An updated overview of K-RAS G12C inhibitors in advanced stage non-small cell lung cancer.

The discovery of KRAS mutations, particularly the KRASG12C variant, has been a milestone in understanding the molecular underpinnings of non-small cell lung cancer (NSCLC). These mutations are associated with aggressive tumor behavior and resistance to conventional therapies, highlighting the urgent need for targeted interventions. In this comprehensive review, we analyze the advancements in KRAS G12C inhibitors for the treatment of non-small cell lung cancer. Literature search is made from PubMed, Medline ASCO and ESMO Annual Meetings abstracts by using the following search keywords: "sotorasib", "adagrasib", "divarasib" and "KRAS G12C inhibitors." The last search was on 5 June 2024. This review highlights the importance of pharmacokinetics, pharmacodynamics and potential adverse effects for treating individual patients and ensuring the best outcomes. Additionally, the review discusses research identifying biomarkers that can predict therapy responses and mentions the combination strategies to overcome resistance. Results of the studies and ongoing clinical trials are also briefly summarized in this review. KRASG12C inhibitors sotorasib, adagrasib and the newer divarasib, has revolutionized treating patients harboring this mutation. Ongoing studies and future clinical trials will refine our understandings with the ultimate goal of improving survival and quality of life for patients with this challenging disease.

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Albumin-myosteatosis gauge as a prognostic factor in patients with advanced pancreatic cancer undergoing first-line chemotherapy.

BACKGROUND: Sarcopenia and myosteatosis have been associated with a poor prognosis for several cancers. The albumin-myosteatosis gauge (AMG) is a novel integrated measure proposed to assess myosteatosis along with serum albumin level as a surrogate of systemic inflammation and malnutrition. The aim of this study was to investigate the prognostic value of AMG in patients with advanced pancreatic ductal adenocarcinoma (PDAC). METHODS: Patients with advanced PDAC treated with chemotherapy between 2013 and 2022 were evaluated. Skeletal muscle radiodensity (SMD) and skeletal muscle index (SMI) were calculated using computed tomography at the level of the L3 vertebra. The AMG was defined as albumin x SMD and expressed as an arbitrary unit (AU). Patients were first categorized by sex-specific quartiles and then dichotomized at the sex-specific median value of the AMG. RESULTS: A total of 196 patients were included. The median age (interquartile range) was 62 (54-67), and 128 (65.3%) were male. With regard to AMG, 142.86 and 114.15 AU were identified as cutoff values for males and females, respectively. In multivariable analyses, lower AMG values (G1-G2 vs. G3-G4) (HR: 1.61, 95% CI 1.17-2.21, p = 0.003), higher ECOG performance score (> 0 vs. 0) (HR: 1.51, 95% CI 1.10-2.06, p = 0.009) and metastatic disease (vs. locally advanced) (HR: 1.88, 95% CI 1.27-2.79, p = 0.001) were associated with OS. CONCLUSION: The study findings suggest the prognostic value of AMG in patients with advanced PDAC undergoing first-line chemotherapy. Further studies are warranted to validate these findings and assess potential predictive role of AMG in guiding treatment selection.

A current comprehensive role of immune-checkpoint inhibitors in resectable non-small cell lung cancer: A narrative review.

OBJECTIVE: The objective of this article is to review the efficacy, safety, and evidence for current use and potential future uses of immune-checkpoint inhibitors (ICIs) in the management of resectable non-small cell lung cancer (NSCLC). DATA SOURCES: A literature review was carried out through PubMed to identify completed and ongoing clinical trials evaluating the use, efficacy, and safety of ICIs in the management of resectable NSCLC. DATA SUMMARY: To date, four phase 3 trials have emerged that have changed our treatment practice concerning the utilization of ICIs during the adjuvant and neoadjuvant settings. The IMpower010 and KEYNOTE-091 trials examined the application of adjuvant atezolizumab and pembrolizumab, respectively, following surgical resection and adjuvant chemotherapy. In the CheckMate 816 trial, the combination of nivolumab and chemotherapy as a neoadjuvant therapy received approval for patients with resectable NSCLC. Also, for patients with resectable NSCLC, the use of a pembrolizumab and chemotherapy combination as a perioperative therapy received approval based on the results of the KEYNOTE-671 trial. Apart from these trials, there are numerous phase 2 and phase 3 trials, some of which have been published while others are still in progress. CONCLUSION: Despite the promising outcomes from these trials there remain several unanswered questions. In this review, we will assess clinical trials involving adjuvant, neoadjuvant, and perioperative ICIs, aiming to address the unresolved questions related to these therapeutic approaches.

