Overall survival by clinical risk category for high dose interleukin-2 (HD IL-2) treated patients with metastatic renal cell cancer (mRCC): data from the PROCLAIMSM registry.

BACKGROUND: Prognostic scoring systems are used to estimate the risk of mortality from metastatic renal cell carcinoma (mRCC). Outcomes from different therapies may vary within each risk group. These survival algorithms have been applied to assess outcomes in patients receiving T-cell checkpoint inhibitory immunotherapy and tyrosine kinase inhibitor therapy, but have not been applied extensively to patients receiving high dose interleukin-2 (HD IL-2) immunotherapy. METHODS: Survival of 810 mRCC patients treated from 2006 to 2017 with high dose IL-2 (aldesleukin) and enrolled in the PROCLAIMSM registry data base was assessed utilizing the International Metastatic RCC Database Consortium (IMDC) risk criteria. Median follow-up is 23.4 months (mo.) (range 0.2-124 mo.). Subgroup evaluations were performed by separating patients by prior or no prior therapy, IL-2 alone, or therapy subsequent to IL-2. Some patients were in two groups. We will focus on the 356 patients who received IL-2 alone, and evaluate outcome by risk factor categories. RESULTS: Among the 810 patients, 721 were treatment-naïve (89%) and 59% were intermediate risk. Overall, of the 249 patients with favorable risk, the median overall survival (OS) is 63.3 mo. and the 2-year OS is 77.6%. Of 480 patients with intermediate risk, median OS is 42.4 mo., 2-year OS 68.2%, and of 81 patients with poor risk, median OS 14 mo., 2-year OS 40.4%. Among those who received IL-2 alone (356 patients), median OS is 64.5, 57.6, and 14 months for favorable, intermediate and poor risk categories respectively. Two year survival among those treated only with HD IL-2 is 73.4, 63.7 and 39.8%, for favorable, intermediate and poor risk categories respectively. CONCLUSIONS: Among mRCC patients treated with HD IL-2, all risk groups have median and 2-year survival consistent with recent reports of checkpoint or targeted therapies for mRCC. Favorable and intermediate risk (by IMDC) patients treated with HD IL-2 have longer OS compared with poor risk patients, with most durable OS observed in favorable risk patients. Favorable risk patients treated with HD IL-2 alone have a 2-year OS of 74%. These data continue to support a recommendation for HD IL-2 for patients with mRCC who meet eligibility criteria. TRIAL REGISTRATION: PROCLAIM, NCT01415167 was registered with ClinicalTrials.gov on August 11, 2011, and initiated for retrospective data collection until 2006, and prospective data collection ongoing since 2011.

LAPAROSCOPIC ADJUSTABLE GASTRIC BANDING. ILLUSIONS AND REALITY.

This work analyzed the results of surgical treatment of 380 patients who underwent the laparoscopic adjustable gastric banding (LAGB) at the period from 2004 to 2015. The patients were initially divided into 2 groups with metabolic syndrome (MS) and without MS according to the sex, age (up to 40 years old or older). As the result of performed analysis, there was stated that LAGB operation wasn't effective and couldn't be recommended for an application on the patients with MS. The patients have to follow necessary advice for life. Otherwise, the probability of complication development and recurrent operation would be really high and because of this, the more effective surgical treatment should be initially used. LAGB operation didn't influence on pathogenetic mechanisms of main components of MS and couldn't be regarded as effective. This LAGB operation is reasonable to apply in women without MS of young age group with initial body mass index lower than 43 kg/m². These women have to be able strictly follow doctor's advice for life.

LAPOROSCOPIC SLEEVE GASTRECTOMY. ROLE AND PLACE IN BARIATRIC SURGERY.

Laparoscopic sleeve gastrectomy (LSG) was performed in 522 patients at the period from 2007 to 2015. The operation was carried out by different methods. It was stated that «the ideal candidates¼ for choosing LSG operation were the patients without metabolic syndrome (MS) and body-weight index, which wasn't higher than 48 kg/m². The operation could be performed on patients younger than 40 years old in order to correct disorders of insulinic and cholesterol metabolism. Patients with MS have limitations for LSG application, because of this reason, the operation is advisable for younger age group without severe accompanying pathology. The operation could be applied in older age group in order to stabilize general condition in case of high risks as the first (sometimes the last) stage of treatment for the patients whom more effective operation couldn't be recommended.

