Impact of antihistamine use on the survival outcomes of immune checkpoint inhibitors in advanced cancer patients.

Histamine and H1 receptors play a crucial role in the tumor microenvironment. Preclinical data showed that concomitant use of antihistamines and immune checkpoint inhibitors (ICIs) might increase the effect of ICIs. This study aimed to evaluate the impact of antihistamines on the oncological outcomes of ICIs. This retrospective study was conducted in a tertiary cancer center. Advanced cancer patients treated with ICIs were included in this study. A total of 133 patients receiving ICIs in the metastatic setting were included. Melanoma (33.1%) was the most common tumor type. The most common ICI was nivolumab (63.2%). Fifty-five (38.4%) patients received antihistamines concomitantly with ICIs. The most common antihistamine was pheniramine (85.5%). The median progression-free survival (PFS) (8.2 vs. 5.1 months, P  = 0.016) and overall survival (OS) (16.2 vs. 7.7 months, P  = 0.002) were longer in patients receiving antihistamines concomitantly with ICIs. In multivariate analysis, PFS [hazard ratio (HR) = 0.63, 95% CI: 0.40-0.98, P  = 0.042] and OS (HR = 0.49, 95% CI: 0.29-0.81, P  = 0.006) were also better in those patients after adjusting for confounding factors, such as performance status, bone or liver metastasis, and concurrent chemotherapy. This study suggested that antihistamines may enhance the efficacy of ICIs in patients with advanced cancer. If validated in prospective trials, antihistamines and ICIs combinations might be new options to improve oncological outcomes.

A late relapse thymoma and pure red cell aplasia case with an over 5 years of clinical response under everolimus.

Although several agents showed some clinical activity in patients with recurrent thymoma, there is no standard treatment option. Here, we report a late relapse thymoma and pure red cell aplasia case, responsive to everolimus with over 5 years of clinical benefit following multiple lines of treatment. Everolimus controlled the rapidly progressive disease in our patient without significant toxicity.

Chronic hyperglycemia based on diabetes is independently associated with decreased survival in patients with advanced cancer treated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have started a new era in treating patients with cancer. The effect of comorbidities and concomitant drug use on ICIs have become of interest in those patients. Data about the impact of hyperglycemia on response to ICIs in cancer patients are limited. All advanced-stage cancer patients treated with ICIs in Ankara University Medical Oncology Department were retrospectively evaluated. Patients treated in expanded access programs or clinical trials were excluded from the study. A total of 137 patients were included in this study. The most common primary tumor type was malign melanoma (32.8%) and nivolumab (62.3%) was the most common used ICI. More than half of patients (57.7%) had lung metastasis at the initiation of ICIs. Thirty-five patients (25.5%) had diabetes before initiating ICIs. Median baseline fasting glucose level was higher in patients with diabetes than those without diabetes (117 mg/dl vs. 99 mg/dl, P = 0.002). In all patients, median overall survival and progression-free survival were 11.3 [95% confidence interval (CI), 8.1-14.4) and 5.9 (95% CI, 3.6-8.3) months, respectively. In multivariate analysis, diabetes was found to increase risk of death [hazard ratio (HR), 2.09; 95% CI, 1.27-3.43, P = 0.004) and disease progression (HR, 2.01, 95% CI, 1.29-3.09, P = 0.002). Hyperglycemia might decrease response to ICIs in patients with advanced cancer. This research area is still an unmet need in the immunotherapy era. Prospective studies are needed to elucidate the effect of hyperglycemia on the response to ICIs.

The role of pericytes on the efficacy of bevacizumab in colorectal cancer.

