RNA sequencing of pancreatic adenocarcinoma tumors yields novel expression patterns associated with long-term survival and reveals a role for ANGPTL4.

BACKGROUND: Pancreatic adenocarcinoma patients have low survival rates due to late-stage diagnosis and high rates of cancer recurrence even after surgical resection. It is important to understand the molecular characteristics associated with survival differences in pancreatic adenocarcinoma tumors that may inform patient care. RESULTS: RNA sequencing was performed for 51 patient tumor tissues extracted from patients undergoing surgical resection, and expression was associated with overall survival time from diagnosis. Our analysis uncovered 323 transcripts whose expression correlates with survival time in our pancreatic patient cohort. This genomic signature was validated in an independent RNA-seq dataset of 68 additional patients from the International Cancer Genome Consortium. We demonstrate that this transcriptional profile is largely independent of markers of cellular division and present a 19-transcript predictive model built from a subset of the 323 transcripts that can distinguish patients with differing survival times across both the training and validation patient cohorts. We present evidence that a subset of the survival-associated transcripts is associated with resistance to gemcitabine treatment in vitro, and reveal that reduced expression of one of the survival-associated transcripts, Angiopoietin-like 4, impairs growth of a gemcitabine-resistant pancreatic cancer cell line. CONCLUSIONS: Gene expression patterns in pancreatic adenocarcinoma tumors can distinguish patients with differing survival outcomes after undergoing surgical resection, and the survival difference could be associated with the intrinsic gemcitabine sensitivity of primary patient tumors. Thus, these transcriptional differences may impact patient care by distinguishing patients who would benefit from a non-gemcitabine based therapy.

Neoadjuvant interferon-based chemoradiation for borderline resectable and locally advanced pancreas cancer: a Phase II pilot study.

OBJECTIVES: Neoadjuvant chemoradiotherapy (CRT) is a viable treatment strategy for patients with pancreatic cancer. This study was conducted to evaluate the Virginia Mason Protocol (5-fluorouracil, cisplatin, interferon-α and radiation) given in the neoadjuvant setting for the treatment of locally advanced pancreatic cancer. METHODS: A Phase II pilot study evaluating interferon-based neoadjuvant CRT in patients with locally advanced pancreatic cancer was performed. RESULTS: A total of 23 patients were enrolled. The mean age of the patients was 58.6 years. Of the 23 patients, seven (30.4%) completed all treatments. In the remaining 16 (69.6%) patients, treatment was interrupted as a result of toxicity. The most commonly reported effects of toxicity were leucopoenia/cytopoenia (n = 19, 82.6%) and gastrointestinal effects (n = 19, 82.6%). Surgical resection was successful in seven (30.4%) patients. Margins were negative in six (85.7%) of these seven patients. Positive lymph nodes were identified in three (42.9%) of seven patients. Overall survival was 11.5 months. Surgery provided improved survival (22.6 months) compared with CRT alone (8.8 months). Disease-free survival in resected patients was 17.2 months. CONCLUSIONS: Interferon-based neoadjuvant CRT may allow for resection of locally advanced pancreatic cancer, but with significant toxicity. In the absence of surgical resection, survival remains dismal.

Neoadjuvant chemoradiotherapy for locally advanced pancreas cancer rarely leads to radiological evidence of tumour regression.

BACKGROUND: Neo-adjuvant chemo-radiotherapy has been proposed to improve resectability of locally-advanced pancreatic cancer (LAPC). However, the ability of neo-adjuvant therapy to induce radiological tumour regression has not been reported. METHODS: Pre- and post-treatment computed tomography (CT) scans of patients undergoing neo-adjuvant chemo-radiotherapy for LAPC were reviewed. LAPC was sub-classified into borderline resectable disease [≤ 180° involvement of the superior mesenteric artery (SMA); short-segment encasement/abutment of the common hepatic artery; or tumour-associated deformity, abutment or short-segment occlusion of the superior mesenteric vein (SMV)/ portal vein (PV) that was amenable to vascular resection and reconstruction] and locally advanced un-resectable pancreatic cancer (vascular involvement more than that described for borderline resectable pancreatic cancer). The radiological response and surgical resection rates were assessed. RESULTS: Sixteen patients received neo-adjuvant therapy for LAPC during 2005-2008. Regression of major vascular involvement, i.e. un-encasement or regression of abutment of any involved vessels was not observed in any patient. Pre- and post-treatment tumour densities were not statistically different. Fifty per cent of patients with borderline resectable disease and none of the patients with locally advanced un-resectable pancreatic cancer eventually underwent surgical resection. CONCLUSION: Neo-adjuvant treatment does not induce radiological tumour regression of LAPC with major vascular involvement. Patient selection for neo-adjuvant trial enrollment should remain focused on borderline disease which may have a potential for surgical resection.

Pathway-based pharmacogenomics of gemcitabine pharmacokinetics in patients with solid tumors.