Axitinib dose titration: analyses of exposure, blood pressure and clinical response from a randomized phase II study in metastatic renal cell carcinoma.

BACKGROUND: In a randomized, double-blind phase II trial in patients with metastatic renal cell carcinoma (mRCC), axitinib versus placebo titration yielded a significantly higher objective response rate. We evaluated pharmacokinetic and blood pressure (BP) data from this study to elucidate relationships among axitinib exposure, BP change, and efficacy. PATIENTS AND METHODS: Patients received axitinib 5 mg twice daily during a lead-in period. Patients who met dose-titration criteria were randomized 1:1 to stepwise dose increases with axitinib or placebo. Patients ineligible for randomization continued without dose increases. Serial 6-h and sparse pharmacokinetic sampling were carried out; BP was measured at clinic visits and at home in all patients, and by 24-h ambulatory BP monitoring (ABPM) in a subset of patients. RESULTS: Area under the plasma concentration-time curve from 0 to 24 h throughout the course of treatment (AUCstudy) was higher in patients with complete or partial responses than those with stable or progressive disease in the axitinib-titration arm, but comparable between these groups in the placebo-titration and nonrandomized arms. In the overall population, AUCstudy and efficacy outcomes were not strongly correlated. Mean BP across the population was similar when measured in clinic, at home, or by 24-h ABPM. Weak correlations were observed between axitinib steady-state exposure and diastolic BP. When grouped by change in diastolic BP from baseline, patients in the ≥10 and ≥15 mmHg groups had longer progression-free survival. CONCLUSIONS: Optimal axitinib exposure may differ among patients with mRCC. Pharmacokinetic or BP measurements cannot be used exclusively to guide axitinib dosing. Individualization of treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors, including axitinib, is thus more complex than anticipated and cannot be limited to a single clinical factor.

[IMMUNE RESPONSE IN PATIENTS WITH COLORECTAL CANCER IN POSTOPERATIVE PERIOD].

It was shown by the authors that changes of the level of cytokines reflected the degree of invasiveness of operative intervention. The endovideosurgical approach was less traumatic and provided a rapid rehabilitation of the patients in postoperative period. It is possible to consider the high levels of IL-10 as a predictor of development of local inflammatory process and as an indicator of probable infectious complications in postoperative period.

[ASSESSMENT OF EFFICACY OF MELATONIN IN SURGICAL TREATMENT OF COLON TUMORS].

Melatonin is neurohormone, which is involved in regulation of many functions of an organism, including the digestive system. Therefore the authors offered to include this hormone as a preconditioner factor in surgical treatment of colon tumors using laparotomy and laparoscopy. Preoperative application of melatonin allowed shortening the terms of postoperative period and hospital stay.

[Prevention for gastroesophageal reflux disease after gastric restriction interventions].

The article analyzed the results of surgery using tree gastric restriction laparoscopic operations which led to high possibility of the development of gastroesophageal reflux disease (GERD). Laparoscopic stomach length resection was performed in 327 (68.1%) out of 480 (62.1%) patients. Laparoscopic gastric bypass surgery took place in 142 (29.5%) cases and laparoscopic biliary-pancreatic bypass surgery--in 11 (2.3%). The diagnosis of GERD was established in 193 (40.2%) patients before the operation and it was usually accompanied by hernia of the esophageal opening (HEO). The patients were arranged in 4 groups. The first group had operations using the standard method and it included 287 (59.8%) patients without any signs of GERD or HEO. The patients of the second group (84 (17.5%) had signs of GERD and HEO and standard operations with a hernia removal and cruroraphy were carried out. The patients of the third group 109 (22.7%) had initial signs of GERD and the standard method was used for them. The developed method was applied for patients of the fourth group (132 (27.5%). All the operations were completed by antireflux valve formation, but in the cases of GERD and HEO presence, they accomplished by hernia removal, cruroraphy. After performing standard operations, the signs of GERD were noted in 51.5% of cases. Thus, patients of the first group (148 (51.5%) had the signs of GERD. It was noted, that the signs of GERD were presented in patients of the second group (79 (94%) and it numbered 97 (89%) patients of the third group. In the case of the fourth group, signs of GERD were in 14 (10.6%) patients.

