Chemotherapy In First-line Treatment Research Articles

A Scoring System Based on Nutritional and Inflammatory Parameters to Predict the Efficacy of First-Line Chemotherapy and Survival Outcomes for De Novo Metastatic Nasopharyngeal Carcinoma.

PurposeWe aimed to develop a simple scoring system based on baseline inflammatory and nutritional parameters to predict the efficacy of first-line chemotherapy and survival outcomes for de novo metastatic nasopharyngeal carcinoma (mNPC).Patients and MethodsWe retrospectively collected ten candidate inflammatory and nutritional parameters from de novo mNPC patients who received platinum-based first-line chemotherapy treatment. We examined the effects of these ten candidate variables on progression-free survival (PFS) using the Cox regression model. We built a risk-scoring system based on the regression coefficients associated with the identified independent prognostic factors. The predictive accuracy of the scoring system was evaluated and independently validated.ResultsA total of 460 patients were analyzed. Four independent prognostic factors were identified in a training cohort and were used to construct the scoring system, including nutritional risk index, C-reactive protein level, alkaline phosphatase level, and lactate dehydrogenase level. Based on the score obtained from the scoring system, we stratified patients into three prognostic subgroups (low: 0–1 point, intermediate: 2–3 points, and high: 4 points) associated with significantly different disease control rates (94.7% vs. 92.5% vs. 66.0%, respectively) and survival outcomes (3-year PFS: 55.8% vs. 29.1% vs. 11.9%, respectively). The scoring system had a good performance for the prediction of short-term disease control (area under the receiver operating characteristic curve [AUC]: 0.701) and long-term survival outcomes (time-dependent AUC for 5-year PFS: 0.713). The results were internally validated using an independent cohort (AUC for predicting disease control: 0.697; time-dependent AUC for 5-year PFS: 0.713).ConclusionWe developed and validated a clinically useful risk-scoring system that could predict the efficacy of first-line chemotherapy and survival outcomes in de novo mNPC patients. This system may help clinicians to design personalized treatment strategies.

Immune Checkpoint Inhibition in Oesophago-Gastric Carcinoma.

Immune checkpoint inhibitors enrich the therapeutic landscape in oesophago-gastric carcinoma. With regard to oesophageal squamous cell carcinoma (ESCC), the selective PD-1 (programmed cell death receptor 1)-inhibitor nivolumab improves disease-free survival in the adjuvant therapy setting (CHECKMATE-577). In first-line treatment, ESCC patients (pts) benefit in overall survival (OS) from the PD-1-inhibitor pembrolizumab in combination with chemotherapy (KEYNOTE-590). In the second-line setting, nivolumab (ATTRACTION-03) and pembrolizumab (KEYNOTE-181) demonstrate a benefit in OS compared with chemotherapy. These data resulted in the approval of nivolumab for the second-line treatment of advanced ESCC pts regardless of PD-L1 (programmed cell death ligand 1) status in Europe, Asia, and the USA, and pembrolizumab for pts with PD-L1 CPS (combined positivity score) ≥ 10 in Asia and the USA. Further approvals can be expected. In gastro-oesophageal junction and gastric cancer, the addition of nivolumab to chemotherapy in first-line treatment improves OS in pts with advanced disease with PD-L1 CPS ≥ 5 (CHECKMATE-649). Additionally, pembrolizumab was non-inferior to chemotherapy for OS in PD-L1 CPS ≥ 1 pts (KEYNOTE-062). In third-line treatment, nivolumab shows benefits in OS regardless of PD-L1 expression (ATTRACTION-02) with approval in Asia, and pembrolizumab prolonged the duration of response in PD-L1 positive pts (KEYNOTE-059) with approval in the USA. We discuss the recent results of the completed phase II and III clinical trials.

Cemiplimab monotherapy in advanced non-squamous and squamous non-small cell lung cancer

Anti-programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) monoclonal antibodies are commonly used for advanced non-squamous and squamous non-small cell lung cancer, preferably in patients with high PD-L1 expression (tumour proportion score [TPS] ≥50%) and no targetable driver mutations in epidermal growth factor receptor (EGFR), MET exon 14 skipping alterations, or gene fusions in ALK, ROS1, RET, and TRK.1 In the phase 3 KEYNOTE-024 study, pembrolizumab significantly improved progression-free survival and overall survival compared with platinum-based chemotherapy in first-line treatment of advanced non-small cell lung cancer patients with a TPS score of 50% or greater.