BACKGROUND: Pericytes are mesenchymal cells surrounding capillary vessels and are known to play an essential role in tumor angiogenesis. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface proteoglycan and its release from pericytes and vascular smooth muscle cells is very important in tumor angiogenesis. Bevacizumab, which is a monoclonal antibody frequently used in the treatment of metastatic colorectal cancer, binds to the ligand of vascular endothelial growth factor A (VEGFA) and inhibits tumor angiogenesis. However, no reliable biomarker for predicting patients that will show a good response to this therapy has been established yet. In this study, we aimed to identify the significance of the presence of pericyte and VEGFA and CSPG4 expressions on the efficacy of Bevacizumab. METHODS: Fifty patients with metastatic or recurrent colorectal cancer who had been treated with Bevacizumab combined chemotherapy treatment were included in the study. The expressions of VEGFA and CSPG4 genes and also human ß-actin as the reference gene were examined using the quantitative real-time polymerase chain reaction method in the formalin-fixed paraffinembedded tumor tissues. For determining vascular and pericyte density in tumor tissue, immunohistochemical analysis was performed with CD31, alpha-smooth muscle actin, and CD34 antibodies. RESULTS: CSPG4 positive group had better objective response rate, as well as longer progression-free and overall survival than CSPG4 negative ones. Progression-free survival was significantly longer in VEGFA low group and CD31 low group. No significant correlation was found between CD34 positivity, SMA positivity, and progression-free and overall survival. DISCUSSION: Our results suggested that bevacizumab may be more effective in patients having less vascular density in the tumor tissue. But further studies are needed to support this finding.

ctDNA as a prognostic factor in operable colon cancer patients: a systematic review and meta-analysis.

Aim: Using circulating tumor DNA (ctDNA) instead of historical clinicopathological factors to select patients for adjuvant chemotherapy (ACT) may reduce inappropriate therapy. Material & methods: MEDLINE was searched on 31 March 2020. Studies, including data related to the prognostic value of ctDNA in the colon cancer patients after surgery and after ACT, were included. The generic inverse-variance method with a random-effects model was used for meta-analysis. Results: Four studies were included for this meta-analysis. ctDNA-positive colon cancer patients after surgery and ACT had a significantly increased risk of recurrence compared with ctDNA-negative patients. Conclusions: ctDNA is an independent prognostic factor, and this meta-analysis is a significant step for using ctDNA instead of historical prognostic factors in the adjuvant setting.

Quality of life study of patients with unresectable locally advanced or metastatic pancreatic adenocarcinoma treated with gemcitabine+nab-paclitaxel versus gemcitabine alone: AX-PANC-SY001, a randomized phase-2 study.

BACKGROUND: Combination of gemcitabine and nab-paclitaxel has superior clinical efficacy than gemcitabine alone. Nevertheless, health-related quality of life. (QoL) associated with this combination therapy when administered at first-line in advanced pancreatic adenocarcinoma is unknown. METHODS: A total of 125 patients were randomized to combination therapy (1000 mg/m2 gemcitabine + 125 mg/m2 nab-paclitaxel) and single-agent gemcitabine (1000 mg/m2) arms to take treatment weekly for 7 of 8 weeks, and following 3 of 4 weeks, until progression or severe toxicity. Primary endpoints were three-months of definitive deterioration free percent of patients, and QoL. RESULTS: Overall QoL analyses showed that 34 and 58.3% of cases in gemcitabine and gemcitabine+nab-P arms had no deterioration in 3rd month QoL scores (p = 0.018). These proportions were 27.3 and 36.6% in 6th month assessments, respectively (p = 0.357). Median overall survivals in combination and single-agent arms were 9.92 months and 5.95 months, respectively (HR: 0.64, 95% CI: 0.42-0.86, p = 0.038). Median progression free survivals in these treatment arms were 6.28 and 3.22 months, respectively (HR: 0.58, 95% CI: 0.39-0.87, p = 0.008). Median time-to-deterioration were 5.36 vs 3.68 months, and objective response rates were 37.1% vs 23.7% (p = 0.009), respectively in combination and single-agent arms. CONCLUSIONS: Combination therapy with gemcitabine + nab-paclitaxel had better overall and progression-free survival than gemcitabine alone. Also, combination therapy showed increased response rate without toxicity or deteriorated QoL. Combination treatment with gemcitabine and nab-paclitaxel may provide significant benefit for advanced pancreatic cancer. TRIAL REGISTRATION: This study has been registered in ClinicalTrials.gov as NCT03807999 on January 8, 2019 (retrospectively registered).

Prognostic factors for survival in patients with mucosal and ocular melanoma treated with ipilimumab: Turkish Oncology Group study.

