductectatic-type carcinomas (DCs), and specimens of 24 normal pancreata were studied. By histochemical staining, normal duct epithelia, areas of MCH, and carcinomas were classified as having sulfo-type or sialo-type mucus. Foci from normal, DC, SC, sulfo-type, or sialo-type specimens were assessed for K-ras mutation at codon 12 by nested polymerase chain reaction and restriction fragment length polymorphism. RESULTS: Of the SCs, 9 were sulfo-type and 65 were sialo-type; all DC specimens were sialo-type, and all normal epithelia were sulfo-type. All foci of sulfo-type, nonneoplastic epithelia were negative for K-ras mutation. In contrast, 124 of 313 sialo-type MCH foci (40%) had a K-ras mutation. Of 74 SCs, only 3 of 9 sulfo-type tumors (33%) were positive for the mutation. Sixty of 65 sialo-type SCs (92%) had a K-ras mutation, whereas 15 of 23 sialo-type DCs (65%) had a mutation. K-ras mutant carcinomas (including both SCs and DCs) were associated with K-ras mutant MCH in 109 of 198 MCHs (55%), whereas carcinomas without a K-ras mutation had mutations in 6 of 68 MCHs (9%). MCH in normal pancreata revealed K-ras mutations in 9 of 51 foci (18%). In addition, in K-ras mutant carcinomas, frequency of K-ras mutation in MCH increased from 27% (11 of 41 foci) of nonpapillary MCHs to 62% (98 of 157 foci) of papillary MCHs; but in K-ras wild-type carcinoma, the mutation rate in MCH was unchanged from 12% (3 of 26 foci) to 7% (3 of 42 foci) in nonpapillary and papillary foci, respectively. CONCLUSIONS: These results suggest a strong relationship between the risk of pancreatic carcinoma and the presence of combinations of K-ras gene mutation, papillary growth, and expression of sialomucin in foci of MCH.

The expression of multidrug resistance protein in human gastrointestinal tract carcinomas.

Takebayashi Y. Akiyama S. Natsugoe S. Hokita S. Niwa K. Kitazono M. Sumizawa T. Tani A. Furukawa T. Aikou T.
Department of Cancer Chemotherapy, Institute for Cancer Research, Faculty of Medicine, Kagoshima University, Sakuragaoka, Japan.
BACKGROUND: Multidrug resistance protein (MRP) is a membrane phosphoglycoprotein with an Mr of 190,000 that is involved in the non-P-glycoprotein mediated multidrug resistance of human tumor cells. The aim of this study was to determine the clinicopathologic relevance of MRP expression in human gastrointestinal tract carcinomas. METHODS: The authors prepared a rabbit antiserum against MRP that does not cross-react with P-glycoprotein and retrospectively examined the expression of MRP in 86 squamous cell carcinomas of the esophagus, 103 adenocarcinomas of the stomach, and 139 colorectal adenocarcinomas by immunohistochemistry. None of the patients in this study had received prior chemotherapy. RESULTS: The proportion of MRP positive samples in the squamous cell carcinomas of the esophagus (62.8%, 54 of 86) was significantly higher than that in the adenocarcinomas of the stomach (34.1%, 35 of 103) and the colorectal adenocarcinomas (40.3%, 56 of 139) (P

Performance status and comorbidity in elderly cancer patients compared with young patients with neoplasia and elderly patients without neoplastic conditions.

Repetto L. Venturino A. Vercelli M. Gianni W. Biancardi V. Casella C. Granetto C. Parodi S. Rosso R. Marigliano V.
Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
BACKGROUND: Elderly people constitute a heterogeneous group and are at an increased risk for the development of cancer. It is not clear whether comorbid conditions and functional status influence clinical decisions and the pattern of referral in elderly cancer patients. The current study investigated functional status measured by Eastern Cooperative Oncology Group performance status, comorbid conditions, and medication taken as well as social environment in three series of patients grouped according to age and diagnosis. METHODS: A total of 593 patients were involved: 138 neoplastic patients age > 70 years with breast, colon, or prostate carcinoma, 177 neoplastic patients age < 70 years with the same types of pathology, and 278 elderly patients with nonneoplastic conditions. Patients with neoplastic disease were recruited from cancer centers; patients with nonneoplastic disease were recruited from either geriatric or general medicine departments. Differences in the distribution of variables were analyzed by univariate and bivariate analyses. RESULTS: No significant differences in social environment, marital status, or education were observed. Statistical differences were noted when comparing the distribution of comorbidities, performance status, and medication taken, elderly neoplastic patients presented in poorer condition compared with younger patients but in better condition compared with elderly patients with nonneoplastic disease. CONCLUSIONS: The overall better health of older cancer patients compared with those without cancer needs to be assessed further. It is possible that cancer is more likely to be diagnosed in healthier elderly, or that primary care providers are reluctant to refer for cancer care patients in poor general health. Studies of comorbidity, function, and social resources are necessary to establish the impact of cancer on survival and quality of life of older patients and to determine the social resources necessary for adequate care.

Overexpression of elongation factor-1gamma protein in colorectal carcinoma.

Mathur S. Cleary KR. Inamdar N. Kim YH. Steck P. Frazier ML.
Department of Gastrointestinal Oncology and Digestive Diseases, The University of Texas, M.D. Anderson Cancer Center, Houston 77030, USA.
BACKGROUND: Elongation factor-1 (EF-1) is a cellular protein that plays a role in protein synthesis by mediating the transfer of aminoacyl-tRNA to 80S ribosomes. It is comprised of four subunits: alpha, beta, gamma, and delta. EF-1gamma is a substrate for the maturation-promoting factor, which determines entry into the M-phase of the cell cycle in all eukaryotic cells. Previously, the authors showed that EF-1gamma RNA is overexpressed in a high proportion of colorectal carcinomas. At that time, there were no antibodies to EF-1gamma, so the EF-1gamma protein could not be examined. Because levels of RNA do not always parallel the levels of the protein it encodes, it was important to develop antibodies to EF-1gamma to examine its expression at the protein level in colorectal carcinoma. METHODS: Twenty-nine patients undergoing surgical resection for colorectal adenocarcinoma were studied. A polyclonal antibody to EF- 1gamma in rabbit was prepared. Tumors and normal-appearing mucosa distant from the tumor (> or = 10 cm) were obtained from each patient. Cytosolic proteins were extracted from the tissues and examined by Western blot analysis with the EF-1gamma antibody. Colonic tumors also were studied by immunohistochemical analysis with another EF-1gamma polyclonal antibody. RESULTS: Using Western blot analysis, the authors observed greater expression of EF-1gamma in the tumors than in the more distal normal-appearing mucosa. Overexpression was not observed in the patients with the two Dukes Stage A tumors, but was observed in four of ten patients with Dukes Stage B tumors, seven of eight patients with Dukes Stage C tumors, and six of nine patients with Dukes Stage D tumors. Overall, 17 of 29 patients (59%) were found to have overexpression of EF-1gamma. Using immunohistochemical analysis, EF-1gamma protein was shown to be located predominantly in tumor epithelium rather than the stroma or infiltrating mononuclear cells. CONCLUSIONS: Previous studies showed that EF-1gamma mRNA frequently is overexpressed in colorectal adenocarcinoma. This study showed that EF-1gamma also was overexpressed at the protein level in colorectal adenocarcinoma relative to more distal normal-appearing mucosa from the same patient. Immunohistochemical analysis demonstrated that this protein was expressed predominantly in the tumor epithelial cells and therefore was not derived from cells involved in the desmoplastic response.

Primary sclerosing cholangitis and colorectal carcinoma in patients with chronic ulcerative colitis: a case-control study.

Nuako KW. Ahlquist DA. Sandborn WJ. Mahoney DW. Siems DM. Zinsmeister AR.
Division of Gastroenterology and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
BACKGROUND: Controversy persists regarding primary sclerosing cholangitis (PSC) as a risk factor for colorectal carcinoma in patients with chronic ulcerative colitis. Small sample size and differing endpoints have contributed to variation among reported studies. This large case-control study was conducted to examine the possible association between PSC and colon carcinoma in patients with ulcerative colitis. METHODS: From Mayo Clinic records spanning 1976-1994, 171 cases with both ulcerative colitis and colorectal carcinoma and 171 contemporaneous controls with ulcerative colitis but no colorectal neoplasia matched with regard to age, gender, extent, and duration of colitis were identified. The diagnosis of PSC required cholangiographic confirmation. Analysis employed a multivariate logistic regression model. RESULTS: The prevalence of PSC was similar in cases (18%) and controls (15%) (P = 0.54). The adjusted odds ratio for colorectal carcinoma with PSC was 1.23 (95% confidence interval, 0.62-2.42). CONCLUSIONS: Based on this large case-control study, there was no association between PSC and colorectal carcinoma in patients with ulcerative colitis.

Interferon decreases hepatocellular carcinogenesis in patients with cirrhosis caused by the hepatitis B virus: a pilot study.

Ikeda K. Saitoh S. Suzuki Y. Kobayashi M. Tsubota A. Fukuda M. Koida I. Arase Y. Chayama K. Murashima N. Kumada H.
Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan.
BACKGROUND: To elucidate the influence of long term interferon administration on the rate of occurrence of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV)-related cirrhosis, the authors analyzed 313 consecutive patients with cirrhosis. METHODS: Of the 313 patients, 94 underwent long term intermittent administration of interferon for > or = 6 months, and the remaining 219 patients received no interferon or other antiviral drug. RESULTS: Cumulative occurrence rates of HCC in the group treated with interferon and the untreated group were 4.5% and 13.3%, respectively, at the end of 3 years; 7.0% and 19.6%, respectively at the end of 5 years; and 17.0% and 30.8%, respectively, at the end of 10 years. The rate of HCC development in the treated group was significantly lower than that of the untreated group (P = 0.0124). The Cox proportional hazard model revealed that interferon treatment was an independent contributing factor in lowering the rate of carcinogenesis (odds ratio = 0.39; P = 0.031) even after correction by significant covariates in multivariate analysis. The virologic study showed that the role of interferon therapy from the viewpoint of cancer prevention was much more significant in patients with a HBV DNA concentration of > or = 10 milliequivalents. CONCLUSIONS: Interferon therapy for patients with HBV-related cirrhosis significantly decreased the HCC rate, especially in patients with a larger amount of serum HBV DNA. If interferon is administered properly for a selected group of patients, an effective strategy of cancer prevention can be achieved, even in patients with cirrhosis.

Papillary serous carcinoma of the peritoneum in a man: a case report.

Shah IA. Jayram L. Gani OS. Fox IS. Stanley TM.
Department of Pathology and Laboratory Medicine, Veterans Affairs Medical Center, Phoenix, Arizona 85012, USA.
BACKGROUND: Papillary serous carcinoma of the peritoneum (PSCP) is a rare primary peritoneal tumor, described exclusively in women. It is believed to arise from the secondary mullerian system, which is comprised of the pelvic and lower abdominal mesothelial lining and subjacent (subcoelomic) mesenchyme in women. Both mesotheliomas and PSCP arise from the coelomic epithelium, but are clinicopathologically and biologically distinct entities. METHODS: The authors report clinicopathologic findings in a man, age 74 years, who died 3 months after the diagnosis of an extensive malignant abdominal disease. RESULTS: The routine histologic and immunocytochemical studies of tumor tissue, obtained during the patient's lifetime and at autopsy, validated the unique occurrence of PSCP in a man. CONCLUSIONS: This case illustrates that PSCP can occur in a man and that this diagnosis may be considered in the differential diagnosis of papillary serous tumors of the peritoneum in male patients. Although rare, PSCP is a diagnostically distinct entity the treatment of which is similar to ovarian serous tumors rather than mesotheliomas.

