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Relative dose intensity of first-line chemotherapy and overall survival in patients with advanced non-small-cell lung cancer

Support Care Cancer

2019 Lyman, Gary H, MD, MPH Gary Lyman

PURPOSE: The effects of chemotherapy dose intensity on survival in patients with advanced non-small-cell lung cancer (NSCLC) are poorly understood. We retrospectively analyzed dose delays/reduction, relative dose intensity (RDI), and the association between chemotherapy intensity and survival in advanced NSCLC. METHODS: This retrospective cohort study included adults with advanced lung cancer who received first-line myelosuppressive platinum-based chemotherapy (January 2007-December 2010) in ~ 230 US Oncology Network community practices. Dose delays >/= 7 days, dose reductions >/= 15%, and RDI relative to standard regimens were described. Overall survival (OS) was measured using Kaplan-Meier and Cox proportional hazard (PH) models. RESULTS: Among 3866 patients with advanced NSCLC, 32.4% experienced dose delays >/= 7 days, 50.1% experienced dose reductions >/= 15%, and 40.4% had RDI < 85%. Reduced RDI was also common regardless of baseline ECOG PS (ECOG PS >/= 2, 56.2%; ECOG PS 0, 33.6%) and tumor subgroup (squamous cell carcinoma, 52.2%; adenocarcinoma, 36.0%). When stratified by chemotherapy intensity measures, significant OS differences were observed only for dose delays. Median (95% CI) OS was 1.02 years (0.96-1.12) for dose delays >/= 7 days and 0.71 years (0.66-0.77) for dose delays < 7 days. In multivariable Cox PH analysis, dose delays >/= 7 days (HR = 0.71; 95% CI = 0.63-0.80) and RDI >/= 85% (HR = 1.18; 95% CI = 1.05-1.32) were significantly associated with decreased mortality. CONCLUSIONS: Dose delays, dose reductions, and reduced RDI were common, and dose delays >/= 7 days and high RDI were significantly associated with decreased mortality. These results can help identify potential risk factors and characterize the effect of chemotherapy dose modification strategies on mortality.

Traditional cardiovascular risk factors and individual prediction of cardiovascular events in childhood cancer survivors

J Natl Cancer Inst

2019 Leisenring, Wendy M, ScD Wendy m Leisenring

BACKGROUND: Childhood cancer survivors have an increased risk of heart failure, ischemic heart disease, and stroke. They may benefit from prediction models that account for cardiotoxic cancer treatment exposures combined with information on traditional cardiovascular risk factors such as hypertension, dyslipidemia, and diabetes. METHODS: Childhood Cancer Survivor Study participants (n = 22,643) were followed through age 50y for incident heart failure, ischemic heart disease, and stroke. Siblings (n = 5,056) served as a comparator. Participants were assessed longitudinally for hypertension, dyslipidemia, and diabetes based on self-reported prescription medication use. Half the cohort was used for discovery; the remainder for replication. Models for each outcome were created for survivors ages 20y, 25y, 30y, and 35y at the time of prediction (n = 12 models). RESULTS: For discovery, risk scores based on demographic, cancer treatment, hypertension, dyslipidemia, and diabetes information achieved areas under the receiver operating characteristic curve (AUC) and concordance (C) statistics >/=0.70 in 9 and 10 of the 12 models, respectively. For replication, AUCs and C-statistics >/=0.70 were observed in 7 and 9 of the models, respectively. Across outcomes, the most influential exposures were anthracycline, radiotherapy, diabetes, and hypertension. Survivors were then assigned to statistically distinct moderate- and high-risk groups corresponding to age 50y cumulative incidences of each target outcome <3% and approximately >/=10%, respectively. Siblings had cumulative incidences </=1% for all outcomes. CONCLUSIONS: Traditional cardiovascular risk factors remain important for predicting risk of cardiovascular disease among adult-aged survivors of childhood cancer. These prediction models provide a framework to base future surveillance strategies and interventions.