[Surgical correction of dislipodemia in patients with obesity].

The results of surgical treatment of 139 patients with metabolic syndrome, obesity and dislipodemia were analyzed. Modern bariatric operations (4 types) were performed by using laparoscopic method. There were regulated bandages of the stomach (RBS), lengthwise gastric resections (LGR), biliopancreatic and stomach bypass surgeries (BBS, SBS). Results of five-year follow-up indicated that restrictive operations on the stomach (RBS, LGR) aimed to correct overweight and dislipodemia had some limitations to application in a varying degree. The RBS operation should be appropriate to use for women of the young age group, when an initial body-weight index wasn't more than 43 kg/m2. The LGR operation was effective for men of the young age group and women in case of moderately expressed dislipodemia and in case when the initial body-weight index didn't exceed more than 45 kg/m2. Combined bariatric operations (BBS, SBS) were most likely effective on body weight and dislipodemia.

Phase Ib study of tivozanib (AV-951) in combination with temsirolimus in patients with renal cell carcinoma.

BACKGROUND: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2 and -3, with a long half-life. Tivozanib has demonstrated clinical activity and acceptable tolerability in renal cell carcinoma (RCC). This phase Ib study determined the recommended phase II dose (RP2D) and evaluated the safety and clinical activity of tivozanib plus temsirolimus, a mammalian target of rapamycin inhibitor. PATIENTS AND METHODS: Patients with advanced RCC were administered open-label tivozanib 0.5, 1.0 or 1.5mg/d orally (3 weeks on/1 week off) and temsirolimus 15 or 25 mg/week intravenously in a 3+3 dose-escalation design and subsequent expansion cohort. RESULTS: Of 27 patients treated, 20 patients had received ≥ 1 prior VEGF-targeted therapy. No dose-limiting toxicities occurred; the RP2D was determined to be tivozanib 1.5mg/d plus temsirolimus 25mg/week. Combination of tivozanib plus temsirolimus demonstrated acceptable tolerability and suggested no synergistic toxicity. The most common grade ≤ 3 adverse events were fatigue and thrombocytopenia (15% each). One patient each required dose reduction of tivozanib or temsirolimus due to an adverse event. Confirmed partial responses and stable disease were achieved at 23% and 68%, respectively. Pharmacokinetic analyses may suggest lack of an interaction between tivozanib and temsirolimus. CONCLUSIONS: In this small phase Ib study, tivozanib and temsirolimus were safely combined at the fully recommended dose and schedule of both agents. The observed clinical activity and manageable toxicity profile of this combination warrant further exploration in patients with RCC.

[Metabolic surgery in treatment of diabetes mellitus of type II].

Nowadays, according to data of WHO, the diabetes mellitus was diagnosed in more than 280 million people. The diabetes mellitus type II had 90% patients. The applied methods of conservative therapy seldom lead to euglycemia condition of patients. Last years the treatment of diabetes mellitus was carried out by the method of different bariatic interventions. Good results was obtained, they should be analyzed and investigate. The results of treatment of 142 patients from 628 patients (with type II) were estimated. The patients were undergone by different bariatic interventions. Modern laparoscopic operations were performed on all the patients. Controlled bandage of stomach had 81 of patients. Gastric resection was performed in 28. Gastric bypass surgery was carried out in 22 of patients and biliopancreatic diversion - in 11. The improvement of control of leukemia level was obtained. Diabetes type II could be treated by surgical methods. The best results were obtained after combined operations, which potentially could present an alternative method of treatment of type II diabetes.

Investigating prostate cancer tumour-stroma interactions: clinical and biological insights from an evolutionary game.