Evaluation of early unplanned readmissions and predisposing factors in an oncology clinic.

BACKGROUND: Unplanned readmission in the first 30 days after discharge is an important medical problem, although the data on cancer patients is limited. So we planned to evaluate the rates and causes of early readmissions and the predisposing factors. METHODS: Patients hospitalized in Hacettepe University Oncology services between August 2018 and July 2019 were included. The demographic features, tumor stages, regular drugs, last laboratory parameters before discharge, and readmissions in the first 30 days after discharge were recorded. The predisposing features were evaluated with univariate and multivariate analyses. RESULTS: A total of 562 hospitalizations were included. The mean age of the patients was 58.5 ± 14.5 years. Almost 2/3 of the hospitalizations were due to symptom palliation and infections. Eighty-three percent of the patients had advanced disease, and over 60% had an ECOG score of 2 and above. In the first 30 days after discharge, 127 patients were readmitted (22.6%). Advanced stage disease, presence of polypharmacy (5 or more regular drugs), hospitalization setting (emergency department (ED) vs. outpatient clinic), and hypoalbuminemia (< 3 gr/dL) were associated with a statistically significant increase in the risk of readmission. Among these factors, advanced-stage disease (HR: 2.847, 95% CI: 1.375-5.895), hospitalization from ED (HR: 1.832, 95% CI: 1.208-2.777), and polypharmacy (HR: 1.782, 95% CI: 1.173-2.706) remained significant in multivariate analyses. CONCLUSIONS: In this study, 22% of cancer patients had early readmissions. The readmission risk increased in patients with advanced disease, hospitalization from ED, and polypharmacy. The optimal post-discharge plan may reduce readmissions in all oncology patients, with priority for these patient groups.

Poorer baseline performance status is associated with increased thromboembolism risk in metastatic cancer patients treated with immunotherapy.

PURPOSE: Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in cancer patients. However, the association of VTE with immunotherapy remains poorly defined. We therefore evaluated the frequency of VTE in patients receiving immunotherapy and tried to determine predisposing factors. METHODS: A total of 133 adult metastatic cancer patients treated with immunotherapy for any cancer between were included. Baseline demographics, ECOG performance status, type of tumors, and baseline blood count parameters were recorded. Possible predisposing factors were evaluated with univariate and multivariate analyses. RESULTS: The median age was 60 (interquartile range (IQR) 48-66) years, and the median follow-up was 10.1 (IQR 5.8-18.5) months. Renal cell carcinoma (26.3%) and melanoma (24.1%) were most common diagnoses. Fifteen patients (11.3%) had an episode of VTE. Most of the VTEs were diagnosed as pulmonary emboli (10/15; 67%). Eighty percent (12/15) of these VTE cases were detected incidentally. Patients with a baseline ECOG performance status of 1 or more (29.3% of patients) had a significantly increased risk of venous thrombosis (ECOG ≥1 vs. 0, HR: 3.023, 95% CI: 1.011-9.039, p=0.048). Other factors, including patient age, tumor type, body mass index, baseline thrombocyte, neutrophil, and lactate dehydrogenase levels were not significantly associated with VTE risk. CONCLUSIONS: In this study, we observed VTE development in more than 10% of immunotherapy-treated patients and increased VTE risk in patients with poorer ECOG status. With the asymptomatic nature of VTEs in most cases, a high index of suspicion level for VTE is required in patients treated with immunotherapy.

Chemoimmunotherapy for the salvage treatment of Ewing sarcoma: A case report.

INTRODUCTION: Although, immune check-point inhibitors changed the course of many cancers, the outcomes in sarcomas were rather disappointing with less than 10% response rates. Ewing sarcoma is a poorly differentiated and aggressive tumor mostly seen in the children and adolescents. It's a distinct type of sarcoma with prominent chemosensitivity in the early stages. However, the relapsing disease has a poor prognosis with limited treatment options. CASE REPORT: Herein, we represent a case of relapsed Ewing sarcoma treated with multiple lines of chemotherapy.Management & outcome: The patient had a very good response to salvage treatment with a combination of paclitaxel and nivolumab which lasted for twelve months after the cessation of treatment. DISCUSSION: We think that chemotherapy plus immunotherapy can be an option for Ewing sarcoma patients treated with multiple lines of chemotherapy.