Cyclophosphamide, methotrexate, and chronic oral tegafur modulated by folinic acid in the treatment of patients with advanced breast carcinoma.

Ribas A. Albanell J. Sole-Calvo LA. Gallardo E. Bellmunt J. Vera R. Vidal R. Carulla J. Baselga J.
Medical Oncology Service, Hospital General Universitari Vall d'Hebron, Passeig Vall d'Hebron Barcelona, Spain.
BACKGROUND: Chronic oral tegafur (a 5-fluorouracil prodrug) modulated by folinic acid has antitumor activity in patients with metastatic breast carcinoma resistant to 5-fluorouracil or doxorubicin-based regimens. In this study, bolus 5-fluorouracil was substituted with chronic oral tegafur and folinic acid in a cyclophosphamide, methotrexate, and 5-fluorouracil-based regimen to study the activity of this novel regimen in patients with advanced breast carcinoma. METHODS: This study was comprised of patients with advanced breast carcinoma and measurable or evaluable disease. Patients with prior chemotherapy were eligible. The regimen was comprised of cyclophosphamide, 600 mg/m2, and methotrexate, 40 mg/m2, both given intravenously on Day 1, and tegafur, 750 mg/m2, with folinic acid, 45 mg/day, both given orally in 3 daily fractions on Days 2-14, every 3 weeks. RESULTS: Forty-seven patients were included, 44 of whom were fully assessable. Three patients (7%) achieved a complete remission and 17 (38.6%) achieved a partial remission, for an objective response rate of 45.5% (95% confidence interval, 29-59%). The median duration of response was 11 months. In previously untreated patients the response rate was 54.5%. In patients previously treated with anthracycline or 5-fluorouracil-based regimens the response rates were 41% and 39%, respectively. Sixteen patients (36.4%) had disease stabilization. The median overall time to progression was 10 months. Toxicities usually were mild and were comprised of leukocytopenia, mucositis, emesis, and diarrhea. CONCLUSIONS: Chronic oral tegafur and folinic acid combined with intravenous cyclophosphamide and methotrexate at the dose and schedule used in the current study has significant antitumor activity both as first-line chemotherapy as well as in other patients with advanced breast carcinoma who had prior chemotherapy. This regimen is well tolerated, with gastrointestinal toxicity being the most frequent and dose-limiting toxicity.

T gamma/delta hepatosplenic lymphoma in a heart transplant patient after an Epstein-Barr virus positive lymphoproliferative disorder: a case report.

Kraus MD. Crawford DF. Kaleem Z. Shenoy S. MacArthur CA. Longtine JA.
Department of Pathology, St. Louis Children's Hospital, Washington University School of Medicine, Missouri 63110, USA.
BACKGROUND: An unusual case of a peripheral T-cell lymphoma of T gamma/delta hepatosplenic type (Tgamma/deltaHSL) that arose in a child 5 years after she received a heart transplant and 9 months after she developed Epstein-Barr virus (EBV) positive, B-cell lymphoid hyperplasia involving the tonsils is presented. The majority of the reported cases of Tgamma/deltaHSL have been described in young adult men without antecedent immunodeficiency; several well documented cases of Tgamma/deltaHSL in the posttransplant setting have been described previously, but none has been described in a child (or an adult) with a previously diagnosed EBV+ B-cell lymphoid hyperplasia. METHODS: Standard histologic, immunohistochemical, flow cytometric, and molecular genetic techniques were used in the evaluation of diagnostic material. RESULTS: The patient's Tgamma/deltaHSL involved the spleen in a predominantly cordal pattern, and infiltrated the liver in an exclusively sinusoidal distribution. Bone marrow involvement was focal and interstitial. In all locations, malignant cells were of intermediate or large size and had oval nuclei with coarse chromatin, with a scant or moderate amount of eosinophilic cytoplasm. This Tgamma/deltaHSL expressed the characteristic CD2+, CD3+, [CD4- CD8-], Tdelta1+ phenotype, and malignant cells also expressed the natural killer cell marker CD56. Cytogenetic studies demonstrated isochromosome 7q with the addition of trisomy 8 as the tumor progressed. Southern blot analysis demonstrated clonal rearrangements of the gamma, delta, and beta loci of the T-cell receptor but did not identify EBV DNA within the tumor cells. CONCLUSIONS: This case highlights the fact that a full range of lymphoid proliferations is possible in the posttransplantation period, and that a prior diagnosis of a B-cell disorder does not preclude the development of a subsequent T-cell posttransplant lymphoproliferative disorder (PTLD), which should be formally evaluated, especially if clinical circumstances appear atypical for a PTLD of the "usual" (EBV-related, B-cell) type.

The role of the HLA-DQA1 gene in resistance to atrophic gastritis and gastric adenocarcinoma induced by Helicobacter pylori infection.

Year 1998
Azuma T. Ito S. Sato F. Yamazaki Y. Miyaji H. Ito Y. Suto H. Kuriyama M. Kato T. Kohli Y.
Second Department of Internal Medicine, Fukui Medical School, Japan.
BACKGROUND: It has been suggested that immunogenetic factors for susceptibility or resistance to disease caused by Helicobacter pylori exist in the host. To examine host genetic factors that increase the risk of gastric adenocarcinoma among H. pylori-infected persons, the HLA-DQA1 locus was examined in patients with gastric adenocarcinoma. METHODS: Eighty-two gastric adenocarcinoma patients and 167 unrelated controls were examined for H. pylori infection and HLA-DQA1 genotyping. In addition, serum pepsinogen A (PGA) and pepsinogen C (PGC) values and the PGA/PGC ratio, which have been characterized as markers of gastric mucosal atrophy, also were analyzed. RESULTS: Of the 167 controls, 121 were H. pylori positive (+) and 46 were H. pylori negative (-). All H. pylori (-) individuals had normal endoscopic and histologic findings. Among the 121 H. pylori (+) controls, 36 had superficial gastritis and 85 had atrophic gastritis. The allele frequency of DQA1*0102 was significantly lower in the H. pylori (+) atrophic gastritis group than in the H. pylori (+) superficial gastritis and H. pylori (-) normal control groups. In addition, the allele frequency of DQA1*0102 also was significantly lower in the H. pylori (+) intestinal type gastric adenocarcinoma group than in the H. pylori (-) normal control, H. pylori (+) superficial gastritis, and H. pylori (-) diffuse type gastric adenocarcinoma groups. Serum PGA and PGC values and the PGA/PGC ratio did not differ significantly among HLA-DQA1 genotypes; however, the PGA/PGC ratio was significantly lower in the H. pylori (+) atrophic gastritis and H. pylori (+) intestinal type gastric adenocarcinoma groups than in the H. pylori (-) normal control and H. pylori (+) superficial gastritis groups. CONCLUSIONS: The DQA1*0102 allele may contribute to resistance against H. pylori-associated gastric atrophy and its association with intestinal type gastric adenocarcinoma, whereas the absence of DQA1*0102 may be a host genetic risk factor for H. pylori-associated atrophic gastritis and intestinal type gastric adenocarcinoma.

Coexpression of MUC1 mucin peptide core and the Thomsen-Friedenreich antigen in colorectal neoplasms.

Year 1998
Baldus SE. Hanisch FG. Kotlarek GM. Zirbes TK. Thiele J. Isenberg J. Karsten UR. Devine PL. Dienes HP.
Institute of Pathology, University of Cologne, Germany.
BACKGROUND: Controversial findings have been reported regarding the expression of the Thomsen-Friedenreich (TF) antigen in colorectal neoplasms when different monoclonal antibodies (MoAbs) have been used. Moreover, there is no information available regarding the carrier protein(s) of this antigen. METHODS: Forty-five colorectal adenomas and 48 carcinomas were studied by avidin-biotin complex-peroxidase immunohistochemistry. The immunohistochemistry employed the MoAb BW835, which was reactive to a carrier specific and site specific TF antigen on MUC1 mucin, as well as reference antibodies directed to MUC1 (HMFG2) or MUC2 core peptides (4F1) and directed to TF antigen irrespective of its carrier (A78-G/A7, peanut agglutinin). To evaluate the coexpression of different epitopes by the same antigen, sandwich enzyme-linked immunoadsorbent assays were performed. RESULTS: Although MUC1 peptide antigen and MUC1-bound TF antigen were not detectable in normal or transitional mucosa surrounding colorectal neoplasms, expression of these antigens in adenomas accompanied the development of high grade dysplasia. By contrast, MUC2 expression detected by the MoAb 4F1 was inversely correlated with the progression of the adenoma-carcinoma sequence. In well- and moderately differentiated colorectal carcinomas, the neo-expressed TF antigen is predominantly bound to MUC1. This feature could be demonstrated by antigen coexpression using peptide and the TF antigen specific MoAbs. However, in mucinous carcinomas exhibiting a weak MUC1 peptide expression in most specimens, the presence of TF antigen on the MUC2 peptide core cannot be ruled out. CONCLUSIONS: TF antigen is strongly coexpressed with MUC1 mucin peptide core in the colorectal adenoma-carcinoma sequence, resulting in well- and moderately differentiated carcinomas. Only in mucinous carcinomas may it be coexpressed with MUC2 antigen.

Prognostic factors affecting long term outcome after liver resection for hepatocellular carcinoma: results in a series of 100 Italian patients.

Year 1998
Lise M. Bacchetti S. Da Pian P. Nitti D. Pilati PL. Pigato P.
Dipartimento di Scienze Oncologiche e Chirurgiche, University of Padova, Italy.
BACKGROUND: Long term results after liver resection for hepatocellular carcinoma (HCC) are disappointing because the disease tends to recur. In this study, the authors assessed prognostic factors affecting long term outcome, in the hope that these factors might be used in selecting HCC patients for surgery. METHODS: During the period 1977-1995, 100 consecutive patients underwent curative liver resection; 78 of 100 had HCC arising on preexisting cirrhosis (53 Child's Class A and 25 Child's Class B). Thirty-five prognostic factors were evaluated for their association with overall survival (OS) and disease free survival (DFS) in univariate and multivariate analysis (Cox proportional hazards model). RESULTS: There were four postoperative deaths. Seven patients died in hospital of hepatorenal failure: six had Child's Class B cirrhosis and had undergone preoperative chemoembolization. Of the remaining 89 patients, 50 developed recurrence. All surviving Child's Class B patients had recurrence. Five-year OS, postoperative deaths included, was 38% (median, 36 months). Five-year DFS, postoperative deaths excluded, was 26% (median, 21 months). Independent prognostic factors for DFS were Child's class, glutamic-oxaloacetic transaminase, gamma-glutamyltransferase, alpha-fetoprotein, number of tumor nodules, width of resection margins, preoperative chemoembolization, and experience of the team that performed the surgery. Factors with an independent effect on OS were Child's class and width of resection margins. CONCLUSIONS: Liver resection can provide long term DFS in HCC patients with normal liver function. In patients with liver function impairment or an inadequate resection margin, recurrences are almost certain to occur. Preoperative chemoembolization significantly prolongs DFS but may increase the risk of postoperative liver failure in patients with liver function impairment.

Ovarian serous borderline tumors with invasive peritoneal implants.

