Double rarity: malignant masquerade biliary stricture in a situs inversus totalis patient.

BACKGROUND: Situs inversus totalis is a rare anatomical variation of both the thoracic and the abdominal organs. Common bile duct strictures can be caused by malignant and benign diseases as well. 7-18% of the latter ones are 'malignant masquerade' cases, as pre-operative differentiation is difficult. CASE PRESENTATION: We present the case of a 68y male patient with known situs inversus totalis and a recent onset of obstructive jaundice caused by a malignant behaving common bile duct stricture. Technically difficult endoscopic retrograde cholangiopancreatography, brush cytology, magnetic resonance cholangiopancreatography, endoscopic ultrasound, and percutaneous transhepatic drainage with stent implantation were performed for proper diagnosis. Cholecystectomy, common bile duct resection with hilar lymphadenectomy, and hepatico-jejunostomy have been performed following multidisciplinary consultation. The final histology report did not confirm any clear malignancy, the patient is doing well. CONCLUSION: In situs inversus patients, both diagnostic and therapeutic procedures can lead to various difficulties. Benign biliary strictures are frequently misdiagnosed preoperatively as cholangiocellular carcinoma. Surgery is usually unavoidable, involving a significant risk of complications. The co-existence of these two difficult diagnostic and therapeutic features made our case challenging.

Novel therapeutic approaches in the treatment of advanced pancreatic carcinoma.

Pancreatic cancer is still a malignant disease of grim prognosis despite all therapeutic efforts. Because clinical symptoms in the early stage are usually absent or aspecific, it is frequently discovered at advanced or metastatic stage, only around 15-20% of tumors are resectable. In the majority of patients only the chemotherapy offers a prolongation of life, but even the first-line chemotherapeutic agent, the gemcitabine has a modest survival benefit, and objective tumor response is rarely achieved. Combination of various cytostatics did not produce a significant improvement either. For that reason, continuous search for other agents is mandatory. Nowadays, in the era of molecular-targeted oncotherapeutic approaches, pancreatic cancer is also a subject such trials: epidermal growth factor receptor blockade, inhibition of angiogenesis, modulation of tumor response through the extracellular matrix, inhibition of cyclooxygenase-2, farnesyl transferase inhibitors, signal transduction inhibitors, ablation of the hormonal influence and some other aspects have all been studies, but to date, no breakthrough in the treatment of pancreatic carcinoma is proven. In several Phase II-III studies these compounds given alone displayed marginal effects, but when combined with the standard cytostatics, some beneficial effects were observed, however, some of them displayed a severe (sometimes fatal) toxicity. To date, the role of the molecular targeted therapy in pancreatic carcinoma is promising, but the results are not convincingly superior to the standard chemotherapeutic treatments. Pancreatic adenocarcinoma remains a great challenge for the oncologists, and continuous search for better molecules and/or combinations is inevitable.

Treatment of N-nitrosobis(2-oxopropyl)amine-induced pancreatic cancer in Syrian golden hamsters with D-Trp-6-LH-RH and somatostatin analogue RC-160 microcapsules.

Antitumoral effects of the agonist of luteinizing hormone-releasing hormone (D-Trp-6-LH-RH) and the somatostatin analog RC-160 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2) on chemically induced ductal pancreatic adenocarcinomas were studied. The tumors were induced in female Syrian golden hamsters by weekly s.c. injections of N-nitrosobis(2-oxopropyl)amine at a dose of 10 mg/kg b.w. for 6 weeks. 18 weeks after the last injection, the peptides in controlled-release microcapsule formulations were administered s.c. The animals received the following therapies: Group 1 (N = 15), vehicle only; Group 2 (N = 13), D-Trp-6-LH-RH microcapsules releasing 25 micrograms/day injected s.c. once a month; Group 3 (N = 14), RC-160 microcapsules, liberating 25 micrograms/day administered s.c. every 15 days; Group 4 (N = 14), the combination of D-Trp-6-LH-RH plus RC-160 microcapsules. The experiment was terminated on the 80th day when all hamsters in the control group were dead, but in the treated Groups 2, 3, and 4, we observed 71, 77, and 86% of survival rate, respectively. In addition to the prolongation of survival, the combination treatment resulted in a significant decrease in the tumorous pancreatic weight, increase in the body weight of the animals, reduction in ascites from 100 to 8.3% and regressive histological changes in 67% of the specimens. Our findings suggest that somatostatin analogues and D-Trp-6-LH-RH could be considered for the development of hormonal therapy for pancreatic cancer.

