tbuckley/cabot-search huggingface dataset:
Safety and clinical activity of MEDI4736, an anti-programmed cell death-ligand 1 (PD-L1) antibody, in patients with non-small cell lung cancer (NSCLC).
Authors: Naiyer A. Rizvi, Julie R. Brahmer, Sai-Hong Ignatius Ou, Neil Howard Segal, Samir Khleif, Wen-Jen Hwu, Martin Gutierrez, Patrick Schoffski, Omid Hamid, Jared Weiss, Jose Lutzky, Michele Maio, John J. Nemunaitis, Dirk Jaeger, Ani Sarkis Balmanoukian, Marlon Rebelatto, Keith Steele, Xia Li, John A. Blake-Haskins, Scott Joseph Antonia
Journal: Journal of Clinical Oncology (2015)

8032 Background: MEDI4736 (M) is a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80 with high affinity and selectivity. PD-L1 is expressed in NSCLC tumors and may be associated with response to anti-PD-L1 treatment. This ongoing Phase 1/2, multicenter, open-label study (NCT01693562) evaluates the safety and clinical activity of M in patients (pts) with multiple solid tumor types including NSCLC. Methods: M is administered at 10 mg/kg IV every 2 wks (q2w) until unacceptable toxicity, disease progression, or for up to 12 months. Safety evaluations occur prior to each dose (toxicities graded by CTCAE v4.0). Response is based on investigator assessment (RECIST v1.1; includes confirmed/unconfirmed responses) at 6, 12, and 16 wks, then every 8 wks. Retreatment is permitted upon progression after 12 months of therapy. PD-L1 expression within the tumor is assessed using Ventana PD-L1 IHC (SP263). Data included represent a larger population with more mature follow up than previously reported.1 Results: As of 31 Oct 2014, 198 pts (116 non-squamous and 82 squamous histology; mean age 64 [range 26–87]; ECOG PS 0 [24%] or 1 [76%]; 81% current/prior smokers; median 2.5 prior treatments [1–9]) have been treated with M 10 mg/kg q2w (median 6 doses; range 1–23). Drug-related AEs were reported in 48% of pts; most frequently fatigue (14%), decreased appetite (9%), and nausea (8%). Grade ≥ 3 drug-related AEs were reported in 6% of pts. Drug-related AEs led to study discontinuation in 2% of pts. Pneumonitis (Grade 1-2) occurred in 2 (1%) pts. In all, 149 pts were evaluable for response with ≥ 24 wks of follow-up; ORR was 14% (23% in PD-L1+), and DCR at 24 wks was 24%. ORR was higher in squamous (21%) than non-squamous pts (10%). Responses were durable with 76% ongoing (DoR range 0.1+ – 35+ wks). Conclusions: With more mature follow up, the safety profile of M in NSCLC is manageable and consistent with previous reports. Responses are durable; ORR appears to be higher in squamous NSCLC and PD-L1+ pts. A broad development program of M alone and in combination with other treatments is underway in NSCLC. Antonia S, et al. Poster presented at ESMO 2014, 1325P Clinical trial information: NCT01693562.
Randomized phase II study comparing the sequence of irinotecan and cisplatin administration in chemo-naïve patients with advanced non-small cell lung cancer
Authors: J.-Y. Han, D. H. Lee, H. Y. Kim, H. G. Lee, J. J. Lee, S. Y. Ju, C. G. Park, J. S. Lee
Journal: Journal of Clinical Oncology (2005)

7133 Background: Irinotecan plus cisplatin combination chemotherapy is active for non-small cell lung cancer (NSCLC), but needs to define the optimal schedule. We conducted this study to evaluate efficacy and toxicity of two different administration schedules of irinotecan and cisplatin chemotherapy in chemo-naïve patients (Pt) with advanced NSCLC. Methods: Treatment consisted of irinotecan 80 mg/m2 i.v. on days 1 and 8 and cisplatin 60 mg/m2 i.v. on day 1 of 21-day cycle, for a maximum of 6 cycles. After stratification by stage (IIIB vs. IV) and by performance status (PS, 0/1 vs. 2), pts were randomly assigned to receive the day 1 chemotherapy either by irinotecan followed by cisplatin (I-P) or cisplatin followed by irinotecan (P-I) sequence. Results: Between 9/2002 and 6/2003, 81 patients were accrued. Sixty-one (75%) were male, 64 (79%) had stage IV, and 71 (88%) had PS of 0 or 1. Pt demographics were well balanced except for gender (female 38% in I-P, 12% in P-I, p=0.007). Of 81 pts, 77 were evaluable for response and 80 for toxicity. No significant difference in toxicity was observed between the two schedules. The difference in response rates by treatment schedule was not statistically significant by univariate analysis, but multivariate analysis showed that significant predictors of better response were P-I sequence (p=0.02) and female gender (p=0.007). Conclusions: Irinotecan plus cisplatin chemotherapy showed promising activity with extended 1-year survival rate. Both schedule showed similar toxicity profile but P-I sequence appears to have better anti-tumor activity when compared with the commonly-used IP sequence. (Supported in part by NCC Grant 0210140 from National Cancer Center). No significant financial relationships to disclose.
Prognostic risk factors for survival following adjuvant chemotherapy for locally advanced urothelial bladder cancer
Authors: I. Cordia, C. H. Ohlmann, U. Engelmann, A. Heidenreich
Journal: Journal of Clinical Oncology (2006)

