Search

Background/aim The p38 family of mitogen-activated protein kinases (MAPK) includes four isoforms: p38α, -β, -γ and -δ. The aim of this study was to elucidate possible functions of p38α and p38β in human pancreatic cancer. Materials and methods Isoform expression was determined in seven human pancreatic cancer cell lines. After shRNA based selective knockdown of p38α and p38β, in vitro growth and migration as well as in vivo tumorigenicity were assessed. Results All pancreatic cancer cells expressed p38 isoforms. Knockdown of p38α and p38β inhibited in vitro growth. Migration was markedly reduced in p38α shRNA expressing clones, but not altered by p38β knockdown. While in vivo inhibition of p38β decreased tumor formation and growth, the knockdown of p38α significantly enhanced tumorigenicity. Conclusion p38 MAPKs may exert isoform specific functions in pancreatic cancer. Selective targeting may contribute to individualized treatment of pancreatic cancer in the future.

BACKGROUND/AIM This study was designed to analyse the effects of the novel, orally bioavailable CDK9-inhibitor Atuveciclib (BAY 1143572) in combination with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) on pancreatic ductal adenocarcinoma (PDAC) cancer cells. MATERIALS AND METHODS To assess the effect of combinatorial use of atuveciclib and TRAIL on pancreatic cancer cells, we used an MTT assay, colony formation assay, flow cytometry, and western blot analysis. RESULTS Atuveciclib combined with TRAIL significantly reduced the viability of pancreatic cancer cells and their colony formation potential by inducing apoptosis and cell-cycle arrest. Atuveciclib sensitised PDAC cells to TRAIL-induced cell death through the concomitant suppression of cFlip and Mcl-1. A gemcitabine-resistant PDAC cell-line and patient-derived xenograft (PDX) cell lines were also suppressed by this combinatorial approach. CONCLUSION This study provides the basis for further preclinical and clinical evaluation of combined treatment with atuveciclib and TRAIL.

Adjuvant treatment is still controversially discussed for elderly colon cancer (CC) patients. Our aim was to investigate the benefit of adjuvant treatment for younger (70 years) and elderly (≥70 years) patients.The long-term outcome of patients (n=855) enrolled in a randomized controlled trial comparing adjuvant chemotherapy with 5-FU alone, 5-FU plus folinic acid (FA), and 5-FU plus interferon-alpha (IFNa) was compared in younger (70 years) and elderly (≥70 years) patients using a quotient of each patient's survival time and his expected residual life expectancy (QSL) and a multivariate Cox proportional hazards model.Eight-year overall survival (OS) rates were 58.3% and 57.4% for younger (n=653) and elderly (n=202) patients, respectively. In elderly patients, 8-year OS rates were 51.4%, 61.8%, and 56.3, and median QSL scores were 0.338, 0.371, and 0.343 for 5-FU (n=59), 5-FU plus FA (n=76), and 5-FU plus IFNa (n=67), respectively. In elderly patients treatment with 5-FU plus FA decreased the risk for an event by 1.5-fold compared to 5-FU (HR=0.657, 95%CI=0.495-0.870, p=0.004) and 5-FU plus INFa (HR=0.685, 95%CI=0.515-0.912, p=0.009).Our analysis clearly demonstrates for the first time an additional benefit of FA for adjuvant treatment of elderly CC patients. We conclude that this regimen is very safe and effective for adjuvant treatment of elderly patients.

We analyzed survival of patients diagnosed with ampullary cancer (AC) and pancreatic ductal adenocarcinomas (PDAC).Between 1996 and 2009, 505 and 69 patients diagnosed with PDAC and AC, respectively, were identified. Overall survival was analyzed according to tumor entity, therapeutic approach and pathological tumor stage.The 5-year overall survival rate of patients with AC (37%; 95% confidence interval 25-49%) was remarkably higher compared to PDAC patients (7%; 95% confidence interval 5-10%). In both cohorts, surgical resection improved survival. Analysis of pathological factors revealed a survival benefit for patients staged with small primary tumors (pT1/2) and exclusion of distant metastases (M0) for both PDAC and AC. Interestingly, absence of lymph node metastasis substantially improved survival in AC, but not in PDAC.Overall survival of patients with AC is superior compared to that of patients with PDAC. Therapeutically, adequate regional lymph node dissection seems particularly important for the surgical management of AC.

Gastric cancer is the fourth cancer in incidence worldwide, with a high disease-related death rate. The aim of this study was to evaluate the importance of clinical and pathological factors for the prognosis of gastric cancer patients.We analysed data from 304 consecutive patients. Clinical and pathological factors and the surgical resection status were analysed by univariate analyses, followed by investigation of important factors using a proportional hazard regression analysis with backward elimination in order to identify important independent prognostic factors.Univariate analysis revealed that age, pT, pN, M, UICC stage, grading, and resection status were significantly associated with survival. Multivariate analysis identified age, pT, pN, M, and resection status as independent prognostic factors.Besides age and pathological parameters, radical R0 resection plays an essential role in the management of gastric cancer and should be aimed at, even if extended resection may be necessary.

