Case report of giant nonmetastatic gastrointestinal solid tumor without clinical manifestations in a middle-aged male petient

ЖЕЛУДКА НОВООБРАЗОВАНИЯРАК ЖЕЛУДКАГАСТРОИНТЕСТИНАЛЬНАЯ СТРОМАЛЬНАЯ ОПУХОЛЬКЛИНИЧЕСКИЕ СЛУЧАИГастроинтестинальные стромальные опухоли (ГИСО, GIST) – одни из наиболее часто встречаемых мезенхимальных опухолей, которые происходят из клеток Каяла. Наиболее часто встречающаяся локализация ГИСО – желудочно-кишечный тракт, однако иногда встречаются и внежелудочно-кишечные формы. Большинство ГИСО имеют малый размер, который чаще всего не превышает 5-8 см в максимальном измерении. Данный клинический кейс описывает случай пациента с неметастатической гигантской опухолью желудка без каких-либо клинических проявлений. Опухоль была локализована в брюшной полости, занимая почти всю ее, сдавливая и смещая окружающие органы. Ввиду кистозно-солидной структуры, ее гигантских размеров и интимного прилегания к окружающим органам, провести точную дифференциальную диагностику до оперативного вмешательства не было возможно. Интраоперационная визуализация опухоли, дальнейшие гистологическое и иммуногистохимическое (CD117, CD34, S100, CD45, PanCK; Ki-67) исследования позволили установить диагноз ГИСО желудка T4N0M0, стадия II. На основании полученных данных, несмотря на гигантские размеры, прогноз заболевания был признан благоприятным (низкий митотический индекс, отсутствие метастазирования). За период клинического наблюдения, в течение 1,5 года после оперативного вмешательства, не было зарегистрировано рецидива или прогрессии заболевания, что говорит о благоприятном прогнозе для пациента.Gastrointestinal stromal tumors (GIST) are one of the most common mesenchymal tumors that originate from the intestinal cells of Cajal. The most common localization of GIST is the gastrointestinal tract, however, extragastrointestinal forms are sometimes found. Most GISTs are small in size, which most often does not exceed 5 - 8 cm in maximum dimension. This article describes the case of a patient with a non-metastatic giant tumor of the stomach without any clinical manifestations. The tumor was localized in the abdominal cavity, occupying almost all of it, squeezing and displacing the surrounding organs. Due to the cystic-solid structure, its gigantic size and intimate adherence to the surrounding organs, it was not possible to carry out an accurate differential diagnosis before surgery. Intraoperative imaging of the tumor, further histological and immunohistochemical (CD117, CD34, S100, CD45, PanCK; Ki-67) studies made possible to establish the diagnosis of gastric GIST T4N0M0 stage II. Based on the data obtained, despite the gigantic size, the prognosis of the disease was considered favorable (low mitotic index, no metastasis). During the period of clinical observation, within 1.5 years after surgery, no relapse or disease progression was recorded, which indicates a favorable prognosis for the patient

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

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

Health-related Quality of Life Analysis from KEYNOTE-426: Pembrolizumab plus Axitinib Versus Sunitinib for Advanced Renal Cell Carcinoma

The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma

Subsequent therapy following pembrolizumab + axitinib or sunitinib treatment for advanced renal cell carcinoma (RCC) in the phase III KEYNOTE-426 study

Background: In the phase III KEYNOTE-426 study, pembrolizumab + axitinib showed significant improvement in OS, PFS, and ORR vs sunitinib in patients with RCC. This analysis assessed subsequent treatment in patients enrolled in KEYNOTE-426. Methods: Treatment-naive patients with clear cell RCC, KPS score �70%, and measurable disease (RECIST v1.1) were randomly assigned 1:1 to receive pembrolizumab 200 mg IV every 3 weeks for up to 35 doses + axitinib 5 mg orally twice daily or sunitinib 50 mg once daily (4 weeks on/2 weeks off) until progression, toxicity, or withdrawal. Type of and time to subsequent therapy were assessed. Results: Of patients in the pembrolizumab + axitinib arm and in the sunitinib arm, 81.4% (349/432) and 90.6% of patients (385/429), respectively, discontinued treatment; radiologic or clinical PD was the most common reason for discontinuation in both (pembrolizumab + axitinib: 65.0% [227/349]; sunitinib: 68.1% [262/385]). Of patients who discontinued, 58.5% of patients (204/349) in the pembrolizumab + axitinib arm and 73.0% (281/385) in the sunitinib arm received subsequent therapy (Table). Although a similar proportion of patients in both arms received subsequent therapy with a VEGF/VEGFR inhibitor (pembrolizumab + axitinib: 88.2% [180/204]; sunitinib: 68.7% [193/281]), a greater proportion of patients in the sunitinib arm (74.4% [209/281]) received subsequent PD-1/PD-L1 inhibitor therapy than in the pembrolizumab + axitinib arm (21.6% [44/204]). Of patients in the pembrolizumab + axitinib arm and the sunitinib arm, 32.4% (66/204) and 22.8% (64/281), respectively, received other therapies

Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial

Background The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma. Methods In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatmentnaive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intentionto-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331. Findings Between Oct 24, 2016, and Jan 24, 2018, 861 patients were randomly assigned to receive pembrolizumab plus axitinib (n=432) or sunitinib monotherapy (n=429). With a median follow-up of 30·6 months (IQR 27·2–34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months [95% CI 33·3–not reached] with sunitinib); hazard ratio [HR] 0·68 [95% CI 0·55–0·85], p=0·0003) and progression-free survival (median 15·4 months [12·7–18·9] vs 11·1 months [9·1–12·5]; 0·71 [0·60–0·84], p<0·0001). The most frequent (≥10% patients in either group) treatmentrelated grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis. Interpretation With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma

Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC): Updated analysis of KEYNOTE-426

The randomized, open-label, phase 3 KEYNOTE-426 study (NCT02853331) demonstrated that pembrolizumab (pembro) + axitinib (axi) significantly improved OS, PFS, and ORR vs sunitinib as first-line therapy for advanced RCC (aRCC) at the first pre-planned interim analysis (minimum study follow-up of 7 mo). Updated analyses are presented here

Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Results from 42-month follow-up of KEYNOTE-426

https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.450

Роль мутацій гена PIK3CA в розвитку раку грудної залози (огляд літератури)