Year 1998
Gershenson DM. Silva EG. Levy L. Burke TW. Wolf JK. Tornos C.
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
BACKGROUND: The objective of the current study was to update the authors' experience with patients with ovarian serous borderline tumors with invasive peritoneal implants to gain additional insight into the biologic behavior of these tumors and a better understanding of the effect of postoperative treatment. METHODS: Thirty-nine patients with ovarian serous borderline tumors with invasive peritoneal implants were identified through a retrospective review. Major endpoints selected for analysis were surgicopathologic response, time to recurrence, type of recurrence, progression free survival, and overall survival. Univariate and multivariate regression analyses also were performed. RESULTS: Median follow-up time was 111 months. Four of 7 evaluable patients who had second-look surgery (57%) had a response to chemotherapy. Twelve of 39 patients (31%) either developed progressive disease or had a recurrence. The median time from date of diagnosis to recurrence was 24 months. In 10 of these 12 patients with a recurrence, tissue was available; 9 had invasive low grade serous carcinoma and 1 had a recurrent borderline tumor. Macroscopic residual disease was the only factor studied that had a significant effect on survival; patients with no macroscopic residual tumor had a significantly better survival than those with any macroscopic residual tumor (P < 0.01). In univariate regression analysis, macroscopic residual disease and the presence of frankly invasive implants were significant predictors of progression free survival. Platinum-based chemotherapy was associated with a significantly shorter progression-free survival. Only macroscopic residual tumor was a significant predictor of survival. CONCLUSIONS: Greater than 30% of patients with ovarian serous borderline tumors with invasive peritoneal implants will develop progressive or recurrent tumor, most commonly serous carcinoma. The presence of macroscopic residual disease appears to be the major predictor of recurrence and survival. However, in this study, the authors were unable to elucidate the role of postoperative therapy or the criteria for selection of patients for such therapy.

The prognostic significance of microvessel density and thymidine phosphorylase expression in squamous cell carcinoma of the esophagus.

Year 1998
Igarashi M. Dhar DK. Kubota H. Yamamoto A. El-Assal O. Nagasue N.
Second Department of Surgery, Shimane Medical University, Izumo, Japan.
BACKGROUND: Squamous cell carcinoma (SCC) of the esophagus is among the most malignant of neoplasms and is associated with a dismal prognosis. Although tumor microvessel density (MVD) is an important prognostic factor in several carcinomas, its role in SCC of the esophagus is still controversial. Also, the role of thymidine phosphorylase (dThdPase), a key angiogenic growth factor, is yet to be delineated in this disease. METHODS: Immunohistochemical staining using monoclonal antibodies was used to quantify microvessel and dThdPase expression in archival tissue specimens from 93 patients with SCC of the esophagus. RESULTS: High dThdPase expression and high MVD were associated with tumor progression (size and stage) and lymph node metastasis, but only MVD was a predictor of survival. dThdPase expression was significantly correlated with depth of tumor invasion (P = 0.015). In multivariate analysis, MVD was an independent predictor of survival in the lymph node negative cases. A significant correlation was noted between MVD and dThdPase expression, with a correlation coefficient of 0.083 (P = 0.002). CONCLUSIONS: MVD is an independent factor in determining the prognoses of lymph node negative patients with SCC of the esophagus. dThdPase could be a key factor in the angiogenesis of this disease and may be responsible for its aggressive behavior.

Recent advances in surgical treatment have improved the survival of patients with gastric carcinoma.

Year 1998
Otsuji E. Yamaguchi T. Sawai K. Hagiwara A. Taniguchi H. Takahashi T.
First Department of Surgery, Kyoto Prefectural University of Medicine, Japan.
BACKGROUND: Mortality resulting from gastric carcinoma is decreasing. This is mainly due to vigorous endoscopic screening and the consequent higher incidence of early detection of the disease. In this study, to evaluate the effect of surgical treatment on the prognoses of patients with gastric carcinoma, the survival of 1579 patients who underwent gastrectomy between 1970 and 1994 was retrospectively analyzed. METHODS: The patients were divided into 5 groups at 5-year intervals. Postoperative survival was compared among the groups. RESULTS: Postoperative survival was significantly improved in the later groups for patients with Stage I, II, III, and IV disease. A multivariate analysis of prognostic factors revealed that the time period during which the gastrectomy was performed was an independent predictor of survival. CONCLUSIONS: It was concluded that survival has been improved by recent advances in the surgical approach to gastric carcinoma.

Prognostic value of cyclin E and p53 expression in gastric carcinoma.

Year 1998
Sakaguchi T. Watanabe A. Sawada H. Yamada Y. Yamashita J. Matsuda M. Nakajima M. Miwa T. Hirao T. Nakano H.
First Department of Surgery, Nara Medical University, Kashihara-city, Japan.
BACKGROUND: Cyclins and wild-type p53 are prime cell cycle regulators and may be involved in tumorigenesis. Cyclin E is a late G1 cyclin and its abnormalities have been reported in several cancers. The authors investigated the correlation between cyclin E expression and progression of gastric carcinoma. METHODS: The expression of cyclin E and p53 proteins was investigated retrospectively in 116 patients with gastric carcinoma. Immunohistochemical staining of the paraffin sections was performed using monoclonal antibodies to cyclin E and p53. RESULTS: The total cyclin E positive rate was 44.0% (51 of 116) of all cases, 26 of which were strongly positive. Strong cyclin E expression frequently was observed in deeply invasive tumors, tumors with lymph node metastasis, and tumors of advanced stage. The incidence of p53 expression was higher in the cyclin E positive tumors than in the other tumors. With regard to prognosis, patients whose tumors had both strong positivity for cyclin E and positivity for p53 had significantly poorer prognosis. In multivariate analysis, the combined variable of cyclin E and p53 was an independent prognostic indicator together with serosal invasion and tumor size. CONCLUSIONS: These data suggest the cyclin E expression correlates with p53 expression and may contribute to the progression of gastric carcinoma. The combined variable of cyclin E and p53 expression could be a useful prognostic indicator in patients with gastric carcinoma.

Intraoperative determinants of unresectability for patients with colorectal hepatic metastases.

Year 1998
Gibbs JF. Weber TK. Rodriguez-Bigas MA. Driscoll DL. Petrelli NJ.
Division of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
BACKGROUND: Intrahepatic and extrahepatic factors are utilized by the surgeon in the decision-making process for the performance of hepatic resection for patients with colorectal metastases. Accurate preoperative and intraoperative staging are mandatory to avoid unnecessary surgery. In this report the intraoperative determinants of hepatic unresectability were evaluated. METHODS: This was a retrospective review of medical records from January 1985 to March 1996 of 62 patients with colorectal hepatic metastases who at the time of exploratory laparotomy were deemed to have unresectable disease based on intrahepatic or extrahepatic factors. The stage of the primary tumor, disease free interval, preoperative carcinoembryonic antigen, computed tomography portography, intraoperative ultrasound, and assessment of intrahepatic and extrahepatic tumor extension were evaluated. RESULTS: Intraoperative determination of the extent of required hepatic resection, including trisegmentectomy (9 patients; 15%) and total hepatectomy (10 patients; 16%), accounted for the majority of unresectable patients. Patients with > 4 metastases (8 patients; 13%) and satellitosis (6 patients; 10%) accounted for 23% of unresectable patients. Four patients had extensive nonmalignant hepatic parenchymal disease precluding resection. Thorough abdominal exploration revealed extrahepatic disease in 13 of 62 patients (21%). Routine periportal/celiac lymph node biopsies revealed metastases in an additional 12 patients (19%), 7 of whom (11%) had only periportal/celiac lymph node metastases. CONCLUSIONS: A meticulous abdominal exploration prior to hepatic resection for patients with colorectal metastases is essential to identify those patients with extrahepatic disease. Periportal and celiac lymph nodes commonly are involved by tumor. Therefore, routine periportal/celiac lymph node biopsies should be performed in the absence of other extrahepatic disease.

Phase II trial of chemoembolization for the treatment of metastatic colorectal carcinoma to the liver and review of the literature.

Year 1998
Tellez C. Benson AB 3rd. Lyster MT. Talamonti M. Shaw J. Braun MA. Nemcek AA Jr. Vogelzang RL.
Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois 60611, USA.
BACKGROUND: Hepatic artery chemoembolization represents an alternative treatment for patients whose neoplastic lesions are not amenable or have become refractory to other treatment modalities. This project was designed to test the feasibility of regional chemoembolization for patients with colorectal carcinoma metastasis to the liver who had experienced failure with one or more systemic treatments. METHODS: Thirty patients who met the study entry criteria underwent one to three hepatic artery chemoembolizations. The chemoembolization regimen consisted of an injection of a bovine collagen material with cisplatin (10 mg/mL), doxorubicin (3 mg/mL), and mitomycin C (3 mg/mL). Repeat treatments were performed at 6- to 8-week intervals. RESULTS: Radiologic responses, as measured by a decrease in lesion density of at least 75% of the lesion or a 25% decrease in the size of the lesion, occurred in 63% of the cases. A decrease of at least 25% of the baseline carcinoembryonic antigen level occurred in 95% of the cases. All responses were transient. Median survival for all 30 patients was 8.6 months after the initiation of chemoembolization and 29 months after the initial diagnosis of metastasis to the liver. Common toxicities included a "postembolization syndrome," which consisted of fever > 101 degrees F (83%), pain in the right upper quadrant (100%), nausea, and vomiting. Lethargy was a common occurrence (in 60+% of cases) and lasted up to 6 weeks. Hematologic toxicities included leukocytosis, anemia, and thrombocytopenia. CONCLUSIONS: Chemoembolization is a feasible treatment modality for patients with colorectal carcinoma metastasis to the liver who have experienced failure with other systemic treatments. It results in high response rates with transient mild-to-moderate toxicity. Responses are measured in months, however, and all patients have eventual progression of disease. Patients who are able to undergo three or more chemoembolization procedures may receive the most clinical benefit.

Circulating platelet-derived endothelial cell growth factor increases in hepatocellular carcinoma patients.

Year 1998
Jin-no K. Tanimizu M. Hyodo I. Nishikawa Y. Hosokawa Y. Endo H. Doi T. Mandai K. Ishitsuka H.
Department of Clinical Research, National Shikoku Cancer Center Hospital, Ehime, Japan.
BACKGROUND: Platelet-derived endothelial cell growth factor (PD-ECGF) is an angiogenic factor that is expressed in various cancer tissues. Little is known regarding plasma PD-ECGF levels in patients with chronic liver disease such as chronic hepatitis (CH), cirrhosis, and hepatocellular carcinoma (HCC) with cirrhosis. The expression of PD-ECGF in HCC tissues also remains to be clarified. METHODS: Plasma PD-ECGF levels in patients with chronic liver disease were determined with an enzyme-linked immunoadsorbent assay system using the mouse monoclonal antibodies specific to PD-ECGF. These were cross-sectionally compared among groups of normal persons, CH, cirrhosis, and HCC patients. The HCC patients were classified into two groups based on TNM stage: early and advanced stage disease groups. PD-ECGF expressions in HCC tissues were immunohistologically examined. RESULTS: The plasma PD-ECGF levels from the normal individuals and those with CH, cirrhosis, and HCC specimens were 4.2+/-0.5, 4.3+/-0.6, 4.6+/-1.1, and 6.0 +/-2.5 U/mL, respectively. The plasma PD-ECGF concentration was highest in HCC (P < 0.05). No significant difference was found among the normal subjects, CH, and cirrhosis specimens. Plasma PD-ECGF concentrations were significantly higher in the advanced stage disease HCC group compared with the early stage disease group (6.75+/-2.62 U/mL vs. 4.19+/-0.34 U/mL) (P < 0.05). Immunohistochemical expression of PD-ECGF in HCC cells increased significantly compared with normal liver cells (P < 0.05). CONCLUSIONS: Circulating PD-ECGF plasma level might be a new tumor marker for progression in patients with HCC. Immunohistological findings correspond to elevation of the plasma PD-ECGF in HCC patients. It is possible that increased production of PD-ECGF in HCC cells causes abundant neovascularization.

Cryosurgery as a treatment for advanced stage hepatocellular carcinoma: results, complications, and alcohol ablation.