Benign cystic teratoma of the pancreas often appears to be potentially malignant in preoperative staging. The final diagnosis is generally obtained after surgical removal. Reliable prediction is mandatory for differential treatment.A Medline query was performed for the terms cystic teratoma, dermoid cyst and pancreas. Data were analyzed for patient characteristics, clinical appearance, diagnostic findings, therapy and follow-up.Including our own, 26 cases of pancreatic cystic teratoma were identified. The majority of patients were symptomatic by unspecific gastrointestinal complaints. Up to date, imaging techniques fail at a distinct preoperative diagnosis. Surgical treatment evolved from various drainage and excision procedures into radical resection.Despite the strictly benign nature of cystic teratoma, oncologic resection is mostly inevitable due to difficult preoperative diagnosis. No reliable predictive marker was found to allow for organ- or parenchyma-preserving procedures. Therefore, surgery remains the treatment of choice to exclude malignancy.

Brain metastases originating from pancreatic cancer are associated with a dismal prognosis and, generally, therapeutic options remain palliative. We present the cases of two patients that developed brain metastases after resection of a pancreatic ductal adenocarcinoma. Brain metastases were resected successfully and neither patients developed any further tumor recurrence. These cases demonstrate that resection of brain metastatic lesions originating from pancreatic ductal adenocarcinoma is a reasonable therapeutic option with a chance for complete cure in some cases.

Irinotecan alone and in combination with 5-fluorouracil (5-FU) displays potent activity in advanced colorectal cancer. The aim of this study was to estimate the potential efficacy of irinotecan for hepatic arterial infusion (HAI) chemotherapy.We investigated the anti-proliferative effects of irinotecan alone and in combination with 5-FU in HT29 and NMG64/84 colon and COLO-357, MIA PaCa-2 and PANC-1 pancreatic cancer cell lines and in fresh tumors from patients with primary colon cancer (n=2) and colorectal liver metastases (n=11) in vitro, using the MTT growth assay and the human tumor colony-forming assay (HTCA), mimicking conditions which are achievable during HAI.Irinotecan displayed concentration- and time-dependent cytotoxic effects in all tested cell lines. Treatment of cell lines with irinotecan followed by 5-FU did not result in synergistic anti-proliferative effects. In the HTCA, the sensitivity of each cell line varied depending on the incubation times (30, 90, 180 and 1440 min). Independent of the individual sensitivity, the IC50 concentration and time products were lowest when incubating with irinotecan for 30 min for all cell lines. The IC50 of irinotecan in HT29, NMG64/84, COLO-357, MIA PaCa-2 and PANC-1 cells at 30 min were 200, 160, 100, 400 and 150 microg/ml, respectively, in the HTCA. All isolated tumor samples displayed concentration-dependent inhibition of colony formation after exposure to irinotecan for 30 min. The IC50 of irinotecan of 5 of the 11 liver metastases was100 microg/ml.Irinotecan seems to be suitable for HAI therapy phase II studies. Due to the observation that several liver metastases had IC50 values that may be clinically achievable by HAI, patients with such tumors may benefit in the future from HAI using irinotecan.

Several studies have demonstrated the efficacy of systemic oxaliplatin (Oxa) in combination with 5-fluorouracil (5-FU) and folinic acid (FA) for the treatment of colorectal liver metastases (CRLM). However, nothing is presently known about the pharmacokinetics of Oxa administered via the hepatic artery and only very little about the feasibility and toxicity of Oxa used for hepatic artery infusion (HAI).We designed a phase II trial using Oxa in combination with 5-FU/FA and mitomycin C (MMC) for HAI treatment of patients with isolated non-resectable CRLM. Oxa (130 mg/m2) was delivered on day (d) 1 as a 120-min infusion followed by FA (140 mg/m2) for 10 min and 5-FU (480 mg/m2) for 120 min from d1 to d5 and MMC (7 mg/m2) for 30 min on d5 every 35 days. For Oxa pharmacokinetics, peripheral venous blood was collected before, during and after arterial infusion. Oxaliplatin was determined by liquid chromatography with post-column derivatization in blood ultra filtrate.A total of 33 HAI cycles were administered to 5 patients with tolerable toxicity, which mainly consisted of grade I and II nausea, vomiting, leucopenia, thrombopenia and abdominal pain. During 4 cycles nausea/vomiting III degree occurred, during 3 cycles diarrhoea and abdominal pain III degree. No neurotoxicityor = II degree and no catheter occlusion was observed. Staging showed 4 PR and 1 PD. Pharmacokinetic analysis revealed an AUC value of 85.3 micrograms x min/ml after HAI. Recalculating these values with the previously reported AUC value for systemic administration (161 micrograms x min/ml) revealed a liver extraction ratio of 0.47 for Oxa.We conclude from our results that Oxa in combination with 5-FU/FA and MMC may be a feasible protocol for HAI treatment without major toxicity, especially avoiding higher grade neurotoxicity. This is probably attributable to the low systemic bioavailability of Oxa.