tbuckley/cabot-search huggingface dataset:
Does time-to-chemotherapy (TTC) impact the outcomes of resected ovarian cancer? Meta-analysis of randomized and observational data.
Authors: Diogo Bugano Diniz Gomes, Pedro Luiz Serrano Uson Junior, Monique Sedlmaier Franca, Yuri Pimentel Antunes, Patricia Taranto, Rafael Kaliks Guendelmann, Auro Del Giglio
Journal: Journal of Clinical Oncology (2016)

e17082 Background: The recommended treatment for ovarian cancer includes optimal surgical resection and adjuvant platinum-based chemotherapy. It is not clear if delaying the start of adjuvant chemotherapy increases the risk of disease recurrence or death. Methods: We performed a meta-analysis of studies published in PubMed (1950-2014) as of April 2014. Inclusion criteria were: randomized controlled trials and prospective or retrospective cohorts; patients with ovarian cancer that had undergone surgery with curative intent and use of adjuvant chemotherapy. We compared rates of disease recurrence and death according to the time-to-chemotherapy (TTC -“early” vs “delayed”) using a random effect model and performed a metaregression to evaluate the impact of covariates on these outcomes. Results: Out of 207 abstracts in the original search, 9 were considered eligible. The cutoffs used for TTC were between 20 and 40 days. All studies used a platinum-based chemotherapy and the rates of patients with suboptimal resection varied from 33% to 70%. A longer TTC was not associated with higher rates of disease recurrence (Odds ratio [OR] 0.89; 95% Confidence interval [CI] 0.63-1.24) or death at 3 years (OR 1.05; 95% CI 0.83-1.31). There was no evidence of significant publication bias (Egger’s test p = 0.557), but data was heterogeneous (I2= 70%). Meta-regression showed that percentage of patients with suboptimal surgery and values used as cutoff to define “delayed” chemotherapy combined were a significant source of bias (residual I2= 0%). Conclusions: In our analysis, time-to-chemotherapy after surgery for ovarian cancer with curative intent was not associated with higher risk of disease recurrence or death. However, this association was influenced by rate of optimal debulking and definition of “late” initiation of chemotherapy, so we must be careful when applying this data to patients with complete resection.
AMPATH Oncology: Baseline HPV detection in Kenyan women enrolled in a longitudinal study of modifiable factors predicting cervical dysplasia.
Authors: Darron R. Brown, Titus Maina, Philip Tonui, John M. Ong’echa, Aaron Ermel, Kapten Muthoka, Stephen Kiptoo, Yan Tong, YeungChing Wong, Ann Moormann, Ann Mwangi, Joseph Hogan, Patrick J. Loehrer, Elkanah Omenge
Journal: Journal of Clinical Oncology (2018)

5533 Background: Cervical cancer is caused by oncogenic HPV types. Kenyan women, HIV-infected or uninfected were studied to define modifiable factors predicting incidence and persistence of HPV and cervical dysplasia. Methods: From 9/21/2015 to 10/4/2016, 223 women ages 18 to 45 years old with normal VIA at enrollment were enrolled in a longitudinal study in Kenya. Cervical swabs, behavioral data, and other data were collected. HPV typing was performed on clinician-obtained cervical swabs using the Roche Linear Array. Results: Analysis of 219 evaluable participants was done, including 115 HIV-infected (median age 36 years) and 104 HIV-uninfected women (median age 33 years) (p = .0009). Among HIV-infected women, 86.8% were receiving anti-retroviral therapy (ART); median duration between HIV diagnosis and enrollment was 7.2 years (IQR 4.1-10.3); median CD4 count was 471 (IQR 310-612). There was a significant difference in number of lifetime sex partners between HIV-infected (median 4, IQR 3-8) and HIV-uninfected women (median 3, IQR 1.5-4), p = .0001. HPV detection is shown in Table 1. Conclusions: Oncogenic HPV types, including types