14510 Background: A recent meta-analysis has demonstrated a 25% relative risk reduction of death and an absolute survival benefit of 9% at 3 years for adjuvant chemotherapy following radical cystectomy (RCx) for lymph node positive bladder cancer. It was the aim of our analysis to identify predictors of survival following standard chemotherapy in lymph node positive bladder cancer. Methods: A retrospective analysis of 156 consecutive patients with lymph node positive urothelial bladder cancer was performed. All patients underwent systemic chemotherapy with 4 cycles gemictabine/cisplatin 4 to 6 weeks after RCx. The prognostic significance of the number of positive lymph nodes, lymph node diameter, extranodal extension, bilateral lymph node involvement, pT stage, grade, tumor diameter, presence of lymphatic (LI) or vascular invasion (VI) was analysed. Statistical analysis was performed by uni- and multivariate analysis. Results: Median follow-up is 6.5 (12 â€“ 3.5) years, minimum follow-up is 36 months. Median survival time is 56 months, 56% of the patients died due to tumor progression. pT stage (p = 0.002), tumor diameter (p = 0.005), LI (p = 0.0015) or VI (p = 0.0028), lymph node diameter (p = 0.026) and extranodal extension (p = 0.0002) were significant risk factors associated with survival by univariate analysis. Neither the number or bilaterality of positive lymph nodes nor tumor grade were associated with survival time. On multivariate analysis only extranodal extension (p = 0.001) and tumor diameter (p = 0.05) remained significant and independent prognostic predictors. Median survival was 64 and 21 months in patients with or w/o extranodal extension (p = 0.0001), resp.; median survival was 81 and 28 months in patients w/o and with LI/VI (p = 0.001). In patients with extranodal extension or LI/VI adjuvant chemotherapy had no impact on survival. Conclusions: Analysis of multiple pathohistological and clinical parameters reveal that extranodal extension, primary tumor diameter and presence of LI/VI represent risk factors predicting survival following adjuvant chemotherapy in lymph node positive bladder cancer. Patients exhibiting these adverse factors might be considered for a more aggressive systemic approach. No significant financial relationships to disclose.
The gamma-glutamyl transpeptidase to platelet ratio (GPR) shows poor correlation with transient elastography measurements of liver fibrosis in HIV-positive patients with chronic hepatitis B in West Africa. Response to: ‘The gamma-glutamyl transpeptidase to platelet ratio (GPR) predicts significant liver fibrosis and cirrhosis in patients with chronic HBV infection in West Africa’ by Lemoine<i>et al</i>
Authors: Alexander J Stockdale, Richard Odame Phillips, Anna Maria Geretti
Journal: Gut (2016)

Lemoine et al 's excellent article from the Gambia reported on non-invasive markers of liver fibrosis in patients with chronic HBV infection.1 They propose a novel biomarker—the gamma-glutamyl transpeptidase (GGT) to platelet ratio (GPR)—as a routinely available test that could identify patients with fibrosis or cirrhosis in resource-limited settings, thereby informing prognosis and guiding monitoring. Notably, the study excluded patients with conditions that might predispose to altered GGT or platelet counts, including pregnancy, significant alcohol consumption, use of antiviral therapy, acute malaria and hepatitis C, hepatitis delta or HIV coinfection. In their letter, Boyd and colleagues subsequently reported that in a French HBV/HIV coinfected cohort, GPR showed reasonable performance for identifying significant liver fibrosis.2

