Islet Cell Carcinoma Research Articles

Induction of pancreatic islet cell tumors in rats by repeated intravenous administration of 4-hydroxyaminoquinoline 1-oxide.

The inducibility of pancreatic islet cell tumors by administration of 4-hydroxyaminoquinoline 1-oxide (4HAQO) was investigated in male 6-week-old Sprague-Dawley rats. Rats were given 4HAQO intravenously at a weekly dose of 5 mg/kg 4 times (group 1) or a single dose of 10 mg/kg (group 2). Control rats received the vehicle alone (group 3). Fifty-six weeks after the first 4HAQO administration, all surviving animals were killed and the pancreas was examined histopathologically, immunohistochemically and ultrastructurally. The incidences and multiplicities of islet cell tumors in groups 1, 2, and 3 were 52.3% (p < 0.05 vs group 2, p < 0.01 vs group 3), 19.2% and 0%, and 0.70/animal (p < 0.05 vs group 2, p < 0.01 vs group 3), 0.23 and 0, respectively. Islet cell carcinomas were induced only in group 1, accounting for 6/44 (26%) tumors. Islet cell hyperplasias were found in 61.4% (p < 0.05 vs group 3), 42.3% and 10.0% of groups 1, 2, and 3, with multiplicities of 0.95 (p < 0.05 vs groups 2 and 3), 0.54 and 0.20, respectively. As compared with normal islets from control subjects, islet cell tumors showed an increase in the number of insulin positive cells associated with cytological features indicative of enhanced insulin synthesis and secretion, and a decrease in the number of glucagon positive cells without ultrastructural signs of modified secretory activity. Thus our results indicate that repeated intravenous administration of 4HAQO to rats is useful for the induction of islet cell tumors at high incidence.

Surgical resection of hepatic tumors-patient selection and technical considerations.

Operative resection remains the principal curative treatment of patients with liver metastasis from colorectal carcinoma, pancreatic islet cell carcinoma, and primary hepatocellular carcinoma. The successful emergence of liver resection has resulted from improvements in imaging and tumor staging, a clearer understanding of hepatic anatomy and resulting surgical technique, and better management of concurrent medical problems. At present, the mortality for liver resection in patients with normal liver function should be below 5%.KeywordsInferior Vena CavaHepatic VeinHepatic ResectionCaudate LobeMiddle Hepatic VeinThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma

We read with interest the article by Cheng et al. addressing the antitumor effect of streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma.1 They concluded that they were unable to confirm the findings from the Eastern Cooperative Oncology Group trial published in 1992.2 In this trial of the 38 patients who received streptozocin and doxorubicin, 36 were evaluable and 69% showed any regression with 14% complete regression. For this study, criteria for response evaluation were a > 50% decrease in hormone production; a > 30% reduction in hepatomegaly; and measurable tumor reduction, with the product of the perpendicular diameters reduced > 50%. Routine use of computed tomography (CT) scan was not indicated. From this study it is in retrospect difficult to calculate how many patients had a response based only on hormone reduction or reduced liver size. Cheng et al. used CT scan, magnetic resonance imaging, or X-rays of bidimensional measurable lesions as the only criteria for response as defined by Miller et al.3 With the same streptozocin and doxorubicin regimen2 given to all of their 16 patients with islet cell tumors, Cheng et al. observed 1 objective response, 9 patients with stable disease, and 6 patients with progressive disease. The median overall survival was not yet reached, with > 60% alive after follow-up ranging from 10 to 67+ months. We would like to add six islet cell tumor patients to this series. From 1995–1999, we treated these patients according to exactly the same chemotherapy scheme. The patients were evaluated as described by Cheng et al. None of the patients were hormone producers. One patient experienced a partial response, three had stable disease, and two had progressive disease. Overall survival after initiation of chemotherapy ranged from 4 to 17+ months. Apart from cardiotoxicity (n = 1), which was most likely due to doxorubicin treatment (with cardiac failure responsive to antidiuretic treatment), no severe toxicity of the regimen was observed. Combining the data from Cheng et al. and ours results in 2 objective tumor responses out of 22 (9%; 95% confidence interval, 1–29%). Although we find with these criteria a lower response rate than Moertel et al., it is also true that in these two series a good effect on survival cannot be denied. In islet cell tumor studies, to report precisely on the objective regression of tumor size may be of major relevance. If there is a regimen that results in a realistic option to create a reduction in tumor size, this would potentially allow surgical tumor resection and thus increase the potential for curative tumor resection. If the main goal of this regimen is quality of life rather than remission, the objective response rate of only 9% with the streptozocin/doxorubicin regimen justifies more interest in interferon treatment of patients with islet cell tumors. After an initial study with leukocyte interferon,4 interferon-α doses of 5–6 MU 3–5 times per week resulted in biochemical responses in 50% of the patients and tumor responses in 12%.5 Surprisingly, this option is not even mentioned in the National Cancer Institute's PDQ information for health care professionals on islet cell carcinoma.6 Treatment with somatostatin analogs is mentioned in the PDQ, reporting improvement of symptoms but little to no effect on tumor size. Attempts to combine the several options have been initiated.5 Because of the rarity of the disease, it is difficult to conduct large studies to confirm earlier interesting results or to design studies to improve these results. It will be of major importance to consider future multicenter studies in order to improve the outcomes of patients in this category. H. de Vries*, N. H. Mulder*, E. G. E. de Vries*, * Division of Medical Oncology, Groningen University Hospital, Groningen, The Netherlands

Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma

Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma

7009 Endoscopic ultrasound guided fine needle aspiration of solid pancreatic lesions: one year md anderson cancer center experience.

Aim: A prospective evaluation of EUS-FNA of solid pancreatic lesions over a one-year period at a quarternary referral center. Methods: 104 consecutive patients undergoing EUS for suspected pancreatic malignancy at MDACC from 11/1/98 to 10/31/99 were prospectively entered into this study. Procedures were performed using the Pentax FG36-UX echoendoscope, Hitachi EUB-525 processor and Wilson-Cook EUS N-1 22 gauge FNA needle. Passes were made until the endosonographer felt adequate material had been obtained. The aspirate was collected by a cytopathology technician who smeared slides in the room. Examination of the slides was performed by a cytopathologist after the procedure had been completed. Final diagnosis was based on biopsy results, surgical specimen, or clinical follow-up. Data collected included size of mass, number of needle passes, complications of procedure, and final diagnosis. 20 patients with pancreatic cysts on EUS were excluded from further analysis. Results: The average age of patients was 64.6 years. The average size of the mass was 3.2cm (range 1.3 - 7cm). The average number of needle passes was 2.5 (range 1 - 5) per patient. No complications occurred. 79 of 84 patients had malignant pancreatic tumors. EUS-FNA correctly identified 73 while cytology showed atypia in one and suspicious for malignancy in another. In the remaining 4 malignant lesions, FNA was non diagnostic due to poor cellularity. There were no false positives. Of the 5 benign lesions, no mass was seen on EUS. 3 of the 5 benign lesions were shown to have chronic pancreatitis. Of the 4 patients with non - diagnostic FNA specimens later proven to be malignant, one had chronic pancreatitis with no mass seen on EUS while 3 had masses clearly identified by EUS. 2 of these 4 patients were found to have adenocarcinoma while the other 2 had a neuroendocrine tumor. Of the 2 patients with atypia or suspicious lesions, surgical resection specimen showed an islet cell carcinoma in one and adenocarcinoma in the other. Among patients in whom adequate cellularity was obtained (counting atypia and suspicious findings on FNA as signs of malignancy), the sensitivity, specificity, positive predictive value, negative predictive value and accuracy was 100%, 100%, 100%,100%, and 95% respectively. Conclusions: EUS-FNA in the hands of an experienced endosonographer is a remarkably powerful tool with a high sensitivity and specificity at diagnosing pancreatic cancer.

Fatal gastrointestinal hemorrhage with gastrinoma in pregnancy

Objective: To describe the first case of fatal hemorrhage secondary to a functioning islet cell carcinoma of the pancreas during pregnancy reported in the literature.Methods: Data used for this case report come from the autopsy report of an obstetric patient and the special stains performed on sections of the tumor that were obtained at surgery.Results: The special stains used reveal this to be a functioning neuroendocrine tumor producing gastrin.Conclusions: No previous cases of a fatal hemorrhage from a gastrinoma in pregnancy were found during literature review.