Year 1998
Wong WS. Patel SC. Cruz FS. Gala KV. Turner AF.
Cryosurgical Center of Southern California, Alhambra Hospital, 91801, USA.
BACKGROUND: The objective of this study was to investigate the use of cryosurgery and to determine whether there is a role for combined therapy with alcohol ablation in the treatment of patients with hepatocellular carcinoma. METHODS: Twelve patients with biopsy proven hepatocellular carcinoma underwent ultrasound-guided cryosurgical ablation of their liver tumor. Postoperative alcohol ablation was performed on those patients who were found to have residual tumor or recurrence after the cryosurgical procedure. RESULTS: Of the 12 patients (9 males, 3 females) the size of the primary tumor ranged from 3-13 cm with average size of 7 cm in greatest dimension. Most patients had advanced disease according to the TNM staging system: 9 patients had Stage IVA disease, 2 Stage III, and 1 Stage II. Three patients had residual tumors after the cryosurgical procedure. The residual tumor was treated with alcohol ablation. The 1-year survival rate for the entire group was 50% (5 of 10) and the 2-year survival rate was 30% (3 of 10). At last follow-up, 1 patient with an 8-cm tumor was disease free for 3 years and another patient with a 13-cm tumor was disease free for 2.5 years. Both of these patients had Stage IVA disease. CONCLUSIONS: The authors found cryosurgery to be promising in the treatment of this extremely aggressive form of cancer, with the ability to prolong patient survival. Follow-up treatment with alcohol ablation is an important adjunct in treating residual tumor and controlling recurrences.

Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas and periampullary region.

Year 1998
Molberg KH. Heffess C. Delgado R. Albores-Saavedra J.
Department of Pathology, University of Texas Southwestern Medical Center, Dallas 75235-9072, USA.
BACKGROUND: Undifferentiated carcinomas with osteoclast-like giant cells are rare pancreatic and periampulary neoplasms that morphologically mimic giant cell tumor of bone. Despite numerous publications based primarily on single case reports, the terminology, histogenesis, and biologic behavior of these tumors remain controversial. METHODS: The authors studied one periampullary and nine pancreatic neoplasms of this type. Immunohistochemistry was performed on nine of the cases and clinical follow-up data was obtained in eight. RESULTS: The neoplasms were large (average 9 cm), partially or completely multicystic, and hemorrhagic. Histologically, they were composed predominantly of ovoid or spindle-shaped bland mononuclear cells and evenly spaced osteoclast-like giant cells. However, three neoplasms had foci in which the nuclear pleomorphism of the mononuclear cells approached that observed in anaplastic spindle and giant cell carcinomas. Other histologic features included phagocytosis of the mononuclear cells by the osteoclast-like giant cells (in 7 of 10 cases), osteoid or bone formation (in 3 of 10 cases), and chondroid differentiation (in 1 of 10 cases). Four neoplasms had foci of conventional adenocarcinoma and two arose in preexisting mucinous cystic neoplasms of the pancreas. The mononuclear cells were positive for epithelial markers in six of nine tumors tested (cytokeratins AE-1, AE-3, Cam 5.2, and/or epithelial membrane antigen). They were negative for the histiocytic markers (CD-68, lysozyme) in all nine cases tested. In contrast, the osteoclast-like giant cells were positive for CD-68 in all nine cases, positive for lysozyme in four cases, and negative for cytokeratins (AE-1, AE-3, and Cam 5.2) in all nine cases. p53 stained the mononuclear tumor cells in three cases and MIB-1 stained the mononuclear tumor cells in four cases, but the osteoclast-like giant cells did not stain with either antibody in all nine cases tested. Most of the patients died of disease within 1 year of diagnosis; only 1 patient was alive and disease free 14 years after surgical excision. CONCLUSIONS: The association of these tumors with conventional adenocarcinoma or mucinous cystic neoplasms, the histologic features, and the immunohistochemical profile supports an epithelial phenotype for the mononuclear cells and a reactive histiocytic lineage for the nonneoplastic osteoclast-like giant cells. These neoplasms, which are better classified as undifferentiated carcinomas, follow an aggressive clinical course; most patients die of disease within 1 year.

The clinicopathologic significance of small areas unstained by Lugols iodine in the mucosa surrounding resected esophageal carcinoma: an analysis of 147 cases.

Year 1998
Nakanishi Y. Ochiai A. Yoshimura K. Kato H. Shimoda T. Yamaguchi H. Tachimori Y. Watanabe H. Hirohashi S.
Pathology Division, National Cancer Center Research Institute, Tokyo, Japan.
BACKGROUND: Small areas unstained with Lugol's iodine are often observed in the mucosa surrounding esophageal carcinomas. METHODS: For light microscopic evaluation, the histologic features of 131 small areas unstained by Lugol's iodine in 12 selected cases were investigated. For clinicopathologic evaluation, the numbers of small areas unstained by Lugol's iodine in the mucosa surrounding 147 consecutively resected esophageal carcinomas, including these 12 cases, were counted. The relation between the incidence of such areas and the development of multiple primary cancers in the upper aerodigestive tract was examined together with data on the patients' tobacco and alcohol consumption. RESULTS: Ninety-two percent (131) of the small areas unstained by Lugol's iodine contained dysplastic lesions. Seventeen (12%) of the 147 resected specimens contained fewer than 5 small unstained areas, whereas 52 (35%) had 6-10 and 78 (53%) had more than 11 such areas. The incidence of multicentric cancer in the upper aerodigestive tract and the average alcohol index scores were significantly higher for patients who had more than 11 unstained areas than for patients who had fewer than 5 such areas (P < 0.01). CONCLUSIONS: Lugol's iodine staining method is useful for detecting groups at high risk of multicentric cancer in the upper aerodigestive tract.

Treatment of patients with advanced gastric carcinoma with a 5-fluorouracil-based or a cisplatin-based regimen: two parallel randomized phase II studies.

Year 1998
Barone C. Corsi DC. Pozzo C. Cassano A. Fontana T. Noviello MR. Landriscina M. Colloca G. Astone A.
Sezione di Oncologia Medica, Istituto di Medicina Interna e Geriatria, Universita del S. Cuore, Rome, Italy.
BACKGROUND: Although many drug combination therapies have been proposed, there is no standard therapy for patients with advanced gastric carcinoma. The superiority of combination therapy over monochemotherapy has not been demonstrated convincingly. To explore the role of monochemotherapy, the authors evaluated 5-fluorouracil (5-FU), modulated by 6S-leucovorin (6S-LV) and a cisplatin-containing regimen, which was comprised of epirubicin, etoposide, and cisplatin with the addition of the reversal agent lonidamine (EEP-L). METHODS: After stratification according to performance status (PS) and resection of the primary tumor, 72 patients with advanced gastric carcinoma were randomized to 2 parallel Phase II trials with 5-FU/6S-LV and EEP-L, respectively. Thirty-six patients in Study A received bolus 6S-LV, 100 mg/m2, followed by bolus 5-FU, 370 mg/m2, on Days 1-5 and 36 others in Study B received epirubicin, 30 mg/m2, on Days 1 and 5; etoposide, 100 mg/m2, on Days 1, 3, and 5; cisplatin, 30 mg/m2, on Days 2 and 4; and lonidamine, 150 mg/day. RESULTS: There were 6 partial responses (18.2%) (95% confidence interval [CI] +/- 13.2) in Study A and 7 partial responses (21.9%) (95% CI +/- 14.3) in Study B. Partial responses were more frequent in patients with resected tumors or with an Eastern Cooperative Oncology Group PS of 0-1. The median duration of response was 8.8 and 8.3 months, respectively, in Study A and Study B. The median survival reached 8 months in Study A and 9 months in Study B. In the whole population of patients survival was significantly higher in patients with a PS of 0-1 (P < 0.05). Patients with a PS of 0-1 and a resected tumor had the significantly longest survival both in EEP-L treated patients and in all evaluable patients in the two studies. The most frequent World Health Organization Grade 3-4 toxic effects were gastrointestinal in Study A and hematologic in Study B. No treatment-related death was observed. CONCLUSIONS: The efficacy of 5-FU, modulated with 6S-LV, is moderate in patients with advanced gastric carcinoma, similar to cisplatin-containing regimens. PS and other prognostic factors could influence the response rate, which does not appear to be a reliable parameter for evaluating the outcome of chemotherapy trials.

Interrelation between tumor-associated cell surface glycoprotein and host immune response in gastric carcinoma patients.

Year 1998
Okuyama T. Maehara Y. Kakeji Y. Tsuijitani S. Korenaga D. Sugimachi K.
Department of Surgery II, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
BACKGROUND: Expression of changes in cell surface glycoprotein may correlate with the malignant potential and development of gastric carcinoma. Immunologic defense mechanisms of the host against the tumor can be effective in preventing the development of gastric carcinoma. The authors studied the effects of immunologic defense of the host against the tumor, using infiltration of S-100 protein positive dendritic cells (DC) as a marker. In cases with or without changes in the surface glycoprotein of tumor cells, determinations were made by binding of Helix pomatia agglutinin (HPA). METHODS: Paraffin blocks of 123 gastric carcinoma specimens were prepared for immunohistochemical staining with the antibody against HPA and S-100 protein. Clinicopathologic factors and patient prognosis were examined for each indicator. RESULTS: Patients with HPA positive tumors had a more aggressive character in several important prognostic aspects and poorer 5-year survival rates compared with patients with HPA negative tumors. The degree of infiltration of DC had no particular correlation with pathologic factors, and there was no significant difference between the prognosis of patients with slight and marked DC infiltration. In the HPA negative patients there was no significant difference in the 5-year survival rates between patients with slight and marked DC infiltration; however, in the HPA positive patients the 5-year survival rates of patients with marked infiltration of DC were higher. Further investigation showed that patients with marked DC infiltration had better 5-year survival rates than patients with slight DC infiltration, especially in patients with HPA positive and histologically advanced disease. CONCLUSIONS: Patients with a higher immunologic defense against cancer cells, as indicated by marked infiltration of DC, had a better prognosis in cases of gastric carcinomas of highly malignant potential, as indicated by a positive HPA.

Factors associated with the use of flexible sigmoidoscopy as a screening test for the detection of colorectal carcinoma by primary care physicians.

Year 1998
Cooper GS. Fortinsky RH. Hapke R. Landefeld CS.
Department of Medicine, University Hospitals of Cleveland and Cleveland VAMC, Case Western Reserve University, Ohio 44106, USA.
BACKGROUND: Despite current recommendations of flexible sigmoidoscopy as a screening test for the detection of colorectal carcinoma, relatively few asymptomatic patients undergo this procedure. To enhance the use of sigmoidoscopy, differences in the use of screening, as well as barriers to screening among specific physician groups, should be defined. METHODS: The authors surveyed 1762 practicing primary care physicians to determine their self-reported ability to perform sigmoidoscopy and perceived obstacles to either initiating or enhancing screening. RESULTS: A total of 884 physicians (50%) responded. Ninety percent of primary care physicians reported that they offered sigmoidoscopic screening to their patients, with 46% referring patients and 44% performing the procedure themselves. Physician characteristics were not associated with the overall use of sigmoidoscopy. In contrast, compared with physicians who referred patients for the procedure, physicians who performed sigmoidoscopy themselves were more often board certified, male, and graduated from medical school after 1970 (P < 0.001). In a multivariate analysis, these characteristics were also independently associated with the ability to perform sigmoidoscopy. The barrier to sigmoidoscopy cited most often was poor patient acceptance, whether or not the physician performed or referred patients for sigmoidoscopic screening. Other barriers cited were lack of training, lack of equipment, and time required, each of which was identified most often by physicians who did not screen at all. CONCLUSIONS: Most physicians surveyed reported using sigmoidoscopic screening to some degree in their practice, although many did not perform the procedure themselves. Population-based interventions to increase screening may benefit from targeting specific physician subgroups and attempting to improve patient acceptance of the procedure.