Efficacy, retention, and safety of tofacitinib in real-life: Hur-bio monocentric experience

Background/aim: To assess the real-life efficacy, retention rate, and safety data of tofacitinib in rheumatoid arthritis (RA) patients. Materials and methods: We analyzed all patients registered in the HURBIO database who received at least 1 dose of tofacitinib. Patients who received at least one dose were included in retention analysis; patients with at least 1 control visit were included in efficacy and safety analysis. Factors predicting good response at the last follow-up visit were analyzed by logistic regression analysis. Drug retention rates were calculated using the Kaplan­Meier method and predictors of drug retention were determined by Cox proportional hazard model. Adverse events, reasons for switching, and discontinuation were also determined. Results: Two hundred and forty-seven (210, 85.0% female) patients were included in the study. The median duration of tofacitinib treatment was 10.2 (20.2) [med, (IQR)] months. Two hundred and four (82.6%) patients were included in safety and efficacy analysis; 45.6% of patients were in low-disease activity (LDA) state (DAS28-CRP ≤ 3.2). Predictors of LDA were being biologic-naïve [aOR 2.53 (1.31­4.88); 95% CI] and RF negativity [aOR 2.14 (1.12­4.07); 95% CI]. At 1 year, the overall tofacitinib retention rate was 63.9% with no relevant predicting factor. Response and retention rates of tofacitinib were similar in patients with and without concomitant csDMARDs. Treatment failure was the most common cause of discontinuation. The most common infectious and laboratory adverse events were herpes zoster infection (3.9 per 100 patient-years) and elevation in ALT (x3UNL: 9.7 per 100 patient-years), respectively. Conclusion: Tofacitinib is effective as monotherapy or in combination with csDMARDs. It is a well-tolerated treatment option in Turkish RA patients.

Evaluation of cancer risk in patients with periodontal diseases

Background/aim: In this study, we aimed to assess the cancer risk among patients with periodontal disease. Materials and methods: Patients diagnosed with periodontal diseases at Hacettepe University between 2007 and 2012 were included and data on the diagnosis of any cancer after periodontal disease were collected from patient files. The age- and sex-standardized incidence rates (SIRs) were calculated using Turkish National Cancer Registry 2013 data. Results: A total of 5199 patients were included. Median follow-up was 7.2 years. Patients with periodontal diseases had 17% increased risk of cancer compared with the expected counts for the corresponding age and sex groups (SIR: 1.17; 95% CI: 1.04­1.3, P = 0.006). The increased cancer risk was statistically significant in women (SIR: 1.24; 95% CI: 1.05­1.45, P = 0.008) but not in men. Among women with periodontal disease, the risks of breast cancer (SIR: 2.19) and head and neck cancer (SIR: 4.71) were significantly increased. Among men, the risks of prostate cancer (SIR: 1.84), head and neck cancer (SIR: 3.55), and hematological cancers (SIR: 1.76) were significantly increased. Conclusion: This study showed that periodontal diseases were associated with increased risk of several cancers. Besides other well-known benefits for health, the provision of oral/dental health should be considered and employed as a cancer prevention measure.

Proceedings of Peer-reviewed and selected articles from Turgut Ozal University Faculty of Medicine 7th International Student Congress.

Turgut Ozal University Scientific Research Committee (TOBAT) was established in at the Turgut Ozal University Faculty of Medicine in 2009 to encourage young medical students and scientists to carry out novel scientific research in addition to their medical education. Every year a Committee (Chair, Student Member and Scientific and Social Committees and Advisory Chair) is set up by the volunteer students and their advisors as chair, general secretary, scientific and social committee with the help of previous year's committee to organize the congress, with the help of previous year's Committee.

Understanding thermal sensitivity at the molecular level and developing temperature-based systems using RNA Thermometers.

PURPOSE: Temperature sensitivity is found in all multicelleular organisms, as well as in most primitive life forms. The ubiquity of this temperature sensitivity is an indicator of its effects at the multicellular, cellular and molecular levels [1]. Previous studies have shown that temperature-based regulation is present in the transcriptional process [2]. RNA Thermometers, temperature-sensitive sequences, have been shown to act on heat-shock genes to regulate temperature-dependant systems in many organisms [3,4]. The goal of this study was to characterize the shifts in the functioning of these RNA Thermometers at various temperatures. In addition, using the principle of transcriptional thermoregulation, an automated temperature-responsive system stimulating inverse endothermic and exothermic enzymatic reactions for heat stabilization was proposed. METHODS: The endothermic enzymatic reaction was designated as the breakdown of urea, reflecting the function of urease, and the exothermic reaction was designated as the breakdown of hydrogen peroxide, reflecting the function of catalase [5]. RESULTS: The proposed system was built upon the translation of urease and the inhibition of catalase translation at higher temperatures, and the inverse at lower temperatures. As RNA Thermometers can be used only to drive transcription at higher temperatures, the installation of a lac-regulated 2-way system was suggested. This system would also provide a synthetic solution to thermoregulation and the current systems employed today. This system could be applied where the current thermoregulatory systems prove insufficient and could be further developed and optimized to replace them in the future.

