Resistance to mTORC1 Inhibitors in Cancer Therapy: From Kinase Mutations to Intratumoral Heterogeneity of Kinase Activity.

Targeting mTORC1 has been thoroughly explored in cancer therapy. Following encouraging preclinical studies, mTORC1 inhibitors however failed to provide substantial benefits in cancer patients. Several resistance mechanisms have been identified including mutations of mTOR and activation of alternate proliferation pathways. Moreover, emerging evidence discloses intratumoral heterogeneity of mTORC1 activity that further contributes to a reduced anticancer efficacy of mTORC1 inhibitors. Genetic heterogeneity as well as heterogeneous conditions of the tumor environment such as hypoxia profoundly modifies mTORC1 activity in tumors and hence influences the response of tumors to mTORC1 inhibitors. Intriguingly, the heterogeneity of mTORC1 activity also occurs towards its substrates at the single cell level, as mutually exclusive pattern of activation of mTORC1 downstream effectors has been reported in tumors. After briefly describing mTORC1 biology and the use of mTORC1 inhibitors in patients, this review will give an overview on concepts of resistance to mTORC1 inhibition in cancer with a particular focus on intratumoral heterogeneity of mTORC1 activity

Preoperative albumin level is a marker of alveolar echinococcosis recurrence after hepatectomy.

To identify a preoperative blood marker predictive of alveolar echinococcosis (AE) recurrence after hepatectomy. All consecutive patients who underwent operation for liver AE at the Lausanne University Hospital (CHUV) between January 1992 and December 2015 were included in this retrospective study. Preoperative laboratory values of leukocytes, mean corpuscular volume (MCV), red blood cell distribution width (RDW), thrombocytes, C-reactive protein (CRP) and albumin were collected and analyzed. Univariate and multivariate Cox regression analyses were performed to determine the risk factors for AE recurrence after liver resection. A receiver operating characteristic (ROC) curve was used to define the best discrimination threshold of the blood marker. Moreover, recurrence-free survival curves were calculated using the Kaplan-Meier method. The cohort included 68 adult patients (37 females) with median age of 61 years [interquartile range (IQR): 46-71]. Eight of the patients (12%) presented a recurrence over a median follow-up time of 76 mo (IQR: 34-128). Median time to recurrence was 10 mo (IQR: 6-11). Median preoperative leukocyte, MCV, RDW, thrombocyte and CRP levels were similar between recurrent and non-recurrent cases. Median preoperative albumin level was 43 g/L (IQR: 41-45) for non-recurrent cases and 36 g/L (IQR: 33-42) for recurrent cases (P = 0.005). The area under the ROC curve for preoperative albumin level to predict recurrence was 0.840 (95%CI: 0.642-1, P = 0.002). The cut-off albumin level value was 37.5 g/L for sensitivity of 94.5% and specificity of 75%. In multivariate analysis, preoperative albumin and surgical resection margins were independent predictors of AE recurrence (HR = 0.099, P = 0.007 and HR = 0.182, P = 0.045 respectively). Low preoperative albumin level was associated with AE recurrence in the present cohort. Thus, preoperative albumin may be a useful biomarker to guide follow-up

Aberrant Right Hepatic Artery with a Prepancreatic Course Visualized Prior to Pancreaticoduodenectomy

Liver vascularization is known to present with several different variations. Generally, a normal vascular anatomy is reported in up to 50-80 % of cases. For this reason, a precise preoperative mapping of the hepatic vascularization prior to pancreatic surgery is essential to avoid injuries and subsequent complications. We report here a case of a young patient scheduled for Whipple procedure, who presented an arterial pattern type Michels IV, variation reported in 0.6 to 3 % in the literature. Another interesting particularity of this case was the fact that the right hepatic artery had a prepancreatic course. We think that every surgeon performing hepatopancreatic surgery should have heard of this special and rare situatio

Future development of gastrointestinal cancer incidence and mortality rates in Switzerland: a tumour registry- and population-based projection up to 2030.

QUESTIONS UNDER STUDY: Since tumour burden consumes substantial healthcare resources, precise cancer incidence estimations are pivotal to define future needs of national healthcare. This study aimed to estimate incidence and mortality rates of oesophageal, gastric, pancreatic, hepatic and colorectal cancers up to 2030 in Switzerland. METHODS: Swiss Statistics provides national incidences and mortality rates of various cancers, and models of future developments of the Swiss population. Cancer incidences and mortality rates from 1985 to 2009 were analysed to estimate trends and to predict incidence and mortality rates up to 2029. Linear regressions and Joinpoint analyses were performed to estimate the future trends of incidences and mortality rates. RESULTS: Crude incidences of oesophageal, pancreas, liver and colorectal cancers have steadily increased since 1985, and will continue to increase. Gastric cancer incidence and mortality rates reveal an ongoing decrease. Pancreatic and liver cancer crude mortality rates will keep increasing, whereas colorectal cancer mortality on the contrary will fall. Mortality from oesophageal cancer will plateau or minimally increase. If we consider European population-standardised incidence rates, oesophageal, pancreatic and colorectal cancer incidences are steady. Gastric cancers are diminishing and liver cancers will follow an increasing trend. Standardised mortality rates show a diminution for all but liver cancer. CONCLUSIONS: The oncological burden of gastrointestinal cancer will significantly increase in Switzerland during the next two decades. The crude mortality rates globally show an ongoing increase except for gastric and colorectal cancers. Enlarged healthcare resources to take care of these complex patient groups properly will be needed

