A phase Ib/II dose expansion study of subcutaneous sasanlimab in patients with locally advanced or metastatic non-small-cell lung cancer and urothelial carcinoma.

BACKGROUND: Sasanlimab is an antibody to the programmed cell death protein 1 receptor. We report updated data of subcutaneous sasanlimab in non-small-cell lung cancer (NSCLC) and urothelial carcinoma dose expansion cohorts from a first-in-human phase Ib/II study. PATIENTS AND METHODS: Patients were ≥18 years of age with NSCLC or urothelial carcinoma, and no prior immunotherapies, who progressed on or were intolerant to systemic therapy, or for whom systemic therapy was refused or unavailable. Patients received subcutaneous sasanlimab at 300 mg every 4 weeks (q4w). Primary objectives were to evaluate safety, tolerability, and clinical efficacy by objective response rate (ORR). RESULTS: Sixty-eight and 38 patients with NSCLC and urothelial carcinoma, respectively, received subcutaneous sasanlimab. Overall, sasanlimab was well tolerated; 13.2% of patients experienced grade ≥3 treatment-related adverse events. Confirmed ORR was 16.4% and 18.4% in the NSCLC and urothelial carcinoma cohorts, respectively. ORR was generally higher in patients with high programmed death-ligand 1 (PD-L1) expression (≥25%) and high tumor mutational burden (TMB; >75%). In the NSCLC and urothelial carcinoma cohorts, median progression-free survival (PFS) was 3.7 and 2.9 months, respectively; corresponding median overall survival (OS) was 14.7 and 10.9 months. Overall, longer median PFS and OS correlated with high PD-L1 expression and high TMB. Longer median PFS and OS were also associated with T-cell inflamed gene signature in the urothelial carcinoma cohort. CONCLUSIONS: Subcutaneous sasanlimab at 300 mg q4w was well tolerated with promising clinical efficacy observed. Phase II and III clinical trials of sasanlimab are ongoing to validate clinical benefit. Subcutaneous sasanlimab may be a potential treatment option for patients with NSCLC or urothelial carcinoma.

[Rigidity of psyche processes and factors predisposing to schizophrenia]. / Rigidnost' psikhicheskikh protsessov v sisteme faktorov predraspolozhennosti k shizofrenii.

To evaluate the rigidity of psychic processes (RPP) as a factor predisposing (vulnerability) to schizophrenia and to study interactions between RPP and other susceptibility factors, psychological characteristics and magnetic resonance tomography data have been studied in 26 families with schizophrenia. Correlation, cluster and regression analyses and trait phenotypic variance decomposing into genetic and environmental components for heritability estimation were used. RPP indices in patients with schizophrenia and their relatives differed significantly from those in the control group of healthy subjects without positive family history of schizophrenia. The RPP heritability was estimated as high (58%). In RPP patients, RPP clustered with parameters of attention, memory, dynamic and intellectual activity; in the siblings--with attention, dynamic and intellectual activity and the width of anterior horns of left and right lateral ventricules next to genum, in the parents--with motivation, attention, memory, dynamic and intellectual activity. In the siblings, heritability for parameters of frontal horn lateral ventricules was estimated as high (66%) for the right ventricles and moderate (30%) for the left ones. Both morphological parameters are among morphological predictors for prognosis of negative symptoms in the patients with schizophrenia. The authors regarded RPP as a factor predisposing to schizophrenia.

[The aged patient's first visit to the outpatient psychiatric clinic]. / Vpervye obrativshiesia v psikhonevrologicheskii dispanser bol'nye pozdnego vozrasta.