Decreased hepatocarcinogenic effect of diethylnitrosamine in experimentally induced liver cirrhosis in rat: delay or inhibition?

The relationship between CCl4 or (CCl4 + phenobarbital)-induced liver cirrhosis and diethylnitrosamine (DEN) hepatocarcinogenesis in male F-344 rats was investigated. DEN given alone produced no liver lesions after 16 weeks, but 4/12 (33%) neoplastic nodules developed when nitrosamine was administered to rats with previously established cirrhosis. On the other hand, (CCl4 + phenobarbital) post-treatment had an even stronger effect, increasing the yield of neoplastic nodules to 100% (28/28). Since the exposure time of DEN was the same in all treated groups (4 months), the results indicate the decreased effectiveness of (CCl4 + phenobarbital) pretreatment on DEN hepatocarcinogenesis.

Presence of membrane binding sites for [D-TRP6]-luteinizing hormone-releasing hormone in experimental pancreatic cancer.

Characteristics of binding sites (dissociation constant: Kd and maximal binding capacity: Bmax) for [D-Trp6]-luteinizing hormone-releasing hormone [( D-Trp6]-LH-RH]), somatostatin (SS-14) and epidermal growth factor (EGF) were evaluated in membrane fractions of N-Nitrosobis (2-oxopropyl) amine (BOP)-induced pancreatic adenocarcinoma of hamsters. Intact, normal hamster pancreata did not show any binding sites for [D-Trp6]-LH-RH, but specific [D-Trp6]-LH-RH binding sites with low affinity and high capacity were found after pancreatic cancer was induced with BOP. Membrane binding sites for SS-14 and EGF, with high affinity and low capacity were present, both in normal and cancerous pancreata. Normal hamster pancreatic tissue had significantly higher levels of SS-14 binding sites and lower concentration of EGF binding sites as compared to pancreatic carcinoma. In vivo treatment of hamsters bearing pancreatic cancers with microcapsules of agonist [D-Trp6]-LH-RH and the somatostatin analog RC-160 alone, or in combination, caused histopathological regression of tumors and concomitantly decreased the Kd and Bmax of [D-Trp6]-LH-RH, and increased the Bmax of the SS-14 binding sites. These findings represent the first demonstration of binding sites for [D-Trp6]-LH-RH in pancreatic cancers. Our results also suggest that tumor inhibitory effects of [D-Trp6]-LH-RH and RC-160 in pancreatic cancer could be mediated not only indirectly through suppression of sex-steroids, gastrointestinal hormones and growth factors, but also directly by an action on specific binding sites located on the tumor membranes.

Inhibitory and promoting effects of carbon tetrachloride-induced liver cirrhosis on the diethylnitrosamine hepatocarcinogenesis in rats.

The modifying effect of the experimentally induced liver cirrhosis on the diethylnitrosamine (DENA)-hepatocarcino-genesis was investigated in male Fischer 344 rats. Cirrhosis was produced by either repeated intragastric doses of CCl4 for 3 months or by simultaneous administration of CCl4 and phenobarbital (PB) in drinking water for 6 weeks. The hepatocarcinogenic regimen consisted of multiple ip. administrations of DENA (10 mg/kg b.w. per dose, up to a total dose of 200 mg/kg b.w.). All the animals were killed 8 months after starting the experiment. The chronic CCl4-post-treatment exerted a strong promoting effect, while the established cirrhosis completely prevented the formation of hepatocellular carcinomas.