Meta-analysis of the Efficacy and Tolerability of Immune Checkpoint Inhibitors Combined With Chemotherapy in First-line Treatment of Small Cell Lung Cancer

PurposeThe present study was conducted to evaluate the efficacy and tolerability of using an immune checkpoint inhibitor (ICI; programmed cell death protein 1/ligand 1 [PD-1/PD-L1] inhibitor or cytotoxic T-lymphocyte antigen [CTLA]-4 inhibitor) combined with chemotherapy in the first-line treatment of small cell lung cancer. MethodsPotential articles and studies were identified using Web of Science, Cochrane Library, and ClinicalTrials.gov. The end points included overall survival, progression-free survival, objective response rate, and adverse events. Significant heterogeneity was represented by a P value (Ph) of <0.05 or an I2 value of ≥50%, and the random-effects model was applied for pooled analysis. Otherwise, the fixed-effects model was used. Subgroup analysis was performed based on the type of ICI. Potential publication bias was evaluated via funnel plot and the Egger test. FindingsFive eligible articles were included. Both overall survival (hazard ratio [HR] = 0.83; 95% CI, 0.75–0.91; P < 0.001) and progression-free survival (HR = 0.80; 95% CI, 0.73–0.86; P < 0.001) were significantly prolonged by joint ICI + chemotherapy treatment. Additionally, the rates of tolerable grade ≥3 adverse events were similar between the ICI combination regimens and conventional chemotherapy (relative risk = 1.05; 95% CI, 0.98–1.12; P = 0.17). Subanalysis demonstrated that patient survival and objective response rate were more efficiently improved with a combination of anti–PD-1/PD-L1, but not anti–CTLA-4, + chemotherapy. ImplicationsBased on data from the available literature, clinical efficacy (as measured by patient survival and objective response rate) was improved with a combination of anti–PD-1/PD-L1 + chemotherapy as first-line treatment compared with chemotherapy alone in patients with small cell lung cancer.

Central Nervous System Lymphomas.

Primary central nervous system (CNS) lymphoma is a rare, aggressive extranodal non-Hodgkin lymphoma confined to the brain, eyes, CSF, or spinal cord without systemic, non-CNS involvement. This article reviews the clinical presentation, imaging characteristics, diagnostic workup, novel pathophysiologic insights, and treatment of immunocompetent patients with primary CNS lymphoma. The prognosis of primary CNS lymphoma has significantly improved over the past few decades because of the introduction of and widespread use of high-dose methotrexate, which is now the backbone of all first-line combination chemotherapy treatments. Despite this progress, durable remission is still observed in only approximately 50% of patients. Novel insights into the pathophysiology of primary CNS lymphoma have identified the B-cell receptor pathway as well as the suppressed tumor immune microenvironment and immune evasion as key mechanisms in the pathogenesis of primary CNS lymphoma. Novel, small molecules and agents targeting these aberrant pathways have been introduced into clinical trials of recurrent/refractory primary CNS lymphomas. Agents such as the Bruton tyrosine kinase (BTK) inhibitor ibrutinib or immunomodulatory drugs such as lenalidomide and pomalidomide have shown promising response rates in the relapsed setting. Diagnosis of primary CNS lymphoma requires a high level of suspicion because clinical signs and deficits can vary and depend on the involved CNS compartments. Rapid initiation of therapy is essential for recovery and prognosis. The optimal treatment regimen has not been defined, but methotrexate-based chemotherapy regimens are considered the standard treatment approach for induction treatment. Novel, targeted agents have recently been introduced into the therapeutic arsenal.

Combination of trastuzumab and taxane-containing intensified chemotherapy in first-line treatment of HER2-positive advanced gastric cancer.

Taxane-containing combinations are recommended for the first-line therapy of advanced gastric cancer. It is not known which chemotherapy regimen is the best with trastuzumab for HER2-positive patients. The aim of this study was to compare taxane-containing intensified chemotherapy versus standard chemotherapy in combination with trastuzumab in the first-line treatment of HER2-positive advanced gastric adenocarcinoma. This study is a retrospective multicenter study of the Turkish Oncology Group. A total of 130 HER2-positive patients with inoperable locally advanced, recurrent, or metastatic gastric adenocarcinoma being given chemotherapy plus trastuzumab as the first-line treatment were included from 16 different oncology centers. Trastuzumab combination with intensified chemotherapy including taxane or standard chemotherapy was compared in terms of progression-free survival (PFS), overall survival (OS), and toxicity. There were 108 patients in the standard and 22 patients in the intensified chemotherapy group. PFS of the standard and intensified group were 5.6 months (95% confidence interval [CI] 4.8-6.4) and 5.3 months (95% CI 2.6-8), respectively (p = 0.70). OS of the standard and intensified group were 11.1 months (95% CI 8.3-13.9) and 15.2 months (95% CI 12.7-17.7), respectively (p = 0.03). Repeated analysis excluding patients given any previous therapy revealed similar results. The intensified group had more fever and febrile neutropenia. Trastuzumab combination with intensified chemotherapy provides better OS in first-line treatment of HER2-positive advanced gastric cancer. Further large-scale studies should be performed in HER2-positive patients.