Lymph node harvest reporting in patients with carcinoma of the large bowel: a French population-based study.

Year 1998
Maurel J. Launoy G. Grosclaude P. Gignoux M. Arveux P. Mathieu-Daude H. Raverdy N. Faivre J.
Service de Chirurgie Digestive-CHU Caen et Registre des Tumeurs Digestives du Calvados, CJF INSERM, France.
BACKGROUND: In patients with resected colorectal carcinoma, lymph node involvement has particular importance for patient prognosis and adjuvant therapy. The network of French cancer registries (FRANCIM) established a study aimed at analyzing the validity of lymph node harvest reporting in a population-based sample. METHODS: The study population was comprised of 1081 resected tumors without distant visceral metastasis and classified using the TNM system. Correlation between the number of examined lymph nodes and the staging of the tumor was examined by logistic regression analysis to establish an estimate of the minimum number of lymph nodes required to determine whether a tumor is lymph node negative. RESULTS: An average of 7.7 +/- 0.2 lymph nodes were examined per specimen in the 851 patients for whom the number of lymph nodes examined was known. The proportion of cases classified as N+ increased significantly with the number of examined lymph nodes (chi-square trend = 24.6; P < 0.0001). If the probability of correct lymph node status assessment is 1 in the reference group (comprised of pathology reports of specimens with > or = 16 examined lymph nodes), the probability of correct N+/N- dichotomization was significantly < 1 for the 1 to 3 lymph nodes group and the 4 to 7 lymph nodes group (i.e., 53.7% of cases). CONCLUSIONS: To comply with current rules for adjuvant chemotherapy, surgeons must provide pathologists with at least eight lymph nodes for optimal N+/N- dichotomization to reduce the risk of misclassification and understaging.

The establishment of a preoperative diagnosis of pancreatic carcinoma using cell specimens from pancreatic duct brushing with special attention to p53 mutations.

Year 1998
Iwao T. Hanada K. Tsuchida A. Hirata M. Eguchi N. Kajiyama G.
First Department of Internal Medicine, Hiroshima University School of Medicine, Japan.
BACKGROUND: Previously, the authors reported that 82% of cases of pancreatic carcinoma were positive for p53 in cytologic specimens obtained by selective endoscopic pancreatic duct brushing (SEPB). However, there was an extreme discrepancy between the authors' data of p53 overexpression using cytologic specimens and other reports using surgically resected specimens. In this study, the authors demonstrate that p53 positive cells precisely reflect its gene mutations, and also establish systematic procedures for the preoperative diagnosis of patients with pancreatic carcinoma. METHODS: The authors examined 44 cases of pancreatic carcinoma, 30 cases of chronic pancreatitis, and 9 cases of papillary adenoma. In all cases, pathologic diagnosis was made by surgery or autopsy. The conventional cytology and p53 immunocytology were performed simultaneously in the cell specimens obtained by SEPB. In the cases immunostained for p53, DNA was extracted selectively from p53 immunostained cells using a light microscope. p53 mutations in exons 5 to 8 were examined by direct sequencing. RESULTS: Forty of 44 pancreatic carcinomas (91%) were diagnosed correctly by the methods of conventional cytology associated with p53 immunocytology. p53 mutations were detected in 12 of 14 cases that were positive for p53 (86%). Four of six cases that were inoperable due to massive metastasis or invasion had the mutation at codon 273 (CGT to CAT) in exon 8. CONCLUSIONS: These results suggest that p53 immunocytology reflects its gene mutations precisely, and that the point mutation at codon 273 (CGT to CAT) of p53 may play an important role in the invasive potential and metastasis of pancreatic carcinoma.

The role of glucagon administration in the diagnosis and treatment of patients with tumor hypoglycemia.

Year 1998
Hoff AO. Vassilopoulou-Sellin R.
Section of Endocrine Neoplasia and Hormonal Disorders, Baylor College of Medicine, Houston, Texas, USA.
BACKGROUND: Tumor hypoglycemia can be recurrent and severe enough to interfere with definitive antineoplastic treatment. Therefore, rapid commencement of effective therapy is essential. This is best accomplished by identifying which of the hypoglycemic processes is involved, as treatments differ. Some patients present with hypoglycemia and liver metastases; among them, only a few develop hypoglycemia as a result of a failure of hepatic glucose production. Most develop hypoglycemia as a result of an insulin-mediated process--either the secretion of insulin by an islet-cell tumor or the secretion of insulin-like growth factor-II by an extrapancreatic tumor. Administration of glucagon can rapidly make the two groups distinguishable, thus allowing institution of therapy and prompt symptomatic control of hypoglycemia. METHODS: The charts of seven patients with tumor hypoglycemia and liver metastases who had a glucagon stimulation test (serial glucose measurements after a 1 mg infusion of glucagon) as part of the workup for hypoglycemia were retrospectively reviewed. Those patients whose test revealed a rise in serum glucose of >30 mg/ dL were subsequently treated as outpatients, with a continuous glucagon infusion delivered by a portable pump. RESULTS: Three patients had an insulinoma and four had non-islet cell tumor hypoglycemia (NICTH) due to hepatocellular carcinoma, colon carcinoma, meningeal sarcoma, and hemangiopericytoma, respectively. All of the patients had liver metastases. Evaluation of these patients included a glucagon stimulation test (1 mg intravenous push), which quickly provided information about the mechanism of tumor hypoglycemia and the direction towards therapy. All patients with insulinoma responded to glucagon with a rise in blood serum glucose levels, indicating adequate glycogen stores. The four patients with NICTH had mixed responses: in two patients, the response suggested that hypoglycemia was due to an insulin-like tumor product; glucose levels did not rise in the other two cases, indicating that hypoglycemia was due to poor hepatic glycogen reserve/liver failure. In all cases, a glycemic response to glucagon predicted good response to long term treatment with glucagon (0.06-0.3 mg/hour, via intravenous infusion pump). CONCLUSIONS: The glucagon stimulation test is a simple and fast approach that serves to clarify the etiology of hypoglycemia (diagnostic use) and guide effective long term strategies for its control (therapeutic use) in patients with neoplastic diseases and liver metastases.

Image cytometry as a discriminatory tool for cytologic specimens obtained by endoscopic retrograde cholangiopancreatography.

Year 1998
Sears RJ. Duckworth CW. Decaestecker C. Bourgeois N. Ledent T. Deviere J. Salmon I. Kiss R. Yeaton P.
Digestive Health Center, University of Virginia Health Sciences Center, Charlottesville 22906-0013, USA.
BACKGROUND: Routine brush cytology is relatively insensitive for the diagnosis of biliary and pancreatic malignancy. Sensitivity can be improved by measuring DNA and proliferation. The goal of this study was to assess the discriminatory capacity of image cytometry using pancreaticobiliary brush cytology specimens obtained during endoscopic retrograde cholangiopancreatography (ERCP). Analysis included morphometry, DNA quantification, and characterization of nuclear chromatin distribution and condensation. METHODS: Brush cytology specimens were obtained during ERCP from 22 chronic pancreatitis specimens, 11 pancreatic adenocarcinoma specimens, 13 primary sclerosing cholangitis specimens, and 11 cholangiocarcinoma specimens and contrasted with 25 normal epithelia specimens. A SAMBA 2005 image processor was used to analyze Feulgen stained chromatin density and distribution. Discriminant analysis of 37 morphonuclear variables was performed to characterize differences between: 1) chronic pancreatitis and pancreatic adenocarcinoma, and 2) primary sclerosing cholangitis and cholangiocarcinoma. RESULTS: Chronic pancreatitis was distinguished from pancreatic adenocarcinoma (P < or = 0.001); sensitivity and specificity were both estimated to be 82%. Primary sclerosing cholangitis was distinguished from cholangiocarcinoma (P < or = 0.01); sensitivity and specificity were estimated to be 82% and 85%, respectively. CONCLUSIONS: Multiparameter image cytometry has potential as an adjuvant diagnostic technique in patients with pancreaticobiliary malignancy.

Monoclonal origin of an esophageal carcinosarcoma producing granulocyte-colony stimulating factor: a case report.

Year 1998
Ota S. Kato A. Kobayashi H. Yonezumi M. Yamaguchi J. Musashi M. Imamura M. Asaka M.
The Third Department of Internal Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
BACKGROUND: Carcinosarcomas are comprised of carcinomatous and sarcomatous elements, and their histogenesis remains unclear. The authors examined the serum concentrations of hematopoietic growth factors and performed immunohistochemical studies on an esophageal carcinosarcoma from a patient with marked granulocytosis to determine its histopathogenesis and clonality. METHODS: The authors examined the case of a 63-year-old man with a polypoid tumor of the esophagus associated with marked leukocytosis (131 x 10(9) per liter). Immunohistochemical staining of the esophageal tumor was performed using monoclonal antibodies against granulocyte-colony stimulating factor (G-CSF), keratin, epithelial membrane antigen (EMA), and vimentin. RESULTS: The patient's leukocyte count was increased (124 x 10(9) per liter) on admission. Because mature granulocytes predominantly were increased despite the absence of apparent infection, the patient's serum G-CSF concentration was examined and found to be 286.0 pg/mL and to increase with time. After thoracic esophagectomy was performed, granulocyte count and serum G-CSF concentration rapidly normalized. G-CSF concentration was 50-fold higher in the tumor tissue extract than in the extract from normal esophageal tissue. Microscopic examination of the resected specimens revealed that the tumor was comprised of squamous cell carcinoma (SCC) and spindle-shaped sarcomatous elements, and transitional features were observed within these two components. Immunohistochemical examination disclosed cells that were positive for keratin and EMA in the carcinomatous element and vimentin positive cells in the sarcomatous element. However, both types of tumor cells were positive for G-CSF. CONCLUSIONS: The presence of G-CSF in both SCC cells and spindle-shaped sarcomatous cells indicated that these two components originated from a single clone.

The relation between the growth patterns of gastric carcinoma and the expression of hepatocyte growth factor receptor (c-met), autocrine motility factor receptor, and urokinase-type plasminogen activator receptor.

Year 1998
Taniguchi K. Yonemura Y. Nojima N. Hirono Y. Fushida S. Fujimura T. Miwa K. Endo Y. Yamamoto H. Watanabe H.
Second Department of Surgery, School of Medicine, Kanazawa University, Kanazawa City, Japan.
BACKGROUND: Hepatocyte growth factor receptor (c-met), autocrine motility factor receptor (AMFR), and urokinase-type plasminogen activator receptor (uPAR) are known to play important roles in tumor cell migration, invasion, and metastasis. The authors studied the relation between the expression patterns of these genes and the growth patterns of human gastric carcinoma. METHODS: The relation between the expression of c-met, AMFR, and uPAR and clinicopathologic parameters was studied using immunohistochemical preparations from 102 paraffin embedded primary gastric carcinomas. RESULTS: Of 102 cases, 43 (42%) had overexpression of c-met, and AMFR and uPAR immunoreactivity was observed in 41 cases (40%) and 38 cases (37%), respectively. Macroscopic examination revealed that all three genes were expressed in 1 (3%) of 32 early stage gastric carcinomas, 0 (0%) of 29 localized carcinomas (Borrmann types 1 and 2), and 16 (39%) of 41 infiltrating carcinomas (Borrmann types 3 and 4). In particular, the incidence (68%, 13 of 19 cases) of simultaneous expression of the three genes was significantly higher in Borrmann type 4 gastric carcinoma than in the other macroscopic types (P < 0.01). The overexpression of these genes was also closely associated with lymph node metastasis and peritoneal dissemination. In addition, the simultaneous overexpression of the three genes was associated with positive lymphatic vessel invasion and infiltrating type. Patients with tumors that simultaneously expressed all three genes had significantly poorer prognoses than those with tumors expressing only one or two of the genes. Furthermore, the number of genes expressed was closely related to the prognosis, and the Cox proportional hazards model identified this as one of the independent prognostic factors. CONCLUSIONS: These results suggest that the expression patterns of c-met, AMFR, and uPAR may be closely associated with the progression and invasion of gastric carcinoma as well as the prognoses of the patients. Borrmann type 4 gastric carcinoma is characterized by the diverse and simultaneous expression of these three genes.