BACKGROUND: Tumours are made up of a mixed population of different types of cells that include normal structures as well as ones associated with the malignancy, and there are multiple interactions between the malignant cells and the local microenvironment. These intercellular interactions, modulated by the microenvironment, effect tumour progression and represent a largely under-appreciated therapeutic target. We use observations of primary tumour biology from prostate cancer to extrapolate a mathematical model. Specifically, it has been observed that in prostate cancer three disparate cellular outcomes predominate: (i) the tumour remains well differentiated and clinically indolent--in this case the local stromal cells may act to restrain the growth of the cancer; (ii) early in its genesis the tumour acquires a highly malignant phenotype, growing rapidly and displacing the original stromal population (often referred to as small cell prostate cancer)--these less common aggressive tumours are relatively independent of the local microenvironment and (iii) the tumour co-opts the local stroma--taking on a classic stromagenic phenotype where interactions with the local microenvironment are critical to the cancer growth. METHODS: We present an evolutionary game theoretical construct that models the influence of tumour-stroma interactions in driving these outcomes. We consider three characteristic and distinct cellular populations: stromal cells, tumour cells that are self-reliant in terms of microenvironmental factors and tumour cells that depend on the environment for resources, but can also co-opt stroma. RESULTS: Using evolutionary game theory we explore a number of different scenarios that elucidate the impact of tumour-stromal interactions on the dynamics of prostate cancer growth and progression, and how different treatments in the metastatic setting can affect different types of tumours. CONCLUSION: The tumour microenvironment has a crucial role in selecting the traits of the tumour cells that will determine prostate cancer progression. Equally important treatments like hormone therapy affect the selection of these cancer phenotypes making it very important to understand how they impact prostate cancer's somatic evolution.

[Surgical correction of damage in complex treatment of patients with metabolic syndrome].

The authors have analyzed results of treatment of 407 patients subjected to different bariatric interventions. In 359 out of them there were different bariatric operations, in 48 patients intragastric balloons were placed. Correcting plastic operations were fulfilled in 36 patients within 1-2 years after bariatric intervention. It was found that bariatric intervention fulfilled in earlier age groups would prevent the development of metabolic syndrome (MS) in patients with obesity at later date. Combined operations are most effective bariatric intervention compared with all main elements of MS. Correcting plastic operations are expedient after bariatric interventions against the background of stabilized decrease of body mass that allows getting valuable therapeutic and esthetic effect, improvement of quality of life of patients.

Vagal-dependent nonlinear variability in the respiratory pattern of anesthetized, spontaneously breathing rats.

Physiological rhythms, including respiration, exhibit endogenous variability associated with health, and deviations from this are associated with disease. Specific changes in the linear and nonlinear sources of breathing variability have not been investigated. In this study, we used information theory-based techniques, combined with surrogate data testing, to quantify and characterize the vagal-dependent nonlinear pattern variability in urethane-anesthetized, spontaneously breathing adult rats. Surrogate data sets preserved the amplitude distribution and linear correlations of the original data set, but nonlinear correlation structure in the data was removed. Differences in mutual information and sample entropy between original and surrogate data sets indicated the presence of deterministic nonlinear or stochastic non-Gaussian variability. With vagi intact (n = 11), the respiratory cycle exhibited significant nonlinear behavior in templates of points separated by time delays ranging from one sample to one cycle length. After vagotomy (n = 6), even though nonlinear variability was reduced significantly, nonlinear properties were still evident at various time delays. Nonlinear deterministic variability did not change further after subsequent bilateral microinjection of MK-801, an N-methyl-D-aspartate receptor antagonist, in the Kölliker-Fuse nuclei. Reversing the sequence (n = 5), blocking N-methyl-D-aspartate receptors bilaterally in the dorsolateral pons significantly decreased nonlinear variability in the respiratory pattern, even with the vagi intact, and subsequent vagotomy did not change nonlinear variability. Thus both vagal and dorsolateral pontine influences contribute to nonlinear respiratory pattern variability. Furthermore, breathing dynamics of the intact system are mutually dependent on vagal and pontine sources of nonlinear complexity. Understanding the structure and modulation of variability provides insight into disease effects on respiratory patterning.

[Sex- and age-specific characteristics of arterial hypertension prevalence in type 2 diabetes mellitus patients with obesity].