Correlation Between Baseline Serum Tumor Markers and Clinical Characteristic Factors in Patients with Advanced Pancreatic Cancer.

PurposeIn pancreatic cancer (PC), CA 19–9, CEA and CA 125 are the most widely used tumor markers. The aim of this study was to explore the prognostic significance of baseline levels of serum CA 19–9, CEA, and CA 125, and to evaluate the clinical significance of these markers in PC patients.Patients and MethodsA total of 278 patients with advanced PC that had received first-line chemotherapy treatments were examined. Correlation analysis between the tumor markers and clinical characteristics was performed using a Pearson’s Chi-squared test or Fisher’s exact test. A Pearson’s correlation test was utilized to investigate the relationship between tumor markers and peripheral blood parameters. Univariate analysis was estimated using a Kaplan–Meier analysis and compared using a Log rank test. Multivariate analysis was performed using a Cox proportional hazards regression model.ResultsBoth individually and collectively, the baseline CA 19–9, CEA and CA 125 levels were positively associated with the primary tumor site (p < 0.01), liver metastasis (p < 0.05), and number of organ metastases (p < 0.05). Furthermore, CA 19–9, CEA and CA 125 were correlated to baseline WBC (p < 0.001) and LDH (p < 0.01) levels. Additionally, CA 19–9 was correlated with years of smoking (p = 0.024); diabetes and years of diabetes (p = 0.012); baseline glycemic levels (p = 0.004); and neutrophil counts (p < 0.001). Moreover, CA 125 levels were associated with the baseline neutrophil counts (p < 0.001) and peritoneal metastasis (p = 0.008). When examining neutrophil, LDH, CA 19–9 and CA 125 levels were found to be associated with overall survival (OS) and shown to be independent prognostic factors.ConclusionCA 19–9, CEA and CA 125 are correlated with multiple clinical factors. Baseline neutrophil, LDH, CA 19–9 and CA 125 levels are associated with OS and may potentially serve as prognostic factors.

Les patients ALK et ROS1 : quelle séquence ?: ALK and ROS1 patients: What sequence?

AbstractCrizotinib is a tyrosine kinase inhibitor of ALK (iALK) more effective and better tolerated that chemotherapy in first-line treatment of advanced non-small cell lung cancer with ALK fusion (ALK+ NSCLC). Crizotinib resistance will eventually occur in all patients. This is about on target resistance mutations in one third of the cases, bypass pathway emergence in one third and central nervous system progression in one third. Next generation iALK (ceritinib, alectinib, brigatinib, lorlatinib, ensartinib) are effective at time of crizotinib failure. The “classic” iALK sequencing with crizotinib followed by next generation iALK is associated with survival from diagnosis of metastatic disease exceeding 4 years. The second-generation iALK alectinib and brigatinib demonstrated their superiority compared to crizotinib in terms of progression-free survival, tolerability and cerebral disease control. This result paves the way for a new standard of care with alectinib/brigatinib front-line followed by lorlatinib. Crizotinib is the standard of care in ROS1+ NSCLC. Treatment at time of crizotinib failure is not well settled.© 2020 SPLF. Published by Elsevier Masson SAS. All rights reserved.

LBA57 MHC-II antigen presentation pathway as a predictive biomarker for sintilimab plus chemotherapy in first-line treatment of locally advanced or metastatic non-squamous non-small cell lung cancer (nsq-NSCLC)

LBA57 MHC-II antigen presentation pathway as a predictive biomarker for sintilimab plus chemotherapy in first-line treatment of locally advanced or metastatic non-squamous non-small cell lung cancer (nsq-NSCLC)

Prophylactic antibiotic treatment with TMP-SMX decreased the incidence of interstitial pneumonia in patients with B-cell lymphoma on chemotherapy