HBV and HIV are highly co-endemic in West Africa, and chronic liver disease is an emerging threat to the long-term health of HIV-positive patients in this region.3 Since 2010, we have been following a prospective cohort of patients attending the HIV clinic at the Komfo Anokye Teaching Hospital in Kumasi, Ghana, where prevalence of HBV co-infection is 14% (95% CI 12.4% to …
Do runners who suffer injuries have higher vertical ground reaction forces than those who remain injury-free? A systematic review and meta-analysis
Authors: Henk van der Worp, Jelte W Vrielink, Steef W Bredeweg
Journal: British Journal of Sports Medicine (2016)

Vertical ground reaction force (VGRF) parameters have been implicated as a cause of several running-related injuries. However, no systematic review has examined this relationship.We systematically reviewed evidence for a relation between VGRF parameters and specific running-related injuries.MEDLINE, Web of Science and EMBASE databases were searched. Two independent assessors screened the articles and rated the methodological quality. The 3 key VGRF parameters we measured were vertical loading rate, impact/passive peak (Fz1) and propulsive/active peak (Fz2). Standardised mean differences of these parameters were calculated using a random-effects model. Meta-regression was performed using injury type, study type and methodological quality as factors.The search yielded 2016 citations and 18 met the inclusion criteria for the systematic review. The loading rate was higher in studies that included patients with a history of stress fractures and patients with all injury types, both compared with controls. Only studies that included patients with a history of symptoms at the time of kinetic data collection showed higher loading rates overall in cases than in controls. There were no differences between injured subjects and controls for the active and passive peaks of the VGRF.The loading rate is higher in respondents with a history of stress fractures than in respondents without running injuries. Owing to the absence of prospective studies on other injury types, it is not possible to draw definite conclusions regarding their relation with loading rate.
Combination chemotherapy using vinblastine and methotrexate for the treatment of progressive desmoid tumor in children.
Authors: S X Skapek, B J Hawk, F A Hoffer, G V Dahl, L Granowetter, M C Gebhardt, W S Ferguson, H E Grier
Journal: Journal of Clinical Oncology (1998)

We report the treatment of 10 children for progressive desmoid tumor not amenable to standard surgical or radiation therapy with the use of vinblastine (VBL) and methotrexate (MTX).Ten patients aged 6.4 to 18 years with primary (two patients) or recurrent (eight patients) desmoid tumor were treated with VBL and MTX for 2 to 35 months. Patients with recurrent tumors had been previously treated with surgical resection with (two patients) or without (five patients) radiation therapy or with radiation therapy alone (one patient). No patient had previously received cytotoxic chemotherapy. The tumor response was assessed at routine intervals by physical examination and magnetic resonance imaging (MRI).Five patients had clinical evidence of response to therapy with complete resolution (three patients) or partial resolution (two patients) of physical examination and radiographic abnormalities. Three patients had stable disease during 10 to 35 months of treatment. Two of these patients had progressive disease 9 and 37 months after treatment stopped; one patient had no progression 16 months after therapy. Two additional patients with stable disease had chemotherapy discontinued after 2 and 3 months. Common side effects included mild alopecia and myelosuppression and moderate nausea and vomiting. In patients with responding tumors, MRI showed decreased tumor size and, in two patients, changes consistent with fibrosis and decreased cellularity of the tumor.Combination chemotherapy with VBL and MTX appears to control desmoid tumor without significant acute or long-term morbidity in most children. This may allow for further growth and development in these patients, which may decrease the morbidity of subsequent definitive therapy.
Higher persistency with i.v. bisphosphonates in patients with bone metastasis
Authors: S. Mangiapane, A. Hoer, H. Gothe, V. Barghout, B. Haeussler
Journal: Journal of Clinical Oncology (2006)

