Search

Pancreatic acinar cell carcinomas (PACs) are rare but are distinct aggressive neoplasms that phenotypically differ from pancreatic ductal adenocarcinomas (PDACs) and pancreatic neuroendocrine neoplasms (PNENs). Despite recent work on the genetic changes of PACs, their molecular pathogenesis is still poorly understood. In this study, we focus on a comparative genomic hybridization analysis. Based on frequent chromosomal imbalances, the involvement of DCC and c-MYC in the pathogenesis of PACs is further investigated. Moreover, we examine markers harboring potential therapeutic relevance (K-RAS, BRAF, EGFR, MGMT, HSP90, L1CAM, Her2). PACs revealed a microsatellite stable, chromosomal unstable genotype, defined by recurrent chromosomal losses of 1p, 3p, 4q, 5q, 6q, 8p, 9p, 11q, 13q, 16q, and 18, as well as gains of 1q, 7, 8q, 12, 17q, and 20q. Subsets of PAC displayed reduction/loss of DCC (79 %) and c-MYC-amplification (17 %). Significant EGFR expression occurred in 42 %, HSP90 expression in 98 %, L1CAM expression in 72 %, and loss of MGMT in 26 %. Two cases carried a K-RAS mutation. Mutations of EGFR or BRAF were not detected. All cases were Her2/neu-negative. PACs display characteristic chromosomal imbalances which are distinctly different from those in pancreatic ductal adenocarcinomas and pancreatic neuroendocrine neoplasms. Our findings suggest that DCC and c-MYC alterations may play an important role in the pathogenesis of PACs. Furthermore, EGFR, MGMT, HSP90, and L1CAM may be useful as therapeutic markers and predictors of response to therapy in a subset of PACs.

Results of chemotherapy for small cell bronchial carcinoma were analysed retrospectively on 36 of 40 consecutive patients with the disease, admitted to an oncology unit between January 1985 and December 1987. The survival curves indicated a highly significant trend (log-rank p = 0.001). Patients with extensive disease and Karnofsky index of 40-50% had a median survival of four months, but for those with Karnofsky index greater than 50% it was 15 months. There was virtually no age difference between the two groups, but there were significant differences regarding additional diseases (e.g. coronary heart disease, arteriosclerosis, etc.) frequency of liver and CNS metastases, rates of complete or partial remission, number of early deaths, haematological toxicity, and severe weight loss (greater than 5 kg). These results suggest that aggressive chemotherapy (primary designed for patients with limited disease) failed to improve the grave prognosis of patients with distant metastases and a low Karnofsky index (less than 50%). Supportive care should be intensified for these patients.

In the course of a phase II study 15 patients (nine women and six men; mean age 58 [45-69] years) received 300 mg clodronate daily during a total of 16 episodes of tumour-induced hypercalcaemia. Four women had breast cancer, four patients had plasmocytoma and four had bronchial carcinoma. One woman each had leiomyosarcoma or squamous cell carcinoma of the uterus or pancreatic carcinoma, respectively. No other calcium-lowering treatment, such as forced diuresis, glucocorticoids, calcitonin or mithramycin, was employed. As early as two days after onset of treatment the serum calcium concentration fell significantly from 3.63 +/- 0.42 to 2.80 +/- 0.40 mmol/l. After a mean interval of 4.3 days the hypercalcaemia had been eliminated during 15 of the 16 episodes. The treatment was not adequate in one patient with paraneoplastic hypercalcaemia. The results indicate that this medication is to be recommended as a standard treatment of tumour-induced hypercalcaemia; side effects are minimal.

Pancreatic endocrine tumors (PET) represent a heterogenous group of neoplasms. Although surgical resection is considered a safe and effective treatment for many PET, therapeutic options for inoperable and progressive PET are limited. The expression of heat-shock protein (HSP) 90 was investigated in 120 clinically and pathomorphologically well-characterized PET from 84 patients using immunohistochemistry. In addition, in 19 snap–frozen PET and in three healthy pancreatic tissues, we performed immunoblot analyses, and in 15 snap–frozen PET and in three healthy pancreatic tissues, we investigated the expression of HSP90 isoforms by means of semiquantitative RT-PCR. Functional tests were conducted using the human pancreas carcinoid cell line BON and the mouse insulinoma cell line β-TC-3. HSP90 was expressed in 95% of the PET patients. The transcript levels of the HSP90 isoforms HSP90α, HSP90β, glucose-related protein 94, and TNF receptor-associated protein 1 were significantly increased in PET compared with non-neoplastic pancreatic tissues. The treatment of the cell lines BON and β-TC-3 with the HSP90 inhibitors 17-allylamino-17-demethoxygeldanamycin and 17-dimethylaminoethylamino-17-demethoxy-geldanamycin resulted in significant, dose-dependent reduction of cell viability, cell cycle arrest, and increased apoptosis. Furthermore, HSP90 inhibition induced the degradation and inactivation of several oncogenetic HSP90 client proteins in a time- and dose-dependent manner. HSP90 inhibitors increased the therapeutic effects of doxorubicin and 5-fluorucacil in BON and β-TC-3 cells. HSP90 is expressed in the vast majority of PET and its inhibition reveals significant treatment effects in vitro. Thus, HSP90 qualifies as a promising new target.

The antiemetic efficacy and safety of granisetron (40 μg/kg), a selective and potent 5-hydroxytryptamine (serotonin) antagonist, was compared with that of metoclopramide (7 mg/kg) plus dexamethasone (12 mg) in patients receiving fractionated chemotherapy. Patients receiving cisplatin at doses of at least 15 mg/m2 or etoposide at least 120 mg/m2 or ifosfamide at least 1.2 g/m2 on each of 5 consecutive days were eligible. A total of 143 patients received granisetron and 141 received the comparator regimen. The 5-day complete response rate (no vomiting, no worse than mild nausea) for granisetron (46.8%) was equivalent to that for metoclopramide plus dexamethasone (43.9%). The overall 5-day response profile was superior for granisetron (P=0.013) because of fewer failures in this group. The overall incidence of adverse experiences was significantly lower in the granisetron group (60.8% versus 77.3%,P=0.003). Headache and constipation, more prevalent in the granisetron group, are recognized side-effects of serotonin antagonists. Extrapyramidal syndrome, not seen in any granisetron patients, occurred in 20.6% of comparator patients (P

In a multicenter trial, 49 patients with histologically proven advanced gastric cancer were treated with a combination chemotherapy consisting of etoposide 120 mg/m2 d 4, 5, 6 adriamycin 20