A polymorphism in a let-7 microRNA binding site of KRAS in women with endometriosis.

Endometriosis is found in 5-15% of women of reproductive age and is more frequent in relatives of women with the disease. Activation of KRAS results in de novo endometriosis in mice, however, activating KRAS mutations have not been identified in women. We screened 150 women with endometriosis for a polymorphism in a let-7 microRNA (miRNA) binding site in the 3'-UTR of KRAS and detected a KRAS variant allele in 31% of women with endometriosis as opposed to 5% of a large diverse control population. KRAS mRNA and protein expression were increased in cultured endometrial stromal cells of women with the KRAS variant. Increased KRAS protein was due to altered miRNA binding as demonstrated in reporter assays. Endometrial stromal cells from women with the KRAS variant showed increased proliferation and invasion. In a murine model, endometrial xenografts containing the KRAS variant demonstrated increased proliferation and decreased progesterone receptor levels. These findings suggest that an inherited polymorphism of a let-7 miRNA binding site in KRAS leads to abnormal endometrial growth and endometriosis. The LCS6 polymorphism is the first described genetic marker of endometriosis risk

Клиническое значение альтераций MET при НМРЛ и современные возможности лекарственной терапии

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality both in Russia and worldwide. At diagnosis, most patients have advanced disease when the use of local treatment modalities is limited and systemic chemotherapy fails to provide a pronounced and sustained benefit. The advent of targeted therapies has significantly changed the treatment paradigm of NSCLC. Genetic alterations representing potential molecular targets have been identified in up to 60 % of non-squamous NSCLC cases, and agents directed against 50 % oncogenic targets have been approved. Various activat ing mutations of the MET signaling pathway (gene amplifications and alterations) associated with unfavorable disease outcomes occur in 2–4 % of NSCLC patients. Recently, significant advances in the development of therapies targeting this signaling pathway have been made. The article provides an overview of the key studies evaluating novel therapeutic options for NSCLC with MET alterations.Немелкоклеточный рак легкого (НМРЛ) является ведущей причиной смерти от рака как в России, так и во всём мире. У большинства пациентов болезнь выявляется на поздней стадии, когда возможности локальных методов лечения ограничены, а системная химиотерапия не дает выраженного, долгосрочного эффекта. Появление таргетной терапии существенно изменило парадигму лечения НМРЛ. До 60% неплоскоклеточного НМРЛ имеют те или иные генетические альтерации, потенциально являющиеся мишенью для терапии, а для 50% уже имеются одобренные лекарственные препараты. Различные варианты активации сигнального пути MET (амплификация, альтерации гена) встречаются у 2–4% пациентов НМРЛ и ассоциированы с неблагоприятным прогнозом заболевания. В последнее время удалось значительно продвинуться в разработке лекарственных препаратов способных воздействовать на этот сигнальный путь. Статья посвящена обзору наиболее важных исследований, посвящённых изучению новых терапевтических возможностей у пациентов НМРЛ с альтерацией сигнального пути МЕТ

Неоперабельный гепатоцеллюлярный рак — перспективы лекарственной терапии ленватинибом

There is a number of unresolved issues regarding the systemic therapy administration for hepatocellular carcinoma (HCC). Their solution is facilitated by accumulating real‑world study results. Lenvatinib therapy is a recognized drug with a good efficacy and safety profile for the treatment of HCC. Subanalyses of the REFLECT study showed that the absence of stratification by baseline AFP and baseline liver function, as well as the lack of options for subsequent drug therapy after lenvatinib, also affects the outcomes. Once these factors are taken into account, the hypothesis of superiority of lenvatinib to sorafenib and other drugs can be tested. Real‑world clinical studies have demonstrated positive results of lenvatinib therapy in patients with Child‑Pugh class B liver function, provided recommendations on the sequence of systemic therapy after lenvatinib and on the use of lenvatinib in patients with BCLC stage B, along with considering the possibility of lenvatinib monotherapy and the prospects for its use in patients with nHCC. Further real‑world studies of lenvatinib for HCC in the Russian population are required.В подходах к назначению лекарственной терапии гепатоцеллюлярного рака (ГЦР) есть ряд еще нерешенных вопросов. Их решению способствует накопление результатов исследований в реальной клинической практике. Методом медикаментозной терапии ГЦР с хорошим профилем эффективности и безопасности признана терапия ленватинибом. В субанализах исследования REFLECT показано, что отсутствие стратификации по исходному уровню альфа-фетопротеина и оценке исходной функции печени, а также дефицит опций последующей после назначения ленватиниба медикаментозной терапии оказывают влияние на результаты. Учет этих факторов даст возможность проверить гипотезу превосходства терапии ленватинибом в сравнении с сорафенибом и другими препаратами. В исследованиях реальной клинической практики продемонстрированы положительные результаты применения ленватиниба у пациентов с нарушением функции печени класса B по шкале Чайлд-Пью, даны рекомендации по последовательности системной терапии после ленватиниба, применению ленватиниба у пациентов стадии BCLC B, а также рассмотрены возможности монотерапии ленватинибом и перспективы его применения у пациентов с нГЦК. Необходимы дальнейшие исследования ленватиниба при ГЦР в реальной клинической практике на российской популяции