OBJECTIVE: To evaluate prognostic factors associated with the use of ipilimumab in patients with mucosal and uveal melanoma. METHODS: In this multicenter, retrospective study, 31 patients with uveal and mucosal melanoma diagnosed between 2010 and 2017 were enrolled. Patients' characteristics, metastatic disease sites, treatment before ipilimumab therapy, performance status, hemoglobin, lactate dehydrogenase levels, B-RAF and c-kit mutation status, toxicity, and survival data were assessed for patients with mucosal and uveal melanoma. SPSS version 17 was used for statistical analysis. Kaplan-Meier method was used for survival analysis. The log-rank test was used for univariate analyses. The Cox regression analysis was used to test the association between multivariate variables and survival. The p-value of less than 0.05 was considered statistically significant. RESULTS: Twenty patients had uveal and eleven patients had mucosal melanoma. The median overall survival was seven months (95% confidence interval: 1.1-12.7). In univariate analysis, while bone metastasis, anemia, high lactate dehydrogenase level, and more metastatic sites were associated with lower overall survival, better treatment response and administration of ipilimumab in first or second lines were associated with favorable overall survival. In multivariate analysis, only treatment response status and administration of ipilimumab in first or second lines were found to be significant as independent prognostic factors for survival. CONCLUSION: Ipilimumab therapy may be associated with increased survival, but this retrospective small N study makes that hard to definitely conclude.

Immune gene therapy of cancer

Cancer gene therapy emerged as a promising treatment modality 3 decades ago. However, the failure of the first gene therapy trials in cancer treatment has decreased its popularity. Likewise, immunotherapy has followed a similar course. While it was a popular and promising treatment with IL-2 and interferon and cancer vaccines in the 1980s, it later lost its popularity. Immunotherapy became one of the main options for cancer treatment with the successful use of immune checkpoint inhibitors in clinics approximately 10 years ago. The success of immunotherapy has increased even more with the introduction of cancer gene therapy methods in this area. With the identification of the oncolytic herpes simplex virus and Chimeric antigen receptor (CAR) T-cells, immune gene therapy has become an essential modality in cancer treatments such as surgery, radiotherapy, chemotherapy, and targeted therapies.

Prognostic factors for survival in patients with metastatic malign melanoma treated with ipilimumab: Turkish Oncology Group study.

PURPOSE: Studies in the last decade show survival improvement with checkpoint blocker therapy in patients with metastatic malign melanoma. Our purpose was to define the efficacy of ipilimumab according to the patient's baseline characteristics including absolute lymphocytes count. METHODS: We collected the data of 97 patients with advanced malign melanoma treated with ipilimumab (3 mg/kg, q3w) retrospectively. Log-rank test was used to analyze the univariate effects of patient's characteristics (age, gender, metastatic sites, ECOG PS, type of melanoma, lactic dehydrogenase levels, anemia, lymphocytes (L), neutrophils (N), N/L ratio), c-kit and BRAF status. Survival analyses were estimated with Kaplan-Meier method. Cox regression analysis was used to assess the possible factors identified with log-rank test. RESULTS: The median age was 58, and 58% were male and 90% of patients had at least one prior systemic therapy. The median survival was 9.7 months for all patients; and the 12- and 24-month survival rates were 43% and 19%, respectively. Absolute lymphocytes count, lactic dehydrogenase level, bone metastasis, the number of metastatic sites, and RECIST response were significantly related to survival. After Cox regression analysis, RECIST response (complete or partial response), absolute lymphocytes count (more than 1500/mm3) and the number of metastatic sites (less than three sites) remained as significant independent prognostic factors for longer survival. CONCLUSION: Ipilimumab improved survival of patients with metastatic malign melanoma. However, patients with fewer metastatic sites and higher absolute lymphocytes count have a significantly better benefit. To determine if these markers could be used to direct patient therapy, further validation analysis is needed.

Diagnostic serum vitamin D level is not a reliable prognostic factor for resectable breast cancer.