Establishment and long-term xenografting of human pancreatic carcinomas in immunosuppressed mice: changes and stability in morphology, DNA ploidy and proliferation activity.

The prognosis of pancreatic carcinoma is grave, therefore the experimental model systems remain major tools for testing new treatment modalities. We have developed human pancreatic cancer lines growing in immunosuppressed mice and characterized them by morphological and flow-cytometric studies. Immunosuppression has been achieved in young (4-week-old) CBA/CA mice by thymectomy, whole-body irradiation and bone marrow reconstruction. Twelve surgically removed human pancreatic carcinomas were implanted subcutaneously and serially transplantable xenografts have been established. Altogether 129 samples derived from 59 generations have been analyzed. Out of 12 carcinomas, 6 developed continuously growing and transplantable xenografts (PZX-2, PZX-5, PZX-11, PZX-15, PZX-16, PZX-20; take rate: 50%). They were successfully maintained for 9-16 passages, for 18-25 months. New subpopulations developed during transplantations in 3 tumor lines and these morphological changes have been reflected by the appearance of an aneuploid peak in flow cytometry. In 1 tumor line, however, DNA aneuploidy was observable despite the unaltered histology. The PZX-20 line retained its original morphology and aneuploid pattern during 9 consecutive passages and over 18 months. The results indicate that the artificially immunosuppressed CBA/CA mice are suitable hosts for accepting and maintaining human pancreatic carcinomas. During successive xenograftings the regular morphological characterization must be supplemented by flow cytometry, because new tumorous clones may develop despite the unchanged histological picture.

Epithelial mesothelioma with deciduoid features.

A rare case of malignant mesothelioma in a 15-year-old girl is described. The patient presented with secondary amenorrhoea and clinical symptoms resembling those of an ovarian cyst. One large and multiple small peritoneal nodules were found at laparoscopy. Histologically the tumour was characterised by an unusual pattern with a superficial resemblance to decidual reaction, but because of significant mitotic activity the diagnosis of a malignant tumour, epithelial mesothelioma with deciduoid features, was made. The patient died 11 months after diagnosis. Post-mortem examination revealed extensive extraperitoneal spread.

Pancreatic leiomyosarcoma. Case report with immunohistochemical and flow cytometric studies.

A leiomyosarcoma originating from the pancreas of a 57-year-old man is presented. A 6x5x4 cm tumour was located in the head region, and the patient underwent surgical palliation. Immunohistochemical studies excluded an epithelial origin; a myogenic origin was suggested by strong vimentin and smooth muscle actin positivity. Flow cytometric analysis revealed an aneuploid pattern (DNA index: 1,561). The patient died with widespread metastases 7 month after the operation.

Membrane receptors for peptides in experimental and human pancreatic cancers.

Membrane receptors for [D-Trp6]-luteinizing hormone-releasing hormone [( D-Trp6]-LH-RH), somatostatin (SS-14), and epidermal growth factor (EGF) were investigated in experimental N-nitrosobis-(2-oxopropyl)-amine (BOP)-induced pancreatic cancers of hamsters and in specimens of normal human pancreas and human pancreatic cancer obtained from autopsies. Membrane receptors for [D-Trp6]-LH-RH were absent in the pancreas of normal hamsters, but appeared after the carcinoma was induced with BOP. Binding capacity of SS-14 receptors was lower in membranes of BOP-induced pancreatic cancers than in the normal pancreas. In the BOP-induced pancreatic cancers, the receptors were also characterized following in vivo treatment of hamsters with microcapsules of the agonist [D-Trp6]-LH-RH, somatostatin analog RC-160, and the combination of both peptides, which resulted in significant tumor inhibition. Therapy with [D-Trp6]-LH-RH and RC-160, alone or in combination, decreased the binding capacity of receptors for [D-Trp6]-LH-RH, but increased Bmax for SS-14. There were no significant changes in characteristics of the EGF receptor following these therapies. Membranes from human pancreatic cancers showed binding sites for [D-Trp6]-LH-RH, but no binding was detected in normal human pancreas. The presence of receptors for LH-RH in pancreatic tumors of hamster and humans raises the intriguing possibility that LH-RH could be involved in complex interactions that contribute to the appearance of pancreatic cancer. The binding capacity of receptors for SS-14 in human pancreatic cancer membranes was lower, while Bmax for EGF was higher, as compared to normal pancreas.(ABSTRACT TRUNCATED AT 250 WORDS)