BackgroundSeveral studies have reported the incidence of interstitial pneumonia (IP) among patients with non-Hodgkin lymphoma (NHL) that are undergoing combination chemotherapy plus rituximab; however, the effective prophylactic treatment for IP remains unclear. This study aims to explore the prophylactic effect of trimethoprim-sulfamethoxazole (TMP-SMX) on IP and identify IP-associated risk factors in NHL patients.MethodsBetween March 2013 and April 2018, 498 patients (264 males, 53%) with B-cell NHL undergoing first-line RCHOP-like chemotherapy treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone were enrolled in this study.ResultsThese patients had a median age of 56 years, and 311 of the 498 patients (62.4%) were administered once daily with the prophylactic treatment of TMP-SMX. IP occurred in 65 patients (13.1%), indicating a significant reduction in the IP incidence rate (21.4% vs. 8.0%; p < 0.001). Among patients treated with TMP-SMX, 2 (1.2%) exhibited rashes, 38 (12.2%) suffered from nausea and vomiting, 52 (16.7%) showed signs of neutropenia, and 18 (5.8%) suffered from kidney dysfunction. Both univariate and multivariate analysis showed that gender (male), history of diabetes, and absence of prophylactic TMP-SMX treatment were significant risk factors associated with IP. Disease progression was observed in 55/311 (17.7%) patients that underwent prophylactic TMP-SMX treatment and in 63/187 (33.7%) patients that did not (p < 0.001).ConclusionsThis study revealed that the occurrence of IP was common in B-cell NHL patients undergoing combined chemotherapy plus rituximab treatment. IP could be reduced with prophylactic treatment of once-daily oral TMP-SMX.

P-272 Sarcopenia in metastatic colorectal cancer patients during first-line chemotherapy

Sarcopenia is a condition characterized by skeletal muscle mass decrease due to physiological aging or concomitant disease such as neoplasia. In cancer patients, a low lean body mass represents a negative prognostic factor for survival and development of dose-limiting chemotherapy toxicities, independent of the stage of disease. The aim of our study was to analyze the association between sarcopenia and overall survival (OS), response to therapy and toxicity in patients with metastatic colorectal cancer (mCRC) in first-line chemotherapy treatment.

Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non–Small Cell Lung Cancer

Checkpoint inhibitors targeting programmed cell death 1 or its ligand (PD-L1) as monotherapies or in combination with anti-cytotoxic T-lymphocyte-associated antigen 4 have shown clinical activity in patients with metastatic non-small cell lung cancer. To compare durvalumab, with or without tremelimumab, with chemotherapy as a first-line treatment for patients with metastatic non-small cell lung cancer. This open-label, phase 3 randomized clinical trial (MYSTIC) was conducted at 203 cancer treatment centers in 17 countries. Patients with treatment-naive, metastatic non-small cell lung cancer who had no sensitizing EGFR or ALK genetic alterations were randomized to receive treatment with durvalumab, durvalumab plus tremelimumab, or chemotherapy. Data were collected from July 21, 2015, to October 30, 2018. Patients were randomized (1:1:1) to receive treatment with durvalumab (20 mg/kg every 4 weeks), durvalumab (20 mg/kg every 4 weeks) plus tremelimumab (1 mg/kg every 4 weeks, up to 4 doses), or platinum-based doublet chemotherapy. The primary end points, assessed in patients with ≥25% of tumor cells expressing PD-L1, were overall survival (OS) for durvalumab vs chemotherapy, and OS and progression-free survival (PFS) for durvalumab plus tremelimumab vs chemotherapy. Analysis of blood tumor mutational burden (bTMB) was exploratory. Between July 21, 2015, and June 8, 2016, 1118 patients were randomized. Baseline demographic and disease characteristics were balanced between treatment groups. Among 488 patients with ≥25% of tumor cells expressing PD-L1, median OS was 16.3 months (95% CI, 12.2-20.8) with durvalumab vs 12.9 months (95% CI, 10.5-15.0) with chemotherapy (hazard ratio [HR], 0.76; 97.54% CI, 0.56-1.02; P = .04 [nonsignificant]). Median OS was 11.9 months (95% CI, 9.0-17.7) with durvalumab plus tremelimumab (HR vs chemotherapy, 0.85; 98.77% CI, 0.61-1.17; P = .20). Median PFS was 3.9 months (95% CI, 2.8-5.0) with durvalumab plus tremelimumab vs 5.4 months (95% CI, 4.6-5.8) with chemotherapy (HR, 1.05; 99.5% CI, 0.72-1.53; P = .71). Among 809 patients with evaluable bTMB, those with a bTMB ≥20 mutations per megabase showed improved OS for durvalumab plus tremelimumab vs chemotherapy (median OS, 21.9 months [95% CI, 11.4-32.8] vs 10.0 months [95% CI, 8.1-11.7]; HR, 0.49; 95% CI, 0.32-0.74). Treatment-related adverse events of grade 3 or higher occurred in 55 (14.9%) of 369 patients who received treatment with durvalumab, 85 (22.9%) of 371 patients who received treatment with durvalumab plus tremelimumab, and 119 (33.8%) of 352 patients who received treatment with chemotherapy. These adverse events led to death in 2 (0.5%), 6 (1.6%), and 3 (0.9%) patients, respectively. The phase 3 MYSTIC study did not meet its primary end points of improved OS with durvalumab vs chemotherapy or improved OS or PFS with durvalumab plus tremelimumab vs chemotherapy in patients with ≥25% of tumor cells expressing PD-L1. Exploratory analyses identified a bTMB threshold of ≥20 mutations per megabase for optimal OS benefit with durvalumab plus tremelimumab. ClinicalT rials.gov Identifier: NCT02453282.