AIM: There are inconsistent results about the effects of vitamin D level on breast cancer prognosis. We aimed to investigate the effect of vitamin D levels on the prognosis of resectable breast cancer in a patient group with highly different clothing styles. PATIENTS & METHODS: A total of 186 breast cancer patients were enrolled in the study. RESULTS: Vitamin D level was sufficient, insufficient and deficient in 17.2, 52.2 and 30.6% of patients, respectively. There was a significant relationship between clothing style and serum 25 (OH) D levels. We could not establish any relation between vitamin D level and tumor characteristics or survival. CONCLUSION: Vitamin D supplementation can be more important than diagnostic serum vitamin D level on prognosis of breast cancer.

Severe drug interactions and potentially inappropriate medication usage in elderly cancer patients.

PURPOSE: Due to more comorbidities, polypharmacy is common in elderly patients and drug interactions are inevitable. It is also challenging to treat an elderly patient with a diagnosis of cancer. Prevalence and clinical impacts of drug interactions and using potentially inappropriate medications (PIMs) have been studied in geriatric patients. However, these are not well defined in oncology practice. The purpose of this study is to define the prevalence of PIMs and severe drug interactions (SDIs) in elderly cancer patients and investigate the factors associated with them. METHODS: Patients more than 65 years of age in both inpatient and outpatient clinics were evaluated. Patient, disease characteristics, and medications used were collected by self reports and medical records. Drug interactions were checked with Lexicomp® and PIM was defined with 2012 update of Beers criteria. Severe drug interactions are defined with category D or X DIs. Logistic regression was used to compute odds ratios (ORs) and 95 % confidence intervals (CIs) for the association between SDIs, PIMs, and clinical parameters. RESULTS: Four hundered and forty-five elderly patients (286 outpatient, 159 inpatient), with a median age of 70 (65-89) were evaluated. SDIs were present in 156 (35.1 %) of patients, 81 (28.3 %), and 75 (47.2 %) for outpatient and inpatients, respectively (p < 0.001). PIMs were present in 117 (26.6 %) of the patients, 40 (14.2 %), and 77(48.4 %) for outpatient and inpatients, respectively (p < 0.001). In multivariate analysis; polypharmacy (≥5 drugs), inpatient status and diagnosis of lung cancer were associated with severe DIs. Polypharmacy, inpatient status, and bad performance score (ECOG 3-4) were associated with PIMs. CONCLUSIONS: Nearly one third of the elderly cancer patients are exposed to severe drug interactions and PIMs. Clinicians dealing with elderly cancer patients should be more cautious when prescribing/ planning drugs to this group of patients. More strategies should be developed in this group of patients to minimize the medications prescribed and prevent severe DIs.

Vaccination in oncology practice and predictors.

PURPOSE: Despite, vaccination is a highly effective and widely recommended for prevention of certain infections, vaccination coverage is very low. The purposes of this study were to evaluate the attitudes of medical oncologists towards vaccination and to identify predictors of intention to recommend vaccination in patients with cancer. METHODS: A structured questionnaire is formed to evaluate the daily practice of vaccination. Turkish medical oncologists were invited to this study via email, SMS, or phone call. Questionnaire was filled out and the data were stored in an online survey platform. RESULTS: Two hundred seventy-three medical oncologists participated in the survey. Influenza, Pneumococcus, and hepatitis B were the most commonly recommended vaccines (87.1, 72.8, 67.0%, respectively). Patients with lung cancer, lymphoma and breast cancer were the main malignancies that medical oncologists suggest vaccination (68.1, 68.1, 24.6%, respectively). The most common times for vaccination were during remission/follow-up period (68.4%) or before beginning chemotherapy (64.1%). Only 23.4% of the physicians thought that their recommendation for vaccination was efficient and adequate. Lack of time and lack of knowledge or experience about vaccination are the most common limitations. There is a positive correlation between experience in the field and evaluating patients for vaccination (r = 0.390, p < 0.001); on the other hand, there is negative correlation between number of patients seen per day and evaluating patients for vaccination (r = -0.080, p = 0.18). Experience with autologous or allogeneic bone marrow transplant patients is related with more tendency to evaluate patients for vaccination (p < 0.001). CONCLUSIONS: Degree of experience in oncology especially in bone marrow transplant units and total number of patients seen per day are important predictors of vaccination practice in oncology. The frequency of recommendation increases with degree of experience, knowledge, and visit time per patient.