Apoptosis-induction and phosphorylation state in human pancreatic carcinoma xenografts following octreotide treatment.

BACKGROUND: Some exocrine pancreatic carcinomas are responsive to hormonal manipulations, but the mechanism is not fully understood. MATERIALS AND METHODS: Human pancreatic cancer xenografts (PZX-15/F4) grown in immunosuppressed mice were treated with Sandostatin (2 x 100 micrograms/b.w. s.c.) for 4 weeks. Mitotic and apoptotic activities were assessed and supplemented with immunohistochemical detection of phosphotyrosine and bcl-2 protein. RESULTS: In the treated group 5/16 tumors exhibited a 20-68% volume reduction, and the number of apoptotic cells was significantly increased (18.1 +/- 3.1/mm2 vs. 6.2 +/- 1.1/mm2 in controls, P < 0.0012). At the same time, a highly significant reduction in the number of the phosphotyrosine-positive tumor cells was observed (40.9% from 64.9%; P < 0.0001). The mitotic activity did not change significantly. Both the untreated and the treated tumors proved to be bcl-2 negative. CONCLUSIONS: The results indicated that the octreotide triggered an apoptosis-induction in a human pancreatic cancer xenograft, coupled with the increased dephosphorylation state in the tumors, but the mitotic activity was not affected and bcl-2 expression has not been induced.

Flow cytometric evidence of apoptosis in human pancreatic cancer xenografts treated with Sandostatin (octreotide).

BACKGROUND: The antiproliferative effect of octreotide (Sandostatin) is partly attributed to induction of apoptosis in the given tumors. In this work, apoptosis was assessed in human pancreatic carcinoma xenografts after a 4-week high-dose Sandostatin treatment. MATERIALS AND METHODS: Subcutaneously growing human pancreatic cancer xenografts (PZX-5) in immunosuppressed mice were treated with 500 micrograms/kgb.w. Sandostatin twice a day i.p. for 4 weeks. Apoptosis was evaluated by means of conventional histology, Apoptag-immunohistochemistry and flow cytometry. RESULTS: The Sandostatin-treatment resulted in a decreased tumor volume in 9 out of 16 animals. Immunohistochemical detection of apoptosis by Apoptag revealed a 75-fold increase of the positively stained tumorous nuclei (210.9 +/- 53.9 per square mm) versus nontreated tumors (2.8 +/- 0.5 per square mm). The sub-G1 fraction was 3.61 +/- 0.4% in untreated samples while it doubled after treatment (p < 0.001). CONCLUSION: A 4-week octreotide (Sandostatin) treatment induced significantly increased apoptosis in human pancreatic carcinoma xenografts evidenced by morphological studies and Apoptag-immunohistochemistry, and these results were clearly reinforced by flow cytometry.

Epidermal growth factor receptor, somatostatin and bcl-2 in human pancreatic tumor xenografts. An immunohistochemical study.

Xenografted human pancreatic tumors (5 ductal adenocarcinomas, 1 leiomyosarcoma, altogether 26 samples) were investigated about their immunohistochemical expression of epidermal growth factor receptor (EGFR), somatostatin (SS) and bcl-2 protein. The expression of the EGFR varied from tumor to tumor. One originally negative carcinoma became immunoreactive during passagings, one tumor has lost its early positive expression, and in 3 cancer lines a phenotypically constant pattern was seen. SS immunoreactivity was practically absent in all tumor samples. Concerning bcl-2 expression, different staining patterns were observed among the carcinomas, but the leiomyosarcoma has retained its strong positivity during xenograftings. In the PZX-5 carcinoma line that was originally negative, the one month Sandostatin treatment induced the strong expression of bcl-2 protein suggesting a development of an acquired resistance against programmed cell death in this tumor.