The prognostic effect of TTF-1 expression in the Chinese population of patients with advanced lung adenocarcinomas.

BackgroundThyroid transcription factor 1 (TTF-1), which is usually expressed by lung adenocarcinomas and small cell carcinomas, is usually used to distinguish adenocarcinoma and small cell carcinoma from cells of another type of lung cancer. We examined the association between TTF-1 expression and overall survival between patients with stage IV pulmonary adenocarcinoma to investigate the role of TTF-1 as a predictive and/or prognostic tumor marker in patients with advanced lung adenocarcinomas.MethodsAnalysis of the clinicopathologic features, treatment regimens, and overall survival of 209 lung adenocarcinoma patients who had been detected for TTF-1 expression and received consecutive treatments in the Affiliated Hospital of Qingdao University.ResultsTTF-1 expression was positive in 166 (79%) and negative in 43 (21%) patients who were reviewed. Moreover, there was no significant difference between the clinicopathologic features of TTF-1 positive and TTF-1 negative tumors. In the multivariable review, the overall survival of TTF-1 positive tumor patients was significantly longer than that of TTF-1 negative tumor patients [22.7 vs. 11.8 months (P<0.0001)], increasing the prognostic effect of Karnofsky performance status and receiving first-line chemotherapy or targeted therapy. Positive TTF-1 and negative TTF-1 patients receiving pemetrexed-based chemotherapy improved the duration of treatment compared to those receiving non-pemetrexed chemotherapy.ConclusionsTTF-1 expression was associated with an improved survival in patients with advanced lung adenocarcinomas. Both patients, either TTF-1 positive or negative, could benefit from the first-line chemotherapy or pemetrexed treatment option. However, as discovered by our investigation, TTF-1 cannot forecast a portion of the lung adenocarcinomas that had a selective sensitivity to pemetrexed.

A multicenter phase II trial of tumor treating fields plus chemotherapy for first-line treatment of gastric adenocarcinoma.

TPS474 Background: Gastric carcinoma (GC) is the third-leading cause of death in China (291,000 deaths in 2015). Current therapies include surgery, chemotherapy, radiotherapy and targeted therapy, which prolong PFS and OS to 6 months and 8-14 months, respectively. Tumor Treating Fields (TTFields) are a non-invasive, regional antimitotic treatment modality approved by the FDA for glioblastoma and malignant pleural mesothelioma. TTFields at specific frequency (100- 500 kHz) are delivered via transducer arrays placed on the skin of the upper abdomen, back, right and left hypochondriac regions where the primary tumor lesion is located. TTFields were effective in preclinical models of gastric cancer and there are several ongoing Phase 3 trials of TTFields in multiple solid tumors. In this phase 2, single arm, open-label, multi-center study, we will investigate for the first time the efficacy and safety of TTFields concomitant with XELOX (oxaliplatin/capecitabine) as the first-line treatment of GC. Methods: Patients (N = 50) with histologically confirmed unresectable, locally advanced or metastatic Gastroesophageal Junction (GEJ) or Gastric Adenocarcinoma (GC), aged ≥ 18 years, ECOG PS 0-1, who had no previous systemic treatment for the recurrent or metastatic disease will be enrolled. Patients will receive TTFields (150 kHz via the NovoTTF-100L (P) medical device for average monthly use of 18 hrs/day) plus XELOX chemotherapy (Oxaliplatin: 130 mg/m2 on day 1 every 3 weeks; Capecitabine: 1000 mg/m2, PO, BID on day 1-14 every 3 weeks). For HER-2 positive patients, trastuzumab is allowed. The primary endpoint is investigator-assessed Objective Response Rate (ORR) per RECIST 1.1. Secondary endpoints are time to tumor progression (TTP), progression-free survival (PFS), overall survival (OS), and 12-month OS rate. Adverse events (AEs) will be graded for severity according to CTCAE 5.0. Based on the historical ORR data in first-line chemotherapy in GC, we assumed that ORR will be higher than 45% with TTFields concomitant with chemotherapy. At least 45 patients need to be enrolled to ensure the lower boundary is 30% of the 95% CI. Estimating a patient drop-out rate of 10%, 50 patients will be actually enrolled.