Survival of children with endemic Burkitt lymphoma in a prospective clinical care project in Uganda

Pediatr Blood Cancer

2019 Uldrick, Thomas, MD Thomas Uldrick

PURPOSE: "Endemic" Burkitt lymphoma (BL) is a common childhood cancer in Africa. Social and treatment factors may contribute to poor survival. With the aim of improving BL outcomes in Uganda, we undertook a comprehensive project (BL Project) that provided diagnostic support, access to standard chemotherapy, nutritional evaluations, and case management. We evaluated survival of children with BL in the context of the project. PATIENTS AND METHODS: Patients followed by the BL Project who consented to research were enrolled in this study. Children with a pathology diagnosis consistent with BL were eligible. Data were collected prospectively. First-line chemotherapy generally consisted of six cycles of cyclophosphamide, vincristine, low-dose methotrexate (COM). We used Kaplan-Meier and Cox regression analyses to evaluate factors associated with overall survival (OS). RESULTS: Between July 2012 and June 2017, 341 patients with suspected BL presented to the BL Project. One hundred eighty patients with a pathology-based diagnosis were included in this study. The median age was seven years (interquartile range, 5-9), 74% lived >/=100 km from the Uganda Cancer Institute, 61% had late-stage disease, 84% had ECOG performance status < 3, 63% reported B-symptoms, and 22% showed neurologic symptoms. Fewer than 10% abandoned therapy. The four-year OS rate was 44% (95% CI, 36%-53%). In a multivariate model, ECOG status was significantly associated with mortality. CONCLUSION: The BL Project reduced effects of lacking supportive care and oncology resources, and allowed patients from Uganda to receive curative intent therapy with minimal loss to follow-up. Nonetheless, OS remains unacceptably low. Improved therapeutic approaches to endemic BL are urgently needed in Africa.

Fate of Barium Sulfate Nanoparticles Deposited in the Lungs of Rats

Scientific Reports

2019 Fu, Dan Evan Yu

We have shown that barium [from BaSO4 nanoparticles (NPs)] was cleared from the lungs faster than other poorly soluble NPs and translocated mostly to bone. We now studied barium biokinetics in rats during Study 1: two-year inhalation exposure to 50 mg/m(3) BaSO4 NP aerosols, and Study 2: single intratracheal (IT) instillation of increasing doses of BaSO4 NPs or BaCl2. Study 1 showed that lung barium content measured by inductively coupled plasma mass spectrometry increased during 360 days of BaSO4 NP aerosol exposures. An equilibrium was established from that time until 2 years. Barium concentrations in BaSO4-exposed animals were in the order (lungs > lymph nodes > hard bone > bone marrow > liver). In Study 2, there was an increase in lung barium post-IT instillation of BaSO4 NPs while barium from BaCl2 was mostly cleared by day 28. Transmission electron microscopy showed intact BaSO4 NPs in alveolar macrophages and type II epithelial cells, and in tracheobronchial lymph nodes. Using stimulated Raman scattering microscopy, specific BaSO4 Raman spectra were detected in BaSO4 NP-instilled lungs and not in other organs. Thus, we posit that barium from BaSO4 NPs translocates from the lungs mainly after dissolution. Barium ions are then incorporated mostly into the bone and other organs.

Epigenome-wide effects of vitamin D on asthma bronchial epithelial cells


2019 Wang, Ting Min Fang

Vitamin D is a nutrient and a hormone with multiple effects on immune regulation and respiratory viral infections, which can worsen asthma and lead to severe asthma exacerbations. We set up a complete experimental and analytical pipeline for ATAC-Seq and RNA-Seq to study genome-wide epigenetic changes in human bronchial epithelial cells of asthmatic subjects, following treatment of these cells with calcitriol (vitamin D3) and Poly (I:C)(a viral analogue). This approach led to the identification of biologically plausible candidate genes for viral infections and asthma, such as DUSP10 and SLC44A1.

Assessment of the Safety of Pembrolizumab in Patients With HIV and Advanced Cancer-A Phase 1 Study