 Today, breast cancer occupies a leading position in the structure of morbidity and mortality among women in Ukraineand and throughout the world. Late diagnosis of the disease adversely affects the prognosis. Since this pathology is characterized by a wide range of gene mutations, the relationship between the molecular genetic characteristics of a tumor and the prognostic and clinical characteristics of breast cancer is an extremely important issue. The PI3K/Akt signaling cascade is one of the key intracellular signaling pathways associated with the control of cell proliferation and regulation of potential oncogene protein kinase B/Akt functions. It can suppress apoptosis in different types of cancer, contributing to tumor cells survival. Also, mutations and amplification of the PI3K/Akt cascade components cause malignant cell transformation of various origin. The PIK3CA gene is one of the oncogenes, somatic mutations in which play an important role in the pathogenesis and progression of breast cancer. It encodes p110-α, the catalytic subunit of phosphatidylinositol-3-kinase-α. The most frequent mutation in PIK3CA gene is H1047R.Conclusions. Numerous studies have shown that PIK3CA gene mutations in breast cancer patients have the potential to become a clinically important biomarker for improving the disease diagnosis and developing individualized targeted therapy. In this literature review we discuss the molecular mechanisms of PI3K signaling cascade activation and the role of PIK3CA mutations in the development of breast cancer.  Сегодня рак молочной железы занимает лидирующие позиции в структуре заболеваемости и смертности среди женщин Украины и всего мира. Позднее выявление заболевания негативно влияет на прогноз. Поскольку для данной патологии характерен широкий спектр генных мутаций, связь молекулярно-генетических особенностей опухоли с прогностическими и клиническими характеристиками рака молочной железы является крайне актуальным вопросом. Сигнальный каскад PI3K/Akt – один из ключевых внутриклеточных сигнальных путей, связанных с контролем пролиферации клеток и регуляцией функций потенциального онкогена протеинкиназы B/Akt. Он может подавлять апоптоз при многих типах рака, способствуя выживанию опухолевых клеток, а мутации и амплификация компонентов каскада PI3K/Akt являются причиной злокачественной трансформации клеток различного происхождения. Ген PIK3CA является одним из онкогенов, соматические мутации в котором играют важную роль в патогенезе и прогрессии рака молочной железы. Он кодирует p110-α, каталитическую субъединицу фосфатидилинозитол-3-киназы-α. Наиболее частая мутация в гене PIK3CA – H1047R.Выводы. Данные многочисленных исследований указывают на то, что мутации гена PIK3CA у больных раком молочной железы имеют потенциал, чтобы стать клинически важным биомаркером для улучшения диагностики заболевания и разработки индивидуализированной таргетной терапии. В данном обзоре литературы рассмотрены молекулярные механизмы активации сигнального каскада PI3K и роль мутаций гена PIK3CA в развитии рака молочной железы.  Нині рак грудної залози посідає провідні позиції у структурі захворюваності та смертності серед жінок України та всього світу. Пізнє виявлення захворювання негативно впливає на прогноз. Оскільки для цієї патології характерний широкий спектр генних мутацій, зв’язок молекулярно-генетичних особливостей пухлини з прогностичними та клінічними характеристиками раку грудної залози є вкрай актуальним питанням. Сигнальний каскад PI3K/Akt – один із ключових внутрішньоклітинних сигнальних шляхів, що пов’язані з контролем проліферації клітин і регуляцією функцій потенціального онкогена протеїнкінази В/Akt. Він може пригнічувати апоптоз при багатьох типах раку, сприяючи виживанню пухлинних клітин, а мутації та ампліфікація компонентів каскаду PI3K/Akt є причиною злоякісної трансформації клітин різного походження. Ген PIK3CA є одним з онкогенів, соматичні мутації в якому відіграють значущу роль у патогенезі та прогресії раку грудної залози. Він кодує p110-α, каталітичну субодиницю фосфатидилінозитола-3-кінази-α. Найчастішою мутацією в гені PIK3CA є H1047R.Висновки. Дані численних досліджень вказують на те, що мутації гена PIK3CA у хворих на рак грудної залози мають потенціал, щоб стати клінічно важливим біомаркером для вдосконалення діагностики захворювання та розроблення індивідуалізованої таргетної терапії. У цьому огляді літератури розглянуто молекулярні механізми активації сигнального каскаду PI3K і роль мутацій гена PIK3CA в розвитку раку грудної залози

Modern Vector in Treatment of Patients with Lung Cancer: Tyrosine Kinase Inhibitors in Epidermal Growth Factor Receptor Mutations (Literature Review)

Tumor molecular profiling in patients with non-small cell lung cancer (NSCLC) is used to identify driver mutations, which lead to premature carcinogenesis in more than 80% of adenocarcinoma cases, including epidermal growth factor receptor (EGFR) mutations. Identification of specific somatic aberrations allows to personalize treatment. Personalization of treatment resulted in improvement of NSCLC outcomes. The aim of our study was to consider scientific data on modern concepts of treatment of patients with non-small cell lung cancer with previously detected oncogenic mutations, especially EGFR mutation. In our study we analyzed scientific papers and data of International scientific literature on the problem of lung cancer treatment. Methods used: scientific research, analytical and generalizing. Different drugs are used in treatment of lung cancer. Choice of treatment scheme depends on type and presence of mutations. Patients with advanced non-small-cell lung cancer and detected mutation in the EGFR can be treated with tyrosine kinase inhibitors (TKIs). Nowadays three first generation drugs are recommended by FDA: afatinib, erlotinib, gefitinib. They showed good clinical benefit. Most patients with metastatic NSCLC typically show disease progression after approximately 9 to 13 months of erlotinib, gefitinib, or afatinib therapy. The first and only commercially available third-generation EGFR TKI is оsimertinib - an oral drug, which selectively inhibits both EGFR-TKI and EGFR T790M resistance mutations. Nowadays scientists are in active investigation of mechanisms of acquired resistance to TKIs, but little is known yet. Clinical success can be observed in patients who were treated with TKIs. EGFR T790M is a mutation that leads to acquired resistance to EGFR TKI therapy. Its incidence is approximately 60% after disease progression on TKI drugs (erlotinib, gefitinib, or aphatinib). Third-generation EGFR TKIs demonstrate high efficacy, but acquired resistance development cannot be avoided. Mechanisms of acquired resistance to these agents are still investigated