Adjuvant Concurrent Chemoradiotherapy (CRT) plus Docetaxel-Cisplatin-Fluorouracil (DCF) versus CRT plus Fluorouracil-Folinic Acid (FUFA) in Stage III Gastric Cancer.

INTRODUCTION: Adjuvant chemoradiotherapy (CRT) is the optimal management strategy in resectable gastric cancer. There is a debate about the efficacy of more aggressive CRT plus chemotherapy regimens in adjuvant setting. This study aimed to compare the efficacy of adjuvant CRT plus docetaxel-cisplatin-fluorouracil (DCF) versus CRT plus fluorouracil-folinic acid (FUFA) in stage III gastric cancer. METHODS: Patients with a diagnosis of stage III gastric cancer treated with adjuvant therapy after curative resection were analyzed. Patients' disease characteristics and impacts of the regimens on median disease-free survival (DFS) and median overall survival (OS) were analyzed retrospectively. RESULTS: One hundred sixty-one patients (102 in FUFA arm and 59 in DCF arm) with a median age of 56.0 (29-79) were evaluated. In the DCF arm, there were more renal toxicities (31.6% vs 6.4% P < 0.001), emergency department admissions (64.9% vs 23.7%, P < 0.001), and dose reductions/treatment modifications in the DCF arm (51.6% vs 37.2, P < 0.001). The median follow-up was 23 months (1-124) in the FUFA arm and 26.0 months (1-77) in the DCF arm. The median DFS was 25.0 months (%95 CI, 12.7-37.2) in the DCF arm and 17.0 months (%95 CI, 2.6-31.3) in the FUFA arm, P = 0.66. The median OS was 28.0 months (%95 CI, 17.0-38.9) in the DCF arm and 25.0 months (%95 CI, 11.9-36.0) in the FUFA arm, P = 0.70. CONCLUSION: In conclusion, when compared with FUFA regimen, more aggressive therapy with DCF was more toxic and did not improve OS in adjuvant setting of stage III gastric cancer.

Impact of low sodium values on survival outcomes of patients with cancer receiving immune checkpoint inhibitors.

Background: Low serum sodium affects cancer prognosis, but its impact on immunotherapy is unclear. Objective: Assessing the association of pre- and post-ICI treatment sodium levels with survival. Methods: We retrospectively analyzed patients receiving ICI in January 2012-December 2023, collecting serum sodium levels at treatment initiation and 4 weeks post-ICI, with overall survival (OS) as the primary outcome. Results: Low sodium was observed in 125 and 119 patients pre-and post-treatment respectively. Pre-ICI and post-ICI low sodium correlated with decreased OS [10.6 vs. 22.9 months (p = 0.001) and 11.6 vs. 27.2 months (p = 0.009)]. Multivariate analysis identified pre-ICI low sodium [HR: 1.685; 95% CI: 1.050-2.705; p = 0.031] as an independent risk factor for worse OS. Conclusion: Low baseline serum sodium was an independent risk factor for poor OS in patients treated with ICIs.

This study explored how sodium levels impact cancer patients' outcomes during treatment with immune checkpoint inhibitors (ICIs). We examined sodium levels before and after ICI treatment in patients with cancer. Low sodium levels both before and after treatment were associated with poorer outcomes. Specifically, patients with low sodium levels before treatment had shorter survival times compared to those with normal levels. Similarly, patients with low sodium levels after treatment had shorter survival times compared to those with normal levels. These findings suggest that low baseline sodium levels could indicate poorer outcomes in patients receiving ICIs.

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.

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.

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.

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 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.

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.

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.

Systemic Immune-Inflammation Index as a Prognostic Marker of Late Recurrence in Operable Gastric Cancer: a Dual-Center Study.

AIM: To evaluate the prognostic role of the systemic immune-inflammation index (SII) in patients with operable gastric cancer. METHODS: We assessed 354 patients with operable gastric cancer from tertiary centers in Turkey. SII was calculated by following formula: [neutrophil (cells × 109/L) × platelet (cells × 109/L)]/lymphocyte (cells × 109/L). The best cut-off value for SII was determined by using "receiver operating characteristics (ROC)" analysis. We used log-rank and Cox-regression analysis for survival analyses. RESULTS: One hundred twenty patients were in the late recurrence group (recurrences have developed 36 months after the surgery). SII was not a prognostic factor in the early recurrence group. However, relapse-free survival (RFS) was longer in SII-low patients than SII-high patients in the late recurrence group. In multivariable analysis, SII was the only independent prognostic factor for RFS in the late recurrence group (hazard ratio (HR): 5.42, 95% CI: 1.18-24.82, p = 0.03). CONCLUSION: SII was an independent prognostic factor for RFS in GC patients with late recurrence. Late recurrence risk was higher in SII-high patients than SII-low patients. Inflammation contributes to tumor progression, invasion, and metastasis. Prolonged exposure to chronic inflammation could explain the results of this study.