18623 Background: Patients with advanced cancer are at high risk for bone metastasis, leading to accelerated bone resorption and skeletal related events and a loss of autonomy. Bisphosphonates can reduce the risk of skeletal complications, provided that patients remain on therapy. The aim of our study was to compare the persistency rates of oral and intravenous (i.v.) bisphosphonate therapy regimes in patients with bone metastasis in a natural setting. Methods: Claims data from a German sickness fund (2002 to 2004) were used. Patients had ICD-10 diagnoses for bone metastasis, were receiving oral or i.v. bisphosphonates (exclusively with a specific approval for patients with bone metastasis) and could be followed-up at least 7 months after their index prescription. Persistency was defined as the continuous prescription refill without an interruption of longer than 30 days. Medication Possession Ratio (MPR) was calculated after 180 days of follow-up and Kaplan Meier curves were analyzed. Results: We identified 233 patients who met our inclusion criteria, 85.8 % getting i.v. and 14.2 % getting oral therapy regime (prescribed bisphosphonates: zoledronate (60.5 %), pamidronate (27.5 %), clodronate (18 %), ibandronate (13.7 %)). Most of them had breast cancer (46.4 %) or prostate cancer (31.8 %). By the end of 6 months, only 64.4 % of all patients on bisphosphonate therapy were defined to be compliant, as they had a MPR ≥ 0.8 (36.4 % of the oral group and 92 % of the i.v. group). Kaplan Meier curves for oral and i.v. bisphosphonate therapy regime differed significantly (p = 0.0012). Conclusions: Persistency rates with oral bisphosphonates are significantly lower than with i.v. bisphosphonates in patients with bone metastasis (36.4 % vs. 92 %). Given the importance of preventing skeletal complications, persistency must be considered when selecting the optimum treatment regime for patients with advanced cancers. [Table: see text]
Abstract 12404: Cardioprotective Diazoxide Inhibits Succinate Dehydrogenase Independent of the Adenosine Triphosphate Sensitive Potassium Channel in Mouse and Human Mitochondria
Authors: M B Janjua, Evelyn M Kanter, Carol M Makepeace, Matt C Henn, Richard B Schuessler, Colin G Nichols, Jennifer S Lawton
Journal: Circulation (2014)

Introduction:  Adenosine triphosphate sensitive potassium channel (K ATP ) opener diazoxide provides cardioprotection during myocyte stress via an unknown mechanism that has been proposed to involve the inhibition of succinate dehydrogenase and the activation of a mitochondrial K ATP  channel (mK ATP ). Diazoxide’s cardioprotection is eliminated by the prevention of its ability to inhibit succinate dehydrogenase (SDH) and by genetic deletion of K ATP  channel subunit SUR1. Interestingly, diazoxide still inhibits SDH in SUR1 deficient mice, suggesting the inhibition of SDH precedes mK ATP  activation; however, the relationship between the succinate dehydrogenase enzyme complex and a mitochondrial K ATP  channel are unknown.   Hypothesis:  We hypothesized that the addition of mK ATP  channel inhibitor, 5 - hydroxydecanoate (5-HD), would alter diazoxide’s ability to inhibit SDH.   Methods:  Mitochondria were isolated from mouse hearts and human left ventricular specimens using serial homogenization and exposed to test groups: 8 mM malonate (inhibitor of SDH), 100 microM diazoxide (DZX), 100 microM 5-HD, DZX + 5 HD, succinate control, no succinate, and no mitochondria. SDH activity was measured by spectophotometric analysis fo 2-6 dicholoroindophenol reduction at 600nm for 20 min.   Results:  Diazoxide inhibited SDH in mouse and human mitochondria (figure demonstrates human SDH activity, percent change in absorbance is inversely proportional to SDH activity) (*p   Conclusions:  Similar to previous results following genetic deletion of mK ATP  subunit SUR1, these data are consistent with the inhibition of SDH by diazoxide as upstream to mK ATP  activation as diazoxide inhibits SDH despite the inhibition of mK ATP  by 5 - HD.
“Reverse Genomics” Predicts Function of Human Conserved Noncoding Elements
Authors: Amir Marcovitz, Robin Jia, Gill Bejerano
Journal: Molecular Biology and Evolution (2016)

Evolutionary changes in cis-regulatory elements are thought to play a key role in morphological and physiological diversity across animals. Many conserved noncoding elements (CNEs) function as cis-regulatory elements, controlling gene expression levels in different biological contexts. However, determining specific associations between CNEs and related phenotypes is a challenging task. Here, we present a computational "reverse genomics" approach that predicts the phenotypic functions of human CNEs. We identify thousands of human CNEs that were lost in at least two independent mammalian lineages (IL-CNEs), and match their evolutionary profiles against a diverse set of phenotypes recently annotated across multiple mammalian species. We identify 2,759 compelling associations between human CNEs and a diverse set of mammalian phenotypes. We discuss multiple CNEs, including a predicted ear element near BMP7, a pelvic CNE in FBN1, a brain morphology element in UBE4B, and an aquatic adaptation forelimb CNE near EGR2, and provide a full list of our predictions. As more genomes are sequenced and more traits are annotated across species, we expect our method to facilitate the interpretation of noncoding mutations in human disease and expedite the discovery of individual CNEs that play key roles in human evolution and development.
Comparative analyses of overall survival of anaplastic lymphoma kinase (ALK)–positive advanced non-small cell lung cancer (NSCLC) patients who did not receive ALK inhibitors.
Authors: D. Kim, J. K. Lee, H. S. Park, K. Kulig, T. M. Kim, S. Lee, Y. Jeon, D. H. Chung, D. S. Heo, W. H. Kim, Y. Bang
Journal: Journal of Clinical Oncology (2011)