Comorbidity and age as predictors of risk for early mortality of male and female colon carcinoma patients: a population-based study.

Year 1998
Yancik R. Wesley MN. Ries LA. Havlik RJ. Long S. Edwards BK. Yates JW.
Geriatrics Program, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892-9205, USA.
BACKGROUND: Colon carcinoma primarily affects persons 65 years and older. Seventy-five percent of the incident tumors affect persons in this age group. Because of their advanced age, older patients already may be coping with other concomitant major physical illnesses. This article documents preexisting diseases in older colon carcinoma patients at diagnosis and evaluates the effects of their comorbidity burden on early mortality. METHODS: Prevalence of comorbid conditions was assessed by a retrospective medical records review of an age-stratified random sample of male and female patients aged 55-64 years, 65-74 years, and 75+ years (males, n=799; females, n=811). Data were collected on comorbidity by the National Institute on Aging (NIA) and National Cancer Institute (NCI) and merged with NCI Surveillance, Epidemiology, and End Results (SEER) tumor registry data. RESULTS: Hypertension, high impact heart conditions, gastrointestinal problems, arthritis, and chronic obstructive pulmonary disease emerged as the most prominent comorbid conditions in the NIA/NCI SEER Study sample. The prevalence of comorbidity in the number and type of conditions was similar for both men and women (e.g., 40% of each gender had > or = 5 comorbidities). Within 2 years of diagnosis, 28% (n=454) of the patients had died. The number of comorbid conditions was significant in predicting early mortality in a model including age, gender, and disease stage (P=0.0007). Certain comorbidities, classified as "current problem," added significantly to a basic model (e.g., heart problems, alcohol abuse, liver disease, and deep vein thrombosis). CONCLUSIONS: Although disease stage at time of diagnosis of colon carcinoma is a crucial determinant of patient outcome, comorbidity increases the complexity of cancer management and affects survival duration. Cancer control and treatment research questions should address comorbidity issues pertinent to the age group primarily afflicted with colon carcinoma (i.e., the elderly).

GIVIO-SITAC 01: A randomized trial of adjuvant 5-fluorouracil and folinic acid administered to patients with colon carcinoma--long term results and evaluation of the indicators of health-related quality of life. Gruppo Italiano Valutazione Interventi i

Year 1998
Zaniboni A. Labianca R. Marsoni S. Torri V. Mosconi P. Grilli R. Apolone G. Cifani S. Tinazzi A.
Modulo di Oncologia, Poliambulanza, Brescia, Italy.
BACKGROUND: In 1989, the authors began a randomized trial to determine whether 5-fluorouracil and high dose folinic acid (HD-FUFA) would increase the event free and overall survival of patients with resectable Dukes B and C (AJCC/UICC Stage II and Stage III) colon carcinoma, and to assess the toxicity of the treatment and its impact on selected health-related quality-of-life indicators. Early results were published as a part of an international multicenter pooled analysis (IMPACT) in 1995. The purpose of this report is to update the survival data for patients enrolled in the trial and describe their reported perceptions of their own health and quality of life. METHODS: The trial involved multiple treatment centers, with a centralized randomization between surgery alone and surgery with chemotherapy. The HD-FUFA regimen employed consisted of 5-fluorouracil (370 mg/m2) plus folinic acid (200 mg/m2) administered daily for 5 days every 4 weeks for 6 cycles. Patients' perceptions of their own health status were obtained by means of 3 self-administered questionnaires, which were completed by patients at the time of discharge from the treatment center and at 6 and 24 months after randomization. RESULTS: Overall, 888 patients with resected Dukes B2 and C colon carcinoma were enrolled in the trial. HD-FUFA significantly reduced mortality by 25% (95% confidence interval, 5-41%; P=0.02) and events by 31% (95% confidence interval, 14-45%; P < or = 0.001). Compliance with treatment was good; more than 80% of patients completed the planned therapy. Toxicity was mild, and oral mucositis was the main side effect. None of the health-related quality-of-life parameters investigated (emotional status, worry about the future, changes in social life, impact of the disease, follow-up, and global quality of life) seemed to be affected by the treatment to which patients were allocated. A positive trend in the evolution of patients' psychologic status was observed. CONCLUSIONS: Long term results of this SITAC study confirm that HD-FUFA is a well-tolerated, effective 6-month adjuvant regimen for patients with colon carcinoma that has no detrimental effect on their quality of life.

Minute nodular intrahepatic cholangiocarcinoma.

Year 1998
Yamamoto M. Takasaki K. Nakano M. Saito A.
Institute of Gastroenterology, Tokyo Women's Medical College, Japan.
BACKGROUND: This study describes the clinicopathologic features of minute intrahepatic cholangiocarcinoma (ICC) and clarifies the relation between minute nodular ICC and hepatitis viral infection. METHODS: The presence of hepatitis C virus antibody (anti-HCV) and hepatitis B surface antigen (HBsAg) was examined in the serum of 50 patients with ICC who underwent hepatectomy from 1990-1996. The ICCs included 12 minute tumors (5 years after surgery. However, 1 patient died 2 years after surgery because of remnant liver and lymph node recurrence. CONCLUSIONS: Minute nodular ICC appears to be related to hepatitis viral infection and could be detected at an early stage, similar to hepatocellular carcinoma, by following up cases of chronic hepatitis or cirrhosis.

A clinicopathologic and immunohistochemical study of ten pancreatic lymphangiomas and a review of the literature.

Year 1998
Paal E. Thompson LD. Heffess CS.
Department of Endocrine and Otorhinolaryngic-Head & Neck Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.
BACKGROUND: Pancreatic lymphangiomas are rare benign tumors, of which only a few cases have been reported in the literature. In this study, the authors present a series of primary pancreatic lymphangiomas. METHODS: Cases of nonepithelial pancreatic cystic tumors (lymphangiomas) diagnosed between 1966 and 1994 were retrieved from the Endocrine Pathology Registry of the Armed Forces Institute of Pathology. Histologic features (in 10 cases) as well as histochemical and immunohistochemical studies (in 6 cases) were reviewed. Long term patient follow-up data were obtained in 9 cases. RESULTS: The patients included 8 females and 2 males ages 2-61 years (mean age, 28.9 years) at initial presentation. The tumors were circumscribed and occurred predominantly (in 6 of 10 cases) in the tail of the pancreas. The multicystic, serous, or chylous fluid-filled cystic tumors ranged from 3 to 20 cm (average, 12.7 cm) in greatest dimension. Histologically, the tumors consisted of multilocular cystic spaces of various sizes, lined by endothelial cells. The stroma contained smooth muscle and mature lymphocytes. Immunohistochemistry determined the endothelial lining cells to be factor VIII-R antigen and CD31 positive (in all cases tested) but usually CD34 negative. All patients for whom follow-up data were obtained (n=9) were alive without evidence of disease an average of 7.2 years after initial diagnosis. CONCLUSIONS: Pancreatic lymphangiomas occur predominantly in females within a wide age range. Multilocular, fluid-filled cysts, with endothelial immunoreactivity for factor VIII-R antigen and CD31, are characteristic of these tumors. Complete surgical excision of these benign tumors resulted in excellent long term prognoses for all patients studied.

Long-term survival of patients with stage IV gastric carcinoma.

Year 1998
Kakeji Y. Maehara Y. Tomoda M. Kabashima A. Ohmori M. Oda S. Ohno S. Sugimachi K.
Department of Surgery II, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
BACKGROUND: Survival of patients with Stage IV (based on general rules established by the Japanese Research Society for Gastric Cancer) gastric carcinoma often is unfavorable. Among patients with a poor prognosis, a few do survive > 5 years. The authors examined pathologic and biologic features of tumors of long term survivors. METHODS: The authors analyzed data from 442 patients with Stage IV gastric carcinoma, including 20 surviving for > 5 years after gastrectomy (Group A) and 422 who died of gastric carcinoma within 5 years (Group B). Mutant p53 was immunohistochemically stained using the monoclonal antibody PAb1801. Proliferative activity was estimated by argyrophilic nuclear organizer region (AgNOR) staining and proliferating cell nuclear antigen (PCNA) staining. RESULTS: Group A had smaller and more localized tumors than Group B (P < 0.05 and P < 0.01, respectively). Lymphatic or venous invasion and peritoneal dissemination were less frequent in Group A than in Group B (P < 0.01). Abnormalities of p53 expression were found in 3 of the 14 tumors in Group A (21%), a value significantly lower than the 58 of 118 tumors in Group B (49%; P < 0.05). AgNOR count and percentage of PCNA labeling were not significantly different between Groups A and B. A multivariate analysis showed that lymph node dissection, liver metastasis, gastric resection, venous invasion, and tumor size were independent prognostic factors. CONCLUSIONS: Even in patients with Stage IV gastric carcinoma, radical gastrectomy and extensive lymph node dissection can lead to long term survival. The authors believe that combination analysis of pathologic features and p53 overexpression predict length of survival for patients with Stage IV gastric carcinoma.

Race, treatment, and survival among colorectal carcinoma patients in an equal-access medical system.

Year 1998
Dominitz JA. Samsa GP. Landsman P. Provenzale D.
Center for Health Services Research and Development, Veterans Affairs Medical Center, Durham, North Carolina, USA.
BACKGROUND: The aim of this study was to assess the influence of race on the treatment and survival of patients with colorectal carcinoma. METHODS: This retrospective cohort study included all white or black male veterans given a new diagnosis of colorectal carcinoma in 1989 at Veterans Affairs Medical Centers nationwide. After adjusting for patient demographics, comorbidity, distant metastases, and tumor location, the authors determined the likelihood of surgical resection, chemotherapy, radiation therapy, and death in each case. RESULTS: Of the 3176 veterans identified, 569 (17.9%) were black. Bivariate analyses and logistic regression revealed no significant differences in the proportions of patients undergoing surgical resection (70% vs. 73%, odds ratio 0.92, 95% confidence interval 0.74-1.15), chemotherapy (23% vs. 23%, odds ratio 0.99, 95% confidence interval 0.78-1.24), or radiation therapy (17% vs. 16%, odds ratio 1.10, 95% confidence interval 0.85-1.43) for black versus white patients. Five-year relative survival rates were similar for black and white patients (42% vs. 39%, respectively; P=0.16), though the adjusted mortality risk ratio was modestly increased (risk ratio 1.13, 95% confidence interval 1.01-1.28). CONCLUSIONS: Overall, race was not associated with the use of surgery, chemotherapy, or radiation therapy in the treatment of colorectal carcinoma among veterans seeking health care at Veterans Affairs Medical Centers. Although mortality from all causes was higher among black veterans with colorectal carcinoma, this finding may be attributed to underlying racial differences associated with survival. This study suggests that when there is equal access to care, there are no differences with regard to race.

A phase II trial of 5-fluorouracil, leucovorin, and carboplatin in patients with unresectable biliary tree carcinoma.