Is fibroblast growth factor 11 (FGF11) a predictive marker for breast cancer?

The prognostic role of fibroblast growth factor 11 (FGF11) has only been reported in cancers such as nasopharyngeal carcinoma and prostate cancer. The role of FGF11 in breast cancer is not fully known. It was aimed to compare FGF11 expression levels in de novo metastatic hormone receptor-positive, human epidermal reseptor-2-negative breast tumor tissue and healthy breast tissue and investigate the effect of the FGF11 expression on survival in breast cancer patients. To determine the FGF11 expression rate, breast tumor tissue of breast cancer patients diagnosed by breast biopsy and healthy breast tissue of healthy individuals who underwent breast biopsy due to benign lesions were used. The study population included 38 breast cancer patients and 24 healthy controls. The number of patients with a FGF11 expression level score of 1 (15.8% vs 12.5%), score of 2 (18.4% vs 12.5%), and score of 3 (31.6% vs 0%) was significantly higher in the patient group compared to the healthy control group. The median overall survival and progression-free survival were numerically better in the group with a FGF11 expression score of 0 to 1 than the group with a FGF11 expression score of 2 and 3, but this difference was not statistically significant. FGF11 may be a predictive marker for breast cancer formation. Additionally, with new FGF11-targeted treatment agents to be developed, endocrine resistance may be reduced, and better survival results may be achieved in hormone receptor-positive, human epidermal reseptor-2-negative breast cancer.

Effect of HER2/CEP17 ratio on survival in metastatic HER2-positive gastric cancer, multicenter study.

AIM: HER2-positive metastatic gastric cancer is still a highly fatal disease despite advances. We aimed to investigate the relationship between HER2/CEP17 ratio and survival in patients with HER2-positive metastatic gastric cancer. METHODS: A total of 99 patients from 8 different centers in Turkey were included in the study. Patients with HER2-positive metastatic gastric cancer and whose HER2/CEP17 ratio was examined were included in the study. Patients were divided into two groups according to HER2/CEP17 values, and survival analysis was performed. RESULTS: The median age was 64 (24-83) years. There were 74 (74.8%) male and 25 (25.2%) female patients. OS in the high HER2/CEP17 ratio group was 21.97 months (95% CI: 16.36-27.58), and in the low ratio group was 16.17 months (95% CI: 10.95-21.38) (p = 0.015). OS was 17.7 months (95% CI: 7.02-28.37) in the high HER2 gene copy number group and 10.13 months (5.55-14.71) in the group with low copy number (p = 0.03). PFS was 10.94 months (95% CI: 7.55-14.33) in the group with high HER2 gene copy number and 7.56 months (4.62-10.49) in the low copy number group (p = 0.06). CONCLUSION: Patients with both high HER2 gene amplification and high HER2/CEP17 ratio had better OS. The PFS of the group with high HER2 gene amplification was also better. To our knowledge, this is the first study in the literature showing that the HER2/CEP17 ratio affects survival in patients with metastatic gastric cancer.

Prognostic and predictive value of tumoral DNA damage repair protein expression in patients with resected pancreatic cancer.

OBJECTIVE: DNA damage repair (DDR) gene mutations gained interest in the treatment of metastatic pancreatic cancer (PC) patients, but their relevance in adjuvant setting is not well characterized. We assessed the prognostic and predictive potential of tumoral expression of DDR proteins along with clinical and tumor characteristics in patients with resected PC. PATIENTS AND METHODS: Patients with PC who underwent pancreatic resection in our institution between 2005 and 2017 were retrospectively retrieved. Tumoral expression of a panel of DDR proteins including BRCA1, BRCA2, ATM, and p53 with immunohistochemistry was evaluated and association with patient and tumor features as well as prognosis was assessed. RESULTS: 130 patients were included in the study. The median age was 61 and 66% were males, 57% had lymph node involvement and 17% had a vascular invasion. 25 patients (19%) had thrombosis at the time of diagnosis. Median overall survival (OS) and disease-free survival (DFS) were 21.6 and 11.8 months, respectively. More advanced disease stage (HR: 3.67 95% CI 1.48-9.12, p = 0.005), presence of thrombosis (HR: 2.01 95% CI 1.04-3.89, p = 0.039), high BRCA1 expression (HR: 2.25, 95% CI 1.13-5.48, p = 0.023) and high post-operative CA 19-9 level (>100 IU/ml) (HR:2.61 95% CI 1.40-4.89, p = 0.003) were associated with shorter DFS. BRCA2, ATM, and p53 expression were not associated with DFS or OS. Adjuvant gemcitabine-cisplatin regimen was not associated with increased DFS or OS in the whole group, neither in low or high expressors of BRCA1, BRCA2, ATM or p53. CONCLUSION: Contrary to BRCA2, ATM, and P53, BRCA1 expression may be beneficial for prognosis in resected pancreatic cancer, while no predictive role was observed in terms of adjuvant platinum efficacy.