7515 Background: There have been limited data on the overall survival (OS) of ALK gene rearranged (ALK-positive) NSCLC patients who did not receive ALK inhibitors. We investigated the OS of advanced ALK-positive NSCLC patients who were managed in the pre-ALK inhibitors era. Methods: This is a retrospective case-case study of ALK-positive patients vs. ALK wildtype (WT) comparators who were treated in Seoul National University Hospital (SNUH), Seoul, Korea. A total of 1,100 stage IIIB/IV patients with non-squamous histology were collected in the NSCLC database of SNUH between 2003 and 2009. To enrich for ALK-positive cases, we performed ALK FISH on 257 cases that were either EGFR WT or non-responders to prior EGFR tyrosine kinase inhibitor (TKI) therapy. We compared survival outcomes between 3 groups of patients: 1) ALK-positive, 2) EGFR mutation positive (EGFR mut+), and 3) ALK WT/EGFR WT. For each comparison, 1 ALK-positive patient was matched to 2 EGFR mut + and 2 ALK WT/EGFR WT patients based on: age at diagnosis, sex, and stage. Progression-free survival (PFS) of 1st-line chemotherapy and EGFR TKIs were also analyzed. Results: Twenty two cases were ALK-positive by FISH and did not receive ALK inhibitors during the follow-up period. The median OS of ALK-positive (n=22), EGFR mut+ (n=44), and ALK WT/EGFR WT (n=44) patients was 10.4, 28.0, and 14.5 months, respectively (P-value; vs. EGFR mut+: 0.012, vs. ALK WT/EGFR WT: 0.384). The PFS of 1st-line platinum-based chemotherapy for the 3 groups was not different. However, the PFS of EGFR TKIs was shorter in ALK-positive patients, compared with the 2 other groups (P-value; vs. EGFR mut+: < 0.001, vs. ALK WT/EGFR WT: 0.048) Conclusions: In the pre-ALK inhibitor era, ALK-positive patients experienced the shortest survival. Although their responses to platinum-based chemotherapy were not different from comparator groups, they were even more resistant to EGFR TKI treatment than were ALK WT/EGFR WT patients.
Abstract 8: Dynamic ECG Changes in Wearable Cardioverter-Defibrillator Patients Predict Sudden Cardiac Arrest
Authors: Darshak Karia, Nicole R Bianco, Chingping Wan, Jo Ann M Glad, Steven J Szymkiewicz
Journal: Circulation (2012)

Purpose: Sudden cardiac arrest (SCA) prediction continues to be an active area of investigation. The wearable cardioverter defibrillator (WCD) records ECG periodically. The objective of this study was to study the predictive value of dynamic ECG changes occurring between baseline (Base), one week prior to SCA (1WK), and immediately prior to shock (pre-S) for ventricular tachyarrhythmias VT/VF Methods: 100 sequential patients (pts) who were prescribed a WCD for bridge to ICD or recovery, and who were shocked for VT/VF between November 2009 and June 2011 were retrospectively analyzed. ECG’s were examined for dynamic changes in heart rate (HR), QRSd, QRS amplitude, QTc, PVCs, rhythm, and NSVT to see if they were predictive of impending shock. Individual manual measurements were collected at Base, 1WK, and pre-S. Only pts wearing the WCD ≥1 week were included for analysis. Results: Pts (68% male, age 59 ± 16 years, mean LVEF 23±7.5%) had dynamic increases in mean HR and PVC burden from Baseline to 1WK to pre-S (p≤0.0001)(Table 1). Interestingly, changes in traditional measures such as QTc or QRSd or amplitude did not predict shock. Conclusions: The WCD provides a unique opportunity to monitor ECG patterns in at-risk pts prior to defibrillation. A dynamic increase in HR and ventricular ectopy changes prior to VT/VF could indicate a shift of sympathetic-vagal balance towards sympathetic predominance and reduced vagal modulation.