Журнал интегративной онкологии

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumors still associated with poor prognosis in advanced stages. Gemcitabine is one of the standard agents for the treatment of PDAC, without having a major impact on the clinical outcome. Combining two compounds acting via different ways of action may result in a better efficacy.
Methods: We investigated the effects of gemcitabine in combination with the dual PI3k/mTOR inhibitor BEZ235 in four human pancreatic cancer cell lines (Panc-1, BxPC-3, MiaPaCa-2 and AsPC-1). The cells were analysed with MTT assay for cell viability, FACS-analysis for cell cycle distribution. Real-time RT-PCR and Western blot for survivin/BIRC5, STAT3, BCl-xL and WNT16 mRNA and protein expression and γH2AX.
Results: Application of NVP-BEZ235 or gemcitabine inhibited cell viability of AsPC-1 and BxPC-3 cells while Panc-1 and MiaPaCa-2 remained nearly unaffected. Combined treatment of gemcitabine and BEZ235, however, enhanced the inhibitory effect on cell viability of Panc-1 and MiaPaCa-2 cells of about 80% compared to control cells. This effect was boosted by time-delayed application of the two compounds. The biggest impact on cell growth, viability and downstream gene regulations were achieved by a sequential incubation with gemcitabine followed by BEZ235 24 hours later.
Conclusions: Combining gemcitabine with dual PI3K/mTOR inhibitors like NVP-BEZ2235 improved the efficacy on growth inhibition in human pancreatic cell lines especially by sequential application of both agents.

Brain metastases are very uncommon in colorectal carcinoma. Only 2-3% of patients at time of diagnosis will have CNS involvement, and only 10% will develop brain lesions during the course of the disease. Patients with rectal carcinoma have brain involvement slightly more frequently than patients with colonic carcinoma; these metastasis are usually found concurrently with lung and/or liver metastasis. Factors associated with longer survival include age less than 65, a single CNS lesion, and the absence of bone metastasis or systemic disease. Our case demonstrates CNS involvement in a patient with known stage III adenocarcinoma of the rectum who presented with syncope and was found to have a brain mass on computed tomography (CT). Surgical management offers prolonged survival in brain metastasis of colorectal cancer. But tumor recurrence following surgery has been as high as 46%. Whole-brain radiotherapy (WBRT) improves outcome and remains the standard therapy. However, delivering this treatment over two weeks period can delay other therapy and is associated with acute and long-term toxicities. Stereotactic radiosurgery is associated with tumor control rates of 73-94% and less morbidity than WBRT. Brachytherapy, intraoperative application of (125I), has high response and control rates, a shorter treatment courses, and minimal toxicity.

Background: Despite of the increasing knowledge and developing technology anastomotic leak (AL) is still a serious complication of colorectal surgery. The aim of this study was to evaluate the management and outcomes of AL after colorectal surgery.
Methods: The study included all patients diagnosed with AL after colorectal surgical procedures between January 2005 and December 2009. Patient demographics, diagnoses, AL management protocols, and outcomes were reviewed. Since the highest AL rate was detected for right hemicolectomy, two groups were identified based on the index surgery in order to determine the differences between the patients: right hemicolectomy and other procedures.
Results: In total, 28 of 550 (5.1%) patients that underwent colorectal surgical procedures were diagnosed with AL. There were 24 males with a median age of 61 (35- 93) years. Right hemicolectomy was associated with the highest procedure-specific AL rate (10.44%). In the right hemicolectomy group, patients had higher ASA scores, underwent more frequent emergency procedures, and majority of them were operated by residents comparing to the other procedures group (p<0.05). Twenty-four patients required surgical intervention for AL, and 23 patients that underwent re-operation required a stoma; end colostomy was the most frequent procedure (50%). AL-specific morbidity rate was 57.1% whereas the mortality rate among the patients with AL was 25%.
Conclusion: AL after colorectal surgery is associated with high morbidity and mortality. Patients with high ASA score, emergency procedure, and inexperienced surgeon may be factors requiring extra attention in terms of high AL risk after right hemicolectomy comparing to the other colorectal procedures.