Breast cancer survivors suffer from persistent postmastectomy pain syndrome and posttraumatic stress disorder (ORTHUS study): a study of the palliative care working committee of the Turkish Oncology Group (TOG).

PURPOSE: Persistent postmastectomy pain syndrome (PMPS) is one of the most important disturbing symptoms. Posttraumatic stress disorder (PTSD) is an anxiety disorder which is characterized by reactions to reminders of the trauma that has been experienced. The purpose of this study is to evaluate the predictors of PMPS and PTSD in Turkish breast cancer survivors and the correlation between PMPS and PTSD. METHOD: The study is designed as a multicenter survey study. Breast cancer patients in remission were evaluated. Patients were evaluated with structured questionnaires to assess the PMPS and clinical parameters associated with it. The Turkish version of the posttraumatic stress disorder checklist-civilian version (PCL-C) was used. RESULTS: Between February 2015 and October 2015, 614 breast cancer survivors in outpatient clinics were evaluated. The incidence of PMPS documented is 45.1 %. In the multivariate analysis low income, presence of PTSD and <46 months after surgery were associated with increased risk of PMPS. PTSD was documented in 75 %, and the mean PCL-C score was 32.4 ± 11.1. PMPS and being married at the time of the evaluation were linked with PTSD. CONCLUSIONS: It is the first data about the association between PMPS and PTSD. The clinicians should be aware of PMPS and PTSD in breast cancer survivors.

The role of melatonin, sirtuin2 and FoXO1 transcription factor in the aging process of colon in male rats.

The protein family of sirtuins and FoXO1 transcription factor have been shown to play significant roles in the aging process. In this study we aimed to investigate the changes in the levels of SIRT2, NFκB and FoXO1 and oxidative parameters of colonic mucosa during aging, and the effects of exogenous melatonin (MLT). A total of twenty-four young (3-months-old) and aged (24 months old) male Wistar rats, divided into control [1% ethanol--phosphate-buffered saline (PBS), s.c. for 21 days] and melatonin (10 mg kg(-1) MLT 1% ethanol in PBS, s.c. for 21 days) were used in the study. The levels of malondialdehyde (MDA) as a parameter of lipid peroxidation, glutathione, NFkB pathway activation, SIRT2 expression, and FoXO1 transcription factor of colonic mucosa were assayed. The MDA levels and SIRT2 expression in the colonic mucosa were significantly increased in the aged group when compared to the younger group. However, the levels of FoXO1 transcription factor were significantly decreased in the aged group. Melatonin significantly decreased the MDA and SIRT2 expression levels of the colonic mucosa in the aged rats. In conclusion, our findings suggest a suppressive role of melatonin in the aging process of colonic tissue via decreasing SIRT2 expression.

Fighting against cigarette smoking among medical students: a success story.

A survey in the year 2007 among medical students of Ankara University Medical School to assess the smoking rates showed that 25.1 % of them were smoking. Moreover, the smoking rate was 35 % at sixth grade students and 60 % of the smokers specified that they started smoking at medical school. This report provides a successful approach to decrease smoking among medical students by measures against starting smoking. An "Antismoking Group" composed of voluntary academic staff, nurses, students, psychologists, and a social worker of the medical school was established to engage in lowering the smoking rate and eliminating it eventually among our students. Several methods including regular monthly meetings, annual "Smoking or Health" symposiums, and lectures to first, second, and third grade students to increase their awareness related to harms of smoking and their role in the fight against smoking were carried out. Our surveys in the years 2009 (641 students) and 2012 (975 students) showed that total smoking rates dropped to 15.0 and 11.0 %, respectively (p < 0.0002). Moreover, the smoking rate for the sixth grade students dropped from 35.0 % in 2007 to 21.8 and 8.8 % in the years 2009 and 2012, respectively (p < 0.0002). In 2012, the smoking rates of first year and sixth year students were 7.8 and 9.0 %, respectively. These close rates of smoking at the first and last years of medical school training and the significant drop in smoking rates in 5 years confirm that our group pursued a realistic and successful strategy against smoking.