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.

Characteristics of Newly Diagnosed Hepatocellular Carcinoma Patients Across Turkey: Prospective Multicenter Observational 3K Registry Study.

AIMS: To evaluate patient profile for epidemiological and clinicopathological characteristics and potential risk/prognostic factors in newly diagnosed hepatocellular carcinoma (HCC) patients across Turkey. METHODS: A total of 547 patients (mean (SD) age 62.6 (10.3) years, 81.9% were males) were included in this registry study. Data on patient characteristics, etiologies of HCC, laboratory values, and tumor characteristics and stages were recorded at study enrollment. RESULTS: HBV infection (68.2%) was the leading etiology, followed by HCV infection (17.2%), HDV infection (5.5%), alcohol (6.4%), and NAFLD (3.5%), as the major etiologies. Considering that 51.6% of the patients had >5 cm HCC, 44% were Child-Pugh B/C and 57% were BCLC B-D, it appears that a significant group of HCC patients were diagnosed at advanced stages. Of 540 patients, 271 (50.2%) were referred or applied with the diagnosis of HCC. Patients with HCC at presentation had larger tumor size (median (min-max) 6.6 (0-30) vs. 4.8 (0-90) cm, P < .001) and more advanced BCLC stage (Stage C-D in 40.8% vs. 26.4%, respectively, P = .005), compared to patients who were diagnosed during follow-up. CONCLUSIONS: Our findings revealed that HBV infection was the leading etiology and a moderate-to-advanced disease was evident in more than half of patients at the time of diagnosis. HCC patients diagnosed at follow-up had smaller tumor size and earlier BCLC stage.

Adjuvant Treatment of Gastric Cancer in the D2 Dissection Era: A Real-life Experience from a Multicenter Retrospective Cohort Study.

BACKGROUND: The role of radiotherapy in the adjuvant treatment of gastric cancer (GC) remains to be elucidated. This study aimed to assess the additional benefit of radiotherapy in the adjuvant treatment of GC. MATERIALS AND METHODS: In this retrospective cohort study, we included 230 gastric adenocarcinoma patients who underwent D2 dissection between January 2004 and December 2019. Patients without R0 resection, who underwent metastasectomy at surgery, and treated with the neoadjuvant treatment were excluded. The co-primary endpoints were overall survival (OS) and disease-free survival (DFS). The secondary endpoints were the locoregional and distant metastasis risk and adverse events (AEs) leading to treatment discontinuation. RESULTS: One hundred and sixty-six and 64 patients were included in the chemoradiotherapy (CRT) and chemotherapy (ChT) arms, respectively. The median OS was 135.8 months [interquartile range (IQR): 99.4-172.2] and 97 months (IQR: 59.7-134.3) in the CRT and the ChT arms, respectively. No statistical significance was observed between the arms in OS (p = 0.3). Locoregional or distant recurrence rates were similar in each group. AEs leading to treatment discontinuation were higher in the CRT arm than in the ChT arm (13.2 vs 9.3%), and the difference between the arms was not statistically significant (p = 0.4). CONCLUSION: In this real-life study, we established that there was no additional benefit of RT in GC patients who underwent D2 dissection. HOW TO CITE THIS ARTICLE: Yekedüz E, Dogan I, Birgi SD, et al. Adjuvant Treatment of Gastric Cancer in the D2 Dissection Era: A Real-life Experience from a Multicenter Retrospective Cohort Study. Euroasian J Hepato-Gastroenterol 2021;11(2):51-58.

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.

Osteopontin is a Prognostic Factor in Patients with Advanced Gastric Cancer.