HER2-HER3 Heterodimer Quantification by FRET-FLIM and Patient Subclass Analysis of the COIN Colorectal Trial.

BackgroundThe phase III MRC COIN trial showed no statistically significant benefit from adding the EGFR-target cetuximab to oxaliplatin-based chemotherapy in first-line treatment of advanced colorectal cancer. This study exploits additional information on HER2-HER3 dimerization to achieve patient stratification and reveal previously hidden subgroups of patients who had differing disease progression and treatment response. MethodsHER2-HER3 dimerization was quantified by fluorescence lifetime imaging microscopy in primary tumor samples from 550 COIN trial patients receiving oxaliplatin and fluoropyrimidine chemotherapy with or without cetuximab. Bayesian latent class analysis and covariate reduction was performed to analyze the effects of HER2-HER3 dimer, RAS mutation, and cetuximab on progression-free survival and overall survival (OS). All statistical tests were two-sided. ResultsLatent class analysis on a cohort of 398 patients revealed two patient subclasses with differing prognoses (median OS = 1624 days [95% confidence interval [CI] = 1466 to 1816 days] vs 461 days [95% CI = 431 to 504 days]): Class 1 (15.6%) showed a benefit from cetuximab in OS (hazard ratio = 0.43, 95% CI = 0.25 to 0.76, P = .004). Class 2 showed an association of increased HER2-HER3 with better OS (hazard ratio = 0.64, 95% CI = 0.44 to 0.94, P = .02). A class prediction signature was formed and tested on an independent validation cohort (n = 152) validating the prognostic utility of the dimer assay. Similar subclasses were also discovered in full trial dataset (n = 1630) based on 10 baseline clinicopathological and genetic covariates.ConclusionsOur work suggests that the combined use of HER dimer imaging and conventional mutation analyses will be able to identify a small subclass of patients (>10%) who will have better prognosis following chemotherapy. A larger prospective cohort will be required to confirm its utility in predicting the outcome of anti-EGFR treatment.

The balance between NRF2/GSH antioxidant mediated pathway and DNA repair modulates cisplatin resistance in lung cancer cells

Lung cancer patients face a dismal prognosis mainly due to the low efficacy of current available treatments. Cisplatin is the first-line chemotherapy treatment for those patients, however, resistance to this drug is a common and yet not fully understood phenomenon. Aiming to shed new light into this puzzle, we used established normal and malignant lung cell lines displaying different sensitivity towards cisplatin treatment. We observed a negative correlation between cell viability and DNA damage induction upon cisplatin treatment. Interestingly, drug sensitivity in those cell lines was not due to either difference on DNA repair capacity, or in the amount of membrane ion channel commonly used for cisplatin uptake. Also, we noted that glutathione intracellular levels, and expression and activity of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) were determinant for cisplatin cytotoxicity. Remarkably, analysis of gene expression in non-small cell lung cancer patients of the TCGA data bank revealed that there is a significant lower overall survival rate in the subset of patients bearing tumors with unbalanced levels of NRF2/KEAP1 and, as consequence, increased expression of NRF2 target genes. Thus, the results indicate that NRF2 and glutathione levels figure as important cisplatin resistance biomarkers in lung cancer.

Avoidance of apoptotic death via a hyperploid salvage survival pathway after platinum treatment in high grade serous carcinoma cell line models.

The alkylating agent platinum is first-line chemotherapy treatment for high-grade serous carcinomas (HGSC) of tubal-ovarian origin. Platinum compounds cause DNA damage and induce apoptotic cell death in the bulk tumor population. However, subpopulations of tumor cells may exhibit diverging behaviors from the bulk tumor due to an alternate stress response that diverts tumor cells from apoptotic death. In this study, we identified a salvage survival pathway in which G2-arrested tumor cells bypassed apoptosis and progressed through aberrant mitotic events to then emerge as a distinct subpopulation of viable large hyperploid cells but with uncertain long-term propagation potential. Platinum-induced large hyperploid cells were flow sorted and showed rare regrowth capacity as compared to their more proficiently regenerating non-hyperploid counterparts. However, detailed time-lapse microscopy provided direct evidence that these hyperploid cells were mitotically active and could divide successfully to produce viable daughter cells. The hyperploid survival response was observed across different cell lines and utilization of this survival pathway was dependent on the strength of the G2-M checkpoint. Conceivably, this salvage survival strategy may contribute to increased genomic diversity of the regenerating tumor cell line through a coupled hyperploidization and de-polyploidization process that may be relevant for drug resistance.