160 patients over 60 years of age appealed to gerontologic unit of out-patient psychiatric clinic for the first time. The patients were divided into two main groups: with organic mental disorders (OMD) and with functional mental disorders (FMD) (79 and 81 patients, respectively). In the group of OMD the main form of disturbances were cases with dementia (74.4%) mainly of the Alzheimer's type, and cerebral vascular dementia. In 25.3% of the patients the cognitive disturbances didn't attain the level of dementia. In a group of patients with different forms of dementia a high frequency of comorbid mental pathology was observed (83%)--confusional states, delusions, depressive conditions as well as disturbed behavior (67.7%) that was one of the reasons for consulting a psychiatrist. In FMD group the prevailing pathology were depressions, both of the major (37.1%) and mild (34.6%) forms. The remaining cases were characterized by delusions (10.1%), anxiety-phobic (7.6%) states and somatoform disturbances (5.1%). Among the patients both of OMD and FMD groups it was possible to diagnose approximately 3-4 different somatic diseases; vascular and gastrointestinal disorders were met more frequently. The study of contribution of brain computer tomography (CT) to diagnosis of mental pathology (according to ICD-10), has demonstrated that in 30.8% of the cases it was decisive, in 41% it confirmed the clinical data and in 21.8% CT provide additional data (detecting latent cerebral vascular damage). And only in 6.4% of the cases CT fails to give definite information in diagnostically complicated cases. In 26.6% of the patients with FMD, CT of brain had detected symptoms of mild vascular pathology.

[Genetic analysis of anatomical and morphologic traits of the brain, determined by magnetic resonance imaging in families of schizophrenic patients]. / Geneticheskii analiz anatomo-morfologicheskikh priznakov golovnogo mozga, vyiavliaemykh s pomoshch'iu magnito-rezonansnogo issledovaniia v se'miakh bol'nykh shizofreniei.

Genetic analysis of clinical data and data obtained by magnetic resonance imaging (MRI) on 26 families of schizophrenic patients (26 probands who were patients with schizophrenia, 47 parents, and 15 siblings) revealed an enlargement of the ventricular brain system both in probands and their affected and healthy relatives. Most MRI parameters had high coefficients of inheritance and tended to be linked with positive and negative psychopathological symptoms. Our results confirm the hypothesis of genetic predisposition to the structural changes in the brains of schizophrenic patients and suggest that such MRI characteristics as the width of the anterior horn of the left lateral ventricle in the region of the caudate nucleus, the width of the central region of the left lateral ventricle, the width of the anterior horn of the right lateral ventricle in the region of the caudate nucleus, and the width of the central region of the right lateral ventricle may serve as a marker of predisposition to schizophrenia.

[Measuring the bleomycin-induced paired damage of two DNA chains by a method of psoralen photocross-linking]. / Izmerenie indutsirovannykh bleomitsinom parnykh povrezhdenii dvukh tsepei DNK metodom fotosshivaniia psoralenom.

DNA of bacteriophage PM2 was allowed to react with bleomycin in the presence of Fe(II) and oxygen and the "paired" DNA lesions of two types were measured: (1) double-strand breaks, (2) lesions converted to double-strand breaks after introducing into the DNA a large number of psoralen cross-links (about 10(-2) per base pair) and alkali treatment. The mean numbers of each lesion type per DNA molecule are found to be proportional to the square of bleomycin concentration over the range of 3 X 10(-7) to 3 X 10(-6) M. These findings indicate that paired lesions are formed as a result of action of two bleomycin molecules at the same DNA site.

[Use of psoralen for detecting the conjugated damage to 2 chains in irradiated phage PM2 DNA]. / Ispol'zovanie psoralen dlia obnaruzheniia sopriazhennykh povrezhdenii dvukh tsepei v obluchennoi DNK faga PM2.

Using psoralen for the photochemical cross-linking of DNA chains the authors have demonstrated the formation of conjugated lesions, of both opposite and non-opposite types, in X-irradiated superhelical DNA of PM2 phage. It is suggested that these lesions result from hitting a DNA molecule by a spur.

[Increased DNA radiosensitivity as affected by reduced derivatives of nitroimidazole and nitrofuran]. / Uvelichenie radiochuvstvitel'nosti DNK pod deistviem vosstanav-livaiushchikhsia proizvodnykh nitroimidazola i nitrofurana.

It was shown that active radiosensitizers, nitroimidazole and nitrofuran, reduced chemically and enzymatically under anaerobic conditions in the presence of DNA, cause singlestrand breaks in the latter. When this modified DNA is exposed to ionizing radiation the yield of single-strand breaks increases as compared to control (unmodified) DNA.