Продукция белков L1 и NuMA1 вируса папилломы человека при цервикальной интраэпителиальной неоплазии

Relevance. Cervical cancer – one of malignant new growths most often met among women. Intraepithelial changes precede to it; these changes can disappear spontaneously or progress to cancer. For the present moment, there are no markers describing the outcome of cervical intraepithelial neoplasia.The objective was to research the expression L1 HPV and NuMA1 as factors of prognosis HPV-positive cervical intraepithelial neoplasias by high-risk human papillomavirus.Material and methods. The biopsies of 178 women from HPV-positive cervical neoplasias were studied by cytological, histological, immunocytochemical methods and PCR.Results. We verified HPV-HR-positive: mild (42.7 %), moderate (34.27 %), severe (21.91 %) dysplasias, Ca in situ (1.12 %). In 81.13 % of researches, CIN with expression of L1 and NuMA1 had regression of dysplasia, in 13.21 % – persistence of grade squamous intraepithelial lesion, in 5.66 % – progression of dysplasia. In 73.33 % of cases, CIN with expression of NuMA1 had regression, in 26.67 % – persistence of dysplasia. In 45.45 % of researches, CIN with expression of L1 had regression of dysplasia, in 48.48 % – persistence of grade squamous intraepithelial lesion, in 6.06 % – progression of dysplasia. Regression or progression of dysplasia with expression L1 and NuMA1 or one of these proteins for the first time was revealed later 6 months.Conclusion. CIN could come to the end with regression, persistence or progression. At expression of atypical cells L1 and NuMA1, the greatest quantity – 81.13 %, of cases of CIN regression was noted. At expression of atypical cells only NuMA1, CIN came to the end with regression or long persistence. Course of CIN with expression L1 HPV was characterized by the greatest parameters of persistence and progression marked, accordingly, in 48.48 and 6.06 % of cases.Введение. Рак шейки матки – одно из наиболее часто встречающихся среди женщин злокачественных новообразований. Ему предшествуют интраэпителиальные изменения, которые могут исчезать спонтанно или прогрессировать к раку. На настоящий момент нет маркеров, характеризующих исход цервикальных интраэпителиальных неоплазий. Цель исследования – изучение информативности белков L1 и NuMA1 в качестве маркеров прогноза цервикальных интраэпителиальных неоплазий, ассоциированных с вирусом папилломы человека (ВПЧ) высокого канцерогенного риска (ВКР).Материал и методы. Биоптаты шейки матки 178 женщин с цервикальными неоплазиями, ассоциированными с ВПЧ ВКР, исследованы цитологическим, гистологическим, иммуноцитохимическим методами и методом полимеразной цепной реакции.Результаты. Верифицированы ВПЧ ВКР-позитивные слабая (42,7 %), умеренная (34,27 %), тяжелая (21,91 %) формы дисплазии, Ca in situ (1,12 %). В 81,13 % исследований CIN с ядерной экспрессией L1 и NuMA1 отметили регресс дисплазии, в 13,21 % – сохранение степени тяжести поражения плоского эпителия, в 5,66 % – прогрессирование дисплазии. В 73,33 % наблюдений CIN с экспрессией только NuMA1 плоский эпителий восстановил типичное строение, в 26,67 % явления атипии были сохранены. В 45,45 % CIN с экспрессией только L1 отметили регресс клеточных поражений, в 48,48 % – персистенцию, в 6,06 % – прогрессирование неоплазии. Регресс или прогрессирование CIN с экспрессией L1 и NuMA1 или одного из этих белков впервые обнаружены спустя 6 месяцев после выявления клеточных изменений. Заключение. Интраэпителиальные неоплазии шейки матки могут завершаться регрессом, персистенцией или прогрессированием. При экспрессии атипичными клетками L1 и NuMA1 отмечено наибольшее число – 81,13 % – случаев регресса CIN. При экспрессии атипичными клетками только белка NuMA1 CIN завершились регрессом или длительной персистенцией. Течение CIN с экспрессией белка L1 характеризовалось наибольшими показателями персистенции и прогрессирования, отмечаемых, соответственно, в 48,48 и 6,06 % случаев