Prognosis in Patients with Human Immunodeficiency Virus Infection and Advanced Clinical Stage Classic Hodgkin's Lymphoma

Classic Hodgkin's lymphoma (cHL) represents 95% of all Hodgkin lymphomas, and is responsible of 0.5% of all cancer types (Siegel, Miller &amp; Jemal, 2016). In HIV positive patients, the incidence of cHL is high (5-20 fold). The use of combination antiretroviral therapy (CART) and CD4 count &gt;200 cells/uL appears to increase the risk; nonetheless, the risk for developing cHL in HIV infected patients remains high, regardless of CD4 count. The median patients' age of HIV-associated classic Hodgkin's lymphoma (HIV-cHL) ranges from 40 to 49 years old, slightly higher than the age observed in general population. It is more common in men, and tends to manifest with extranodal disease (67% vs 32%), B-symptoms (77% vs 43%), and stage III or IV disease (82% vs 42%) (Shiels et al, 2014). Recent recommendations state that HIV-cHL should receive first-line ABVD chemotherapy treatment while continuing CART (Blanca et al, 2007)(Montoto et al, 2012). To determine the prognosis of de novo advanced stage HIV-cHL and compare it with non-HIV-cHL, we designed an observational, descriptive study, including all HIV-cHL (WHO 2016 criteria) from August 2004 to December 2018, paired with a non-HIV-cHL group by clinical stage and gender. Clinical features between positive and negative HIV groups were compared by standard statistical methods. Overall survival (OS) and relapse-free survival (RFS) were calculated by Kaplan-Meier methodology. Analysis for mortality predictors was performed with a univariate Cox regression model. Data was collected from 21 patients with HIV-cHL, all male and with advanced clinical stage, and compared with 58 non-HIV-cHL patients with the same characteristics. The mean age observed was 42.9 (± 10.88) years in HIV-cHL, and 45.1 (± 17.56) years in non-HIV-cHL (p = 0.50). Among the clinical characteristics, the presence of B symptoms was documented in 85.7% of HIV-cHL, and in 91.4% of non-HIV-cHL (p = 0.43). Among biochemical characteristics in both groups, we observed a significantly lower leucocyte count in HIV-cHL (4.6x103 cells/uL) compared with non-HIV-cHL (6.7x103 cells/uL) (p = 0.02). In the monocyte line, we found that HIV-cHL had lower absolute counts (340 cells/uL) than non-HIV-cHL (708 cells/uL) (p = 0.01). A high IPS was reported in 66.7% of HIV-cHL, and in 67.2% of non-HIV-cHL (p = 1.00). The most common reported histologic subtype was mixed cellularity for both groups, with a prevalence of 38.1% and 38.9%, respectively (p = 0.25). The positivity for Epstein-Barr virus was tested in the biopsies of 18 HIV-cHL, and was 100%. Regarding HIV status in infected patients, a 40-month period was the median time between HIV and cHL diagnosis. The median CD4 cell count was 109 cells/uL. 90.5% of patients were treated with CART at time of cHL diagnosis. Other clinical, biochemical and prognostic characteristics are in Table 1. The median follow-up time for all patients was 31 months; the median follow-up time for HIV-cHL was 10 months, shorter than the median follow-up time for non-HIV-cHL (45 months) (p = 0.01). 85.7% of HIV-cHL and 96.6% of non-HIV-cHL received chemotherapy, with a median of 6 cycles (p = 0.11). Complete response (CR) was documented in 61.1% of HIV-cHL, and in 66.1% of non-HIV-cHL (p = 0.77). RFS was 36.5 months for all patients, being less for HIV-cHL (24 months) compared with non-HIV-cHL (51 months) (p = 0.03). The OS median at the time of last follow-up had not yet been reached in all patients (Figure 1). The univariate analysis showed that age ≥45 years old and stage IV cHL are adverse prognostic factors (p = 0.02, p = 0.03, respectively). IPS ≥4 was an adverse outcome factor for mortality, with statistical significance (p = 0.01) (Figure 2). At last follow-up, 22 (27.8%) patients had died, 6 (28.6%) HIV-cHL and 16 (27.6%) non-HIV-cHL (p = 1.00). Clinical, biochemical and prognostic variables, as well as treatment outcomes were similar between HIV-cHL and non-HIV-cHL. Although follow-up time in the HIV-cHL group is shorter, prognosis in terms of OS is similar. RFS is statistically different between both groups and is shorter in HIV-cHL, but as the OS in both groups remains similar, it is possible that rescue chemotherapy is effective in relapsed patients. There was no difference observed in the likelihood of achieving CR in both groups. IPS ≥4 and CR were independent prognostic factors for OS. IPS as an adverse factor and CR as a favorable one. Prognosis of advanced stage HIV-cHL is similar to non-HIV-cHL patients. Disclosures No relevant conflicts of interest to declare.

