[The prognostic value of uveal melanoma cell type]. / Prognosticheskoe znachenie kletochnogo tipa uveal'noi melanomy.

OBJECTIVE: To determine the prognostic value of a uveal melanoma (UM) cell type for the development of metastases (MTS). SUBJECTS AND METHODS: The investigation enrolled 96 patients (96 eyes) with UM after enucleation. Forty-one patients without signs of MTS were included in this group, who were followed up for more than 36 months (mean, 70.5 months (36 to 105 months)), 55 patients with MTS who were followed up for an average of 21 months (2 to 44 months). The MTS and non-MTS groups were statistically homogeneous in age, gender, tumor size, location, and ciliary body involvement in the process, as well as in extrabulbar growth. RESULTS: There were spindle cell, mixed cell, and epithelioid cell UMs in 44, 35, and 21% of patents, respectively. The tumors in patients without MTS were noted to be significantly more likely to have spindle cell-type UM (p<0.0001). Mixed cell and epithelioid cell UMs were more frequently detected in patients with MTS (p<0.0001), which was believed to be due to the presence of epithelioid cells in both cell types. A survival analysis showed that the 3- and 5-year survival rates for patients with spindle cell UM were significantly higher than that for those with epithelioid cell or mixed cell UM (p<0.001); the 3-and 5-year survival rates for spindle cell UM were 78 and 70%, respectively; those for mixed cell UM were 37 and 24%; and those for epithelioid cell UM were 50 and 31%. CONCLUSION: The similar survival rates for patients with mixed cell or epithelioid cell type UM could conclude that it is advisable to use the binary principle - the presence or absence of epithelioid cells in the tumor, when assessing a UM cell type as a prognostic factor.

[Transcription Factor SAP30 Is Involved in the Activation of NETO2 Gene Expression in Clear Cell Renal Cell Carcinoma].

Clear cell renal cell carcinoma (ccRCC) is a common oncourological disease with a high mortality level. The incidence of this type of cancer is constantly increasing, while molecular mechanisms involved in the disease initiation and progression remain far from being fully understood. A problem of the search for novel markers is crucial for improvement of diagnosis and therapy of ccRCC. We have previously found that the disease is characterized by increased expression of the NETO2 gene. In the present study, we showed that isoform 1 (NM_018092.4) makes the main contribution to the upregulation of this gene. Using original CrossHub software, "The Cancer Genome Atlas" (TCGA) project data were analyzed to identify possible mechanisms of NETO2 gene activation in ccRCC. The absence of significant contribution of methylation to the increase of mRNA level of the gene was observed. At the same time, a number of genes encoding transcription factors, which could potentially regulate the expression of NETO2 in ccRCC, were identified. Three such genes (MYCBP, JMY, and SAP30) were selected for the further analysis of their mRNA levels in a set of ccRCC samples with quantitative PCR. We showed a significant increase in mRNA level of one of the examined genes, SAP30, and revealed its positive correlation with NETO2 gene expression. Thus, upregulation of NETO2 gene is first stipulated by the isoform 1 (NM_018092.4), and the probable mechanism of its activation is associated with the increased expression of SAP30 transcription factor.

[Suppression of NR0B2 gene in Clear Cell Renal Cell Carcinoma Is Associated with Hypermethylation of Its Promoter].

Clear cell renal cell carcinoma (ccRCC) is a common urologic malignancy. Understanding of the transcriptional regulation of oncogenes and tumor suppressor genes involved is critical for the development of the treatments for renal tumors. Using ccRCC subdivision of the TCGA dataset, we identified NR0B2 encoding orphan nuclear receptor as a tumor suppressor candidate in renal tissue. In independent cohort of primary renal tumors, quantitative PCR experiments confirmed significant suppression of NR0B2 mRNA in 86% of ccRCC samples studied. In 80% of these cases, we detected the hypermethylation of the NR0B2 pro-moter region. These results suggest that NR0B2 is a tumor suppressor gene in ccRCC, and that the hypermethylation of promoter region is the main mechanism of its downregulation.

NON-INVASIVE MONITORING OF EGFR MUTATIONS IN NONSMALL CELL LUNG CANCER (NSCLC) DURING TARGETED THERAPY: STATE OF THE ART AND OUR EXPERIENCE.