Knowledge, Attitudes, and Perception towards COVID-19 Vaccination among the Adult Population: A Cross-Sectional Study in Turkey.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic continues to wreak havoc on lives and ravage the world. Several vaccines have been approved for use against COVID-19; however, there may be hesitancy and negative perceptions towards vaccination, which may reduce the willingness to be vaccinated. Further, studies assessing the current perception toward COVID-19 vaccination are scarce. This study aimed to assess community knowledge, attitudes, and perceptions regarding COVID-19 vaccines among the general population of Turkey. METHODS: A cross-sectional survey was carried out among 1009 adult participants from the 13-20 April 2021. Demographic data were collected, and attitudes and perceptions toward COVID-19 vaccines were evaluated. A multivariable regression analysis was performed to identify the factors predicting perception towards COVID-19 vaccinations. RESULTS: Just over half of participants were male (52.6%) and the majority of respondents were aged between 30 and 39 years (33.8%). Our study revealed that 62.7% of participants had positive perceptions of COVID-19 vaccines. Logistic regression analysis results showed that older people (≥30 vs. <30) were less likely to have a positive perception towards COVID-19 vaccines (OR = 0.70, 95% CI = 0.51-0.94). We also found participants who had a previous history of influenza vaccines (OR = 2.01, 95% CI = 1.43-2.84), bachelor's degrees or above (OR = 1.47, 95% CI = 1.12-1.91), and a personal history of COVID-19 (OR = 1.58, 95% CI = 1.10-2.26) were more likely to have a positive perception regarding COVID-19 vaccines. CONCLUSION: The proportion of the general population in Turkey who believe in COVID-19 vaccine effectiveness is not inferior to that of other countries. However, the low positive perception even among the population applying for vaccination indicates that understanding the perception of the general population and its influencing factors may contribute to developing a strategy for improving vaccination rates by addressing these factors.

The association between antibiotic use and survival in renal cell carcinoma patients treated with immunotherapy: a multi-center study.

BACKGROUND: Immunotherapy improves overall survival (OS) in the second and later lines of renal cell carcinoma (RCC) treatment. Recent studies have suggested that antibiotic (ATB) use either shortly before or after the start of immunotherapy could lead to decreased OS. Herein, we evaluate the impact of ATB use on OS in RCC patients treated with nivolumab in a multi-center cohort from Turkey. METHODS: The data of 93 metastatic RCC patients treated with nivolumab in the second line or later were retrospectively collected from 6 oncology centers. Previous treatments, sites of metastases, International Metastatic RCC Database Consortium risk classification, and ATB use in the three months before (-3) or three months after (+3) the start of immunotherapy were recorded together with survival data. The association of clinical factors with OS and progression-free survival (PFS) was analyzed with univariate and multivariable analyses. RESULTS: The median age was 61 (interquartile range 54-67), and 76.3% of the patients were male. The median OS of the cohort was 23.75 ± 4.41, and the PFS was 8.44 ± 1.61 months. Thirty-one (33.3%) patients used ATBs in the 3 months before (-3) or 3 months after (+3) nivolumab initiation. In the multivariable analyses, ATB exposure (HR: 2.306, 95% confidence interval [CI]: 1.155-4.601, P = 0.018) and the presence of brain metastases at the baseline (HR: 2.608, 95% CI: 1.200-5.666, P = 0.015) had a statistically significant association with OS, while ATB exposure was the only statistically significant parameter associated with PFS (HR: 2.238, 95% CI: 1.284-3.900, P = 0.004). CONCLUSION: In our study, patients with ATB exposure in the 3 months before or 3 months after the start of immunotherapy had shorter OS. Our findings further support meticulous risk-benefit assessments of prescribing ATBs for patients who are either receiving or are expected to receive immunotherapy.