Tumor cells utilize multiple pathways to down-modulate apoptosis. Lessons from a mouse model of islet cell carcinogenesis.

Apoptosis, the process of programmed cell death, plays a critical role in many normal and pathological (disease) processes. In normal tissues, apoptosis functions in the homeostatic maintenance of proper tissue and organ size by eliminating aged cells to offset the birth of new cells that arise by mitosis. In disease, apoptosis can affect the pathological process is two disparate ways. There are diseases that have too much apoptosis such as autoimmune diabetes and Alzheimer's, or those that have too little apoptosis, such as cancer. This review will focus on the latter and, more specifically, detail and summarize some important lessons learned about apoptosis and cancer from studying a transgenic mouse model of islet cell carcinoma, RIP-Tag, as outlined below.

RITA / Registry of Industrial Toxicology Animal Data: A comparative immunohistochemical study of 77 islet cell carcinomas in Sprague-Dawley and Wistar rats using antibodies against insulin, glucagon, somatostatin and gastrin

The objective of this study was to investigate spontaneous islet cell carcinomas with particular reference to possible existing strain differences between Sprague Dawley (SD) and Wistar (W) rats in incidence and immunohistochemical staining pattern. Secondly the occurrence of somatostatin and/or gastrin-positive islet cell tumors should be tested. Islet cell adenocarcinomas (34 from SD, 43 from W-rats) were selected from the RITA-data base and company in-house data base out of an animal pool of 3915 (1681 SD, 2234 W-rats). They were untreated or sham-treated (vehicle) control animals from carcinogenicity studies and whole life-span experiments. Islet cell carcinomas occurred in a higher incidence in male rats (2.98% for SD, 3.23% for W) than in female rats (1.07% for SD, 0.63% for W). All specimens were immunohistologically stained with antibodies against insulin, glucagon, somatostatin and gastrin and, selected specimens with additional antibodies (pancreatic polypeptide, lipase, chymotrypsin, S100-protein, actin and cytokeratin). 94% (SD) and 93% (W), respectively, were insulin-positive and the mean staining intensity (on a scale ranging from 0-4) for insulin was 3.58 (SD) versus 3.37 (W). This high insulin staining incidence and intensity characterized most islet cell carcinomas as malignant insulinomas. 24% (SD) and 37% (W), respectively, were glucagon-positive. Except two tumors in W-rats with a focal strong glucagon expression, the mean staining intensity for glucagon was low (0.38 SD, 0.72 W). 38% (SD) and 44% (W), respectively, were somatostatin-positive, but except for five cases having a focal to multifocal, moderate to marked staining, only a few tumor cells were positive for somatostatin in the other cases and the mean staining intensity for somatostatin was low (0.50 SD, 0.84 W). 6% (SD) and 23% (W), respectively, were gastrin-positive, but only one case of a male Wistar rat exhibited a focal strong staining in parts of the tumor. The other cases showed only a few tumor cells which were positive for gastrin. The mean staining intensity for gastrin was low (0.06 SD, 0.35 W). In all tumors with marked glucagon, somatostatin or gastrin expression, the immunostaining for insulin was still predominating. Thus, insulin was the major hormone produced by most of the tumor cells. Five out of 77 tumors evaluated were immunohistologically negative with all applied antibodies. This study presents the first immunohistochemical survey on spontaneous islet cell carcinomas in SD and Wistar rats stained with antibodies against the endocrine pancreas hormones insulin, glucagon, somatostatin and gastrin. No major differences in incidence or immunohistochemical staining pattern between SD and W-rats could be detected. In contrast to SD rats, Wistar rats had multihormonal coexpression in 16.3%. The multihormonal appearance of the neoplasms is well comparable with the findings in other animal species and human insulinomas. Moreover, this is the first study in rats which reports five cases with a marked co-expression of somatostatin and one case with marked focal co-expression of gastrin in malignant islet cell adenocarcinomas.

Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma

BACKGROUND The combination regimen of streptozocin plus doxorubicin is the current standard chemotherapeutic treatment of symptomatic or progressing metastatic islet cell carcinoma. This regimen previously has been reported to have a major objective response rate of 69% in a randomized cooperative group trial. However, the authors believed that this favorable response rate was not consistent with their institutional experience at Memorial Sloan-Kettering Cancer Center (MSKCC). METHODS The authors retrospectively reviewed the records of all islet cell carcinoma patients under care at MSKCC who were treated with streptozocin plus doxorubicin since the publication of the study mentioned earlier. Sixteen such patients treated between February 1992 and February 1998 were identified. Their clinical characteristics, sites of measurable disease, response to treatment, time to treatment failure, and survival status were reviewed. RESULTS All patients were treated with the starting doses as outlined by the published cooperative group report. All had bidimensionally measurable disease on computed tomography (CT) scans. Only 1 of 16 patients (6%; 95% confidence interval, 0–30%) achieved a major objective response by standard CT response criteria, with response ongoing during treatment at 18 months. Nine patients (56%) had stable disease while receiving treatment (range of treatment, 2–17+ months). Six patients (38%) had progression of disease as their best response while receiving treatment. The median overall survival of this patient group had not yet been reached at last follow-up, with > 60% of patients alive with follow-up ranging from 10–67+ months. CONCLUSIONS A retrospective analysis of the authors' 6-year experience with the combination of streptozocin plus doxorubicin in patients with islet cell carcinoma failed to confirm the high objective response rate previously reported for this regimen. There remains an urgent need for improved chemotherapeutic alternatives for patients with this disease. Cancer 1999;86:944–8. © 1999 American Cancer Society.

Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma

The combination regimen of streptozocin plus doxorubicin is the current standard chemotherapeutic treatment of symptomatic or progressing metastatic islet cell carcinoma. This regimen previously has been reported to have a major objective response rate of 69% in a randomized cooperative group trial. However, the authors believed that this favorable response rate was not consistent with their institutional experience at Memorial Sloan-Kettering Cancer Center (MSKCC). The authors retrospectively reviewed the records of all islet cell carcinoma patients under care at MSKCC who were treated with streptozocin plus doxorubicin since the publication of the study mentioned earlier. Sixteen such patients treated between February 1992 and February 1998 were identified. Their clinical characteristics, sites of measurable disease, response to treatment, time to treatment failure, and survival status were reviewed. All patients were treated with the starting doses as outlined by the published cooperative group report. All had bidimensionally measurable disease on computed tomography (CT) scans. Only 1 of 16 patients (6%; 95% confidence interval, 0-30%) achieved a major objective response by standard CT response criteria, with response ongoing during treatment at 18 months. Nine patients (56%) had stable disease while receiving treatment (range of treatment, 2-17+ months). Six patients (38%) had progression of disease as their best response while receiving treatment. The median overall survival of this patient group had not yet been reached at last follow-up, with > 60% of patients alive with follow-up ranging from 10-67+ months. A retrospective analysis of the authors' 6-year experience with the combination of streptozocin plus doxorubicin in patients with islet cell carcinoma failed to confirm the high objective response rate previously reported for this regimen. There remains an urgent need for improved chemotherapeutic alternatives for patients with this disease.

Transgene Expression and Repression in Transgenic Rats Bearing the Phosphoenolpyruvate Carboxykinase-Simian Virus 40 T Antigen or the Phosphoenolpyruvate Carboxykinase-Transforming Growth Factor-α. Constructs