Year 1998
Sanz-Altamira PM. Ferrante K. Jenkins RL. Lewis WD. Huberman MS. Stuart KE.
Division of Hematology/Oncology, Boston Center for Liver Cancer, Harvard Medical School, Massachusetts, USA.
BACKGROUND: Unresectable adenocarcinoma of the biliary tree are associated with a very poor prognosis. 5-fluorouracil (5-FU) combination regimens have produced objective response rates in approximately 10-20% of patients. Leucovorin increases the selective cytotoxicity of 5-FU. There also are encouraging reports of carboplatin in combination with 5-FU in other gastrointestinal tract malignancies. METHODS: Fourteen consecutive eligible patients were treated with a combination of carboplatin, 300 mg/m2, intravenously (i.v.) on Day 1 only and 5-FU, 400 mg/m2, i.v. with leucovorin, 25 mg/m2, i.v. on Days 1-4. All patients were required to have a histologically confirmed diagnosis and measurable disease. Patients were evaluated for response, survival, and toxicity. RESULTS: A total of 48 cycles of therapy were delivered. The median survival was 5 months. One patient achieved complete remission and two others partial remission, for a total response rate of 21.4%. Four additional patients had stable disease for a median duration of 4 months. The therapy was well tolerated, with moderate myelosuppression as the main dose-limiting toxicity. CONCLUSIONS: The current combination regimen of leucovorin-modulated 5-FU with carboplatin is well tolerated with appropriate supportive care, produces significant objective responses in 21% of patients with biliary tree carcinoma, and should be considered for the treatment of this disease.

Nonsteroidal antiinflammatory drug use and reduced risk of large bowel carcinoma.

Year 1998
Rosenberg L. Louik C. Shapiro S.
Slone Epidemiology Unit, Boston University School of Medicine, Brookline, Massachusetts 02146, USA.
BACKGROUND: Animal experiments and epidemiologic data have suggested that the use of nonsteroidal antiinflammatory drugs (NSAIDs) may decrease the incidence of large bowel carcinoma. Our purpose was to assess the relation of the use of aspirin and nonaspirin NSAIDs with the risk of large bowel carcinoma. METHODS: A population-based case-control study of colon and rectal carcinoma was conducted in Massachusetts from 1992 to 1994. Data on NSAID use and risk factors for large bowel carcinoma were collected by interview from 1201 incident cases of large bowel carcinoma and 1201 controls matched by age, gender, and area of residence. RESULTS: Regular NSAID use that continued into the year before diagnosis was associated with a significantly decreased relative risk estimate overall (0.7; 95% confidence interval [CI], 0.5-0.8) and among Stage II-IV tumors (0.6; 95% CI, 0.4-0.7). There was no reduction in risk for discontinued use. The inverse association with regular continuing use was present across age and gender and for both colon and rectal carcinoma. Similar inverse associations were present for regular continuing use of aspirin and nonaspirin NSAIDs. There was no significant evidence of a trend for the relative risk to decrease as the duration of use increased, nor was there a trend across the dose of aspirin, which ranged from less than one-half of a 325 mg tablet per day to > or = 2 tablets per day. Discontinuation of use in response to symptoms of carcinoma did not appear to explain the inverse association, nor did bias related to diagnosis of the carcinoma. CONCLUSIONS: These data add to the growing body of evidence that suggests a protective effect of NSAIDs against large bowel carcinoma.

Phenotype 2 of deoxyribonuclease I may be used as a risk factor for gastric carcinoma.

Year 1998
Tsutsumi S. Asao T. Nagamachi Y. Nakajima T. Yasuda T. Kishi K.
First Department of Surgery, Gunma University School of Medicine, Maebashi, Japan.
BACKGROUND: Human deoxyribonuclease I (DNase I) (EC3.1.21.1) is one of the candidate nucleases that acts in mammalian cells during apoptosis. Genetic polymorphism of DNase I has been classified into 15 phenotypes controlled by 5 autosomal codominant alleles. The purpose of this study was to determine whether DNase I polymorphism is closely related to the incidence of gastric carcinoma. METHODS: The phenotype distribution was examined using urine samples obtained from unrelated Japanese patients with gastric carcinoma (n = 97) and benign gastric diseases (n = 76). Phenotyping was performed using isoelectric focusing electrophoresis in thin polyacrylamide gel and immunoblotting with an antihuman DNase I antibody. RESULTS: A close statistical association was found between patients with gastric carcinoma and a high frequency of DNase I phenotype 2. However, there was no significant difference in the phenotype distribution between the group of patients with benign gastric diseases and the controls. CONCLUSIONS: The findings of the current study suggest that DNase I phenotype 2 may be a marker for gastric carcinoma. Therefore, compared with other phenotypes, DNase I phenotype 2 may have potential for identifying patients who are at risk of harboring or developing gastric carcinoma.

High expression of thymidylate synthase is associated with the drug resistance of gastric carcinoma to high dose 5-fluorouracil-based systemic chemotherapy.

Year 1998
Yeh KH. Shun CT. Chen CL. Lin JT. Lee WJ. Lee PH. Chen YC. Cheng AL.
Department of Oncology, National Taiwan University Hospital, Taipei, Republic of China.
BACKGROUND: In the past 4 years, the weekly 24-hour infusion of high dose 5-fluorouracil (5-FU) and leucovorin in the treatment of patients with advanced gastric carcinoma has been prospectively studied at the authors' institution. This has enabled them to explore the possibility that the level of expression of thymidylate synthase (TS), the target enzyme of 5-FU, is related to the drug sensitivity of gastric carcinoma to 5-FU-based chemotherapy. METHODS: To be eligible for this study, patients were required to have received high dose 5-FU and leucovorin chemotherapy (weekly 24-hour infusions of 5-FU, 2,600 mg/m2, and leucovorin, 300 mg/m2) and to have had adequate prechemotherapy gastric carcinoma tissues for immunohistochemical study. TS106 monoclonal antibody was used to detect the expression of TS. A visual scoring system, which ranged from 0 to 3+, was adopted by 2 independent pathologists to semiquantitate the intensity of TS expression. RESULTS: Between 1993 and 1996, a total of 30 patients, 18 men and 12 women, with a median age of 61.5 years, were enrolled. Of these patients, 16 (53.3%) and 14 (46.7%) had high and low expression of TS, respectively. Two of the 16 patients (12.5%) with high expression of TS and 13 of the 14 patients (92.9%) with low expression of TS responded to chemotherapy (P < 0.001, chi-square test). The median overall survival was 10 months for patients with low TS expression and 4 months for patients with high TS expression (P < 0.01, log rank test). CONCLUSIONS: The data from this study suggest that the expression of TS, as determined by immunohistochemistry, is a relatively reliable indicator of whether 5-FU should be used in the treatment of patients with gastric carcinoma.

A cost-effectiveness analysis of colorectal screening of hereditary nonpolyposis colorectal carcinoma gene carriers.

Year 1998
Vasen HF. van Ballegooijen M. Buskens E. Kleibeuker JK. Taal BG. Griffioen G. Nagengast FM. Menko FH. Meera Khan P.
The Netherlands Foundation for the Detection of Hereditary Tumours, Department of Gastroenterology, Leiden University Medical Centre.
BACKGROUND: It has been estimated that the prevalence of carriers of a mutated mismatch repair (MMR) gene among the general population in Western countries is between 5 and 50 per 10,000. These carriers have a risk of >85% of developing colorectal carcinoma (CRC) and therefore need careful follow-up. The objective of this study was to analyze the cost-effectiveness of CRC surveillance of carriers of a mutated MMR gene. METHODS: The authors constructed a model to estimate the potential health effects (life expectancy) and healthcare costs of two strategies: 1) surveillance, with colonoscopy every 2-3 years, and 2) no CRC surveillance. Estimates of the lifetime risk of developing CRC and the stage distribution of CRC for symptomatic patients were derived from the Dutch hereditary nonpolyposis colorectal carcinoma (HNPCC) registry. The CRC stage specific relative survival rates and the effectiveness of surveillance in preventing or detecting cancer early were based on Finnish studies. The costs of surveillance and treatment were derived from recent American studies. RESULTS: The results showed that 1) surveillance of gene carriers led to an increase in life expectancy of 7 years, and 2) the costs of surveillance under a wide range of assumptions are less than the costs of no CRC surveillance. CONCLUSIONS: CRC surveillance of HNPCC gene carriers appears to be effective and considerably less costly than no CRC surveillance and therefore deserves to be supported by governmental agencies and health insurance organizations.

Needle tract implantation of hepatocellular carcinoma after percutaneous ethanol injection.

Year 1998
Ishii H. Okada S. Okusaka T. Yoshimori M. Nakasuka H. Shimada K. Yamasaki S. Nakanishi Y. Sakamoto M.
Department of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan.
BACKGROUND: Percutaneous ethanol injection (PEI) therapy currently is widely used for small hepatocellular carcinoma (HCC). However, only limited information is available regarding needle tract implantation after PEI treatment. METHODS: Records of HCC patients who underwent PEI between March 1990 and April 1997 at the National Cancer Center Hospital (n = 177) were reviewed to clarify the incidence, risk factors, and outcome of needle tract implantation of HCC. RESULTS: PEI was performed for 348 HCC patients with a median tumor size of 20 mm. Needle tract implantation was found in 4 patients (10, 13, 15, and 46 months, respectively, after PEI). The size of the PEI-treated HCC tumors in these patients was 20, 27, 28, and 30 mm, respectively, in greatest dimension. All tumors were enhanced in the early phase on dynamic computed tomography (CT), and were found to have moderate tumor cell differentiation on biopsied specimens. Of the four implanted tumors, three were resected and the remaining tumor was treated with extrabeam radiotherapy. At last follow-up, 2 of the 4 patients had died (1 of variceal bleeding 60 months after PEI and the other from cancer 61 months after PEI) and 2 were still alive (14 and 20 months, respectively, after PEI) with no evidence of active tumor. CONCLUSIONS: Needle tract implantation after PEI is not unusual, especially when HCC tumors are > or =2 cm in greatest dimension, enhanced in the early phase on dynamic CT, and/or moderately differentiated on biopsied specimens.

The usefulness of determining des-gamma-carboxy prothrombin by sensitive enzyme immunoassay in the early diagnosis of patients with hepatocellular carcinoma.

Year 1998
Mita Y. Aoyagi Y. Yanagi M. Suda T. Suzuki Y. Asakura H.
Department of Internal Medicine, Niigata University School of Medicine, Japan.
BACKGROUND: Measurements of serum concentrations of des-gamma-carboxy prothrombin (DCP) are widely used for diagnosing hepatocellular carcinoma (HCC). However, the DCP is not always sensitive enough to detect small HCCs. In the current study, the authors investigated the usefulness of DCP in the early diagnosis of HCC, using a more sensitive enzyme immunoassay than is conventionally employed. METHODS: The authors examined 148 serum samples with DCP concentrations from a conventional assay of less than 100 mAU (arbitrary unit)/mL from 91 patients with HCC and 57 with cirrhosis. DCP concentrations were determined by a more sensitive enzyme immunoassay (ED-036 kit, Eisai Laboratory, Tokyo, Japan) with a minimal detection level of 10 mAU/mL. Ninety-one HCC patients had 43 solitary small HCCs (with a greatest dimension of less than 2 cm). Of these 43 HCCs, 12 were well differentiated. RESULTS: The mean serum concentration of DCP in HCC (48.3 +/- 24.3, mean +/- standard deviation [SD]) was higher than in cirrhosis (20.3 +/- 10.3); this difference was statistically significant. When the tentative cutoff level of 40 mAU/mL (almost corresponding to the mean value + 2SD in patients with cirrhosis) was used as the level of discriminating HCC from cirrhosis, 62% of patients (56 of 91) with HCC had DCP values above this level (sensitivity). However, only three patients with cirrhosis had higher DCP levels. Thus, the specificity of this test was 95% (54 of 57 patients). The total accuracy was 74% (56 + 54/91 + 57). Twenty-three of 43 solitary small HCCs (53%) had DCP values above the cutoff level. Furthermore, 7 of 12 (58%) small, well-differentiated HCCs less than 2 cm in greatest dimension had higher DCP values. CONCLUSIONS: The results of this study indicate that DCP determination by sensitive enzyme immunoassay is useful in the early diagnosis of HCC because a high specificity is maintained.