AIM: To investigate sex- and age-specific characteristics of arterial hypertension prevalence in type 2 diabetics with obesity. MATERIAL AND METHODS: Sex- and age-specific features of hypertension prevalence were studied in 6177 (1345 males and 4832 females) type 2 diabetic obese citizens of the Novgorod region. RESULTS: The highest incidence of mild hypertension was found in obesity degrees I and II (50-68%). Prevalence of moderate and severe hypertension reached 20-31 and 4-5%, respectively, in obesity of degree I and II, 15% in males and 11% in females in obesity degree III. CONCLUSION: In type 2 DM obese patients mild hypertension occurs most frequently. Severe hypertension develops often in males with obesity degree II and III in age groups 50-59 and 60-69 years, in females--in any obesity at the age of 70 and older.

The use of infliximab for treatment of hospitalized patients with acute severe ulcerative colitis.

BACKGROUND/AIM: The use of infliximab in severe ulcerative colitis (UC) is established; however, its role in severe acute UC requires clarification. The present multicentre case series evaluated infliximab in hospitalized patients with steroid-refractory severe UC. METHODS: Patients from six hospitals were retrospectively evaluated. Data collection included demographics, duration of disease and previous treatments. The primary end point was response to in-hospital infliximab; defined as discharge without colectomy. RESULTS: Twenty-one patients (median age 26 years) were admitted between May 2006 and May 2008 with severe UC requiring intravenous steroids and given infliximab (median time to infusion eight days). Sixteen (76%) patients were discharged home without colectomy; three of these underwent colectomy at a later date. Of the remaining 13 patients (62%), all but two did not require further courses of steroids; six patients had infliximab as a bridge to azathioprine and seven patients were maintained on regular infliximab. Five patients required in-hospital colectomy after the initial infliximab. CONCLUSIONS: In this real-life experience of infliximab in patients with steroid-refractory severe UC, infliximab appears to be a viable rescue therapy. The majority of patients were discharged without surgery and 62% maintained response either as a bridge to azathioprine or maintenance infliximab.

[Complications after the operation of laparoscopic adjustable gastric banding in treatment of patients with obesity].

Operations of laparoscopic adjustable gastric banding (LAGB) have been fulfilled on 2958 patients for treatment of different forms of obesity. The age of the patients was 38 +/- 7.5 years (from 16 to 60 years). There were 80% of women (2366) and 20% of men (592). Mean preoperative body mass index was from 35 to 54 kg/m2, i.e 43 +/- 3.8 kg/m2, fluctuating from 35 kg/m2 to 54 kg/m2. Bands of the following firms were used: Lap Band, Inamed, (USA), AMI Soft Band, Austria, Swedish Band J & J, USA. A description of complications in the early and late postoperative periods are given, associated with the dilatation of the formed "miniature ventricles, occlusion of intercommunication between the miniature ventricle and large ventricle with disturbed evacuation of the content, erosion of the gastric mucosa in the area of the band without its penetration, slippage of the band, complications associated with the regulation system etc. Recommendations were worked out for decreasing the number of complications. The data obtained suggest that LAGB is a highly effective method giving good results of treatment of patients with obesity and coexisting diseases. Most of the appearing complications can be eliminated laparoscopically.

[Laparoscopic adjustable gastric banding in treatment of patients with obesity].

Laparoscopic adjustable gastric banding (LAGB) has been fulfilled in 2958 patients in the period since 1998 through 2006 for treatment of different forms of obesity. The age of the patients was from 16 to 60 years (mean age 38 years). There were 80% of women (2366) and 20% of men (592). Mean preoperative body mass index was from 35 to 54 kg/m2, i.e 43+/-3.8 kg/m2, fluctuating from 35 kg/m2 to 54 kg/m2. The observation of 2485 (84%) patients operated in the terms in question showed the influence of LAGB on metabolic derangement, arterial pressure. Statistical data on possible early and late postoperative complications are presented. The operation of LAGB is one of minimally invasive methods for adjustable decreasing the excess body weight and its effectiveness exceeds other methods of restrictive interventions on the stomach, has a number of advantages compared with other bariatric interventions, it is relatively safe and completely reversible bariatric operation with all advantages of minimally invasive techniques.