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

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

Neuropathy After Herniorrhaphy: Indication for Surgical Treatment and Outcome

Background: Chronic neuropathy after hernia repair is a neglected problem as very few patients are referred for surgical treatment. The aim of the present study was to assess the outcome of standardized surgical revision for neuropathic pain after hernia repair. Methods: In a prospective cohort study we evaluated all patients admitted to our tertiary referral center for surgical treatment of persistent neuropathic pain after primary herniorrhaphy between 2001 and 2006. Diagnosis of neuropathic pain was based on clinical findings and a positive Tinel's sign. Postoperative pain was evaluated by a visual analogue scale (VAS) and a pain questionnaire up to 12months after revision surgery. Results: Forty-three consecutive patients (39 male, median age 35years) underwent surgical revision, mesh removal, and radical neurectomy. The median operative time was 58min (range: 45-95min). Histological examination revealed nerve entrapment, complete transection, or traumatic neuroma in all patients. The ilioinguinal nerve was affected in 35 patients (81%); the iliohypogastric nerve, in 10 patients (23%). Overall pain (median VAS) decreased permanently after surgery within a follow-up period of 12months (preoperative 74 [range: 53-87] months versus 0 [range: 0-34] months; p<0.0001). Conclusions: The results of this cohort study suggest that surgical mesh removal with ilioinguinal and iliohypogastric neurectomy is a successful treatment in patients with neuropathic pain after hernia repai

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

Transanal endoscopic microsurgical excision of rectal tumors: Indications and results

Transanal endoscopic microsurgery (TEM) allows local excision of rectal tumors located 4 to 18 cm above the anal verge. The technique is not yet generally established because of the necessary special instrumentation and tools, the unusual technical aspects of the approach, and the stringent patient selection criteria. The aim of this prospective, descriptive study was to analyze the currently accepted indications for TEM and to evaluate the use of this procedure for treating rectal cancer. Over a 4-year period 50 patients aged 31 to 86 years (mean 64 years) underwent TEM for treatment of rectal tumors located 12 cm above the anal verge (range 4-18 cm). The local complication rate was 4%. Altogether, 76% of lesions were benign, and 24% were T1 and T2 tumors. Of 12 cancer cases, 4 required reoperation by total mesorectal resection; the other 8 are currently under follow-up management. Over the follow-up period of 30.6 months (range 11-54 months) the recurrence rate of T1 tumors was 8.3%. TEM is a minimally invasive surgical technique that may benefit a small, specific population of patients with rectal tumors. Compared with conventional transanal resection, TEM provides superior exposure of tumors higher up in the rectum (i.e., up to 18 cm from the anal verge). The greater precision of resection combined with low morbidity (10%, relative to that of anterior resection) and short duration of hospitalization (5.5 days) make this technique a reliable and in some cases more effective surgical approach than laparotomy and low anterior resectio