Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial.

BACKGROUND: Nivolumab plus cabozantinib (NIVO + CABO) was approved for first-line treatment of advanced renal cell carcinoma (aRCC) based on superiority versus sunitinib (SUN) in the phase III CheckMate 9ER trial (18.1 months median survival follow-up per database lock date); efficacy benefit was maintained with an extended 32.9 months of median survival follow-up. We report updated efficacy and safety after 44.0 months of median survival follow-up in intent-to-treat (ITT) patients and additional subgroup analyses, including outcomes by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk score. PATIENTS AND METHODS: Patients with treatment-naïve aRCC received NIVO 240 mg every 2 weeks plus CABO 40 mg once daily or SUN 50 mg for 4 weeks (6-week cycles), until disease progression/unacceptable toxicity (maximum NIVO treatment, 2 years). Primary endpoint was progression-free survival (PFS) per blinded independent central review (BICR). Secondary endpoints were overall survival (OS), objective response rate (ORR) per BICR, and safety and tolerability. RESULTS: Overall, 323 patients were randomised to NIVO + CABO and 328 to SUN. Median PFS was improved with NIVO + CABO versus SUN [16.6 versus 8.4 months; hazard ratio (HR) 0.59; 95% confidence interval (CI) 0.49-0.71]; median OS favoured NIVO + CABO versus SUN (49.5 versus 35.5 months; HR 0.70; 95% CI 0.56-0.87). ORR (95% CI) was higher with NIVO + CABO versus SUN [56% (50% to 62%) versus 28% (23% to 33%)]; 13% versus 5% of patients achieved complete response, and median duration of response was 22.1 months versus 16.1 months, respectively. PFS and OS favoured NIVO + CABO over SUN across intermediate, poor and intermediate/poor IMDC risk subgroups; higher ORR and complete response rates were seen with NIVO + CABO versus SUN regardless of IMDC risk subgroup. Any-grade (grade ≥3) treatment-related adverse events occurred in 97% (67%) versus 93% (55%) of patients treated with NIVO + CABO versus SUN. CONCLUSIONS: After extended follow-up, NIVO + CABO maintained survival and response benefits; safety remained consistent with previous follow-ups. These results continue to support NIVO + CABO as a first-line treatment for aRCC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03141177.

Pharmacological Properties of Sulfonamide Derivatives, New Inhibitors of Carbonic Anhydrase.

Selective blocking of individual isoforms of carbonic anhydrase (CA) is now one of the main directions in the development of its inhibitors. The new 1,2,4-oxadiazole-containing sulfonamides B12 and B13 predominantly block CA II and CA IX. The study of acute toxicity of B12 and B13 showed their safety. Substance B13 caused a relatively short-term, but rapid (within 30 min) decrease in the intraocular pressure in rabbits, which indicates the promise of its use for the emergency decrease in the intraocular pressure in medical practice. Analysis of the effects of sulfonamides on the functions of CNS showed that compound B12 probably exhibit tranquilizing activity; B13 is promising for the creation of drugs that have an antidepressant effect and at the same time increase the mental and physical performance.

Tight focusing of electromagnetic fields by large-aperture mirrors.

We derive nonparaxial input conditions for simulations of tightly focused electromagnetic fields by means of unidirectional nonparaxial vectorial propagation equations. The derivation is based on the geometrical optics transfer of the incident electric field from significantly curved reflecting surfaces such as parabolic and conical mirrors to the input plane, with consideration of the finite thickness of the focusing element and large convergence angles, making the propagation vectorial and nonparaxial. We have benchmarked numerical solutions of propagation equations initiated with the nonparaxial input conditions against the solutions of Maxwell equations obtained by vectorial diffraction integrals. Both transverse and longitudinal components of the electric field obtained by these methods are in excellent agreement.

[Endoscopic surgery for benign diseases and injuries of the esophagus (with commentary)]. / Endokhirurgiya dobrokachestvennykh zabolevanii i povrezhdenii pishchevoda (s kommentariem).

AIM: To analyze the results of surgical treatment of patients with benign diseases and injuries of the esophagus. MATERIAL AND METHODS: We summarized the experience of different endoscopic interventions in 159 patients with various benign diseases and perforation of the esophagus. Patients with achalasia (72 cases) underwent videolaparoscopic Geller's esophagomyotomy with anterior hemiesophagofundoplication by Dor. Video-assisted thoracoscopic extirpation of the esophagus with simultaneous or delayed esophagocolo/gastroplasty was performed in 56 patients with post-ambustial cicatricial stenosis of the esophagus. Patients with esophageal perforation (14 cases) underwent videolaparoscopic transhiatal mediastinal drainage. Esophageal leiomyoma has been excised through thoracoscopic (9 cases) or laparoscopic access (4 cases). Removal of esophageal diverticulum was made via VATS-access in 4 patients. RESULTS: Satisfactory early and remote results were achieved in all patients with achalasia. Mortality rate was 5.4% (3 out of 56 patients) and 14.3% (2 out of 14 patients) in groups of cicatricial esophageal stenosis and esophageal perforation respectively. Sutures failure after removal of the diverticulum and leiomyoma occurred in 2 and 1 patient respectively and has been successfully cured. CONCLUSION: Endoscopic technologies allow to perform successfully complex reconstructive interventions for dysphagia in patients with cicatricial esophageal stenosis and achalasia even at late stages, to remove benign tumors and diverticula of thoracic esophagus and provide adequate drainage of posterior mediastinum in case of esophageal perforation.