Качество жизни пациенток пожилого и старческого возраста с гормонозависимым раком молочной железы при использовании первичной гормонотерапии

Introduction. Elderly and senile patients are a special category of patients and standard methods in breast cancer treatment are not suitable due to the frequent presence of serious comorbidities and personal preferences and concerns about treatment options. Аn available treatment option for these patients with hormone-receptor positive breast cancer may be the primary endocrine therapy (PET).The objective was to assess the quality of life of patients treated by PET or surgical treatment with adjuvant endocrine therapy (ET) and identifying the reasons of choosing a conservative treatment strategy.Methods and materials. Our study included 65–89-year-old patients with hormone-receptor positive breast cancer with stages I–II, some of whom received only endocrine therapy (ET) (n=20), and others are prescribed adjuvant ET after surgical treatment (n=20). Quality of life was assessed by analyzing the EORTC QLQ C-30 and QLQ-BR23 questionnaires filled in by patients at different stages of treatment. An analysis of outpatient records was carried out to identify the reasons for choosing a conservative treatment strategy.Results. The choice of conservative treatment strategy was justified by the presence of a serious concomitant pathology in 65 % of cases. Performing breast surgery was associated with a decline in the quality of life in the postoperative period.Conclusions. PET is an alternative treatment option for some of the elderly patients with hormone-receptor positive breast cancer, since it has similar results in overall survival compared to standard complex treatment (surgery + adjuvant ET), but also does not make the quality of life worst during treatment.Введение. Пациентки пожилого и старческого возраста представляют собой особую категорию, для которых зачастую не подходит стандартное лечение рака молочной железы (РМЖ) ввиду наличия серьезной сопутствующей патологии, а также личных предпочтений и опасений относительно вариантов лечения. Для ряда таких пациенток с гормонозависимым РМЖ возможным вариантом лечения может быть первичная гормонотерапия (ПГТ).Цель – оценка качества жизни пациенток при различных видах лечения – ПГТ и стандартном комплексном лечении, а также определение причин выбора консервативного метода лечения.Методы и материалы. В исследование включены пациентки 65–89 лет с гормонозависимым РМЖ I–II стадии, часть из которых получают только гормонотерапию (ГТ) (n=20), а другим назначена адъювантная ГТ после хирургического лечения (n=20). Качество жизни оценивали путем анализа опросников EORTC QLQ C-30 и QLQ-BR23, заполненных пациентками на разных этапах лечения. Для выявления причин выбора консервативной тактики проводили анализ данных амбулаторных карт пациентов.Результаты. В 65 % случаев назначение консервативного лечения было обусловлено наличием серьезной сопутствующей патологии, а проведение хирургического вмешательства на молочной железе ассоциировалось с ухудшением качества жизни в послеоперационном периоде.Заключение. ПГТ является возможным вариантом лечения гормонозависимого РМЖ у пожилых пациенток, так как не только имеет сопоставимые показатели общей выживаемости в сравнении со стандартным комплексным лечением (операция + адъювантная ГТ), но и не ухудшает качество жизни

Long-term efficacy and safety of CT-P6 versus trastuzumab in patients with HER2-positive early breast cancer: final results from a randomized phase III trial