AIM: The aim of this study was to evaluate the association of gemcitabine pathway SNPs with detailed pharmacokinetic measures obtained from solid tumor patients receiving gemcitabine-based therapy. MATERIALS & METHODS: SNPs within nine gemcitabine pathway genes, namely CDA, CMPK, DCK, DCTD, NT5C2, NT5C3, SLC28A1, SLC28A3 and SLC29A1 were analyzed for association with gemcitabine pharmacokinetics. RESULTS: Significant association of gemcitabine clearance with SNPs in NT5C2 was identified. Clearance of 2´,2´-difluorodeoxyuridine, a gemcitabine metabolite was significantly predicted by CDA, SLC29A1 and NT5C2 SNPs. This study reports an association of formation clearance of 2´,2´-difluoro-2´-deoxycytidine triphosphate, an active form of gemcitabine with SNPs within uptake transporters SLC28A1, SLC28A3 and SLC29A1. CONCLUSION: Genetic variation in gemcitabine pathway genes is associated with its pharmacokinetics and hence could influence gemcitabine response. Our study identified pharmacogenetic markers that could be further tested in larger patient cohorts and could open up opportunities to individualize therapy in solid tumor patients.

Severe electrolyte disturbances after hyperthermic intraperitoneal chemotherapy: oxaliplatin versus mitomycin C.

BACKGROUND: Oxaliplatin (OX) is increasingly used for hyperthermic intraperitoneal chemotherapy (HIPC) for patients with peritoneal metastases. Our aim was to review electrolyte disturbances and complications after HIPC with oxaliplatin (OX) versus mitomycin C (MMC). MATERIALS AND METHODS: We included patients enrolled in single-institution prospective clinical trials who underwent cytoreductive surgery and HIPC with MMC or OX. We reviewed patient demographics, pathology, perioperative course, HIPC administration, and postoperative electrolyte disturbances. Measured postoperative sodium values were corrected for systemic hyperglycemia using the formula: (measured Na(+)) × [(glucose - 100/100) × 1.6]. RESULTS: From January 2002 to April 2009 we performed 80 HIPC procedures. A total of 60 patients (75%) received MMC (dose range 12.5-50 mg/m(2)) carried in lactated ringers solution. There were 20 patients (25%) who received OX (dose range 300 × 400 mg/m(2)) carried in 5% dextrose solution. For patients receiving HIPC with OX, electrolyte disturbances were the most common complication. Compared with MMC, patients receiving OX had significant 24-h postoperative uncorrected hyponatremia (P < 0.001), corrected hyponatremia (P < 0.001), hyperglycemia (P < 0.001), and metabolic acidosis (P < 0.001). In the OX group, corrected (mean 130.5) and uncorrected (mean 127.4) sodium levels were significantly lower than preoperatively (mean 139.9, P < 0.001). The overall nonelectrolyte complication rate was 56.2%. (MMC n = 33, 55.0%; OX n = 12, 60%); the 30-day mortality rate was 0% in both groups. CONCLUSIONS: Compared with MMC, HIPC with OX was associated with significant but predictable electrolyte disturbances; however, these electrolyte disturbances were not associated with higher overall complication rates. Close monitoring with early correction is imperative to maximize perioperative care. Further studies are needed to provide mechanistic insight.

Chemotherapy-induced thrombosis.

Venous thromboembolism (VTE) is a frequent and potentially life-threatening complication associated with hematological and solid tumor malignancies. In patients with cancer, VTE portends a poor prognosis; in fact, only 12% of those who suffer an event will survive beyond one year. There are several different risk factors for the development of VTE in cancer patients that are well-described in the literature. One that has become increasingly recognized over the past two decades is the independent risk factor of chemotherapy. The annual incidence of VTE in patients receiving chemotherapy is estimated at 11%. This risk can climb to 20% or higher depending on the type of drug(s) being administered. In addition to chemotherapy, there are many other anti-neoplastic and supportive therapies that are also associated with an increased risk for the development of VTE. At present, several original basic science studies and clinical trials are underway in an effort to enhance our understanding of the mechanisms by which different chemotherapeutic agents can generate a prothrombotic state. The purpose of this article is to review the pertinent literature related to VTE in malignancy, and more specifically, chemotherapy and other cancer-related treatments associated with VTE.

Cholecystitis as the presenting manifestation of acute myeloid leukemia: report of a case.

We report a case of acute leukemia, which presented as cholecystitis in a previously healthy middle-aged adult. Leukemic involvement of the gastrointestinal tract is a well-known clinicopathological entity. However, leukemic infiltration of the gall bladder wall is a rare occurrence. It has only been previously described in the setting of relapsed disease and, to our knowledge, has never been reported as the primary manifestation of de novo acute leukemia. The patient in question was treated with standard induction and consolidation chemotherapy and remains in complete remission 19 months after his presentation with symptoms consistent with cholecystitis.