Pancreatic carcinoma: correlation between E-cadherin and alpha-catenin expression status and liver metastasis.

Year 1998
Gunji N. Oda T. Todoroki T. Kanazawa N. Kawamoto T. Yuzawa K. Scarpa A. Fukao K.
Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.
BACKGROUND: Dysfunction of the E-cadherin/catenin-mediated cell-cell adhesion system has been associated with invasiveness and poor differentiation of human carcinomas. However, its importance in the genesis of liver metastasis has not been examined sufficiently. METHODS: A series of 26 primary pancreatic carcinomas and the concomitant liver metastases from 15 of them, obtained at autopsy, were analyzed for E-cadherin and alpha-catenin protein expression by immunohistochemistry. RESULTS: Both E-cadherin and alpha-catenin expression were preserved in 15 (58%) and reduced in 11 (32%) of the 26 primary pancreatic carcinomas. In the former 15 primaries, carcinoma cells were attached to each other tightly, whereas the latter 11 primaries showed isolated or loosely connected attachments. The metastatic ratio was higher in tumors exhibiting tight adhesion than in those with loose adhesion: 73% and 36%, respectively (P = 0.059). E-cadherin and alpha-catenin expression patterns in liver metastases basically followed those in the corresponding primaries (P < 0.01). CONCLUSIONS: Reduced E-cadherin and alpha-catenin expression in primary pancreatic carcinoma has no significant predictive value regarding the presence of liver metastasis. Rather, there is a greater tendency for liver metastasis in cases in which the integrity of the E-cadherin/catenin-mediated cell-cell adhesion system is intact.

The risk of subsequent primary carcinoma of the pancreas in patients with cutaneous malignant melanoma.

Year 1998
Schenk M. Severson RK. Pawlish KS.
Department of Family Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
BACKGROUND: Carcinoma of the pancreas is the fifth leading cancer in the U.S. and has the poorest survival rate of the major malignancies. Recent studies have reported an increased risk of carcinoma of the pancreas in malignant melanoma-prone kindreds and have suggested a link between malignant melanoma and pancreas carcinoma and mutations in the p16INK4 gene. This study evaluates the risk of carcinoma of the pancreas in a population-based cohort of patients with malignant melanoma. METHODS: The malignant melanoma patients were identified from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. The cohort was followed within the SEER system to ascertain the occurrence of subsequent microscopically confirmed primary carcinoma of the pancreas from January 1973 through December 1993. The time of follow-up was expressed as person-years of observation. Standardized incidence ratios (SIR) and 95% confidence intervals (95% CI) were calculated. RESULTS: There were 43,781 malignant melanoma patients providing 263,528 person-years of follow-up. A nearly 2-fold increased risk of subsequent carcinoma of the pancreas in patients diagnosed with malignant melanoma before age 50 years was observed (SIR = 1.76; 95% CI = 0.80-3.34) and the greatest estimated risk occurred in young white females (SIR = 2.27; 95% CI = 0.73-5.30). CONCLUSIONS: These results provide some evidence in support of observations in recent studies that not only a family history of malignant melanoma but also malignant melanoma diagnosed at an early age may be associated with the subsequent development of carcinoma of the pancreas. Further research with larger numbers of melanoma patients is necessary to explore these potential associations.

Interferon-alpha and chemohormonal therapy for patients with advanced melanoma: final results of a phase I-II study of the Cancer Biotherapy Research Group and the Mid-Atlantic Oncology Program.

Year 1998
Stark JJ. Dillman RO. Schulof R. Wiemann MC. Barth NM. Honeycutt PJ. Soori G.
Maryview Medical Center, Portsmouth Virginia, USA.
BACKGROUND: The treatment of metastatic melanoma remains unsatisfactory despite encouraging results with biotherapy and combination chemotherapy. Combining these two modalities may improve outcomes for such patients. METHODS: Patients who were eligible for this study had metastatic melanoma and were in good medical condition. The following regimen was used: dacarbazine 220 mg/m2 and cisplatin 25 mg/m2 administered intravenously (i.v.) daily x 3 days every 3 weeks, carmustine 150 mg/m2 i.v. every 6 weeks, tamoxifen 10 mg administered orally twice a day, and interferon-alpha2b 3.0 thousandths of an International Unit (mIU)/m2 administered subcutaneously on Days 1, 3, and 5 of each week a patient was on study. Patients were analyzed for toxicity, tumor response, and survival. Because of severe toxicity, partway through the trial the regimen was modified as follows: dacarbazine and cisplatin were given at the same dose every 4 weeks, and carmustine was reduced to 100 mg/m2 every 8 weeks. RESULTS: Forty-two patients with a median age of 61 years were enrolled. Twenty had liver metastases and 18 had lung metastases. Forty patients were evaluable for toxicity, 17 at the original dose and 23 at the new dose; of these, 35 were evaluable for response. Hematologic toxicity was severe at the original dose: 10 patients had a nadir < 500/microL, 10 had platelets < 25,000/microL, and 2 discontinued treatment because of toxicity. At the reduced dose, 5 had a nadir absolute neutrophil count < 500, and 10 had platelets < 25,000. Of the 35 patients evaluable for response, there were 10 partial responses (29%) and 2 minimal responses. Median duration of disease control was 4 months. Median survival was 8.9 months. One partial and one minimal responder were removed from the study because they experienced toxicity while still responding. CONCLUSIONS: The addition of interferon-alpha to this chemohormonal therapy regimen greatly increased toxicity without improving the response rate or survival for patients with metastatic melanoma.

Development of unfavorable hepatoblastoma in children of very low birth weight: results of a surgical and pathologic review.

Year 1998
Ikeda H. Hachitanda Y. Tanimura M. Maruyama K. Koizumi T. Tsuchida Y.
Department of Surgery, Gunma Children's Medical Center, Japan.
BACKGROUND: The incidence of hepatoblastoma in children of very low birth weight (< 1500 g) is increasing in Japan. The authors reviewed surgical and pathologic aspects of the tumor to clarify the characteristics of the patients. METHODS: Fifteen patients (9 boys and 6 girls) who were diagnosed between the ages of 6-77 months (median, 16 months) were identified from the data in the Japan Children's Cancer Registry and the data base of medical journals. The patients' birth weights ranged from 560-1380 g (median, 826 g) and the gestational age ranged from 23-33 weeks (median, 25 weeks). The medical records of all patients were reviewed and the patient's stage of disease according to the classification of the Japanese Society of Pediatric Surgeons, treatment, and outcome were analyzed. RESULTS: Ten tumors (67%) were classified as Stage II or IIIA and 5 (33%) were classified as Stage IIIB or IV. There was a significant correlation between the gestational age and tumor stage (correlation coefficient - 0.6851; P = 0.0048). The gestational age of the 5 patients with Stage IIIB or IV tumors was 23-25 weeks (median, 24 weeks), whereas it was 25-33 weeks (median, 27.5 weeks) for the 10 patients with Stage II or IIIA tumors (P = 0.0036). Birth weight ranged from 560-826 g (median, 734 g) in Stage IIIB and IV patients, which was significantly lower than that in Stage II and IIIA patients (range, 607-1380 g, median, 909 g; P = 0.0500). Complete tumor resection was achieved in 7 patients (47%). The actuarial 2-year survival of all patients was 0.42, and the 2-year survival of patients who underwent complete tumor resection was 0.69, which was significantly better than the 2-year survival of those who underwent incomplete resection (0.17; P = 0.0211). The 2-year survival of the patients with tumors of well differentiated histology was 0.60, which also was significantly better than the 2-year survival of those with tumors of poorly differentiated histology (0.19; P = 0.0453). CONCLUSIONS: These results indicate that children of very low birth weight (< 1500 g) are at high risk of developing advanced hepatoblastomas and that hepatoblastoma with unfavorable biologic behavior develops in children who are extremely premature at birth. These new findings suggest the presence of etiologic factors relevant to the patient's immaturity and the development of unfavorable hepatoblastoma.

Telomerase activity in precancerous hepatic nodules.

Year 1998
Hytiroglou P. Kotoula V. Thung SN. Tsokos M. Fiel MI. Papadimitriou CS.
Department of Pathology, Aristotle University Medical School, Thessaloniki, Greece.
BACKGROUND: Recent studies have demonstrated that telomerase, a reverse transcriptase linked to cellular "immortalization," is activated in a variety of malignant human tumors. This study was conducted to determine whether telomerase activity represents a marker of malignant transformation in precancerous (dysplastic) nodules arising in patients with cirrhosis. METHODS: Telomerase activity was evaluated in frozen tissue samples of 14 cirrhotic liver specimens and 30 large nodular lesions contained therein, including 13 large regenerative nodules/low grade dysplastic nodules, 10 high grade dysplastic nodules, and 7 hepatocellular carcinomas (HCCs). A modified telomeric repeat amplification protocol was used. RESULTS: There was a clear-cut difference in telomerase activity levels between HCC (positive or strongly positive) and cirrhotic liver samples (weakly positive or negative). The majority of large noncancerous nodules (86%) exhibited telomerase activity levels similar to HCCs. However, such activity was not limited to dysplastic lesions but also was detected in some large regenerative nodules. CONCLUSIONS: These findings suggest that telomerase activation is an early event in large nodule formation in cirrhosis, which may facilitate the action of other factors in the process of carcinogenesis. Telomerase activity in large hepatic nodules is not always indicative of malignant transformation.

Histologic and biologic patterns of microscopic pancreatic ductal adenocarcinomas detected incidentally at autopsy.

Year 1998
Kimura W. Morikane K. Esaki Y. Chan WC. Pour PM.
Department of Surgery, University of Tokyo, Japan.
BACKGROUND: The major clinical problems with pancreatic carcinoma are its silent course and late, fatal clinical manifestation. The results of treatments of small pancreatic carcinomas (

How tumor stage affects surgeons surveillance strategies after surgery for carcinoma of the upper aerodigestive tract.

Year 1998
Johnson FE. Virgo KS. Clemente MF. Johnson MH. Paniello RC.
Department of Veterans Affairs Medical Center, St. Louis, Missouri, USA.
BACKGROUND: The factors that influence decision-making among surgeons are not well understood. The authors evaluated how tumor stage in otherwise healthy patients subjected to potentially curative surgery for upper aerodigestive tract (UADT) epidermoid carcinoma affects the self-reported follow-up strategies employed by practicing surgeons. METHODS: Hypothetical patient profiles and a detailed questionnaire based on these profiles were mailed to the 824 members of the Society of Head and Neck Surgeons (SHNS) and the 522 members of the American Society for Head and Neck Surgery who were not members of SHNS. The effect of TNM stage on the surveillance strategies chosen by the respondents was analyzed. RESULTS: Ten of the 14 most commonly employed surveillance modalities were ordered significantly more frequently with increasing TNM stage. This effect persisted through 5 years of follow-up, but the differences across stages were small. Only 30% of respondents modified their strategies according to the patient's TNM stage. CONCLUSIONS: Most surgeons performing surveillance after potentially curative surgery in otherwise healthy patients with UADT carcinoma use the same follow-up strategy irrespective of TNM stage. These data permit rational design of a randomized clinical trial of two alternate follow-up plans.