preventable by vaccination were prevalent in Kenyan women. HIV-infected women were more likely to have detection of HPV 16, other oncogenic HPV types, and multiple types in spite of ART. In this longitudinal study, other factors will be included such as behaviors, the effect of HIV viral load, CD4 count, and details of ART. HPV detection in 115 HIV-infected and 104 HIV-uninfected women. HPV Types HIV Infected HIV Uninfected P value Any HPV (%) 59.1 35.6 .0005 HR-HPV1 (%) 47.0 27.9 .0037 LR-HPV2(%) 32.2 17.3 .0113 HPV 16 (%) 10.4 2.9 .0272 Nine-valent HR-HPV vaccine types3(%) 26.1 17.3 .1168 HR-HPV not covered by nine-valent vaccine4(%) 32.2 15.4 .0038 Two or more HR-HPV types (%) 20.0 6.7 .0041 Number of HR-HPV types (mean) 1.3 0.6 .0001 1Oncogenic (High-Risk) HPV 2Non-oncogenic (Low-Risk) HPV 3HPV 16, 18, 31, 33, 45, 52, 58 4HPV 26, 35, 39, 51, 53, 56, 59, 66, 67, 68, 69, 70, 73, 82, IS39
Chromogranin A levels to predict survival in resectable pancreatic neuroendocrine tumors.
Authors: Khurram Bilal Tariq, Brandon Roberts, Asha Nayak Kapoor
Journal: Journal of Clinical Oncology (2017)

e15775 Background: To determine whether Chromogranin A (CGA) predicts outcome after Cytoreductive Surgery (CRS) for Pancreatic Neuroendocrine Tumors (PNETs). CGA is used by clinicians to monitor progression of disease and response to treatment, but has not been objectively evaluated. Methods: A retrospective study of patients with PNETs seen at the Georgia Cancer Center, formerly the Medical College of Georgia, from 1980 to 2011 was performed. All patients who had CGA concentrations measured were evaluated (n = 126). Data relating to diagnosis, therapies, and survival outcome were noted. Patients with resectable and unresectable disease were included. Those with unresectable disease where evaluated for receiving Octreotide treatment. Results: The initial patient pool yielded a group (n = 118) with 72% (n = 85) having undergone Cytoreductive Surgery (CRS). Within the CRS group decreased survival was noted in patients with an elevated CGA level 4 months post-operatively (p = 0.002) and an elevated median CGA level of &gt; 224ng/ml correlated with a shorter survival time (p = &lt; 0.005). Increased survival was seen in CRS patients with median CGA levels of &lt; 200ng/ml between 4-12 months post-operatively with a 4 year survival of 91.08%. The median time to death was 80.27 months. Elevated CGA levels in CRS patients correlated with a survival probability of 63.25% at 4 years with a median death of 48.25 months. Overall 28% of the total patient group had unresectable disease (n = 33): 61% of this subgroup (n = 20) received Octreotide therapy and exhibited significant decrease in CGA level at a median of 3.6 months (p = &lt; 0.024); no correlation existed between CGA levels and survival. Conclusions: PNETs amenable to resection by Cytoreductive Surgery (CRS) and had a median Chromogranin A (CGA) level &lt; 200 ng/ml measured post-operatively after 4 months showed increased survival. No correlation existed between CGA levels and survival in patients with unresected disease despite Octreotide therapy lowering CGA levels. As such, CGA is predictive of survival in patients with resectable PNETs and worthy of prospective study.
The hippocampus in multiple sclerosis
Authors: Maria A Rocca, Frederik Barkhof, John De Luca, Jonas Frisén, Jeroen J G Geurts, Hanneke E Hulst, Jaume Sastre-Garriga, Massimo Filippi, Frederik Barkhof, Olga Ciccarelli, Nicola De Stefano, Christian Enzinger, Massimo Filippi, Jette L. Frederiksen, Claudio Gasperini, Ludwig Kappos, Jacqueline Palace, Maria A. Rocca, Alex Rovira, Jaume Sastre-Garriga, Hugo Vrenken, Tarek A. Yousry
Journal: The Lancet Neurology (2018)
Total neoadjuvant treatment versus chemoradiotherapy in locally advanced rectal cancer: A propensity score analysis from two prospective phase II clinical trials.