Transgenic Sprague-Dawley rats expressing either human transforming growth factor-alpha (TGFalpha) or simian virus 40 large and small T antigen (TAg), each under the control of the phosphoenolpyruvate carboxykinase (PEPCK) promoter, were developed as an approach to the study of the promotion of hepatocarcinogenesis in the presence of a transgene regulatable by diet and/or hormones. Five lines of PEPCK-TGFalpha transgenic rats were established, each genetic line containing from one to several copies of the transgene per haploid genome. Two PEPCK-TAg transgenic founder rats were obtained, each with multiple copies of the transgene. Expression of the transgene was undetectable in the TGFalpha transgenic rats and could not be induced when the animals were placed on a high-protein, low-carbohydrate diet. The transgene was found to be highly methylated in all of these lines. No pathological alterations in the liver and intestine were observed at any time (up to 2 years) during the lives of these rats. One line of transgenic rats expressing the PEPCK-TAg transgene developed pancreatic islet cell hyperplasias and carcinomas, with few normal islets evident in the pancreas. This transgene is integrated as a hypomethylated tandem array of 10 to 12 copies on chromosome 8q11. Expression of large T antigen is highest in pancreatic neoplasms, but is also detectable in the normal brain, kidney, and liver. Mortality is most rapid in males, starting at 5 months of age and reaching 100% by 8 months. Morphologically, islet cell differentiation in the tumors ranges from poor to well differentiated, with regions of necrosis and fibrosis. Spontaneous metastasis of TAg-positive tumor cells to regional lymph nodes was observed. These studies indicate the importance of DNA methylation in the repression of specific transgenes in the rat. However, the expression of the PEPCK-TAg induces neoplastic transformation in islet cells, probably late in neuroendocrine cell differentiation. T antigen expression during neoplastic development may result in a pervasive change in the islet cell growth properties with selection of a transformed phenotype as a possible requirement for cell viability.

Autoaggression and tumor rejection: it takes more than self-specific T-cell activation.

Establishment of self-tolerance prevents autoaggression against organ-specific self-antigens. This beneficial effect, however, may in turn be responsible for tumor immune evasion. Thus, dissecting the mechanisms leading to the breakdown of self-tolerance in autoimmune diseases might provide insights for successful antitumor immune therapies. In a variety of animal models, organ- or tumor-specific immunity has been described, focusing on antigen-specific T-cell activation. Here, we discuss two transgenic mouse models which demonstrate that both autoaggression and tumor rejection require more than activated, self-reactive T cells. TCR transgenic mice, which are tolerant to a liver-specific MHC class I antigen, Kb, can be activated to reject Kb-positive grafts, but fail to attack Kb-expressing liver. However, autoaggression occurs when activated T cells are combined with "conditioning" of the target organ by irradiation or infection with a liver-specific pathogen. Similarly, in a mouse model of islet cell carcinoma, neither co-stimulatory tumor cells nor highly activated antitumor lymphocytes provoke an effective immune response against the tumor. Instead, a combination of activated lymphocytes and irradiation is required for lymphocyte infiltration into solid tumors. Both model systems provide evidence that although activated antigen-specific lymphocytes are a prerequisite for autoaggression, effector cell extravasation and appropriate interaction with the target organ/tumor are equally important. Thus, we propose that the organ/tumor microenvironment is a critical parameter in determining the effectiveness of an anti-self immune response.

Nonfunctioning islet cell carcinoma of the pancreas: an evaluation of seven patients who underwent resection followed by long-term survival.

Islet cell carcinoma of the pancreas is a rare, indolent malignancy associated with a higher resectability rate and better survival than ductal carcinoma. This retrospective study presents the results of surgical treatment for nonfunctioning islet cell carcinoma of the pancreas in seven patients diagnosed and treated at Kurume University Hospital. There were two men and five women, with an average age of 54 years. Of the five tumors, four were located in the head of the pancreas, and the other three tumors were located in the body or tail of the pancreas. Epigastric pain was frequently the primary clinical symptom. By the time of diagnosis, four of the patients had regional disease, one of whom had lymph node and liver metastases, and one, liver metastases. Another patients was found to have lymph node metastases intraoperatively. Only one of the patients died of recurrent cancer, 21 years after the original operation. All of the patients who had liver metastases at the time of initial surgical treatment are now living at home. Thus, we conclude that nonfunctioning islet cell carcinomas are slow-growing tumors with a good prognosis if the main tumors and metastatic lesions are removed.

