Real-world treatment outcomes from nationwide Onco-colon Turkey registry in RAS wild-type patients treated with biologics second-line mCRC.

BACKGROUNDS AND OBJECTIVES: Colorectal cancer is one of the leading causes of mortality both globally and in our country. In Turkey, we conducted a multicenter investigation into the effectiveness of second-line treatments and real-life data for patients with RAS wild-type metastatic colorectal cancer (NCT04757311). MATERIALS AND METHODS: In this retrospective analysis, records from 28 centers were collected, and histopathological, molecular, and clinical characteristics were documented. Patients were categorized into groups based on their second-line biological treatments: anti-EGFR (Group A and Group B, panitumumab and cetuximab) and anti-VEGF (Group C, bevacizumab and aflibercept). They were then compared within these groups. RESULTS: A total of 588 patients with documented RAS wild-type status were evaluated. The median OS was 15.7, 14.3 and 14.7 months in Group A, Group B and Group C, respectively (p = 0.764). The median PFS of the patients in second-line setting that received panitumumab, cetuximab and bevacizumab/aflibercept were 7.8, 6.6 and 7.4 months, respectively (p = 0.848). CONCLUSION: According to the results of our real-life data study, there is no significant difference in efficiency between the combination of biological agent and chemotherapy used in the second-line treatments.

Comparing the efficacy of regorafenib and 5-fluorouracil-based rechallenge chemotherapy in the third-line treatment of metastatic colorectal cancer.

BACKGROUND: The optimal treatment for metastatic colorectal cancer (mCRC) after the second line is still controversial. Regorafenib has been the standard of care in this setting as it improved overall survival (OS) compared to placebo. In real-world practice chemotherapy rechallenge is also a preferred option even though supporting evidence is not enough. We aim to compare the efficacy of regorafenib and 5-fluorouracil-based (5-FU) rechallenge treatment in the third line setting of mCRC. METHODS: In this retrospective multi-institutional trial, mCRC patients from 21 oncology centers who progressed after 2 lines of chemotherapy were analyzed. Patients who were treated with regorafenib or rechallenge therapy in the third-line setting were eligible. Rechallenge chemotherapy was identified as the re-use of the 5-FU based regimen which was administered in one of the previous treatment lines. OS, disease control rate (DCR), progression free survival (PFS) and toxicity were analyzed. RESULTS: Three hundred ninety-four mCRC patients were included in the study. 128 (32.5%) were in the rechallenge, and 266 (67.5%) were in the regorafenib group. Median PFS was 5.82 months in rechallenge and 4 months in regorafenib arms (hazard ratio:1.45,95% CI, p = 0.167). DCR was higher in the rechallenge group than regorafenib (77% vs 49.5%, respectively, p = < 0.001). Median OS after the third-line treatment was 11.99 (95% CI, 9.49-14.49) and 8.08 months (95% CI, 6.88-9.29) for rechallenge and regorafenib groups, respectively (hazard ratio:1.51, 95% CI, p < 0.001). More adverse effects and discontinuation were seen with regorafenib treatment. CONCLUSION: Our study revealed that higher disease control and OS rates were achieved with rechallenge treatment compared to regorafenib, especially in patients who achieved disease control in one of the first two lines of therapy.

Effect of the MiR-99b and MiR-135b on peritoneal carcinomatosis and liver metastasis in colorectal cancer.