Authors: Jianwei Zhang, Huabin Hu, Yue Cai, Dianke Chen, Jian Xiao, Jiayu Ling, Yanhong Deng
Journal: Journal of Clinical Oncology (2018)

3600 Background: Fluorouracil-based neoadjuvant chemoradiotherapy (CRT) is still the standard of treatment for locally advanced rectal cancer, but it delays administration of systemic chemotherapy, leading to high incidence of distant metastases. To enhance systemic chemotherapy and improve the outcome of rectal cancer, totally neoadjuvant therapy (TNT) has been investigated recently. Here, we aimed to compare the efficacy of TNT with CRT in locally advanced rectal cancer. Methods: A total of 180 patients with clinical stage II or III locally advanced rectal cancer who received either total neoadjuvant treatment (n = 79) or CRT (n = 101) followed by total mesorectal excision (TME) were identified from two prospective clinical trials (NCT01211210 and NCT02217020) in our institutional database. Propensity score analysis was performed to mitigate selection biases. The patients in TNT group received 1 cycle of mFOLFOX6 as induction chemotherapy and radiotherapy would be delivered accompanied with 3 cycles of mFOLFOX6. Another 4 cycles would be added after radiotherapy and before TME. The CRT group received five 2-week cycles of infusional fluorouracil plus radiotherapy. Results: Of the 180 patients, the pathologic complete response (pCR) rate was 21.7%. Following propensity score matching, each group contained 79 patients. The baseline characteristics were well balanced. The pCR rate of TNT group and CRT group was 34.2% vs. 15.2%, respectively (p < 0.005). And the tumor downstaging rate was 60.8% vs. 35.4%, respectively (p = 0.001). Grade3/4 neutropenia was the more common in TNT group, which was 30.4% vs. 8.9% (P = 0.0007) in the TNT group and CRT group, respectively. Grade 3/4 Leukopenia (21.5% vs. 12.7%, p = 0.14) and thrombocytopenia (5.1% vs. 11.4%, p = 0.15) was similar between the two groups. Conclusions: TNT showed higher pCR rate and tumor downstaging rate than that of CRT, which was a promising strategy for improving outcome of rectal cancer, although the grade 3-4 adverse events were a little bit higher in TNT group. But this finding requires further analysis from long-term survival data. The phase III study comparing TNT with CRT is ongoing.
A phase I/II study of enadenotucirev, a chimeric Ad11/Ad3 oncolytic group B adenovirus, administered intraperitoneally (IP) in platinum-resistant epithelial ovarian cancer: Pharmacokinetic (PK) and tolerability data from phase I.