WNT1 gene expression alters in heterogeneous population of prostate cancer cells; decreased expression pattern observed in CD133+/CD44+ prostate cancer stem cell spheroids.

PURPOSE: Established cancer cell lines contain cancer stem cells (CSCs) which can propagate to form three dimensional (3D) tumor spheroids in vitro. Aberrant activation of WNT signaling is strongly implicated in the progression of cancer and controls CSCs properties. In this study we hypothesized that when cells were maintained as spheroids, the structure of CSCs could show differentiation between CSCs and non- CSCs. METHODS: CD133+/CD44+ cancer-initiating cells were isolated from DU-145 human prostate cancer cell line monolayer cultures, propagated as tumor spheroids and compared with the remaining heterogeneous cancer cells bulk population. The expression levels of WNT1, FZD1, ADAR, APC, AXIN, BTRC, FRAT1 and PPARD genes were measured by polymerase chain reaction (PCR) array assay and the protein expression levels of WNT1, FZD and AXIN by immunohistochemistry. RESULTS: The expression levels of WNT pathway-related molecules were found to increase in both CSCs and non- CSCs when CSCs were maintained as spheroids. However, different expression profiles were observed when CSCs and non-CSCs were compared. In spheroids, the expression levels of FZD1, APC, ADAR, WNT1, PPARD genes in CSCs decreased when compared to non-CSCs. Interestingly, when CSCs from spheroids were compared with CSCs from monolayers the most significant decrease was observed in FZD1 and increase in APC genes. CONCLUSION: It is possible to assume that intracellular signaling of WNT-related molecules in the nucleus and/or cytoplasm might play an important role but it is independent from increased ligand expression and this expression strongly differentiate CSCs and non-CSCs population. This unexpected expression could be important for CSCs behavior and targeting this pathway could have therapeutic implications in cancer.

Incubation Temperature and Period During Denarase Treatment and Microfiltration Affect the Yield of Recombinant Adenoviral Vectors During Downstream Processing.

Adenoviral vectors (AV) are commonly used as vaccine and gene therapy vehicles because of their ease of construction, ability to grow to high titers in the large-scale production process, and safety for human applications. However, the efficiency rate of downstream processes for adenoviral vectors still varies greatly. In the current study, we aimed to investigate the effect of the downstream treatment protocol and microfiltration of the harvested upstream material on viral vector yield. We compared the performance of the repeated freeze-thaw (RFT) and the Tween-20 detergent lysis (DLT) methods. In addition, the effects of the cell lysis method, incubation temperature, and time on viral yield were investigated. The samples were incubated at either room temperature or 37 °C for 1-, 2-, and 4-h periods. Samples were filtered with PES and SFCA membrane. Virus yield and infectivity were assayed by qPCR and immuno-titration. In conclusion, our results suggest that 2-h incubation gives the best results when incubated at 37 °C for denarase activity when Tween-20 is used for virus recovery. If the room temperature is preferred, 4-h incubation could be preferred. A phase 1 clinical trial (NCT05526183, January 21, 2022) was started with the recombinant adenovirus used in the study.

The effects of anti-PD-L1 monoclonal antibody on the expression of angiogenesis and invasion-related genes.

Background/aim: The role of PD-L1 in regulating the immunosuppressive tumor microenvironment via its binding on PD-1 receptors is extensively studied. The PD-1/PD-L1 axis is a significant way of cancer immune escape, and PD-L1 expression on tumor cells is suggested as a predictive marker for anti-PD-1/PD-L1 monoclonal antibodies (MoAbs). However, the tumor-intrinsic role of PD-L1 is not known well. Therefore, we aimed to investigate the effects of anti-PD-L1 antibodies on the expression of angiogenesis and metastasis-related genes in tumor cells. Materials and methods: The experiments were done with prostate cancer and melanoma cells with low PD-L1 expression (<5%) and prostate and breast cancer cells with high PD-L1 expression (>50%). The gene and protein expressions of VEGFA, E-cadherin, TGFß1, EGFR, and bFGF in tumor cells were assayed at the 3 different doses of the anti-PD-L1 antibody. Results: We found that VEGFA, E-cadherin and TGFß1 expressions increased in PD-L1 high cells but decreased in PD-L1 low cells after anti-PD-L1 treatment. EGFR expression levels were variable in PD-L1 high cells, while decreased in PD-L1 low cells upon treatment. Also, the anti-PD-L1 antibody was found to increase bFGF expression in the prostate cancer cell line with high PD-L1 expression. Conclusion: Our results suggest that the binding of PD-L1 on tumor cells by an anti-PD-L1 monoclonal antibody may affect tumor-intrinsic mechanisms. The activation of angiogenesis and metastasis-related pathways by anti-PD-L1 treatment in PD-L1 high tumors might be a tumor-promoting mechanism. The decrease of VEGFA, TGFß1 and EGFR upon anti-PD-L1 treatment in PD-L1 low tumor cells provides a rationale for the use of those antibodies in PD-L1 low tumors.