OBJECTIVE: Osteopontin (OPN), a phosphorylated sialoprotein, has been shown to overexpress in a variety of cancers and to contribute tumor progression and metastasis by increasing cell migration and adhesion. In the current study, we aimed to investigate the prognostic and predictive role of OPN in patients with advanced gastric cancer. METHODS: A total of 42 consecutive chemonaive patients with advanced gastric cancer and 29 healthy controls were included. The patients were treated with a modified DCF regimen. The blood samples were obtained before each chemotherapy cycle from the patients and once from the healthy controls. The plasma OPN is measured by ELISA. RESULTS: The overall response and disease stabilization rates were 25% and 72%, respectively. The median serum OPN level of the patient group was significantly higher compared to healthy controls (176.9 ng/ml (range: 41.5 -521.4) vs 64.3 ng/ml (range 42.1-105.3 ng/ml), p<0.0001). The median overall survival time was 7.0 ± 1.1 (95% CI: 4.9-9.2) months and 1-year overall survival rate was 20.8%. The patients who responded to mDCF had lower plasma OPN levels than the non-responding ones (110.7±29.3 ng/mL, 211.9±24.4 ng/mL respectively, p=0.002). The performance status and the plasma OPN levels were found to be significant factors for overall survival in the multivariate analysis (p=0.004 and 0.016, respectively). CONCLUSION: The serum OPN seems to be a novel significant prognostic and predictive factor in patients with advanced gastric cancer who were treated with DCF regimen.

Impact of the COVID-19 Pandemic on Cancer Care: A Global Collaborative Study.

PURPOSE: The COVID-19 pandemic affected health care systems globally and resulted in the interruption of usual care in many health care facilities, exposing vulnerable patients with cancer to significant risks. Our study aimed to evaluate the impact of this pandemic on cancer care worldwide. METHODS: We conducted a cross-sectional study using a validated web-based questionnaire of 51 items. The questionnaire obtained information on the capacity and services offered at these centers, magnitude of disruption of care, reasons for disruption, challenges faced, interventions implemented, and the estimation of patient harm during the pandemic. RESULTS: A total of 356 centers from 54 countries across six continents participated between April 21 and May 8, 2020. These centers serve 716,979 new patients with cancer a year. Most of them (88.2%) reported facing challenges in delivering care during the pandemic. Although 55.34% reduced services as part of a preemptive strategy, other common reasons included an overwhelmed system (19.94%), lack of personal protective equipment (19.10%), staff shortage (17.98%), and restricted access to medications (9.83%). Missing at least one cycle of therapy by > 10% of patients was reported in 46.31% of the centers. Participants reported patient exposure to harm from interruption of cancer-specific care (36.52%) and noncancer-related care (39.04%), with some centers estimating that up to 80% of their patients were exposed to harm. CONCLUSION: The detrimental impact of the COVID-19 pandemic on cancer care is widespread, with varying magnitude among centers worldwide. Additional research to assess this impact at the patient level is required.

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.

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).

Application of vascular endothelial growth factor at different phases of intestinal ischemia/reperfusion: What are its effects on oxidative stress, inflammation and telomerase activity?

BACKGROUND: Intestinal ischemic reperfusion injury (IRI) represents a great challenge in clinical practice, with high morbidity and mortality. Vascular endothelial growth factor (VEGF), as a signal protein, contributes to vasculogenesis and angiogenesis. OBJECTIVES: To evaluate the local effectiveness of VEGF following intestinal IRI and its relation with application time. MATERIAL AND METHODS: Thirty Wistar albino rats were allocated to 5 groups and underwent laparotomy. The superior mesenteric arteries (SMA) were dissected in 4 groups, while the control group (Gr C) underwent a resection of small and large intestines. The VEGF group (Gr V) received VEGF following SMA dissection, with no further intervention, and the remaining 3 groups were subjected to ischemia for 90 min through occlusion of SMA and reperfusion for 4 h. Ischemic reperfusion group (Gr I/R) received no additional medication, while the remaining 2 groups received VEGF just before ischemia (Gr V+I/R) and during reperfusion (Gr I/R+V). RESULTS: Both applications of VEGF caused decreases in plasma levels of interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), intestinal malondialdehyde (MDA), oxidized glutathione, protein carbonyl levels, and increases in intestinal total glutathione and superoxide dismutase (SOD) levels. Telomerase activity, which disappeared for Gr I/R, was found to be elevated following both treatment groups. Similarly, the histopathological scores were found better for both treatment groups, but Gr V-I/R represented best outcomes. CONCLUSIONS: The findings of our study revealed that VEGF, applied either before ischemia or during reperfusion, is effective on local damage following intestinal IRI. By interpreting the biochemical analysis and histopathological findings, we conclude either treatment option to be considered according to the reason of intestinal IRI.