Cesarean Scar Pregnancy, Incidence, and Recurrence: Five-Year Experience at a Single Tertiary Care Referral Center

(Obstet Gynecol. 2018;132:1285–1295)Cesarean scar pregnancy, in which a gestational sac implants on the site of a previous hysterotomy, is associated with life-threatening complications. Although numerous treatment modalities have been described (expectant management, methotrexate, intrauterine balloon compression, resection, and more), data on optimal treatment modalities, pregnancy outcomes, treatment decisions, and patient counseling are limited. In order to add to the available literature, the authors of the present study described the treatment and follow-up of women with cesarean scar pregnancy at Yale-New Haven Hospital, a tertiary care center, from 2013 to 2018

Role of palbociclib in the treatment of hormone receptor-positive HER2-negative metastatic breast cancer. Generalizing results of randomized trials and real clinical practice

Palbociclib is the first-in-class drug of CDK 4/6 inhibitors group. The use of palbociclib in combination with endocrinotherapy (ET) opens up new possibilities for the treatment of metastatic hormone receptor-positive (HRP+) HER2-negative (HER2-) breast cancer (mBC). Palbociclib has gained world attention and is included in all clinical guidelines, both international and domestic, as a new standard of first- and second-line therapy of HRP+ HER2- mBC. The article presents the updated results of PALOMA-2 and PALOMA-3 studies and the results of use of palbociclib in combination with ET in real clinical practice

Maternal-fetal medicine fellows' perception and comfort with obstetrical ultrasound and prenatal diagnosis.

BackgroundUltrasound training is a vital component of maternal-fetal medicine fellowships in the United States. Of the 18 months of core clinical training, the American Board of Obstetrics and Gynecology currently requires a minimum of 3 months to be dedicated to ultrasound to be eligible for board certification. However, the experience and degree of hands-on training differ among the fellowship programs and have not been reassessed for nearly a decade.ObjectiveTo assess regional heterogeneity in the ultrasound training experience during maternal-fetal medicine fellowship in the United States.Study designA survey was distributed to postgraduate year (PGY)-6 maternal-fetal medicine fellows registered to attend an annual ultrasound training course before the conference (n=114). For programs with >1 fellow attending (n=39), only 1 of them completed the survey to represent the program. The questions included demographics of the program, ultrasound training structure, the fellows' self-perception of ultrasound capabilities, research, mentorship, and technical aspects of sonography.ResultsSeventy two postgraduate year 6 fellows with a wide geographic distribution as follows completed the survey (96% response rate): 10 (14%) from the West, 16 (22%) from the Midwest, 17 (24%) from the South, and 29 (40%) from the Northeast. Respondents undergoing training in the South were less likely to report feeling comfortable performing nuchal translucency and detailed anatomic surveys than those from other regions (nuchal translucency: P=.046; anatomy: P=.011). Most of the respondents reported feeling comfortable performing growth (78%) and umbilical artery Doppler (58%) and feeling uncomfortable with three-dimensional ultrasound, neurosonography, and fetal echocardiography. Respondents in the Northeast were more likely to report feeling comfortable performing chorionic villus sampling (P=.001). There was no difference among fellowship programs in the presence or absence of ultrasound curriculum, bedside teaching, ultrasound-focused research mentorship, or months of ultrasound training.ConclusionDespite the standardization of ultrasound training structure across the United States, there remains regional heterogeneity in fellow self-reported comfort with specific ultrasound techniques and chorionic villus sampling at a midpoint in their fellowship training. The maternal-fetal medicine attending involvement at the bedside did not affect the fellow self-reported comfort with ultrasound surveys. This study highlights the need for further optimization of maternal-fetal medicine fellowship ultrasound training, especially in advanced sonography and diagnostic procedures