Coccidioidomycosis in Hungary. The first import case.

A case of an isolated subcutaneous coccidioidomycosis in a 61-year-old man is presented. The patient has lived and worked in Arizona for 3 years previously but developed no apparent clinical signs of the disease. The painless, cavitating, tumor-like mass was surgically excised and the diagnosis was established by histological demonstration of the fungi and confirmed by serum counterimmunoelectrophoresis. This represents the first imported case of coccidioidomycosis in Hungary.

Papillary microcarcinoma of the thyroid gland in renal transplant patients.

Among organ transplant recipients there is a world wide increase in the number of de novo tumors as well as a decrease in the time of the first appearance after the transplantation. Between 1973 and the 31st of August 1999 1709 cadaver renal allograft transplantations were performed in our Department. Four thyroid cancers were detected among the renal transplanted patients. Two of them proved to be papillary microcarcinomas. Although the elevated risk of thyroid cancers is well established in the literature papillary microcarcinomas have never been reported before in an immunosuppressed patient. Authors highlight that the thyroid gland should always be carefully checked in organ transplant recipients, since better survival might be achieved even in the immunosuppressed population. Metastatic tumor is relatively benign which is in correlation with the literature, but there has been little experience in organ transplanted patients so far.

The nucleolar organizer regions in hyperplastic and tumorous lesions of the human liver.

The alterations of the argyrophil nucleolar organizer regions (AgNORs) have been studied in hyperplastic and neoplastic human liver lesions. The material studied included: 11 focal nodular hyperplasias (FNH), 3 adenomas, 19 hepatocellular carcinomas (HCC), 2 hepatoblastomas, 8 liver metastases. In 5 cases tumor-free (normal) liver was also available for study. The mean AgNOR numbers were significantly increased in all of these lesions (in FNHs 3.36 +/- 1.43, in the adenomas 2.48 +/- 1.29, in the HCCs 3.32 +/- 1.43, in the hepatoblastomas 3.33 +/- 1.33 and in the metastases 4.86 +/- 1.54) compared to those observed in normal liver (0.86 +/- 0.85). The highly increased AgNOR number in FNHs was particularly surprising and it seemed to us that based on AgNOR numbers the FNHs could be divided into two groups. With the exception of hepatoblastomas in all primary liver lesions the AgNOR counts distributed on a rather broad scale resulting in overlapping in hyperplastic and tumourous cases. The authors concluded that the AgNOR counts reflect only the proliferative activity of a given cell population and at least in the liver they cannot serve as basis for distinction between the hyperplastic, benign and malignant neoplastic lesions.

The pathomorphology of a human xenotransplanted basaloid squamous cell carcinoma.

To elucidate some factors related to the malignant phenotype of an oral tumor with mixed cell population the question has been raised whether the biological behavior of the basaloid or the squamous cells show any difference in an immunosuppressed host organism. Basaloid squamous cell carcinoma (BSCC) surgically removed from sublingual location was xenotransplanted either subcutaneously or in the oral submucosa and the histology, ultrastructures, LDH isoenzyme pattern were investigated. The epithelial origin of the established tumor line (HTB-1) could be recognized according to the characteristic epithelial ultrastructures, while the type of the LDH isoenzymes proved its human origin. The squamous cell population dominating the parent surgical specimen of BSCC regressed during xenotransplantation in the subcutan location, on the contrary the basaloid cells grew and maintained the tumor. Interestingly the basaloid cells transplanted from the subcutis to the oral submucosa generated a squamous cell population with an infiltrative growth pattern. The xenografted BSCC offer a promising model to investigate the contribution of each cell populations in the malignant phenotype. The presented data indicate that the basaloid cells are responsible for maintaining the tumor cell population, but certain malignant features (i.e. infiltrative growth) is associated to the squamous cells which are generated from the basaloid cells only under specific circumstances. Thus this particular model system showed that different malignant features could be associated to the basaloid and to the squamous cell component.