Accessing Extreme Spatiotemporal Localization of High-Power Laser Radiation through Transformation Optics and Scalar Wave Equations.

Although tightly focused intense ultrashort laser pulses are used in many applications from nano-processing to warm dense matter physics, their nonparaxial propagation implies the use of numerical simulations with vectorial wave equations or exact Maxwell solvers that have serious limitations and thus have hindered progress in this important field up to now. Here we present an elegant and robust solution that allows one to map the problem on one that can be addressed by simple scalar wave equations. The solution is based on a transformation optics approach and its validity is demonstrated in both the linear and the nonlinear regime. Our solution allows accessing challenging problems of extreme spatiotemporal localization of high power laser radiation that remain almost unexplored theoretically until now.

[Endosurgery of benign diseases and injuries of esophagus].

AIM: To analyze the results of endoscopic interventions for benign diseases and injuries of the esophagus. MATERIAL AND METHODS: 159 patients with benign diseases and perforation of the esophagus were operated. There were 72 (45.3%) cases of achalasia, 56 (35.2%) with post-ambustial stenosis of esophagus, 14 (8.8%) with esophageal perforation, 13 (8.2%) with leuomyoma of esophagus and 4 (2.5%) with diverticulum of thoracic esophagus. RESULTS AND DISCUSSION: In long-term period 56 patients with achalasia were followed-up after laparoscopic Heller cardiomyotomy with Dor fundoplication. Good results were observed in all cases. Three patients died in early postoperative period after thoracoscopic extirpation of esophagus with esophagoplasty via laparotomy at the stage of development of the technique. There were no deaths after thoracoscopic extirpation of esophagus with simultaneous laparoscopic gastroplasty. Postoperative period was significantly less after thoracoscopic extirpation of esophagus with simultaneous laparoscopic esophagogastroplasty using whole stomach compared with esophagogastroplasty and esophagocoloplasty via laparotomy. In long-term postoperative period different complications occurred in 17 cases. Two patients with esophageal perforation died after video-assisted laparotranshiatal drainage of posterior mediastinum. Scarring of esophageal defect was observed in others. Seam failure after esophageal leuomyoma removal was diagnosed in 2 patients that required video-assisted laparotranshiatal drainage of posterior mediastinum and Maydl jejunostomy. Seam failure in thoracic esophagus after thoracoscopic removal of diverticulum was observed in 1 case. The complication was cured by video-assisted laparotranshiatal drainage of posterior mediastinum.

[Terahertz radiation influence on stressed Drosophila life span].

Virgin fruit fly females and males were stressed by placement into a confined space without food for 3 hours. Part of stressed flies were subjected to terahertz irradiation (0.1-2.2 THz) during 30 min. Life span of individual flies was evaluated. Terahertz radiation had some positive influence on male survival during the stage of monotonic decrease in flies number and negative effect during the stage of relatively stable number of flies. The survival of irradiated females on the stage of sharp decline in the number of flies was higher than in stressed and control females. Authors propose that terahertz radiation has an indirect effect on gene expression and signaling pathways which control the survival and life span of Drosophila.

Biodistribution of rhenium cluster complex K4[Re6S8(CN)6] in the body of laboratory rats.

We studied the biodistribution of luminescent octahedral rhenium cluster complex K4[Re6S8(CN)6], a promising agent for photodynamic therapy. It was shown that rhenium complex [Re6S8(CN)6](4-)is mainly accumulated in the liver, the central organ of metabolism, and can be excreted by the kidneys. The cluster complex was also accumulated in the spleen in significant amount, which makes it a promising agent for creation of preparations for diagnostics and treatment of lymphoproliferative disorders. The mean lethal dose of the cluster complex was 0.38 g/kg.

[Survival and life span of Drosophila melanogaster in response to terahertz radiation].