Meta-analysis of Cinobufacini Injection combined with platinum-contained first-line chemotherapy in treatment of non-small cell lung cancer

To systemically evaluate the efficacy and safety of Cinobufacini Injection in combination with platinum-contained first-line chemotherapy for treatment of non-small cell lung cancer(NSCLC). The randomized controlled trials(RCT) about the Cinobufacini in combination with platinum-contained first-line chemotherapy(versus chemotherapy alone) were collected through PubMed,Cochrane library,CNKI,VIP,CBM,and Wan Fang Database from database inception to December 2018. Two researchers extracted data and assessed the literature quality separately,and made a Meta-analysis by using Rev Man 5. 3 software. Twenty-seven RCTs were included in the present review,involving 2 125 patients,1 082 in treatment group and 1 043 in control group. The Meta-analysis results showed that as compared with chemotherapy alone,the combination of Cinobufacini and platinum-contained first-line chemotherapy could enhance one year survival rate(RR = 1. 34,95%CI[1. 17,1. 55],P< 0. 01),two year survival rate(RR = 1. 84,95% CI[1. 31,2. 59],P<0. 01),objective tumor response rate(RR = 1. 47,95%CI[1. 33,1. 63],P<0. 01); improve the quality of life for patients(RR =1. 54,95%CI[1. 37,1. 72],P < 0. 01); and reduce the incidences of WBC toxicity(RR = 0. 63,95% CI[0. 49,0. 80],P < 0. 01),platelet toxicity(RR = 0. 54,95%CI[0. 35,0. 84],P<0. 01),gastrointestinal reactions(RR = 0. 60,95%CI[0. 45,0. 80],P<0. 05),pain(RR = 1. 68,95% CI[1. 38,2. 03],P< 0. 01),and hair loss reaction(RR = 0. 76,95% CI[0. 59,0. 98],P < 0. 05). The results showed that for the treatment of NSCLC,the addition of cinofacini to conventional platinum-contained chemotherapy can increase the long-term and short-term efficacy of chemotherapy,improve the quality of life for patients,and reduce the side effects of platinumbased chemotherapy drugs. However,more high quality and large-scale randomized controlled trials are required to verify this conclusion in the future.

Molecular response with blinatumomab in relapsed/refractory B-cell precursor acute lymphoblastic leukemia

AbstractMinimal residual disease (MRD), where leukemic cell levels are lower than the morphologic detection threshold, is the most important prognostic factor for acute lymphoblastic leukemia (ALL) relapse during first-line chemotherapy treatment and is standard of care in treatment monitoring and decision making. Limited data are available on the prognostic value of MRD response after relapse. We evaluated the relationship between MRD response and outcomes in blinatumomab-treated adults with relapsed/refractory (R/R) B-cell precursor ALL. Of 90 patients with complete remission (CR) or CR with partial hematologic recovery (CRh), 64 (71.1%) achieved a complete MRD response (no detectable individual rearrangements of immunoglobulin/T-cell receptor genes by polymerase chain reaction [PCR] at a minimum sensitivity level of 10−4). Eleven patients had MRD <10−4. Therefore, overall, 75 (83.3%) experienced an MRD response (no detectable MRD or detectable MRD) measured by PCR within the first 2 treatment cycles. Overall survival (OS) and relapse-free survival (RFS) were significantly longer in patients who achieved CR/CRh and MRD response (median, 20.6 and 9.0 months, respectively) compared with CR/CRh patients without MRD response (median, 12.5 and 2.3 months, respectively). In conclusion, longer durations of OS and RFS associated with MRD response support the value of achieving MRD response and its use as a prognostic factor for blinatumomab treatment in R/R ALL. This trial was registered at www.clinicaltrials.gov as #NCT01466179.