JAMA Oncol

2019 Uldrick, Thomas, MD Thomas Uldrick

Importance: Anti-PD-1 (anti-programmed cell death 1) and anti-PD-L1 (anti-programmed cell death ligand 1) regimens are preferred therapies for many cancers, including cancers associated with HIV. However, patients with HIV were excluded from most registered trials. Objective: The primary objective was to evaluate the safety of pembrolizumab in people with HIV and advanced cancer; the secondary objective was to evaluate tumor responses. Design, Setting, and Participants: Open-label, nonrandomized, phase 1 multicenter study conducted at 7 Cancer Immunotherapy Trials Network sites. Patients with HIV and advanced cancer as well as a CD4 count greater than or equal to 100 cells/muL, antiretroviral therapy (ART) for 4 or more weeks, and an HIV viral load of less than 200 copies/mL were eligible. Exclusion criteria included uncontrolled hepatitis B or C infection, active immunosuppressive therapy, or a history of autoimmune disease requiring systemic therapy. Interventions: Pembrolizumab, 200 mg, administered intravenously every 3 weeks for up to 35 doses in 3 CD4 count-defined cohorts. Participants continued ART. Main Outcomes and Measures: Safety and tolerability were assessed using current NCI Common Terminology Criteria for Adverse Events. Immune-related adverse events grade 2 or higher were considered immune-related events of clinical interest (irECI). Tumor responses were evaluated using standard tumor-specific criteria. Results: Thirty participants (28 men and 2 women; median [range] age, 57 [39-77] years) were enrolled from April 2016 through March 2018; 6 had Kaposi sarcoma (KS), 5 had non-Hodgkin lymphoma (NHL), and 19 had non-AIDS-defining cancers. Safety was observed over 183 cycles of treatment with pembrolizumab. Most treatment-emergent adverse events at least possibly attributed to pembrolizumab were grade 1 or 2 (n = 22), and 20% (n = 6) were grade 3. The irECI included hypothyroidism (6 participants), pneumonitis (3 participants), rash (2 participants), an elevated aminotransferase/alanine aminotransferase level (1 participant), and a musculoskeletal event (1 participant). One participant with pretreatment KS herpesvirus (KSHV) viremia developed a polyclonal KSHV-associated B-cell lymphoproliferation and died. HIV was controlled in all participants. Increases in CD4 count were not statistically significant (median increase, 19 cells/muL; P = .18). Best tumor responses included complete response (lung, 1 patient), partial response (NHL, 2 patients), stable disease for 24 weeks or more (KS, 2 patients), stable disease for less than 24 weeks (15 patients), and progressive disease (8 patients); 2 patients were not evaluable. Conclusions and Relevance: Pembrolizumab has acceptable safety in patients with cancer, HIV treated with ART, and a CD4+ T-cell count of greater than 100 cells/muL but may be associated with KSHV-associated B-cell lymphoproliferation. Clinical benefit was noted in lung cancer, NHL, and KS. Anti-PD-1 therapy is appropriate for US Food and Drug Administration-approved indications and clinical trials in this population. Trial Registration: identifier: NCT02595866.

Tumor downstaging as an intermediate endpoint to assess the activity of neoadjuvant systemic therapy in patients with muscle-invasive bladder cancer


2019 Yu, Evan, MD Evan Yu

BACKGROUND: Achieving a pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC) has been associated with improved overall survival (OS). This study was aimed at evaluating the impact of pathologic downstaging (pDS; ie, a pT stage at least 1 stage lower than the pre-NAC cT stage) on the OS of patients with MIBC treated with NAC. METHODS: The Retrospective International Study of Cancers of the Urothelial Tract (RISC) and the National Cancer Database (NCDB) were queried for cT2-4N0M0 patients treated with NAC. A multivariable Cox model including either pDS or pCR was generated. A nested model was built to evaluate the added value of pDS (excluding patients achieving a pCR) to a model including pCR alone. C indices were computed to assess discrimination. NCDB was used for validation. The treatment effect of NAC versus cystectomy alone in achieving pDS was estimated through an inverse probability-weighted regression adjustment. RESULTS: Overall, 189 and 2010 patients from the RISC and NCDB cohorts, respectively, were included; pDS and pCR were achieved by 33% and 35% and by 20% and 15% in RISC and NCDB, respectively. In both data sets, pDS and pCR were associated with better OS and C indices. Adding pDS excluding pCR to the model with pCR fit the data better (likelihood ratio, P = .019 for RISC and P < .001 for NCDB), and it yielded better discrimination (incremental C index, 4.2 for RISC and 1.6 for NCDB). The treatment effect of NAC in achieving pDS was 2.07-fold (P < .001) in comparison with cystectomy alone. CONCLUSIONS: A decrease of at least 1 stage from the cT stage to the pT stage is associated with improved OS in patients with MIBC treated with NAC.