Life span control is realized by an interaction of many genetic factors with environment. Due to development of new modern technologies based on non-ionized terahertz radiation (0,1-10 THz) the investigation of this radiation influence on living organisms becomes actual. In our study terahertz radiation effects on survival and life span of Oregon R line of Drosophila meanogaster were multidirectional depending on the age of the insects. Terahertz effect on survival was negative or neutral in the early life and positive in the later life. In Drosophila response to terahertz radiation sex differences were manifested. Males were not very sensitive to terahertz radiation. Irradiated female survival was increased significantly in the second half of imago life. Irradiation of Drosophila not influenced significantly on average and maximal values of life span, but the gap between the values of average life span of males and females in this group of insects was increased. Mechanisms of terahertz radiation effects on survival and life span maybe associated with changes in cellular membrane, gene expression and signaling pathways, controlling these properties.

[Treatment of patients with chronic pancreatitis complicated by pseudoaneurysms of the celiac trunk basin arteries].

The authors have analyzed results of treatment of 26 patients with chronic pancreatitis complicated by pseudoaneurysms. Hospitalization and treatment of such patients should be performed in specialized hospitals which can fulfill special examination in detail and carry out roentgen-endovascular operations. Intraintestinal bleeding is an absolute indication for emergent surgery for performing hemostasis. Conservative treatment is indicated for intestinal bleedings and after arrest of bleeding the patients should be transported to specialized institutions. Two types of the appearance of pseudoaneurysms were established depending on the pathological mechanism: when there was a relationship of the pseudocyst with the main pancreatic duct (I type) and when there was not (II type). For the I type roentgen-endovascular treatment (RET) followed by operation is indicated, for the II type RET is thought to be enough.

[False arterial aneurysms of celiac trunk system in patients with chronic pancreatitis].

20 patients with chronic pancreatitis complicated by development of false aneurysms of arteries in celiac trunk system were observed. Diagnostics utilities included ultrasound study, contrasted computed tomography and angiography. Two types of aneurysms are distinguished: parencchymal and pseudocysts. Radioendovascular operation is the method of choice for aneurism treatment. Surgical treatment is carried out in case of aneurism rupture with voluminous bleeding or on necessity of elimination other complications of chronic pancreatitis (pseudocyst, pancreatic hypertension, wirsungolithiasis).

[Clinical course, diagnosis and treatment of cholelithic intestinal obstruction].

Forty-seven cases of intestinal obstruction due to gall-stones are analyzed. All the patients underwent surgery including enterolithotomy with two-layer intestinal closure (40), passage of stone into cecum (3), intestinal resection due to wall necrosis (3). Two patients died due to intestinal perforation with retroperitoneal phlegmon and multiple organ failure. It is concluded that clinical symptoms of cholelithic intestinal obstruction are wave-like. Intestinal X-ray and ultrasonic examinations are the most informative for final diagnosis.

[Reconstructive surgeries after extensive resections of anterior abdominal and chest walls for tumors].

Experience of reconstructive surgeries after extensive resections of anterior abdominal and chest walls performed on account of tumors is described. Recovery of integrity of anterior abdominal wall was performed by serial grafting with dura mater and polypropylene net implant. The thorax was repaired with special grafts of the ribs and sternum. The integrity of the skin was reestablished with either suturing of the separated flaps or transposition of myodermal flap on vascular pedicle.

Pancreatic head cancer: accuracy of CT in determination of resectability.

BACKGROUND: Pancreatic cancer is a devastating disease whose early detection remains difficult. There is no 100% reliable imaging test to diagnose and stage pancreatic cancer. We assessed the surgical value of contrast-enhanced spiral computed tomography (CT) in predicting the resectability and survival rates of patients who had pancreatic head cancer. METHODS: Eighty-nine patients who had pancreatic head cancer were investigated with spiral CT. Based on the preoperative CT results, we assigned patients to one of three CT groups based on resectability. RESULTS: A correlation between classification of CT resectability and intraoperative finding was found in 83% of patients. The sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of spiral CT in identifying predictive unresectability were 79%, 82%, 91%, 62%, and 81%, respectively. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of CT in diagnosis of vascular invasion were 94%, 84.2%, 94%, 84%, and 91.3%, respectively. CONCLUSION: The use of CT in the evaluation of pancreatic tumors provides valuable preoperative assessment of surgical resectability and should be performed for clinical examination. Classifying patients by tumor resectability on CT helps to estimate more precisely the tumor stage and to prognosticate survival rates of these patients.

[Radio-frequency ablation appliance in resection of the liver]. / Ispol'zovanie apparata radiochastotnoi ablatsii pri rezektsii pecheni.

Pilot experience with "Radionics Cool-Tip RF System" appliance for radio-frequency ablation (RFA) in hepatic resection in the patients with focal lesions of the liver is presented. Advantages of RFA as an alternative method for hemostasis are demonstrated. With this technique bisegmentectomy (II - III) was performed in 4 patients, right-sided hemihepatectomy - in 2 patients. RFA permitted to minimize intraoperative blood loss without increase of surgery time. There were no severe complications during surgery and in early postoperative period. The method permits to perform combined surgeries without a significant increase of surgical risk.