Simultaneous induction of liver cirrhosis and hepatocellular carcinomas in F-344 rats: establishment of a short hepatocarcinogenesis model.

The relationship between liver cirrhosis and diethylnitrosamine (DEN)-induced hepatocarcinogenesis in male F-344 rats was studied. Hepatic cirrhosis was produced by combined administration of CCl4 (0.5 ml/kg b.w. by gavage, three times a week) and phenobarbital (PB) (0.05% in drinking water, continuously for 6 weeks), while the carcinogenic nitrosamine compound was given either preceding or following CCl4 + PB treatment at a single dose of 200 mg/kg b.w., ip. Liver lesions were evaluated histologically at the end of the 4th month. The established cirrhosis completely prevented the formation of hepatocellular carcinomas (HCCs), however, CCl4 + PB posttreatment resulted in a strong enhancing effect on DEN-hepatocarcinogenesis: 16 weeks after initiation severe cirrhosis and HCCs occurred simultaneously in more than 90% of the animals. Although the explanation of this highly accelerated carcinoma formation is not known at present, the authors hypothesize that the modulation of the drug-metabolizing enzyme system might play a central role in this profoundly altered host response.

Experimental studies on the effect of hepatoprotective compounds.

The hepatopharmacological actions of Prostacyclin, 1-phosphate-4-amino 5-carboxamido-imidazole (AICA-P), Catergen, Silymarin and a thiazolidine compound were investigated by applications in in vitro and in vivo model systems. The usefulness of the in vitro system to screen for potential hepatoprotective agents and to investigate the molecular mechanism of these substances is shown. It was concluded that different patterns of hepatoprotective action were elaborated by the same drug depending on the model system used for testing. PGI2 and the thiazolidine compound showed remarkable protection in acute liver damage. However PGI2 circumvented only the CCl4 induced cellular injury, and was inactive in the galactosamine model system. The induction of cirrhosis could be modified by the simultaneous treatment with PGI2 or by the thiazolidine compound but the fully developed cirrhosis was not affected. On the contrary AICA-P and Silymarin treatment resulted in reduction of the amount of collagen in cirrhotic liver.

[Pathologic diagnosis of pancreatic cancer--facts, pitfalls, challenges]. / A hasnyálmirigyrák patológiai diagnosztikája--tények, buktatók, kihívások.

Discrimination between the well differentiated pancreatic carcinoma and the chronic fibrotizing pancreatitis is one of the most difficult diagnostic problems in the field of pancreatology, and it is also a challenge for the pathologist. The author outlines those objective facts that might lead to diagnostic errors. The two diseases may coexist; on the one hand, malignant tumor can be developed as a complication of a long-standing chronic pancreatitis, while on the other hand, pancreatic carcinoma is frequently accompanied by chronic inflammation. The majority of adenocarcinomas induce a striking desmoplastic stromal reaction, but the chronic pancreatitis is also characterized by a vigorous fibroblast proliferation leading to the possibility of macroscopical misdiagnosis. Microscopically, the pancreatitis can be mistaken for carcinoma, because the actively growing connective tissue irregularly separates the ducts and in addition, the continuous regenerative activity may lead to regressive atypia. For that reason, cytopathologist must evaluate several criteria together, because the nuclear alterations by themselves can be misleading. Although there are some promising new differential diagnostic techniques (apomucins, CAM 17.1, telomerase activity, loss of chromosome Y), so far the most reliable method has been the meticulous evaluation of the cellular and histological findings by the well trained pathologist. To date, molecular pathological methods have shown no advantage in the differential diagnosis.