Meta-Analysis in Metastatic Uveal Melanoma to Determine Progression-Free and Overall Survival Benchmarks: an International Rare Cancers Initiative (IRCI) Ocular Melanoma study

Ann Oncol

2019 Bhatia, Shailender, MD Shailender Bhatia

BACKGROUND: Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) and overall survival (OS), we performed a meta-analysis using individual patient level trial data. METHODS: Individual patient variables and survival outcomes were requested from 29 trials published from 2000-2016. Univariable and multivariable analysis were performed for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated. RESULTS: OS data were available for 912 patients. The median PFS was 3.3 months (95%CI 2.9 to 3.6) and 6-month PFS rate was 27% (95% CI 24 to 30). Univariable analysis showed male sex, elevated (i.e. > vs </= upper limit of normal (ULN)) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (>/=3cm vs < 3cm) to be significantly associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH, and elevated ALP were significantly associated with shorter PFS. The most significant factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2 months (95% CI 9.5 to 11.0) and 1 year OS was 43% (95% CI 40 to 47). The most significant prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS. CONCLUSION: Benchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.

Brief Report: SWOG S1400B (NCT02785913), A Phase II Study of GDC-0032 (Taselisib) for Previously Treated PI3K-Positive Patients with Stage IV Squamous Cell Lung Cancer (Lung-MAP Sub-Study)

J Thorac Oncol

2019 Redman, Mary W, PhD Mary Redman

BACKGROUND: S1400B is a biomarker-driven Lung-MAP sub-study evaluating the phosphatidylinositide 3-kinase (PI3K) inhibitor taselisib (GDC-0032) in patients with PI3K pathway-activated squamous NSCLC (SqNSCLC). METHODS: Eligible patients had tumoral PIK3CA alterations by next generation sequencing and disease progression after at least one line of platinum-based therapy. Patients received 4 mg taselisib orally daily. The primary analysis population (PAP) was a subset of patients having substitution mutations believed to be associated with clinical benefit of PI3K inhibitors. Primary endpoint was response by RECIST 1.1; secondary endpoints included progression-free survival (PFS), overall survival (OS) and duration of response (DoR). RESULTS: Twenty-six patients treated with taselisib comprised the full eligible population (FEP); 21 patients comprised the PAP. Median age in FEP was 68 y (53-83), 19 were male (73%). The study was closed for futility at interim analysis with one responder in the PAP (5% RR, 95% CI 0%-24%). Two possibly treatment-related deaths (1 respiratory failure, 1 cardiac arrest) were observed; 1 patient had Grade 4 and 11 had Grade 3 adverse events. Median PFS and OS in the PAP were 2.9 months (95% CI, 1.8-4.0 mos) and 5.9 months (95% CI, 4.2-7.8 mos), respectively. These numbers were nearly the same in the FEP. CONCLUSIONS: Study S1400B evaluating taselisib in PIK3CA altered SqNSCLC failed to meet its primary endpoint and was closed after an interim futility analysis. The trial is unique in cataloguing the diversity of PIK3CA mutations in SqNSCLC.

Physical Proximity and Functional Cooperation of Glycoprotein 130 and Glycoprotein VI in Platelet Membrane Lipid Rafts

J Thromb Haemost

2019 Oehler, Vivian G, MD Vivian Oehler

OBJECTIVE: Clinical and laboratory studies have demonstrated that platelets become hyper-active and prothrombotic when patients are in conditions of inflammation. We have previously shown that the proinflammatory cytokine IL-6 forms a complex with soluble IL-6 receptor alpha to prime platelets for activation by subthreshold concentrations of collagen. Upon activation, the transcription factor STAT3 phosphorylated and dimerized to act as a protein scaffold to facilitate the catalytic action between the kinase Syk and the substrate PLCgamma2 in collagen-induced signaling. However, it remains unknown how collagen induces the phosphorylation and dimerization of STAT3. APPROACH & RESULTS: We conducted complementary in vitro experiments to show that the IL-6 receptor subunit GP130 was in physical proximity with the collagen receptor GP VI in membrane lipid rafts of platelets. This proximity allows collagen to induce STAT3 activation and dimerization and the IL-6-sIL-6Ralpha complex to activate the kinase Syk and the substrate PLCgamma2 in the GP VI signal pathway, resulting in enhanced platelet response to collagen. Disrupting lipid rafts or blocking GP130-JAK-STAT signaling abolished the cross-activation and reduced platelet reactivity to collagen. CONCLUSION: These results demonstrate a cross-talk between collagen and IL-6 signal pathways. This cross-talk could potentially provide a novel mechanism for inflammation-induced platelet hyper-activity and identify the IL-6-GP130-JAK-STAT pathway as a potential target to block this hyper-activity. This article is protected by copyright. All rights reserved.