Liquid biopsy is a promising approach to molecular tumor testing in the context of targeted therapy. During this pilot study we applied a high-sensitivity protocol for detection of tumor-derived mutations in circulating plasma DNA of EGFR-positive non-small cell lung cancer (NSCLC) patients during EGFR-TKI therapy. We showed that this protocol was well suited for dynamic monitoring during targeted therapy as well as for detection of acquired resistance mutations.

[Evaluation of Gene Expression of Hexokinases in Colorectal Cancer with the Use of Bioinformatics Methods].

One of the hallmarks of cancer is the change of energy metabolism, mainly activation of glycolysis that occurs even at early stages of tumorigenesis. The glycolysis activation can be caused by overexpression of hexokinases, primarily HK1 and HK2. Colorectal cancer, which takes the third place in the cancer morbidity and mortality rates worldwide, is believed to be accompanied with overexpression of HK2, which is .considered a marker of poor prognosis. With the use of the developed CrossHub tool, we performed the analysis of the Cancer Genome Atlas RNA-Sequencing data, which, on the contrary, revealed the prevalence of the down-regulation of HK2 gene and only slight expression alterations in HK1 gene. The Cancer Genome Atlas is the largest resource in the field of molecular oncology that accumulated genomic, transcriptomic and methylomic data for thousands of sample of more than 20 cancers. The transcriptome analysis data for colorectal cancer (283 tumor samples and 41 matched normal samples) were in accord with the results of further qPCR expression level evaluation. Up-regulation of HK1 and HK2 genes was observed only in a part of samples: 12% for HK1 and 30% for HK2. At the same time, the HK2 mRNA level decrease was shown in 50% of cases. Correlation analysis revealed the consistency in HK1 and HK2 expression alterations (Spearman's rank correlation coefficient r(s) = 0.43, p < 0.01), that could be explained by common deregulation mechanisms of these genes in colorectal tumors. The HK3 expression level was significantly increased in 60% of samples. Most likely, just hexokinase 3 contributes significantly to the activation of glycolysis in colorectal cancer.

Intratumoral immunoglobulin isotypes predict survival in lung adenocarcinoma subtypes.

BACKGROUND: The role of tumor-infiltrating B-cells (TIBs) and intratumorally-produced antibodies in cancer-immunity interactions essentially remains terra incognita. In particular, it remains unexplored how driver mutations could be associated with distinct TIBs signatures and their role in tumor microenvironment. METHODS: Here we analyzed associations of immunoglobulin isotypes and clonality with survival in TCGA RNA-Seq data for lung adenocarcinoma (LUAD), stratifying patients into 12 driver mutation and phenotypic tumor subgroups. RESULTS: We revealed several unexpected associations between TIBs behavior and prognosis. Abundance and high proportion of IgG1 isotype, and low proportion of IgA among all intratumorally produced immunoglobulins were specifically associated with improved overall survival for KRASmut but not KRASwt LUAD, revealing the first link between a driver mutation and B-cell response. We found specific IgG1 signature associated with long survival, which suggests that particular specificities of IgG1+ TIBs could be beneficial in KRASmut LUAD. In contrast to our previous observations for melanoma, highly clonal IgG1 production by plasma cells had no meaningful effect on prognosis, suggesting that IgG1+ TIBs may exert a beneficial effect in KRASmut cases in an alternative way, such as efficient presentation of cognate antigens or direct B cell attack on tumor cells. Notably, a high proportion of the IgG1 isotype is positively correlated with the non-silent mutation burden both in the general LUAD cohort and in most patient subgroups, supporting a role for IgG1+ TIBs in antigen presentation. Complementing the recent finding that the presence of stromal IgG4-producing cells is associated with a favorable prognosis for patients with stage I squamous cell carcinoma, we show that the abundance of IgG4-producing TIBs likewise has a strong positive effect on overall survival in STK11mut and proximal proliferative subgroups of LUAD patients. We hypothesize that the positive role of IgG4 antibodies in some of the lung cancer subtypes could be associated with reported inability of IgG4 isotype to form immune complexes, thus preventing immunosuppression via activation of the myeloid-derived suppressor cell (MDSC) phenotype. CONCLUSIONS: We discover prominent and distinct associations between TIBs antibody isotypes and survival in lung adenocarcinoma carrying specific driver mutations. These findings indicate that particular types of tumor-immunity relations could be beneficial in particular driver mutation context, which should be taken into account in developing strategies of cancer immunotherapy and combination therapies. Specificity of protective B cell populations in specific cancer subgroups could become a clue to efficient targeted immunotherapies for appropriate cohorts of patients.