Video-assisted sacral nerve stimulation

Background: Sacral nerve simulation (SNS) is an accepted therapy for patients with urinary or bowel dysfunction. However, infection rates are as high as 20% and can result in removal of the expensive device. We present a new video-assisted technique minimizing the risk of infection. Methods: Between April and July 2005, six consecutive women of median age 68 years (range, 60-74), with faecal incontinence (4 patients) and idiopathic constipation (2 patients) underwent video-assisted electrode implantation for SNS. The motor response of the pelvic floor during percutaneous nerve evaluation and implantation of the permanent lead was monitored by a video optic (same as that normally used for laparoscopic or endoscopic procedures) placed between the legs of the patients. The video optic and the perianal area were completely covered with drapes, separating them from the operating field. Results: All but one screening was successful, and no wound infections at the electrode or at the pocket of the stimulator were noted (mean postoperative follow-up, 8 weeks). Conclusions: With the use of a video optic, the anus and the implantation site can be completely separated and contamination during the operation becomes unlikely. Furthermore, the response of the pelvic floor to the stimulation is better visualized. We routinely recommend the use of video equipment for SNS electrode implantatio

Management of severe blunt hepatic injury in the era of computed tomography and transarterial embolization: A systematic review and critical appraisal of the literature.

BACKGROUND: During the last decade, the management of blunt hepatic injury has considerably changed. Three options are available as follows: nonoperative management (NOM), transarterial embolization (TAE), and surgery. We aimed to evaluate in a systematic review the current practice and outcomes in the management of Grade III to V blunt hepatic injury. METHOD: The MEDLINE database was searched using PubMed to identify English-language citations published after 2000 using the key words blunt, hepatic injury, severe, and grade III to V in different combinations. Liver injury was graded according to the American Association for the Surgery of Trauma classification on computed tomography (CT). Primary outcome analyzed was success rate in intention to treat. Critical appraisal of the literature was performed using the validated National Institute for Health and Care Excellence "Quality Assessment for Case Series" system. RESULTS: Twelve articles were selected for critical appraisal (n = 4,946 patients). The median quality score of articles was 4 of 8 (range, 2-6). Overall, the median Injury Severity Score (ISS) at admission was 26 (range, 0.6-75). A median of 66% (range, 0-100%) of patients was managed with NOM, with a success rate of 94% (range, 86-100%). TAE was used in only 3% of cases (range, 0-72%) owing to contrast extravasation on CT with a success rate of 93% (range, 81-100%); however, 9% to 30% of patients required a laparotomy. Thirty-one percent (range, 17-100%) of patients were managed with surgery owing to hemodynamic instability in most cases, with 12% to 28% requiring secondary TAE to control recurrent hepatic bleeding. Mortality was 5% (range, 0-8%) after NOM and 51% (range, 30-68%) after surgery. CONCLUSION: NOM of Grade III to V blunt hepatic injury is the first treatment option to manage hemodynamically stable patients. TAE and surgery are considered in a highly selective group of patients with contrast extravasation on CT or shock at admission, respectively. Additional standardization of the reports is necessary to allow accurate comparisons of the various management strategies. LEVEL OF EVIDENCE: Systematic review, level IV

Short-term outcomes after distal pancreatectomy: Laparotomy vs. laparoscopy - A single-center series.

Laparoscopic distal pancreatectomy was introduced 15 years ago, but it is still not widely used. The aim of the study was to compare the postoperative complications and length of stay between open and laparoscopic distal pancreatectomy. A search of our institutional pancreas database was performed. All consecutive distal pancreatectomy patients from 2000 to 2015 were identified. Demographics, peri- and postoperative outcomes were reviewed. Postoperative complications were graded using Clavien classification. Standard statistical analyses were performed. One hundred and five patients underwent distal pancreatectomy (45 women, 60 men, median age of 63 years). Seventy-nine cases were performed open and 26 by laparoscopy (conversion rate from laparoscopy to laparotomy: 7/26). Characteristics of both groups were similar. The tumor proportion was similar in both groups (56/79 and 23/26, p = 0.114). Overall complication rate was 41/79 (52%) in the open group and 9/26 (36%) in the laparoscopy group (p = 0.175). Two patients died during hospital stay in the open group compared to 0 in the laparoscopy group (p = 1). The fistula rates were comparable (17/79 and 5/26, p = 1). Median length of stay was shorter for the laparoscopy group (8 vs. 12 days, p < 0.001), as well as the median intermediate care stay (1 vs. 3 days, p = 0.004). Short-term outcomes after open and laparoscopic distal pancreatectomy regarding postoperative complications and mortality were similar, but length of stay was significantly shorter for the laparoscopic approach. Hence, laparoscopic distal pancreatectomy should be offered to all suitable patients

Fine-Tuning Tumor Endothelial Cells to Selectively Kill Cancer.

Tumor endothelial cells regulate several aspects of tumor biology, from delivering oxygen and nutrients to shaping the immune response against a tumor and providing a barrier against tumor cell dissemination. Accordingly, targeting tumor endothelial cells represents an important modality in cancer therapy. Whereas initial anti-angiogenic treatments focused mainly on blocking the formation of new blood vessels in cancer, emerging strategies are specifically influencing certain aspects of tumor endothelial cells. For instance, efforts are generated to normalize tumor blood vessels in order to improve tumor perfusion and ameliorate the outcome of chemo-, radio-, and immunotherapy. In addition, treatment options that enhance the properties of tumor blood vessels that support a host's anti-tumor immune response are being explored. Hence, upcoming anti-angiogenic strategies will shape some specific aspects of the tumor blood vessels that are no longer limited to abrogating angiogenesis. In this review, we enumerate approaches that target tumor endothelial cells to provide anti-cancer benefits and discuss their therapeutic potential