Neuroglycopenic and other symptoms in patients with insulinomas

PURPOSE: To characterize neuroglycopenic symptoms in the clinical presentation of patients with insulinomas. SUBJECTS AND METHODS: Patients with histologically confirmed islet cell adenomas or carcinomas were identified at a single institution. Patient symptoms and clinical features of the insulinomas were obtained by retrospective medical record review with special attention to neuroglycopenic and autonomic symptoms. RESULTS: Of the 59 patients, 51% were female. Patients’ ages ranged from 17 to 79 years (median 55) at the time of surgery. The interval from the onset of symptoms to diagnosis ranged from 1 month to 30 years (median 24 months). Most patients were diagnosed within 1 to 5 years (53%). Prior diagnoses included neurologic disorders (64%), especially seizure disorders (39%); 7 (12%) patients were treated with antiseizure medications. All patients had neuroglycopenic symptoms including confusion (83%) and personality change or bizarre behavior (64%). Amnesia for hypoglycemia was common (41%). Autonomic symptoms (83%) were usually diaphoresis (69%) or tremulousness (24%). Food ingestion relieved symptoms in 71% of patients; 39% reported weight gain. CONCLUSIONS: Despite improving diagnostic techniques, the diagnosis of an insulinoma is often delayed. Careful inquiry about neuroglycopenic symptoms from patients and persons who know them well is necessary whenever hypoglycemia due to endogenous hyperinsulinemia is a clinical consideration. A history of neuroglycopenic symptoms should suggest the diagnosis of hypoglycemia associated with a hyperinsulinemic state.

Nonfunctioning Islet Cell Carcinoma of the Pancreas: An Evaluation of Seven Patients Who Underwent Resection Followed by Long-Term Survival

Nonfunctioning Islet Cell Carcinoma of the Pancreas: An Evaluation of Seven Patients Who Underwent Resection Followed by Long-Term Survival

Adrenal Tumors and Pregnancy

Although adrenal tumors detected during pregnancy are extraordinarily rare, the pathophysiologic repercussions of untreated adrenal neoplasms are enormous to both mother and fetus. From our computer-based registry of pregnant patients from 1975 through 1996 (n = 30,246), four cases of adrenal neoplasms associated with pregnancy were identified (0.013%), analyzed, and compared with the current medical literature. Four women ages 36, 29, 22, and 21 years had adrenal neoplasms diagnosed with pregnancy. Patient 1 had an unsuspected pheochromocytoma identified at autopsy. At 27 weeks into her pregnancy the patient suffered a myocardial infarction, and both she and the fetus died. Patient 2 was incidentally found to have adrenal and pancreatic neoplasms on screening abdominal computed tomography for von Hippel-Lindau disease. The study identified a pregnancy. She elected to terminate the pregnancy and underwent resection of both tumors. She died 3 years later of metastatic islet cell cancer. Both of these patients had previously delivered healthy babies, but both pregnancies were complicated by hypertension. Patient 3 had a functional adrenal tumor identified initially by urinary aldosterone studies because of symptoms of severe hypertension, and patient 4 had an adrenal mass diagnosed via ultrasonography at 30 weeks' gestation because of concerns for right-sided pyelonephritis. These two women underwent careful monitoring throughout the remainder of their pregnancies with eventual delivery of healthy babies. Both women later underwent successful operative resection of benign adrenal adenomas. Adrenal neoplasms discovered during pregnancy are rare. The onus, however, is on physicians to consider this diagnosis in pregnant women with hypertension, headaches, or other manifestations of adrenal disorders. Surgical management of identified adrenal lesions is thereafter straightforward. Missing the diagnosis has grave implications for these young women and their fetuses.

Selective Hepatic Arterial Chemoembolization for Liver Metastases in Patients with Carcinoid Tumor or Islet Cell Carcinoma

In many patients with liver metastases from islet cell or carcinoid tumor, vascular occlusion therapy results in prolonged control of symptoms, biochemical response, and also tumor regression. Chemotherapy agents were added to evaluate safety and efficacy. Thirty patients with liver metastases from either carcinoid tumor or islet cell carcinoma underwent sequential vascular occlusion therapy combined with che-motherapeutic agents. In patients with carcinoid tumor, a combination of cisplatin (150 mg) and doxorubicin (50 mg) was used. In patients with islet cell carcinoma, a combination of 5-fluorouracil (350 mg) and streptozotocin (1000–2000 mg) was used. Sixteen patients had carcinoid tumor and 14 had islet cell carcinoma. Biochemical response was observed in 12 of 16 (75%) carcinoid patients and 9 of 10 (90%) islet cell patients. The overall partial response rate was 37% (11/30 patients). Partial response occurred in 4 of 16 (25%) patients with carcinoid tumor and 7 of 14 (50%) with islet cell carcinoma. The median duration of partial responses was 24 months (range, 6–63+ months). The median survival of all patients was 15 months (range, 2–67+ months). No treatment-related deaths occurred. Our data suggest that the addition of these chemotherapeutic agents to vascular occlusion, although safe, has no additional benefit.