Current cannabis use and tardive dyskinesia.

The aim of this study was to examine the relationship between substance abuse and tardive dyskinesia (TD) in 51 chronic, neuroleptic-treated, community outpatients with a DSM-III-R diagnosis of schizophrenia. In the presence of a clinical researcher, subjects completed a questionnaire on past and current alcohol and drug use, and provided information pertaining to variables which have, in the past, been implicated in the development of TD: smoking habits, caffeine consumption, and current neuroleptic dose. Subjects were also administered the Abnormal Involuntary Movement Scale (AIMS) in an interview format with either two or three trained raters present in the room. Consistent with previous reports, our results indicated a trend for females and older patients with a longer duration of illness to show elevated scores on the AIMS. In a hierarchical multiple regression analysis, however, cannabis use was found to correlate best with the presence of TD, out-ranking other putative factors.

Ultrasound microneurosurgery.

This work focuses on the use of an ultrasound neurosurgical unit which includes frequency generator and acoustic converter with different types of surgical attachments according to the surgical peculiarity. These attachments were designed to be used for ultrasonic resection, ultrasonic aspiration, ultrasonic disintegration and other applications. High cutting ability, possibility of local disintegration, specific hemostatic effects and other benefits of ultrasonic surgical tools (in the experimental level) were behind the efforts to create the ultrasound microneurosurgical unit with different attachments of cutting, disintegration, aspiration and separation tools. We used the ultrasound microneurosurgical unit during 299 operations involving meningiomas; acoustic neurinomas; gliomas; hordomas; pituitary adenomas; craniopharyngiomas; tuberculoma; paroxysmal pain in the patients with brachial plexus injuries, facial pain, phantom limb pain, intercostal neuralgia, post-mastectomy syndrome, syringomyelia and tumors of nerve trunks. The experience of using the surgical instruments based on ultrasound oscillation of the working edge showed their high efficiency and good perspective in experimental research as well as in practical application in different ramifications of surgery.

Failure of early postnatal dexamethasone to prevent chronic lung disease in infants with respiratory distress syndrome.

OBJECTIVE: To study the effect of early postnatal dexamethasone (days 1-3) on the incidence and severity of chronic lung disease in preterm infants with respiratory distress syndrome. METHODS: A multicentre, randomised, placebo controlled, blinded study was carried out in 18 neonatal intensive care units in Israel. The primary outcome measure was survival to discharge without requirement for supplemental oxygen therapy beyond 28 days of life. The secondary outcome measures were requirement for mechanical ventilation at 3 and 7 days, duration of ventilation or oxygen therapy, need for subsequent steroids for established chronic lung disease and incidence of major morbidities. RESULTS: The study consisted of 248 infants (dexamethasone n = 132; placebo n = 116). No differences were found in the outcome variables except for a reduction in requirement for mechanical ventilation at age 3 days in treated infants (dexamethasone 44%, placebo 67%; P = 0.001). Gastrointestinal haemorrhage, hypertension, and hyperglycaemia were more common in treated infants, but no life threatening complications, such as gastrointestinal perforation, were encountered. CONCLUSIONS: These data do no support the routine use of early postnatal steroids, but may justify further study in a selected, high risk group of infants.

Brain stem auditory evoked potentials: reduction of evaluation errors.

The commonly used method of BAER evaluation is measuring the latency to the extreme points of the components. Because of the influence of noise it is sometimes impossible to determine precisely the true top of the peak. It is possible to avoid this defect by estimating the latency to the middle of the peak front. In this research S.D.s for both methods of evaluation were calculated for all interpeak intervals. According to the obtained data the use of the middle of the front of the peak for the latency evaluation gave 24% reduction in S.D.s.

Cognitive therapy for bipolar depression: a pilot study.

OBJECTIVE: While the efficacy of cognitive-behaviour therapy (CBT) for the treatment of acute unipolar major depression is well-documented, there is almost no data evaluating its utility in the treatment of bipolar depression. This pilot study compares the efficacy of CBT combined with mood-stabilizer pharmacotherapy for bipolar depression and CBT alone for unipolar depression. METHOD: A matched-case control design was used to evaluate outcomes following 20 sessions of CBT in 11 depressed bipolar patients and 11 matched recurrent unipolar depressed control subjects. RESULTS: Bipolar depressed patients achieved similar levels of reduction in depressive symptoms following CBT, as did the unipolar depressed group. However, on measures of more pervasive dysfunctional attitudes, bipolar patients did not improve to the same degree. CONCLUSIONS: Preliminary findings suggest that CBT warrants further investigation as an effective psychosocial intervention for depression in bipolar patients already receiving ongoing mood-stabilizing pharmacotherapy.

