Background: Success of chemotherapy and alleviation of pain are frequently less than optimal in pancreatic cancer patients, leading to increasing interest in new pharmacological substances, such as vanilloids. Our study addressed the question of whether vanilloids influence pancreatic cancer cell growth, and if vanilloids could be used for pain treatment via the vanilloid 1 receptor (VR1) in pancreatic cancer patients. Methods: In vitro, the effect of resiniferatoxin (vanilloid analogue) on apoptosis and cell growth in pancreatic cancer cells-either alone, combined with 5-fluorouracil (5-FU), or combined with gemcitabine-was determined by annexin V staining, FACS analysis, and MTT assay, respectively. VR1 expression was evaluated on RNA and protein level by quantitative polymerase chain reaction and immunohistochemistry in human pancreatic cancer and chronic pancreatitis. Patient characteristicsespecially pain levels-were registered in a prospective database and correlated with VR1 expression. Results: Resiniferatoxin induced apoptosis by targeting mitochondrial respiration and decreased cell growth in pancreatic cancer cells without showing synergistic effects with 5-FU or gemcitabine. Expression of VR1 was significantly upregulated in human pancreatic cancer and chronic pancreatitis. VR1 expression was related to the intensity of pain reported by cancer patients but not to the intensity of pain reported by patients with chronic pancreatitis. Conclusions: Resiniferatoxin induced apoptosis in pancreatic cancer cells indicates that vanilloids may be useful in the treatment of human pancreatic cancer. Furthermore, vanilloid might be a novel and effective treatment option for neurogenic pain in patients with pancreatic cancer.

Purpose: Phosphoinositide 3-kinase (PI3K) signaling is well established as important in cancer. To date most studies have been focused on the PI3K/p110α isoform, which has been found to be mutated in several different cancers. The aim of our study was to determine which specific PI3K isoforms are involved in pancreatic ductal adenocarcinoma (PDAC) and investigate the effects of these isoforms on proliferation, survival, and induction of Akt activation in pancreatic cancer cells.Experimental Design: The expression of all PI3K isoforms and downstream targets was analyzed by immunohistochemistry in human pancreatic cancer tissue and normal counterparts. Isoform selective inhibitors and short interfering RNA (siRNA) were employed to investigate the effects of the different PI3Ks on proliferation, survival, and intracellular signaling in PDAC cell lines.Results: Immunohistochemical screening revealed high specific expression of the PI3K/p110γ isoform. Scoring indicated that 72% of the PDAC tissue stained positive for PI3K/p110γ, whereas no stain was detected in normal pancreatic ducts. Proliferation analyses after selective inhibition and siRNA downregulation of PI3K/p110γ showed that PI3K/p110γ, but not other PI3K isoforms, was required for cell proliferation. Overexpression of PI3K/p110γ indeed increased cell numbers and mediated activation of Akt in PDAC cell lines. Moreover, PI3K/p110γ was required for Akt activation via lysophosphatidic acid receptors.Conclusions: These data represent the first identification of a tumor-specific accumulation of the PI3K isoform p110γ in human cancer. Further, our results signify a critical role for PI3K/p110γ in pancreatic cancer, and we hypothesize that PI3K/p110γ overexpression is a key event in the disease progression. Clin Cancer Res; 16(20); 4928-37. ©2010 AACR.

BackgroundMalignant perivascular epitheliod cell tumor (PEComa) is a very rare entity composed of distinctive perivascular epitheliod cells with variable immunoreactivity for melanocytic and muscle markers. At present this neoplasm does not have a known normal cellular counterpart and the natural history is often unpredictable. Up to now, few cases of PEComa have been described and treatment modalities are still controversial, particularly in advanced conditions.Case presentationWe handled the case of a 42-year-old man with unresectable PEComa of the abdomen. A 7 cm hepatic hypodense lesion between segment V and VIII of the liver and diffuse intraperitoneal nodules of 0,3-3,5 cm along the right subcapsular hepatic region, were documented by a CT scan. Radiological images showed abnormal lymph nodes of the right internal mammary chain and anterior mediastinum. The patient underwent an explorative laparotomy for uncontrolled intrabdominal hemorrhage without a well-defined preoperative tumor diagnosis. At surgery, multiple lobulated nodules containing hemorrhagic fluid on the liver surface, peritoneum and omentum were confirmed. The procedure had a palliative intent and consisted of hemostasis, hematomas evacuation and omentectomy. The diagnosis of PEComa was made after surgery on the basis of morphological and immunohystochemical criteria. Radiological and intra operative findings suggest that the mass has an hepatic origin with diffuse involvement of hepatic capsule and suspensory ligaments. The patient received medical support care with blood and plasma transfusions. In our experience, PEComa was clinically malignant, leading to a fatal outcome 25 days after hospital admission of patient.ConclusionsHere we report and discuss the peculiar clinical, radiological and morphological presentation of unresectable PEComa. Although in the majority of the reported series, PEComas show a more better prognosis, our case presents with a particular aggressive biological behaviour. The importance of a correct preoperative diagnosis, the need for more effective targeted therapies based on tumor molecular knowledge and evidence-based clinical studies are emphasized together with a revision of the concerning scientific literature.

Purpose. To analyse perioperative and oncological outcomes of minimally invasive simultaneous resection of primary colorectal neoplasm with synchronous liver metastases. Methods. A Medline revision of the current published literature on laparoscopic and robotic-assisted combined colectomy with hepatectomy for synchronous liver metastatic colorectal neoplasm was performed until February 2015. The specific search terms were “liver metastases”, “hepatic metastases”, “colorectal”, “colon”, “rectal”, “minimally invasive”, “laparoscopy”, “robotic-assisted”, “robotic colorectal and liver resection”, “synchronous”, and “simultaneous”. Results. 20 clinical reports including 150 patients who underwent minimally invasive one-stage procedure were retrospectively analysed. No randomized trials were found. The approach was laparoscopic in 139 patients (92.7%) and robotic in 11 cases (7.3%). The rectum was the most resected site of primary neoplasm (52.7%) and combined liver procedure was in 89% of cases a minor liver resection. One patient (0.7%) required conversion to open surgery. The overall morbidity and mortality rate were 18% and 1.3%, respectively. The most common complication was colorectal anastomotic leakage. Data concerning oncologic outcomes were too heterogeneous in order to gather definitive results. Conclusion. Although no prospective randomized trials are available, one-stage minimally invasive approach seems to show advantages over conventional surgery in terms of postoperative short-term course. On the contrary, more studies are required to define the oncologic values of the minimally invasive combined treatment.