AIM: This study aimed to evaluate the expression levels of miR-99b and miR-135b in peritoneal carcinoma and liver metastases associated with Colorectal Cancer (CRC), assess their association with the intracellular signaling pathway proteins Kirsten Rat Sarcoma Virus (KRAS) and Akt, and investigate their effects on survival. MATERIALS AND METHODS: Changes in the KRAS gene and Akt proteins, expression levels of miR-99b and miR-135b, and factors affecting survival were compared between colorectal cancer-associated peritoneal carcinomatosis and liver metastasis. RESULTS: The expression levels of miR-99b and miR-135b and the immunohistochemical grade classification score of Akt were higher in colorectal cancer, peritoneal carcinomatosis, and liver metastasis than in normal tissues (p < 0.05). MiR-99b expression was highest in CRC, whereas miR-135b expression was highest in peritoneal carcinomatosis (p < 0.05). The expression level of miR-99b decreased and that of miR-135b increased in peritoneal and liver metastases compared with that in the tumor tissue. MiR-99b, Akt, and recurrence were risk factors that affected the overall survival rate in the model of clinical predictions (p = 0.045, p = 0.006, and p = 0.012, respectively). CONCLUSION: While the expression of miR-99b was highest in the primary tumor, its decrease in liver metastasis and peritoneal carcinomatosis suggests that miR-99b has a protective effect against liver metastasis and peritoneal carcinomatosis. However, the detection of miR-135b expression was highest in peritoneal carcinomatosis and liver metastasis compared with that in the colorectal cancer tissues suggesting that it facilitates peritoneal carcinomatosis and liver metastasis. Furthermore, miR-99b, KRAS mutations, and Akt are risk factors for the overall survival of colorectal cancer.

Prospective analysis of febrile neutropenia patients with bacteraemia: the results of an international ID-IRI study.

OBJECTIVES: Bacteraemia during the course of neutropenia is often fatal. We aimed to identify factors predicting mortality to have an insight into better clinical management. METHODS: The study has a prospective, observational design using pooled data from febrile neutropenia patients with bacteraemia in 41 centres in 16 countries. Polymicrobial bacteraemias were excluded. It was performed through the Infectious Diseases-International Research Initiative platform between 17 March 2021 and June 2021. Univariate analysis followed by a multivariate binary logistic regression model was used to determine independent predictors of 30-d in-hospital mortality (sensitivity, 81.2%; specificity, 65%). RESULTS: A total of 431 patients were enrolled, and 85 (19.7%) died. Haematological malignancies were detected in 361 (83.7%) patients. Escherichia coli (n = 117, 27.1%), Klebsiellae (n = 95, 22% %), Pseudomonadaceae (n = 63, 14.6%), Coagulase-negative Staphylococci (n = 57, 13.2%), Staphylococcus aureus (n = 30, 7%), and Enterococci (n = 21, 4.9%) were the common pathogens. Meropenem and piperacillin-tazobactam susceptibility, among the isolated pathogens, were only 66.1% and 53.6%, respectively. Pulse rate (odds ratio [OR], 1.018; 95% confidence interval [CI], 1.002-1.034), quick SOFA score (OR, 2.857; 95% CI, 2.120-3.851), inappropriate antimicrobial treatment (OR, 1.774; 95% CI, 1.011-3.851), Gram-negative bacteraemia (OR, 2.894; 95% CI, 1.437-5.825), bacteraemia of non-urinary origin (OR, 11.262; 95% CI, 1.368-92.720), and advancing age (OR, 1.017; 95% CI, 1.001-1.034) were independent predictors of mortality. Bacteraemia in our neutropenic patient population had distinctive characteristics. The severity of infection and the way to control it with appropriate antimicrobials, and local epidemiological data, came forward. CONCLUSIONS: Local antibiotic susceptibility profiles should be integrated into therapeutic recommendations, and infection control and prevention measures should be prioritised in this era of rapidly increasing antibiotic resistance.

The cytotoxic effects of indoleamine 2, 3-dioxygenase inhibitors on triple negative breast cancer cells upon tumor necrosis factor α stimulation.