A CASE OF NON-FUNCTIONING ISLET CELL CARCINOMA WHICH INFILTRATED INTO THE MULTIPLE ORGANS AND EXTENDED TO THE MAIN PANCREATIC DUCT

A 78-year-old man was admitted to the hospital because of anal bleeding. CT scan showed a mixed density tumor at the body of the pancreas and varices around the tumor. Angiography (arterial phase) revealed the hypervascular tumor with irregular border. And co-lateral vessels developed around the tumor at venous phase. Endiscopic retrograde pancreatography was performed unsuccesfully. Leiomyosarcoma of the pancrease was suspected and a laparotomy was performed in Januuary 1997. The tumor infiltrated into the multiple organs, including stomach, spleen, transeverse colon, left adreanal gland and capsule of left kidney, and extended to the main pancreatic duct. Thus a distal pancreatectomy and a resection of the invaded organs were performed. The main tumor was 9×8×3cm in size and the extending tumor to the duct was 4.5cm in length. Histologically, the tumor was an islet cell tumor with evident trabecular and ribbon-like structures. The immunochemical stainings for chromogranin A, Glimerius, insulin, glucagon and somatostatin were negative, and hormonal concentrations measured in the operation were normal. Finally this tumor was diagnosed as non-functional islet cell carcinoma. No recurrence has been detected in a year and eight month since the operation.

Cloning and chromosomal mapping of the human p53-related KET gene to chromosome 3q27 and its murine homolog Ket to mouse chromosome 16.

KET is a member of the newly discovered family of proteins that is related to the tumor suppressor p53. Here we describe the molecular cloning of a human cDNA of 4846 bp encoding a protein of 680 amino acids. The human KET protein shares 98% identity with the previously characterized rat homolog. The remarkably high degree of conservation lends support to the notion that KET proteins have important basic functions in development and differentiation. Using the GeneBridge 4 radiation hybrid panel, we have mapped KET to human Chromosome (Chr) 3q27. KET is located between the somatostatin gene SST (proximal) and the apolipoprotein D gene APOD (distal) in a region of conserved synteny to mouse Chr 16. This chromosomal region is deleted in early stages of tumorigenesis of mouse islet cell carcinomas and contains the hitherto unidentified Loh2 gene, a putative suppressor of angiogenesis. The murine homolog Ket was mapped in an interspecific backcross panel and falls into this region of loss of heterozygosity. From our mapping data we infer that KET might act as a tumor suppressor and is considered as a candidate for Loh2.

Immunohistochemical localization of chromogranin A in endocrine tissues and endocrine tumors of dogs.

Chromogranin A is present in the secretory granules of endocrine cells and functions in hormone packaging, secretory granule stabilization, and regulation of hormone secretion. Immunohistochemical identification of chromogranin A can facilitate diagnosis of endocrine neoplasia. Normal and neoplastic canine tissues were stained immunohistochemically for chromogranin A. Staining of normal endocrine tissues demonstrated chromogranin A in chromaffin cells of the adrenal medulla, C cells of the thyroid gland, and pancreatic islets. The parathyroid chief cells and anterior pituitary stained lightly positive for chromogranin A. Pheochromocytomas (7/7), chemodectomas (5/7), islet cell carcinomas (2/6), pituitary adenomas (4/6), parathyroid adenomas (3/7), and a C-cell carcinoma (1/1) stained positive for chromogranin A. The data indicate that chromogranin A is widely distributed in canine endocrine tissues, and immunohistochemical staining of chromogranin A can be used to confirm the presence of secretory granules in endocrine tumors.