Genomic Landscape of Actionable Mutations in Primary and Metastatic Tissues of Colon Adenocarcinoma.

Aim To assess the actionable genomic landscape of colon adenocarcinoma in the primary and metastatic tumor tissues. Methods The data from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) were used in this study. Colon adenocarcinoma patients with primary and metastatic tissue samples (distant organ and lymph node) were selected. Patients with samples from a local recurrence, not otherwise specified tumor samples, and data not collected for sampling localization were excluded. Results A total of 3286 and 1727 patients were included in the primary and metastatic tissue sample groups, respectively. There was no difference between the groups in Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation rates. The rates of v-Raf murine sarcoma viral oncogene homolog B (BRAF) and mismatch repair (MMR) gene mutations were higher in the primary tumor tissues than in the metastatic tumor tissues. There was also no difference between the groups in other actionable gene alterations (e.g. ERBB2 amplification and neurotrophic receptor tyrosine kinase (NTRK) 1 and NTRK3 fusions). In contrast to all cohorts, in Asian and black patients, there was no difference in actionable genomic landscape between the primary and metastatic tumor tissues. Conclusion This study had the largest number of colon cancer patients that evaluated the actionable genomic alterations in primary and metastatic tumor tissues. BRAF and MMR gene alterations were more frequent in the primary tumor tissues than the metastatic tumor tissues.

SIRT2 and FOXO3a expressions in the cerebral cortex and hippocampus of young and aged male rats: antioxidant and anti-apoptotic effects of melatonin.

Melatonin has antioxidant, anti-apoptotic and anti-aging effects in the brain. Sirtuin2 (SIRT2) accumulates in the central nervous system with aging, and its inhibition appears to be protective in aging and aging-related neurodegenerative diseases. Forkhead Box-class O3a (FOXO3a) transcription factor is one of the main targets of SIRT2, and SIRT2-mediated FOXO3a deacetylation is closely related to aging, oxidative stress, and apoptosis. This study aimed to investigate the effects of melatonin on SIRT2 and FOXO3a expressions in the cerebral cortex and hippocampus of aged rats. Young (3 months, n = 18) and aged (22 months, n = 18) male Wistar rats were divided into control (4% DMSO-PBS, sc, for 21 days), melatonin (10 mg/kg, sc, for 21 days) and salermide (1 mM; 25 µl/100 g bw, ip, for 21 days) groups. SIRT2, FOXO3a, Bcl-2, Bax and Bim expressions in the cerebral cortex and hippocampus were demonstrated by Western blotting. SIRT2 and FOXO3a protein levels were also measured by a sandwich ELISA method. Oxidative stress index (OSI) was calculated by measuring total oxidant status (TOS) and total antioxidant status (TAS). Aging increased SIRT2, FOXO3a, Bim (only in the cerebral cortex), Bax (only in the hippocampus), TOS, and OSI, while decreasing Bcl-2, Bcl-2/Bax and TAS in both brain regions. Melatonin decreased SIRT2, FOXO3a, oxidative stress parameters and pro-apoptotic proteins, while increasing TAS, Bcl-2 and Bcl-2/Bax, more specifically in the hippocampus of the aged brain. Our results indicate that inhibition of SIRT2 and FOXO3a expressions appears to be involved in the protective effects of melatonin in the hippocampus of aged rats.