Context: Overexpressed indoleamine 2,3-dioxygenase (IDO) has been observed in many types of cancer and plays an essential role in the tumor microenvironment through immune cells function. Aims: In our study, the therapeutic potentials of two different IDO inhibitors (Epacadostat [EPA] and 1-methyl-L-tryptophan [L-1MT]) in triple-negative breast cancer (TNBC) cells were assessed with and without tumor necrosis factor-α (TNF-α) stimulation. Materials and Methods: The anticancer activity of EPA and L-1MT alone and in combination with TNF-α was analyzed by WST-1, annexin V, cell cycle analysis, and acridine orange/ethidium bromide staining. In addition, the relationship between IDO1 and programmed death-ligand 1 (PD-L1) expressions in TNBC cells upon treatment with IDO inhibitors was evaluated by reverse transcription-polymerase chain reaction analysis. Statistical Analysis Used: SPSS 22.0 was conducted for statistical analysis. The one-way analysis of variance with Tukey's multiple comparison test was performed for multiple groups. Independent (unpaired) t -test was used for the comparison of two groups. Results: EPA and L-1MT alone significantly suppressed the TNBC cell viability through the induction of apoptotic cell death and G0/G1 arrest (P < 0.05). TNF-α alone induced the overexpression of IDO1 and PD-L1 in TNBC cells compared with MCF-10A control cells. However, IDO inhibitors significantly inhibited overexpressed IDO1 mRNA levels. Furthermore, EPA alone and co-treated with TNF-α suppressed the mRNA level of PD-L1 in TNBC cells. Therefore, TNF-α stimulation enhanced the therapeutic effects of IDO inhibitors on TNBC. Conclusions: Our findings showed that the efficacy of IDO inhibitors was mediated by pro-inflammatory cytokine. However, different molecular signaling pathways are associated with pro-inflammatory cytokines production, and the expression of IDO1 and PD-L1 calls for further investigations.

The prognostic and predictive values of differential expression of exosomal receptor tyrosine kinases and associated with the PI3K/AKT/mTOR signaling in breast cancer patients undergoing neoadjuvant chemotherapy.

PURPOSE: Cancer cell-derived exosomes are the mediator of the tumor microenvironment and the molecular content of exosomes presents a promising prognostic or predictive marker in tumor progression and the treatment response of cancer patients. The aim of this study was to identify the expression levels of receptor tyrosine kinases (RTKs) and AKT1 and mTOR before and after neoadjuvant chemotherapy (NACT) in the exosomes of BC patients compared with healthy females. METHODS: After isolating exosomes in the serum of 25 BC patients and characterization by flow cytometry, the mRNA levels of FGFR2, FGFR3, PDGFRB, AKT1 and mTOR in the exosomes were analyzed by RT-PCR. RESULTS: Our preliminary findings showed that FGFR2, PDGFRB, AKT1 and mTOR levels were significantly upregulated in BC patients before NACT compared with the healthy group (p < 0.05). Furthermore, the mRNA levels PDGFRB and AKT1 were significantly down-regulated after NACT compared with control. PDGFRB expression level could predict pathological non-response and significantly correlated with tumor size after NACT. CONCLUSION: Therefore, especially FGFR2, PDGFRB and AKT1 could be a therapeutic target as a prognostic marker, whereas PDGFRB may be a promising predictive indicator of therapy response in BC patients. However, the prognostic or predictive role of RTKs and PI3K/AKT/mTOR signaling in the exosomes should be further investigated in a large patient population.

Effect of the MiR-99b and MiR-135b on peritoneal carcinomatosis and liver metastasis in colorectal cancer

Abstract Aim This study aimed to evaluate the expression levels of miR-99b and miR-135b in peritoneal carcinoma and liver metastases associated with Colorectal Cancer (CRC), assess their association with the intracellular signaling pathway proteins Kirsten Rat Sarcoma Virus (KRAS) and Akt, and investigate their effects on survival. Materials and methods Changes in the KRAS gene and Akt proteins, expression levels of miR-99b and miR-135b, and factors affecting survival were compared between colorectal cancer-associated peritoneal carcinomatosis and liver metastasis. Results The expression levels of miR-99b and miR-135b and the immunohistochemical grade classification score of Akt were higher in colorectal cancer, peritoneal carcinomatosis, and liver metastasis than in normal tissues (p< 0.05). MiR-99b expression was highest in CRC, whereas miR-135b expression was highest in peritoneal carcinomatosis (p< 0.05). The expression level of miR-99b decreased and that of miR-135b increased in peritoneal and liver metastases compared with that in the tumor tissue. MiR-99b, Akt, and recurrence were risk factors that affected the overall survival rate in the model of clinical predictions (p= 0.045, p= 0.006, and p= 0.012, respectively). Conclusion While the expression of miR-99b was highest in the primary tumor, its decrease in liver metastasis and peritoneal carcinomatosis suggests that miR-99b has a protective effect against liver metastasis and peritoneal carcinomatosis. However, the detection of miR-135b expression was highest in peritoneal carcinomatosis and liver metastasis compared with that in the colorectal cancer tissues suggesting that it facilitates peritoneal carcinomatosis and liver metastasis. Furthermore, miR-99b, KRAS mutations, and Akt are risk factors for the overall survival of colorectal cancer.

The Anticancer Potential of Chlorine Dioxide in Small-Cell Lung Cancer Cells.

Background Chlorine dioxide (ClO2) is an effective disinfectant consisting of oxygen, chloride, and potassium. Because of its high oxidative capacity, ClO2 exerts antimicrobial, antiviral, and antifungal effects. However, its anticancer effects remain to be elucidated. Methodology The anticancer activity of CIO2 was assessed on DMS114 small-cell lung cancer (SCLC) cells and human umbilical vein endothelial cells (HUVEC) as control by WST-1, Annexin V, cell cycle analysis, and acridine orange staining. We for the first time investigated the possible therapeutic effects of long-term stabilized ClO2 solution (LTSCD). Results Our preliminary findings showed that LTSCD significantly inhibited the proliferation of SCLC cells (p < 0.01) with less toxicity in HUVEC cells. Additionally, LTSCD induced apoptotic cell death in SCLC cells through nuclear blebbing and vacuolar formation. However, LTSCD treatment did not induce cell cycle arrest in both cell lines. Conclusions LTSCD can be a therapeutic potential for the treatment of SCLC. However, further investigations are required to assess the LTSCD-induced cell death in SCLC both in vitro and in vivo.

Predicting the Overall Survival in Patients with Advanced Pancreatic Cancer by Calculating L3 Skeletal Muscle Index Derived from CT.

BACKGROUND: Pancreatic cancer is mostly diagnosed in advanced stages, and treatment results are not satisfactory. L3 skeletal muscle index (SMI) has emerged as a prognostic factor in pancreatic cancer patients. We aimed to assess the association between sarcopenia and overall survival in patients with pancreatic cancer in this study. METHODS: Patients who were admitted to the Department of Oncology between March 2012 and December 2019 and diagnosed with pancreatic cancer were evaluated. The computerized tomography images and laboratory parameters of a total of 115 patients were included in this retrospective singlecenter study. We defined sarcopenia as an SMI <43,56 cm²/m² for females and <56,44 cm²/m² for males using the receiver operating characteristics (ROC) curve in the study population. Univariate and multivariate analyses were performed by using Cox-regression modelling, and survival curves were constructed by using Kaplan-Meier method. RESULTS: 70% of the patients were male, and the mean age was 64.9±9.9 years (mean ± SD). 70.6% of female patients and 67.9% of male patients were diagnosed with stage 4 cancer. The prevalence of sarcopenia in the whole patient group was 29.6%. By multivariate analysis, SMI (p=0.009) and advanced stage (p=0.003) were found as poor prognostic factors for overall survival (OS). The neutrophil to lymphocyte ratio (NLR) was statistically significantly higher in sarcopenic patients than in nonsarcopenic patients (p=0.031). CONCLUSION: Patients having sarcopenia at the time of diagnosis may demonstrate poorer overall survival of pancreatic cancer, and SMI may be considered as a potential prognostic factor.

Morbidity and long-term results in patients with wild and mutant type Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations undergoing colorectal cancer surgery.

BACKGROUND: In colorectal cancer (CRC), the mutation of the K(N)RAS gene has a significant impact on the clinical course, and is associated with a negative prognosis. We aim to present the morbidity and long-term results in patients with wild/mut-K(N)RAS, undergoing CRC surgery. METHODS: A total of 116 patients who underwent surgery for colorectal cancers with wild/mut-K(N)RAS were included in this retrospective study. The patients were divided into two groups: wild-K(N)RAS patients (Group 1) and mutant- K(N)RAS patients (Group 2). Results were evaluated for clinical, operative, morbidity and long-term survival outcomes. MATERIALS AND METHODS: The highest surgical site infection (SSI) rate (OR=140.339)(4.303-4581.307)(P=0.005) was seen in patients given Bevacizumab during neoadjuvant treatment. Meanwhile, the SSI site infection rate was at its lowest in cases where minimally invasive surgery was preferred (OR=0.062)(0.006-0.628)(P=0.019). In addition, the overall median survival rate for the total cohort was 38±3.1 (31-44) months. Multivariate analysis showed that CEA (>5ng/mL)(HR 2.94)(1.337-6.492))(P=0.007); tumor stage (P=0.034), T(T4) stage (HR 1.91)(1.605-252.6)(P=0.02); metastasectomy/ablation (HR 0.19)(0.077-0.520)(P=0.001); the number of removed metastatic lymph nodes (HR 1.08)(1.010-1.155)(P=0.025); tumor implant or nodule (HR 2.71)(1.102-6.706)(P=0.03); curative resection (HR 2.40)(0.878-6.580)(P=0.042) to be factors affecting the overall survival rate. CONCLUSION: Treatment with Bevacizumab during the neoadjuvant period in mut-K(N)RAS cases, surgical technique and complications of Grade 3 or higher are risk factors for SSI on morbidity in patients with mut/wild-K(N)RAS undergoing colorectal cancer surgery. Moreover, CEA (>5ng/mL), tumor stage, T stage, metastasectomy/ablation, the number of removed metastatic lymph nodes, tumor implant/nodule and curative resection are risk factors on the overall survival rate. KEY WORDS: Bevacizumab, Colorectal cancer, K(N)RAS mutation, Morbidity, Mortality.

Efficacy of 5-aminolevulinic acid-based photodynamic therapy in different subtypes of canine mammary gland cancer cells.

Canine mammary gland tumors (CMGTs) are heterogeneous disease and subclassified [sarcomas (S), carcinomas (C), and carcinosarcomas (CS)] according to histopathological differentiation. Photodynamic therapy (PDT) is a promising treatment strategy based on the use of a photosensitizer (PS) activated by light. However, the therapeutic potential of PDT in the treatment of CMGTs has not been investigated, yet. Therefore, the aim of this study was to determine the in vitro protocol of 5-ALA-based-PDT for the treatment of three subtypes of CMGTs, for the first time. The intracellular PpIX florescence intensity was measured for 5-ALA (0.5 and 1 mM). After irradiation with different light doses (6, 9, 12, 18, and 24 J/cm2) for two different modes [continuous wave (CW) and pulse radiation (PR)], the cytotoxic effects of 5-ALA (0.5 and 1 mM) on the subtypes (C, S, and CS) of CMGTs were analyzed by WST-1. Finally, the optimal PDT treatment protocol was validated through Annexin V and AO/EtBr staining. Our results showed that 1 mM 5-ALA for 4-h incubation was the best treatment condition in all subtypes of CMGTs due to higher intracellular PpIX level. After irradiation with different light doses, PR mode was more effective in S primary cells at 9 J/cm2. However, a significant decrease in the viability of C and CS cells was detected at 12 /cm2 in CW mode (p < 0.05). Additionally, 1 mM 5-ALA induced apoptotic cell death in each subtype of CMGTs. Our preliminary findings suggest that (i) each subtype of CMGTs differentially responds to PDT and (ii) the light dose and mode could play an important role in the effective PDT treatment. However, further studies are needed to investigate the role of the different light sources and PDT-based apoptotic cell death in CMGTs cells.

Mechanisms of abemaciclib, a CDK4/6 inhibitor, induced apoptotic cell death in prostate cancer cells in vitro.

The therapeutic effects of abemaciclib (ABE), an inhibitor of cyclin- dependent kinases (CDK) 4/6, on the proliferation of two types of prostate cancer (PC) cells were revealed. In this study, in vitro cytotoxic and apoptotic effects of ABE on metastatic castration-resistant prostate cancer (mCRPC) androgen receptor (AR) negative PC-3 and AR mutant LNCaP PC cells were analyzed with WST-1, Annexin V, cell cycle, reactive oxygen species (ROS), mitochondrial membrane potential, RT-PCR, western blot, and apoptosis protein array. ABE considerably inhibited the growth of PC cells in a dose-dependent manner (p<0.01) and caused significant apoptotic cell death through the suppression of CDK4/6-Cyclin D complex, ROS generation and depolarization of mitochondria membrane potential. However, PC-3 cells were more sensitive to ABE than LNCaP cells. Furthermore, the expression levels of several pro-apoptotic and cell cycle regulatory proteins were upregulated by ABE in especially PC-3 cells with the downregulation of apoptotic inhibitor proteins. Our results suggest that ABE inhibits PC cell growth and promotes apoptosis and thus ABE treatment may be a promising treatment strategy in especially mCRPC. Further preclinical and clinical studies should be performed to clarify the clinical use of ABE for the treatment of PC.

Has the COVID-19 Pandemic Increased Mortality Among Patients with Cancer Receiving Systemic Anticancer Treatments?

OBJECTIVE: To evaluate the mortality rates in patients receiving anticancer therapy in the coronavirus disease-19 (COVID-19) pandemic period. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Department of Medical Oncology, Sakarya University Training and Research Hospital, Sakarya, Turkey, from December 2017 to May 2020. METHODOLOGY: Only patients who received chemotherapy and immunotherapy were selected and enrolled in the study. All patients (n=3,204) were divided into three groups, namely the first group (1st December 2017-31st May 2018, n=918), second group (1st December 2018-31st May 2019, n=1,147), and the pandemic period group (PPG) (1st December 2019-31st May 2020, n=1,139), according to the period during which they received anticancer treatment. The clinical and demographic characteristics and mortality rates of these three groups of patients were compared. RESULTS: The median age of the total of 3,204 patients was 61 (53-69). In this study, 51.1% (n=1,636) were females and 48.9% were males. The mortality rates were 13.5% (n=124) in the first group, 13.4% (n=154) in the second group, and 13.0% (n=148) in the PPG, respectively. Overall mortality rates did not differ among patients with cancer in the three different six-month periods analysed (p = 0.931). CONCLUSION: There was no unexpected increased in mortality rate among patients undergoing cancer therapy during the COVID-19 pandemic as compared to the previous years of the same timeline. No increase in monthly mortality rates among patients receiving anti-cancer treatment were demonstrated during the pandemic period.

Comparison of real-life data of abiraterone acetate and enzalutamide in metastatic castration-resistant prostate cancer.

To compare enzalutamide (E) and abiraterone acetate (AA) in terms of efficacy, survival and to characterize prognostic factors affecting survival in metastatic castration-resistant prostate cancer (mCRPC) patients. A total of 250 patients treated with E or AA in 5 centers were included. The number of patients with no prostate specific antigen (PSA) decline was higher in the AA group than that in the E group, and the proportion of patients with a PSA decline of ≥ 50% was higher in the E group (p = 0.020). Radiological progression free survival (rPFS) and overall survival (OS) were significantly longer in the E group when compared to that in the AA group (p < 0.001 and p = 0.027, respectively). In the E group, rPFS was significantly longer than that in the AA group in both pre- and post-docetaxel settings (p = 0.010 and p = 0.003, respectively). OS was similar in the pre-docetaxel setting; but in the post-docetaxel setting, E group had a significantly longer OS than the AA group (p = 0.021). In the multivariate analysis performed in the whole patient group, we found that good prognostic factors for rPFS were E treatment, being ≥ 75 years and a PSA decline of ≥ 50% while there was no factor affecting OS. With longer OS and PFS, E seems to be more suitable for mCRPC patients in the post-docetaxel setting than AA.

Some, but not all of the premenstrual syndrome symptoms affect the medical exam scores in medical students.

OBJECTIVES: This research aims to identify the effects of premenstrual syndrome (PMS) symptoms on the school exam scores in medical students. METHODS: This cross-sectional study was designed at Sakarya University School of Medicine The study included medical students who were in the first, second, and third year of class. In this study, there were 193 male and 100 female students. The study investigated how PMS symptoms affected medical student's exam scores and school success. All exam scores were recorded during the two-consecutive semester so duration of study was one year. RESULTS: There were 100 female students, and they had five different committee exams for one year. Female student's exam scores were significantly higher for four committees and an average score of all year. The mean age of female students was 19.9 ±1.5. Acne, nausea/vomiting, sleeping, abdominal bloating, and prurience change had significantly different exam scores compared to the group without these symptoms. Students with acne had substantially higher exam scores than without acne; inversely, the other four symptoms negatively affected exam scores. CONCLUSION: Some of the PMS symptoms can be more annoying and should change the quality of life more than the other symptoms, so we should define these symptoms to improve our student's quality of life and school success.

The efficacy of indoximod upon stimulation with pro-inflammatory cytokines in triple-negative breast cancer cells.

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) inhibition has received much attention in cancer immunotherapy due to its role in immune escape in cancer cells. Additionally, changes in the pro-inflammatory cytokine levels can affect tumor growth and metastasis as well as the effectiveness of immunotherapy. The purpose of this study was for the first time to determine the effects of indoximod as an IDO inhibitor on triple-negative breast cancer (TNBC) and to assess the link between the efficacy of indoximod and IFN-γ or TNF-α stimulation. METHODS: The cytotoxic and apoptotic effects of indoximod alone or IFN-γ or TNF-α induction to mimic an inflammatory environment were evaluated by WST-1, Annexin V, cell cycle analysis, and acridine orange (AO)/ethidium bromide (EtBr) staining. Furthermore, the expression levels of IDO1 and PD-L1 expression were analyzed by RT-PCR. RESULTS: Our results demonstrated that indoximod significantly decreased the TNBC cell viability through apoptotic cell death (p < .05). The combination of indoximod and TNF-α was more effective than indoximod and IFN-γ stimulation or indoximod alone in TNBC cells. Additionally, PD-L1 expression level was significantly up-regulated after treatment with indoximod and TNF-α or IFN-γ combinations (p < .05). CONCLUSIONS: Indoximod exhibited a therapeutic potential in TNBC cells and pro-inflammatory cytokines could affect the effectiveness of indoximod. However, further studies are required to identify the role of the IDO-associated signaling pathways, the molecular mechanisms of indoximod induced apoptotic cell death, and the relationship between IDO inhibition by IDO inhibitors and pro-inflammatory cytokine levels.

Comparative assessment of three different second-line regimens in chemotherapy resistant / refractory small-cell lung cancer.

PURPOSE: Small cell lung cancer (SCLC) patients unresponsive or relapsing within 90 days following frontline chemotherapy have poor prognosis and they should be treated with different chemotherapy regimens other than those used in the first-line regimen. Currently there is no globally accepted standard chemotherapeutic regimen for the treatment of these patients. This retrospective study was designed to compare CAV (Cyclophosphamide, Doxorubicin, Vincristine), weekly topotecan and weekly irinotecan regimens and to evaluate the efficacy of the three regimens in patients with chemotherapy resistant/refractory (CRR) SCLC. METHODS: A total of 67 CRR-SCLC patients, who were treated with CAV, weekly topotecan and weekly irinotecan were reviewed for weekly irinotecan (27 for 60 mg/m2 intravenously on days 1, 8 and 15 of a 28-day cycle,24 for CAV (Cyclophosphamide 750 mg/m² on day 1, Doxorubicin 50 mg/m² on day 1 and Vincristine 1.4mg/m2 on day 1 every 3 weeks), 16 for weekly topotecan (4 mg/m2 intravenously on days 1, 8 and 15 of a 28-day cycle). RESULTS: The median follow-up time was 12.45 months, there was no difference about disease control rates (DCR) between three chemotherapy regimens (DCR; 25.9% with irinotecan, 29.2% with CAV and 31.3% with topotecan, p=0.92). Objective response rates (ORR) for irinotecan, CAV and topotecan groups were 3,7%, 8,8%, and 0%, respectively (p=0.63). Median progression free survival (PFS) and overall survival (OS) were similar according to irinotecan, CAV, and topotecan (PFS: 1.93 months, 2.30 months and 3.45 months; OS: 2.89 months, 4.79 months and 5.81 months, respectively). The adverse events were generally mild and manageable for both hematological and nonhematological toxicities in all three arms. CONCLUSIONS: Weekly irinotecan, CAV and weekly topotecan are similarly effective and safe chemotherapy protocols for the treatment of CRR-SCLC patients.

Has the COVID-19 Pandemic Increased Mortality Among Patients with Cancer Receiving Systemic Anticancer Treatments?

OBJECTIVE: To evaluate the mortality rates in patients receiving anticancer therapy in the coronavirus disease-19 (COVID-19) pandemic period. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Department of Medical Oncology, Sakarya University Training and Research Hospital, Sakarya, Turkey, from December 2017 to May 2020. METHODOLOGY: Only patients who received chemotherapy and immunotherapy were selected and enrolled in the study. All patients (n=3,204) were divided into three groups, namely the first group (1st December 2017-31st May 2018, n=918), second group (1st December 2018-31st May 2019, n=1,147), and the pandemic period group (PPG) (1st December 2019-31st May 2020, n=1,139), according to the period during which they received anticancer treatment. The clinical and demographic characteristics and mortality rates of these three groups of patients were compared. RESULTS: The median age of the total of 3,204 patients was 61 (53-69). In this study, 51.1% (n=1,636) were females and 48.9% were males. The mortality rates were 13.5% (n=124) in the first group, 13.4% (n=154) in the second group, and 13.0% (n=148) in the PPG, respectively. Overall mortality rates did not differ among patients with cancer in the three different six-month periods analysed (p = 0.931). CONCLUSION: There was no unexpected increased in mortality rate among patients undergoing cancer therapy during the COVID-19 pandemic as compared to the previous years of the same timeline. No increase in monthly mortality rates among patients receiving anti-cancer treatment were demonstrated during the pandemic period.

An individual patient-data meta-analysis of metronomic oral vinorelbine in metastatic non-small cell lung cancer.

INTRODUCTION: Several non-comparative phase II studies have evaluated metronomic oral vinorelbine (MOV) in metastatic non-small cell lung cancer (NSCLC) but the small size of each study limits their conclusions. PURPOSE: To perform an individual patient-data metaanalysis of studies evaluating MOV in metastatic NSCLC in order to measure survival and safety of treatment with this regimen. METHODS: Studies were selected if (1) administration of oral vinorelbine thrice a week; (2) fixed daily dose comprised between 30 and 50 mg, and; (3) being published before October 4th 2018. Database encompassed 8 variables characterizing disease and demography, 3 informing therapy, and 12 describing survival and toxicity. RESULTS: Nine studies encompassing 418 patients fulfilled the selection criteria, 80% of them having frailty characteristics. Median overall survival (OS) was 8.7 months (95%CI: 7.6-9.5). OSrates at 6 months, one year and at two years after starting vinorelbine were 64%, 30.3% and 8.9%, respectively. In the Cox model, Eastern Cooperative Oncology Group (ECOG) performance status (PS) = 2, and anemia of any grade were significant determinants of shorter OS. Median progression-free survival(PFS) was 4.2 months (95%CI: 3.9-5). At 6 months and at one-year, PFS rates were 35% and 11.9% respectively. In the Cox model stratified for the variable "study", PS = 2and stage IV were significant determinants of shorter PFS. No toxicity was reported for 40% of patients, and 66 (15.8%) patients experienced a grade 3-4 toxicity. The most frequent toxicity was anemia of any grade (35.8%) that was higher with the 50 mg dosage. CONCLUSION: MOV is an active and well-tolerated chemotherapy in metastatic NSCLC and is a manageable therapy in frail patients.