Congenital disseminated neurofibromatosis: a "benign" diagnosis with malignant prognosis.

A neonate with congenital disseminated neurofibromatosis involving skin, subcutaneous tissues retropharyngeal, retroperitoneal and urinary bladder is presented. The massive presentation precluded radical surgical approach. This seems to be the first report of congenital widely disseminated neonatal neurofibromatosis in the English literature.

Cryohemostasis of uncontrolled hemorrhage from liver injury.

Uncontrolled hemorrhage is the primary cause of death in both blunt and penetrating liver trauma. Cryohemostasis was attempted in the past for elective liver surgery but did not gain popularity. During past decades, cryoequipment was refined and successfully used for tumor ablation. The purpose of the present study was to assess the efficacy of cryosurgery as a potential adjuvant hemostatic technique in the treatment of grades III-IV liver injuries. A standard liver crush-evulsion injury was created in pigs. In the control group, the liver was left to bleed freely. In the experimental group, the severed liver surface was immediately frozen to -160 degrees C for 10 min, spontaneously thawed, and left to bleed thereafter. Blood pressure, pulse rate, urine output, and serum lactate were monitored. The total blood loss was measured 180 min after liver injury was inflicted. The volume of frozen liver parenchyma was measured. For further laboratory evaluation, three additional experimental animals were not sacrificed and recovered. Cryohemostasis significantly reduced blood loss and substantially attenuated hemorrhagic shock. The frozen liver parenchyma underwent necrosis but did not jeopardize survival. Cryosurgery may be an efficient adjuvant technique in the early control of hemorrhage in grades III-IV liver injury.

Are dependency and self-criticism risk factors for major depressive disorder?

OBJECTIVE: To determine whether dependent and self-critical personality traits are associated with specific types of life events and whether these traits change with pharmacotherapy. METHOD: Overall, 142 depressed outpatients completing 8 weeks of fluoxetine treatment were administered the Life Experiences Survey (LES) at baseline and the Dysfunctional Attitude Scale (DAS) and Hamilton Depression Rating Scale (HDRS) at baseline and endpoint. RESULTS: The DAS dependency subscale, but not the self-criticism subscale, showed significant correlations with life events regardless of congruency. Baseline HDRS scores were positively correlated with both DAS subscales and total score. The DAS subscales, the total DAS score, and the HDRS all improved significantly with treatment. CONCLUSIONS: These results confirm a growing body of research that has found an association between sociotropic or dependent personality traits and life events.

A randomized trial comparing wireless capsule endoscopy with push enteroscopy for the detection of small-bowel lesions.

BACKGROUND & AIMS: Wireless capsule endoscopy is a new, painless method of imaging the entire small bowel. It has not been compared with push enteroscopy. We compared the sensitivity, specificity, and safety of capsule and push enteroscopy in detecting small-bowel lesions. METHODS: Nine to 13 radiopaque, colored beads (3-6 mm diameter) were sewn in random order inside 9 canine small bowels, half within the first meter, and confirmed on x-ray. After recovery, the number, order, and color of beads were assessed in 23 capsule enteroscopies and 9 push enteroscopies in a random order. The surgeons, push enteroscopists, capsule video interpreters, and pathologist were blinded to the others' findings. RESULTS: The capsules identified more beads than push enteroscopy (median, 6 [range, 2-9] vs. 3 [range, 2-6 beads]; P < 0.001). The sensitivity of the capsule was 64% compared with 37% for push enteroscopy. The specificity was 92% for capsule enteroscopy and 97% for push enteroscopy. The capsules identified significantly more beads beyond the reach of the push enteroscope (median, 4 [range, 2-7] vs. 0; P < 0.0001). Hair, ingested plastic, ulceration, submucosal swelling, and worms were clearly identified by the capsule. The capsules passed safely through the animals with no significant histologic findings. CONCLUSIONS: Wireless capsule endoscopy detected more abnormalities in the small bowel than push enteroscopy.