Purpose Equivalent efficacy was demonstrated for the biosimilar CT-P6 and trastuzumab following neoadjuvant therapy for patients with human epidermal growth factor receptor-2 (HER2)-positive early breast cancer. Following adjuvant treatment, efficacy and safety were comparable between treatments. We report updated safety and efficacy data after up to 3 years’ follow-up. Methods Following neoadjuvant chemotherapy with CT-P6/trastuzumab, patients underwent surgery and continued receiving adjuvant CT-P6/trastuzumab. The primary endpoint (previously reported) was pathological complete response. Time-to-event analyses (disease-free survival [DFS], progression-free survival [PFS], and overall survival [OS]), study drug-related and cardiac adverse events, and immunogenicity were assessed during post-treatment follow-up. Results Most patients entered the follow-up period (CT-P6: 259 [95.6%]; trastuzumab: 269 [96.8%]). After a median follow-up of 38.7 (CT-P6) and 39.6 (trastuzumab) months, medians were not reached for time-to-event parameters; estimated hazard ratios (HRs) and 3-year survival rates were similar between groups. Estimated HRs (95% confidence intervals) for CT-P6 versus trastuzumab were 1.23 (0.78–1.93) for DFS, 1.31 (0.86–2.01) for PFS, and 1.10 (0.57–2.13) for OS (intention-to-treat population). Safety findings were comparable between groups for the overall study and follow-up period, including study drug-related cardiac disorders (CT-P6: 22 [8.1%] patients; trastuzumab: 24 [8.6%] patients [overall]) and decreases in left ventricular ejection fraction. Immunogenicity was similar between groups. Conclusion The similarity of the time-to-event analyses between CT-P6 and trastuzumab supports the equivalence in terms of efficacy established for the primary endpoint. CT-P6 was well tolerated, with comparable safety and immunogenicity to trastuzumab. ClinicalTrials.gov: NCT02162667 (registered June 13, 2014

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Claudin 18.2 – a novel treatment target in the multicenter, randomized, phase II FAST study, a trial of epirubicin, oxaliplatin, and capecitabine (EOX) with or without the anti-CLDN18.2 antibody IMAB362 as 1st line therapy in advanced gastric and gastroesophageal junction (GEJ) cancer

Background: Claudin(CLDN)18.2 is a stomach specific tight junction protein. The chimeric monoclonal anti-CLDN18.2 antibody IMAB362 potently activates complement and antibody dependent cellular cytotoxicity. FAST investigated CLDN18.2 tumor expression and therapy with IMAB362 in combination with first line chemotherapy in pts with advanced gastric and GEJ cancer. Methods: Pts with advanced gastric and GEJ cancer were centrally evaluated for CLDN18.2 by immunohistochemistry (CLAUDETECT18.2® Kit). CLDN18.2 expression of ≥ 2+ in ≥ 40% tumor cells was defined positive. Eligible pts required CLDN18.2+ tumors, an ECOG PS of 0–1, and no medical need for trastuzumab treatment

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Final results of the FAST study, an international, multicenter, randomized, phase II trial of epirubicin, oxaliplatin, and capecitabine (EOX) with or without the anti-CLDN18.2 antibody IMAB362 as first-line therapy in patients with advanced CLDN18.2+ gastric and gastroesophageal junction (GEJ) adenocarcinoma

Background: IMAB362, a chimeric monoclonal antibody that mediates specific killing of cancer cells expressing the tight junction protein Claudin18.2 (CLDN18.2) by activation of immune effector mechanisms, has demonstrated single-agent activity and tolerability in patients ( pts) with heavily pretreated gastric cancer. Methods: Pts with advanced/recurrent gastric and GEJ cancer were centrally evaluated for CLDN18.2 expression by immunohistochemistry (CLAUDETECT® 18.2 Histology Kit). Eligible pts had a CLDN18.2 expression of ≥2+ in ≥40% tumor cells, an ECOG PS of 0–1 and were not eligible for trastuzumab. Pts were randomized 1:1 to first-line EOX (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 d1, and capecitabine 625 mg/m2 bid, d1–21; qd22) with or without IMAB362 (loading dose 800 mg/m2, then 600 mg/m2 d1, qd21). An exploratory arm (N = 85) was added to investigate a higher dose IMAB362 (1000 mg/m2) plus EOX. The primary study endpoint was PFS (Arm1 vs 2,70% power, hazard ratio [HR] 0.72, 1-sided p = 0.1). Here we present the final study results

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN