Durvalumab ± Tremelimumab + Platinum-Etoposide in Extensive-Stage Small Cell Lung Cancer (CASPIAN): Outcomes by PD-L1 Expression and Tissue Tumor Mutational Burden.

PURPOSE: In the CASPIAN trial, first-line durvalumab plus platinum-etoposide (EP) significantly improved overall survival (OS) versus EP alone in extensive-stage small cell lung cancer (ES-SCLC). We report exploratory analyses of CASPIAN outcomes by programmed cell death ligand-1 (PD-L1) expression and tissue tumor mutational burden (tTMB). EXPERIMENTAL DESIGN: Patients were randomized (1:1:1) to durvalumab (1,500 mg) plus EP, durvalumab plus tremelimumab (75 mg) plus EP, or EP alone. Treatment effects in PD-L1 and tTMB subgroups were estimated using an unstratified Cox proportional hazards model. RESULTS: The PD-L1 and tTMB biomarker-evaluable populations (BEP) comprised 54.4% (438/805) and 35.2% (283/805) of the intention-to-treat population, respectively. PD-L1 prevalence was low: 5.7%, 25.8%, and 28.3% had PD-L1 expression on ≥1% tumor cells (TC), ≥1% immune cells (IC), and ≥1% TCs or ICs, respectively. OS benefit with durvalumab plus EP versus EP was similar across PD-L1 subgroups, with HRs all falling within the 95% confidence interval (CI) for the PD-L1 BEP (0.47‒0.79). OS benefit with durvalumab plus tremelimumab plus EP versus EP was greater in PD-L1 ≥1% versus <1% subgroups, although CIs overlapped. There was no evidence of an interaction between tTMB and treatment effect on OS (durvalumab plus EP vs. EP, P = 0.916; durvalumab plus tremelimumab plus EP vs. EP, P = 0.672). CONCLUSIONS: OS benefit with first-line durvalumab plus EP in patients with ES-SCLC was observed regardless of PD-L1 or tTMB status. PD-L1 expression may prove to be a useful biomarker for combined treatment with PD-(L)1 and CTLA-4 inhibition, although this requires confirmation with an independent dataset. See related commentary by Rolfo and Russo, p. 652.

KRAS Mutation Status in Bulgarian Patients with Advanced and Metastatic Colorectal Cancer.

RAS somatic variants are predictors of resistance to anti-EGFR therapy for colorectal cancer (CRC) and affect the outcome of the disease. Our study aimed to evaluate the frequency of RAS, with a focus on KRAS variants, and their association with tumor location and some clinicopathological characteristics in Bulgarian CRC patients. We prospectively investigated 236 patients with advanced and metastatic CRC. Genomic DNA was extracted from FFPE tumor tissue samples, and commercially available kits were used to detect RAS gene somatic mutations via real-time PCR. A total of 115 (48.73%) patients tested positive for RAS mutations, with 106 (44.92%) testing positive for KRAS mutations. The most common mutation in exon 2 was c.35G>T p.Gly12Val (32.56%). We did not find a significant difference in KRAS mutation frequency according to tumor location. However, patients with a mutation in exon 4 of KRAS were 3.23 times more likely to have a tumor in the rectum than in other locations (95% CI: 1.19-8.72, p = 0.021). Studying the link between tumor location and KRAS mutations in exon 4 is crucial for better characterizing CRC patients. Further research with larger cohorts, especially in rectal cancer patients, could provide valuable insights for patient follow-up and treatment selection.

Prognostic value of translationally controlled tumor protein in colon cancer.

The translationally controlled tumor protein (TCTP) is a highly conserved protein involved in a variety of normal cell functions and disease processes. Preclinical studies revealed that TCTP has anti-apoptotic properties, promotes cell growth and division and is involved in cancer progression by promoting invasion and metastasis. The present study explored the potential value of TCTP as a prognostic marker in colon cancer. A retrospective analysis of 74 patients with colon cancer was performed. Using immunohistochemistry, TCTP levels in the primary tumor were assessed semi-quantitatively by the calculation of cytoplasmic and nuclear H-score. Cytoplasmic TCTP levels in the primary tumor had no statistically significant association with disease-free survival (DFS), progression-free survival (PFS) and overall survival (OS) in the present patient population. Patients whose primary tumors had a negative nuclear TCTP expression had significantly improved clinical outcomes. The PFS for the negative nuclear TCTP expression group was 7.7 months [95% confidence interval (CI), 5.8-9.5] compared with 5.5 months (95% CI, 3.2-7.8) in the group with positive nuclear expression (P=0.023, Mantel-Cox log-rank). Patients with a negative nuclear expression of TCTP had a significantly higher median OS (22.2 months; 95% CI, 16.1-28.3) compared with those with positive TCTP nuclear expression (median 13.2 months; 95% CI, 10.1-16.3; P=0.008, Mantel-Cox log-rank). In a multivariate Cox regression model, a positive nuclear TCTP H-score was an independent risk factor for worse PFS and OS. The 1-year OS rate in the group with negative nuclear TCTP expression was 86.3% compared with 56.5% in patients with positive nuclear TCTP expression (P=0.008). The present study suggested that semiquantitative H-score measurement of TCTP levels in the nuclei of tumor cells from the primary tumor is a potential prognostic marker for clinical outcomes in patients with colon cancer.

Circulating Histones to Detect and Monitor the Progression of Cancer.

Liquid biopsies have emerged as a minimally invasive cancer detection and monitoring method, which could identify cancer-related alterations in nucleosome or histone levels and modifications in blood, saliva, and urine. Histones, the core component of the nucleosome, are essential for chromatin compaction and gene expression modulation. Increasing evidence suggests that circulating histones and histone complexes, originating from cell death or immune cell activation, could act as promising biomarkers for cancer detection and management. In this review, we provide an overview of circulating histones as a powerful liquid biopsy approach and methods for their detection. We highlight current knowledge on circulating histones in hematologic malignancies and solid cancer, with a focus on their role in cancer dissemination, monitoring, and tumorigenesis. Last, we describe recently developed strategies to identify cancer tissue-of-origin in blood plasma based on nucleosome positioning, inferred from nucleosomal DNA fragmentation footprint, which is independent of the genetic landscape.

Lower fluorodeoxyglucose positron emission tomography maximum standardized uptake value may show a better response to stereotactic body radiotherapy of adrenals in oligometastatic disease.

Introduction: Stereotactic body radiotherapy (SBRT) is well established for oligometastatic disease, and it is increasingly used to treat adrenal metastases. Material and methods: In this retrospective study we performed an analysis of 75 metastatic adrenal lesions in 64 patients with oligometastatic disease. According to the fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) maximum standardized uptake value (SUVmax) of adrenal metastases, patients were categorized into three groups: low, intermediate, and high SUVmax. Results: For all clinicopathological characteristics we found significant relationships for levels of SUVmax and objective response rate (Kendall Tau-c = 0.290; p = 0.017). Patients who responded to SBRT had a significantly lower SUVmax value than those who did not respond (7.6 ±2.4 vs. 9.7 ±3.8; p = 0.015). At the appropriate SUVmax cut-off values, the biomarker distinguished between patients with and without a response significantly and moderately (area under the curve = 0.670, 95% confidence intervals: 0.540-0.790; p = 0.015). Conclusions: Lower SUVmax is associated with a better response to SBRT in patients whose disease progressed mainly in the adrenal glands.

Impact of Brain Metastases on Treatment Patterns and Outcomes With First-Line Durvalumab Plus Platinum-Etoposide in Extensive-Stage SCLC (CASPIAN): A Brief Report.

Introduction: In the phase 3 study involving the use of durvalumab with or without tremelimumab in combination with platinum-based chemotherapy in untreated extensive-stage SCLC (CASPIAN study), first-line durvalumab plus platinum-etoposide (EP) significantly improved overall survival (OS) versus EP alone (p = 0.0047). We report exploratory subgroup analyses of treatment patterns and outcomes according to the presence of baseline brain or central nervous system metastases. Methods: Patients (WHO performance status 0 or 1), including those with asymptomatic or treated-and-stable brain metastases, were randomized to four cycles of durvalumab plus EP followed by maintenance durvalumab until progression or up to six cycles of EP and optional prophylactic cranial irradiation. Prespecified analyses of OS and progression-free survival (PFS) in subgroups with or without brain metastases used unstratified-Cox proportional hazards models. The data cutoff was on January 27, 2020. Results: At baseline, 28 out of 268 patients (10.4%) in the durvalumab plus EP arm and 27 out of 269 patients (10.0%) in the EP arm had known brain metastases, of whom 3 of 28 (10.7%) and 4 of 27 (14.8%) had previous brain radiotherapy, respectively. Durvalumab plus EP (versus EP alone) prolonged OS (hazard ratio, 95% confidence interval) in patients with (0.79, 0.44-1.41) or without (0.76, 0.62-0.92) brain metastases, with similar PFS results (0.73, 0.42-1.29 and 0.80, 0.66-0.97, respectively). Among patients without brain metastases, similar proportions in each arm developed new brain lesions as part of their first progression (8.8% and 9.5%), although 8.3% in the EP arm received prophylactic cranial irradiation. Similar proportions in each arm received subsequent brain radiotherapy (20.5% and 21.2%), although more common in patients with than without baseline brain metastases (45.5% and 18.0%). Conclusions: The OS and PFS benefit with first-line durvalumab plus EP were maintained irrespective of the presence of brain metastases, further supporting its standard-of-care use.

Impact of travel burden on clinical outcomes in lung cancer.

PURPOSE: Our study explores the influence of travel burden (measured as travel distance and travel time) on clinical outcomes in lung cancer patients. METHODS: A retrospective analysis of a single Bulgarian center was performed. A total of 9240 lung cancer patients were included in the study. Travel distance and travel time between patients' city of residence and the treating facility were calculated with an online tool to determine the shortest route for travel using the existing road network. The probability of survival was estimated using the Kaplan-Meier method, and differences in survival in each subgroup were evaluated with a log-rank test. RESULTS: About one third of all included patients were living in the same city as the treating facility (n = 2746, 29.7%). Overall survival in our patient population was significantly lower with increasing travel distance (p < 0.001, Mantel-Cox log rank) and travel time (p < 0.001, Mantel-Cox log rank). The 1-year OS rate according to travel distance was 27.1% in the same city group, 22.4% in < 50-km group, and 20.5% in ≥ 50-km group (p < 0.001). The corresponding values for the 5-year OS rate were 2.9%, 2.6%, and 1.4% (p < 0.001). CONCLUSION: In this retrospective study, we discovered significant differences in the overall survival of patients with lung cancer depending on travel distance and travel time to the treating oncological facility. Despite having similar clinical and pathological characteristics (age, sex, stage at initial diagnosis, histologic subtype), the median overall survival was significantly lower in those subgroups of patients with a higher travel burden.

Single Nucleotide Polymorphisms in microRNA Genes and Colorectal Cancer Risk and Prognosis.

There is growing interest in single nucleotide polymorphisms (SNPs) in the genes of microRNAs (miRNAs), which could be associated with susceptibility to colorectal cancer (CRC) and therefore for prognosis of the disease and/or treatment response. Moreover, these miRNAs-SNPs could serve as new, low-invasive biomarkers for early detection of CRC. In the present article, we performed a thorough review of different SNPs, which were investigated for a correlation with the CRC risk, prognosis, and treatment response. We also analyzed the results from different meta-analyses and the possible reasons for reported contradictory findings, especially when different research groups investigated the same SNP in a gene for a particular miRNA. This illustrates the need for more case-control studies involving participants with different ethnic backgrounds. According to our review, three miRNAs-SNPs-miR-146a rs2910164, miR-27a rs895819 and miR-608 rs4919510-appear as promising prognostic, diagnostic and predictive biomarkers for CRC, respectively.

New Circulating Circular RNAs with Diagnostic and Prognostic Potential in Advanced Colorectal Cancer.

Circular RNAs (circRNAs) are a group of special endogenous long non-coding RNAs which are highly stable in the circulation, and, thus, more suitable as new biomarkers of colorectal cancer (CRC). The aim of our study was to explore the plasma expression levels of four circRNAs: has_circ_0001445, hsa_circ_0003028, hsa_circ_0007915 and hsa_circ_0008717 in patients with CRC and to evaluate their associations with clinicopathological characteristics and the clinical outcome of the patients. CircRNAs were extracted from patients' plasma obtained prior to chemotherapy. Their expression levels were measured by qPCR and calculated applying the 2-ΔΔCt method. The levels of all four circRNAs were significantly increased in the plasma of CRC patients. At the optimal cut-off values hsa_circ_0001445 and hsa_circ_0007915 in plasma could significantly distinguish between patients with or without metastatic CRC with 92.56% sensitivity and 42.86% specificity, and with 86.07% sensitivity and 57.14% specificity, respectively. The mean overall survival (OS) of patients with high/intermediate expression of hsa_circ_0001445 was 30 months, significantly higher in comparison with the mean OS of the patients with low expression-20 months (log-rank test, p = 0.034). In multivariate Cox regression analysis, the low levels of hsa_circ_0001445 were also associated with shorter survival (HR = 1.59, 95% CI: 1.02-2.47, p = 0.040). A prognostic significance of hsa_circ_0001445 for patients with metastatic CRC was established.

Circulating miR-618 Has Prognostic Significance in Patients with Metastatic Colon Cancer.

The present study evaluated the prognostic role of circulating miRNA-618 in patients with metastatic colon cancer (mCC) and whether miR-618 gene rs2682818 single nucleotide polymorphisms (SNP) are associated with colon cancer susceptibility and expression levels of mature miR-618. In total, 104 patients with mCC before starting the chemotherapy were investigated. The expression status of circulating miR-618 in mCC was evaluated by quantitative PCR. TaqMan PCR assay was used for rs2682818 SNP genotyping. miR-618 was overexpressed in serum of mCC patients. Patients with high and intermediate expression of miR-618 had a significantly longer mean overall survival (OS) of 21 months than patients with low expression-16 months. In addition, multivariate Cox regression analysis confirmed the association between high/intermediate levels of miRNA-618 and longer OS, HR = 0.51, 95% CI: 0.30-0.86, p = 0.012. miR-618 rs2682818 SNP significantly decreased the risk of colon cancer susceptibility in both heterozygous codominant (AC vs. CC, OR = 0.39, 95% CI: 0.17-0.88, p = 0.024) and overdominant (AC vs. CC + AA, OR = 0.37, 95% CI: 0.16-0.85, p = 0.018) genetic models. Our data suggest that circulating miRNA-618 could be useful as a prognostic biomarker in mCC. Patients harboring AC rs2682818 genotype have a decreased risk for colon cancer in comparison with patients with CC and AA genotypes.

Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial.

BACKGROUND: First-line durvalumab plus etoposide with either cisplatin or carboplatin (platinum-etoposide) showed a significant improvement in overall survival versus platinum-etoposide alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) in the CASPIAN study. Here we report updated results, including the primary analysis for overall survival with durvalumab plus tremelimumab plus platinum-etoposide versus platinum-etoposide alone. METHODS: CASPIAN is an ongoing, open-label, sponsor-blind, randomised, controlled phase 3 trial at 209 cancer treatment centres in 23 countries worldwide. Eligible patients were aged 18 years or older (20 years in Japan) and had treatment-naive, histologically or cytologically documented ES-SCLC, with a WHO performance status of 0 or 1. Patients were randomly assigned (1:1:1) in blocks of six, stratified by planned platinum, using an interactive voice-response or web-response system to receive intravenous durvalumab plus tremelimumab plus platinum-etoposide, durvalumab plus platinum-etoposide, or platinum-etoposide alone. In all groups, patients received etoposide 80-100 mg/m2 on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL/min or cisplatin 75-80 mg/m2 on day 1 of each cycle. Patients in the platinum-etoposide group received up to six cycles of platinum-etoposide every 3 weeks and optional prophylactic cranial irradiation (investigator's discretion). Patients in the immunotherapy groups received four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks. The two primary endpoints were overall survival for durvalumab plus platinum-etoposide versus platinum-etoposide and for durvalumab plus tremelimumab plus platinum-etoposide versus platinum-etoposide in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered at ClinicalTrials.gov, NCT03043872. FINDINGS: Between March 27, 2017, and May 29, 2018, 972 patients were screened and 805 were randomly assigned (268 to durvalumab plus tremelimumab plus platinum-etoposide, 268 to durvalumab plus platinum-etoposide, and 269 to platinum-etoposide). As of Jan 27, 2020, the median follow-up was 25·1 months (IQR 22·3-27·9). Durvalumab plus tremelimumab plus platinum-etoposide was not associated with a significant improvement in overall survival versus platinum-etoposide (hazard ratio [HR] 0·82 [95% CI 0·68-1·00]; p=0·045); median overall survival was 10·4 months (95% CI 9·6-12·0) versus 10·5 months (9·3-11·2). Durvalumab plus platinum-etoposide showed sustained improvement in overall survival versus platinum-etoposide (HR 0·75 [95% CI 0·62-0·91]; nominal p=0·0032); median overall survival was 12·9 months (95% CI 11·3-14·7) versus 10·5 months (9·3-11·2). The most common any-cause grade 3 or worse adverse events were neutropenia (85 [32%] of 266 patients in the durvalumab plus tremelimumab plus platinum-etoposide group, 64 [24%] of 265 patients in the durvalumab plus platinum-etoposide group, and 88 [33%] of 266 patients in the platinum-etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]). Any-cause serious adverse events were reported in 121 (45%) patients in the durvalumab plus tremelimumab plus platinum-etoposide group, 85 (32%) in the durvalumab plus platinum-etoposide group, and 97 (36%) in the platinum-etoposide group. Treatment-related deaths occurred in 12 (5%) patients in the durvalumab plus tremelimumab plus platinum-etoposide group (death, febrile neutropenia, and pulmonary embolism [n=2 each]; enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%) patients in the durvalumab plus platinum-etoposide group (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis [n=1 each]), and two (1%) in the platinum-etoposide group (pancytopenia and thrombocytopenia [n=1 each]). INTERPRETATION: First-line durvalumab plus platinum-etoposide showed sustained overall survival improvement versus platinum-etoposide but the addition of tremelimumab to durvalumab plus platinum-etoposide did not significantly improve outcomes versus platinum-etoposide. These results support the use of durvalumab plus platinum-etoposide as a new standard of care for the first-line treatment of ES-SCLC. FUNDING: AstraZeneca.

Fast time perception is associated with high levels of anxiety in cancer patients prior to starting chemotherapy.

Our study explored the potential relationship between time perception and the level of anxiety in cancer patients prior to starting chemotherapy. Time perception was assessed in 162 chemonaïve patients with solid tumors by evaluating each subject's prospective estimation of how fast one minute passed compared to the actual amount of time passed. The median value of time perception was used to stratify the patients into two categories of fast and slow time perception. We used the generalized anxiety disorder questionnaire (GAD-7) as a screening tool for detecting levels of anxiety. Scores ≥ 10 were considered high. In total, 45 (27.8%) patients had high levels of anxiety. The pattern of the time perception distributions significantly changed according to the reported levels on the GAD-7 scale. Scores ≥ 10 correlated with fast time perception and the female gender. Patients with a fast time perception had significantly higher levels of anxiety (8.44 ± 5.1) than patients with a slow time perception (3.49 ± 4.3). ROC analysis revealed that at the optimal cut-off value of time perception, clinically significant levels of anxiety can be discriminated with an AUC = 0.78 (95% CI: 0.70-0.85, p < 0.001), a sensitivity of 82.2% and a specificity of 64.1%. Moreover, in a multivariate logistic regression model, fast time perception was an independent predictor of clinically significant levels of anxiety (OR: 8.24; 95% CI: 3.16-21.41, p < 0.001). Time perception is a novel potent indicator for high levels of anxiety in cancer patients.

Neutrophil to lymphocyte ratio as a potential predictive marker for treatment with pembrolizumab as a second line treatment in patients with non-small cell lung cancer.

The aim of this multicentric retrospective study is to evaluate the predictive and prognostic performance of neutrophil to lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and their dynamics in patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab as a second line. Patients with metastatic NSCLC (n = 119), whose tumors expressed programmed death-ligand 1 (PD-L1) ≥ 1%, were retrospectively analyzed between Apr 2017 and Apr 2019. All patients received platinum-containing chemotherapy as a first line treatment. Pre-treatment NLR was calculated by dividing the number of neutrophils by the number of lymphocytes in peripheral blood before the first pembrolizumab infusion. Progression free survival (PFS) and overall survival (OS) was compared by Kaplan-Meier method and Cox Proportional Hazard model. Patients with NLR > 5 before immunotherapy showed significantly shorter mean PFS of 6.86 months (95% CI: 5.81-7.90) as compared to those with NLR ≤ 5 of 18.82 months (95% CI: 15.87-21.78) (long rank test p < 0.001). Furthermore in the multivariate analysis, only NLR > 5 was an independent predictive factor for shorter PFS (HR: 4.47, 95% CI: 2.20-9.07, p < 0.001). In multivariate analysis, presence of bone metastases (HR: 2.08, 95% CI: 1.10-4.94, p = 0.030), NLR > 5 before chemotherapy (HR: 8.09, 95% CI: 2.35-27.81, p = 0.001) and high PLR before chemotherapy (HR: 2.81, 95% CI: 1.13-6.97, p = 0.025) were found to be independent negative prognostic factors for poor OS. Our data suggests that NLR ≤ 5 is a potential predictive marker, which may identify patients appropriate for immunotherapy as a second line treatment.

Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Most patients with small-cell lung cancer (SCLC) have extensive-stage disease at presentation, and prognosis remains poor. Recently, immunotherapy has demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN trial assessed durvalumab, with or without tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum-etoposide) in treatment-naive patients with ES-SCLC. METHODS: This randomised, open-label, phase 3 trial was done at 209 sites across 23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO performance status 0 or 1 and measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a 1:1:1 ratio) to durvalumab plus platinum-etoposide; durvalumab plus tremelimumab plus platinum-etoposide; or platinum-etoposide alone. All drugs were administered intravenously. Platinum-etoposide consisted of etoposide 80-100 mg/m2 on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL per min or cisplatin 75-80 mg/m2 (administered on day 1 of each cycle). Patients received up to four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles of platinum-etoposide every 3 weeks plus prophylactic cranial irradiation (investigator's discretion) in the platinum-etoposide group. The primary endpoint was overall survival in the intention-to-treat population. We report results for the durvalumab plus platinum-etoposide group versus the platinum-etoposide group from a planned interim analysis. Safety was assessed in all patients who received at least one dose of their assigned study treatment. This study is registered at ClinicalTrials.gov, NCT03043872, and is ongoing. FINDINGS: Patients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumab plus platinum-etoposide group and 269 to the platinum-etoposide group. Durvalumab plus platinum-etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0·73 (95% CI 0·59-0·91; p=0·0047]); median overall survival was 13·0 months (95% CI 11·5-14·8) in the durvalumab plus platinum-etoposide group versus 10·3 months (9·3-11·2) in the platinum-etoposide group, with 34% (26·9-41·0) versus 25% (18·4-31·6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum-etoposide group and 166 (62%) of 266 in the platinum-etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients. INTERPRETATION: First-line durvalumab plus platinum-etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received. FUNDING: AstraZeneca.

RIPK3 expression as a potential predictive and prognostic marker in metastatic colon cancer.

BACKGROUND: Colorectal cancer is one of the primary causes of cancer-related deaths and 5-fluorouracil (5-FU) therapy remains the cornerstone of treatment in these patients. Resistance to 5-FU represents a major obstacle; therefore, finding new predictive and prognostic markers is crucial for improvement of patient outcomes. Recently a new type of programmed cell death was discovered-necroptosis, which depends on receptor interacting protein 3 (RIPK3). Preclinical data showed that necroptotic cell death is an important effector mechanism of 5-FU-mediated anticancer activity. PURPOSE: To investigate the predictive and prognostic performance of RIPK3 expression in primary tumors. METHODS: Colon cancer patients (n=74) with metastatic stage were included in this retrospective study and all were treated with first-line 5-FU based chemotherapy. Immunohistochemical staining was performed. RESULTS: The progression free survival for the low expression group of RIPK3 was 5.6 months (95% CI, 4.4-6.8) vs 8.4 months (95% CI, 6.4-10.3) of the group with high expression (p=0.02). Moreover, patients with high expression of RIPK3 were associated with lower risk of disease progression HR 0.61 (95% CI, 0.38-0.97; p=0.044). Patients with high expression levels of RIPK3 also had significantly longer mean overall survival (OS) of 29.3 months (95% CI, 20.8-37.8) as compared with those with low expression: 18.5 months (95% CI, 15.06-21.9) (p= 0.036). In addition, univariate analysis showed that high level of RIPK3 expression was associated with a longer OS HR 0.59 (95% CI, 0.35-0.98; p=0.044). CONCLUSIONS: This study suggests that expression of RIPK3 in primary tumors of metastatic colon cancer patients should be further investigated for its potential as a promising predictive and prognostic marker.

One-minute time interval estimation as a novel ultrashort tool for distress screening.

PURPOSE: Our study explores the potential relationship between time estimation and level of distress in cancer patients prior to starting chemotherapy. METHODS: Time estimation was assessed in 262 chemonaïve patients with solid tumors by evaluating each subject's prospective estimation of how fast 1 min passed compared to the actual time. The median value (40 s) of time estimation was used to stratify the patients into two categories of fast and slow time estimation. The National Comprehensive Cancer Network Distress Thermometer was used at the beginning of treatment to evaluate levels of distress. Patients scoring 4 or above (51.9%) were regarded as having high levels of distress. RESULTS: The pattern of the time estimation distributions significantly changed according to the level of distress. Patients with a fast time estimation had significantly higher levels of distress (4.55 ± 3.1) than patients with a slow time estimation (3.3 ± 2.9) (p = 0.001). ROC analysis revealed that at the optimal cutoff value of time estimation, patients with low and high distress levels can be discriminated with an AUC = 0.60 (95% CI: 0.53-0.67, p = 0.005) and with a sensitivity of 62.5% and specificity of 53.2%. Moreover, in a multivariate logistic regression model, fast time estimation was an independent predictor of high levels of distress. CONCLUSION: Time estimation is a novel potent indicator of high levels of distress in cancer patients. This test is an easily performed, time-saving, and nonintrusive ultrashort screening tool that is even suitable for patients who are not willing to reveal their level of distress via direct questionnaires.

Association Between Serum CK-18 Levels and the Degree of Liver Damage in Fructose-Induced Metabolic Syndrome.

BACKGROUND: The pathogenesis of nonalcoholic fatty liver disease as a component of metabolic syndrome (MetS) involves the activation of apoptosis in steatotic hepatocytes. Caspase-generated fragments such as cytokeratin-18 (CK-18) in patients with various hepatic impairments are investigated as markers for diagnosis and assessment of disease severity. The goal of the study was to capture early biomarkers of apoptosis and elucidate their role in assessing the presence and extent of hepatic damage in a MetS model. MATERIALS AND METHODS: We used male Wistar rats, divided into two groups (n = 7): control and high-fructose drinking (HFD) (35% fructose corn syrup for 16 weeks). Metabolic disorders and liver damage were studied by histochemistry (hematoxylin and eosin), immunohistochemical, immunological, and biochemical testing. RESULTS: Our results showed significant increase in liver and serum levels of CK-18 and pro/antiapoptotic Bax/Bcl2 ratio, and decreased levels of HMGB1 (marker of necrosis) in the HFD group when compared with the control. All HFD rats developed obesity, hyperglycemia, hepatomegaly, microvesicular steatosis, an imbalance in hepatic antioxidative defense by measuring malondialdehyde and sulfhydryl groups (SH) with no inflammation and fibrosis, elevated serum levels of triglycerides, tumor necrosis factor alpha (TNF-α), and C-reactive protein without changes in serum aminotransferase levels relative to the control group. As a result of the applied regression analysis, we have determined that the variables TNF-α (0.92) and SH (0.659) have a strong complex effect on hepatic CK-18 levels with predicted value of the model R = 0.9. CONCLUSION: The elevated CK-18 serum levels in the HFD group and their association with the histological changes in the liver and biochemical indicators demonstrate the key role of apoptosis in the pathogenesis of HFD-induced liver damage and the reliability of CK-18 as a biomarker for noninvasive assessment of liver damages in MetS.

Rare case of ameloblastoma with pulmonary metastases.

Ameloblastoma is a rare low-grade odontogenic tumor of epithelial origin. The World Health Organization (WHO) has defined malignant ameloblastoma (MA) as a histologically benign-appearing ameloblastoma that has metastasized. Treatment of the primary ameloblastoma usually consists of radical excision of the tumor and adjuvant radiotherapy. Chemotherapy should be used to treat metastases due to its indolent clinical course. Presented here is the case of a 43-year-old woman who was admitted to a hospital in 2006 with a large mass involving the neck and left mandible. The mass had formed over years and had been neglected. The woman was diagnosed with a primary ameloblastoma of the mandible. Surgical resection was performed, followed by adjuvant radiotherapy. In September 2016, she was admitted again, and the findings were consistent with metastases of the previously identified ameloblastoma to the lungs. The patient was evaluated for further chemotherapy with 6 cycles of cisplatin at a dose of 100 mg/m2 on day 1, 5-FU at a dose of 1000 mg/m2/day on day 1-4 (3 wk), and pegylated filgrastim. The current case represents the classical course of a rare disease, which in this instance involved the common presentation of MA. This case is a valid incidence of MA based on the typical histology, findings from a lung biopsy, the immunohistochemical profile of the tumor, the typical clinical features, and a history of a previous primary disease.

Role of the pretreatment 18F-fluorodeoxyglucose positron emission tomography maximal standardized uptake value in predicting outcomes of colon liver metastases and that value's association with Beclin-1 expression.

The current study sought to evaluate the predictive and prognostic performance of the maximum standardized uptake value (SUVmax) prior to treatment in 43 patients with colon cancer and unresectable liver metastases. Patients with colon cancer who underwent 18F-FDG-PET/computed tomography (CT) scans for staging before the start of first-line 5-fluorouracil-based chemotherapy were retrospectively analyzed. Expression of Beclin-1 in cancer cells was evaluated in primary tumors using immunohistochemical staining. The pretreatment SUVmax for liver metastases was not able to predict progression-free survival but was significantly associated with poorer overall survival, with a hazard ratio of 2.05 (95 % CI, 1.016-4.155). Moreover, a negative correlation was noted between SUVmax and expression of a marker of autophagy - Beclin-1 (rho = -0.42, p = 0.006). This suggests that the pretreatment SUVmax in 18F-FDG PET/CT is a useful tool to help predict survival outcome in patients with colon cancer and unresectable liver metastases and may significantly distinguish between patients with low and high levels of Beclin-1 expression (AUC = 0.809, 95% CI: 0.670-0.948, p = 0.001).

Primary Adenoid Cystic Carcinoma of the Skin with Multiple Local Recurrences.

Primary adenoid cystic carcinoma (PACC) of the skin is a rare tumor with fewer than 70 cases studied in detail in the English literature. This type of tumor shows a prolonged course and a growth pattern usually manifested by multiple local recurrences and has a low potential for distant metastases. The most important modality for primary treatment is surgical resection followed by radiotherapy. We report a woman aged 43 years at the time of diagnosis, who presented with a slow-growing nodule in the right axilla without lymph node enlargement. A wide local excision was performed, and the histology revealed an adenoid cystic carcinoma. During the next 24 years, another four local recurrences were excised (the last one in 2015) and confirmed histologically to be adenoid cystic carcinoma. The patient was given 44 Gy of radiotherapy after the second surgery in 1996. PACC of the skin is a rare tumor with insufficient data concerning the efficacy of the surgical technique and chemotherapy and radiotherapy treatment, even more so in the case of multiple recurrences. After the last recurrence, the patient was offered an active follow-up based on the long tumor-free intervals in the past and because the site of the primary tumor allowed further surgical excisions in future recurrences.