A number of recent studies indicate that many cancers express receptors for advanced glycation end products (RAGEs), and that stimulation of these receptors make these cancers more invasive and, in some cases, boosts their proliferation. In some of these cancers, autocrine production of protein agonists for RAGE (HMGB1, S1100A) promotes their spread; the typically aggressive growth of cancers in diabetics may reflect activation of RAGE by endogenously produced advanced glycation end products (AGEs). But RAGE can also be activated by dietary “glycotoxins” – compounds produced by Maillard reactions in highly heated foods that are structurally and functionally similar to AGEs produced in diabetics. In rodents, dietary glycotoxins promote oxidative stress and pathologies linked to oxidative stress, presumably via RAGE activation. These considerations suggest that low-glycotoxin diets may have potential for slowing the spread of certain cancers expressing RAGE, a proposition that can readily be tested in rodent tumor models. Guidelines for achieving such diets have been published; low-fat foods of plant origin are typically low in glycotoxins, and the glycotoxin content of animal products and fatty plant products can be minimized by cooking at low heat (e.g. boiling, steaming). It may also be feasible to suppress the downstream signaling of RAGE in cancers by inhibiting the activity of NADPH oxidase, which appears to be the chief source of the oxidative stress triggered by RAGE; a role for NADPH oxidase in the aggressive growth of many cancers has been established. By mimicking the physiological antioxidant role of free bilirubin, the phycocyanobilin richly supplied by spirulina has the potential to down-regulate NADPH oxidase activity, and thereby impede RAGE signaling.

Objective: Pre-clinical studies have shown that chronic systemic buffering may have a beneficial impact in cancer care. This is a Phase 0/I clinical trial to determine if a sodium bicarbonate dose concentration of 0.5 g/kg/day is feasible and well tolerated as measured by the proportion of subjects with first evidence of adherence failure. The secondary objective was to determine if the dose concentration of 0.5 g/kg/day sodium bicarbonate is safe for long term consumption (90 days) as measured by vital signs and basic metabolic blood panels (BMP).
Methods: Healthy volunteers were recruited to consume 2-3 times per day a total maximum dose of 0.5 g/kg/ day sodium bicarbonate. Volunteers were permitted to downward dose to find a tolerable dose they were willing to consume daily for 90 days. Volunteers returned to the clinic on day 10, 30, 60, and 90 to monitor vital signs, BMP, and urine pH. In between visits, the volunteers recorded their urine pH before and after sodium bicarbonate consumption. Volunteer journals and routine communication between clinical personnel and volunteers was maintained to monitor adherence and adverse events (AEs).
Results: The trial accrued 15 volunteers, 11 women and 4 men. The average age of volunteer was 55 years. The average daily dose was 0.17 ± 0.03 g/kg. Most adverse events were Grade 1. Two AEs were Grade 2. Most symptoms were gastrointestinal in nature. Two subjects withdrew from the study before the 90 day time point. One incidence of metabolic alkalosis occurred and was resolved by downward dose adjustment.
Conclusions: The study demonstrates that voluntary long-term consumption of sodium bicarbonate is feasible and safe, but the predicted upward tolerable dose was too high for healthy volunteers.

Epithelial to Mesenchymal Transition (EMT) is a central feature of embryonic development and is also a critical early event in cancer progression and metastasis. Our understanding of the complexity of the chromatin platform and the epigenetic mechanisms that contribute to transcriptional control has expanded dramatically in recent years. These mechanisms include the presence/absence of histone modifications, which form epigenetic signatures that mark active or inactive genes. These signatures are dynamically added or removed by a wide variety of histonemodifying epigenetic enzymes, which more recently have been found to include chromatin-associated signalling kinases. Here, we discuss the multi-layered regulation of gene transcription during EMT in cancer. Given that epigenetics-based therapeutics are showing promise for the treatment of cancer, unravelling the detail of these epigenetic signatures during EMT is crucial to the development of novel therapeutic strategies that exploit these mechanisms.