Authors: Iain A. McNeish, Agnieszka Michael, Gordon C. Jayson, Rosalind Margaret Glasspool, Richard Brown, Kerry Fisher, Simon Alvis, Julie Barrett, Christine Wilkinson Blanc, Hilary McElwaine-Johnn
Journal: Journal of Clinical Oncology (2016)

5543 Background: Enadenotucirev (EnAd) is a tumor selective Ad11/Ad3 group B adenovirus that has demonstrated preclinical activity in a model of platinum-resistant ovarian cancer. Synergy has also been reported between oncolytic adenoviruses and microtubule targeted drugs such as paclitaxel. This study aims to establish the maximum-tolerated dose (MTD) of EnAd delivered IP, both as a monotherapy (Phase [Ph.] Ia) and combined with weekly paclitaxel (Ph. Ib) and provide early proof of concept data (Ph. II). Methods: Ph. I follows a standard 3+3 dose escalation scheme and Ph. II is a single arm. Patients with platinum-resistant ovarian cancer receive EnAd as 3 separate weekly IP doses followed by 1 week rest (one cycle) in Ph.Ia and EnAd IP on d1, 8 and 15 (±1d) and weekly paclitaxel (80 mg/m2) IV on d9, 16 and 23 (±1d) of each 28-day cycle in Ph.1b. The starting dose for EnAd in Ph. I is 1 x 1012vp. The MTD determined in Ph. Ib is to be tested in Phase II. Primary endpoints include determination of MTD for Ph.I and progression-free survival using RECIST v1.1 for Ph. II. Secondary endpoints include safety and tolerability, blood and IP kinetics, shedding, blood and IP immune response to EnAd, and blood cytokine response. PK and shedding is detected by qualified quantitative PCR assay for the specific detection of EnAd DNA. Primers are specific for the unique E2B sequence of EnAd. Results: PK analyses indicate that EnAd is detectable in the peritoneal fluid of all patients following IP delivery. The persistence of virus in the peritoneal cavity throughout the treatment cycle is strongly suggestive of virus replication in the tumor. Blood PK sampling shows limited systemic exposure with little or no effect on cytokine levels. Ph.I dose levels are well tolerated allowing the planned dose escalation. Conclusions: Phase I data has provided evidence of successful viral delivery and replication of EnAd in platinum-resistant ovarian cancer patients, with an acceptable safety profile. Ph.II dosing in a larger patient group will aim to identify efficacy signals (Clinical trial information: EUDRACT 2013-001276-38). Clinical trial information: NCT02028117.
Gene expression profiling with a 31-gene test to identify a population of melanoma patients with a low sentinel lymph node biopsy positive rate.
Authors: Eddy C. Hsueh, John T. Vetto, Sancy Ann Leachman, Federico A. Monzon, Robert W. Cook, Adam C. Berger, Brian Gastman, Martin D. Fleming
Journal: Journal of Clinical Oncology (2018)

e21611 Background: Recommendations for sentinel lymph node biopsy (SLNB) in melanoma patients are based on the likelihood of a SLN positive result, which is mostly influenced by tumor thickness and ulceration. A prognostic 31-gene expression profile (GEP) test determines a melanoma patient’s risk for metastatic disease, classifying patients into low (Class 1) or high (Class 2) risk groups. We explored whether this GEP test could be used to inform SLNB decisions. Methods: Bioinformatics modeling was performed on a retrospective cohort (n = 946) to identify a population with a positive SLNB rate below 5%. Validation was then performed in two multi-center, prospective cohorts with a combined population of 1421 patients. Survival rates were derived from 690 melanoma patients from the retrospective cohort with known outcomes. Results: Tumors with GEP Class 1A and T1-T2 thickness showed a SLNB positivity rate of ≤5%, which was confirmed in both validation cohorts. Class 1A, T1-T2 tumors in the combined cohort had a SLN positivity rate of 4.6% (95% CI 3.2-6.3%), while tumors from patients ≥65 years old had a SLN positivity rate of 1.6% (95%CI 0.5-3.6%). In Class 1A patients who were SLNB eligible or assessed, the positivity rate for all patients was 6.6%, and 2.4% for the group ≥65 years old. By comparison, Class 2B, T1/T2 tumors demonstrated positivity rates of 18.8% in all patients, and 19.5% in patients who were eligible for (T1b-T2), or assessed with, SLNB. Five-year melanoma specific, overall, distant-metastasis free and recurrence-free survival rates for Class 1A, T1/T2 patients were 99.6% 98.2%, 95.3% and 93.5%, respectively. Conclusions: The 31-gene GEP along with tumor thickness and age can help identify patient populations with ≤5% likelihood of a positive SLN, as shown with patients ≥65 years old, and has potential utility to inform SLNB decisions in melanoma patients with T1-T2 tumors. Results from the retrospective cohort analysis shows that T1-T2 tumors with a Class 1A GEP signature are expected to have excellent survival outcomes, comparable with T1a tumors in which SLNB is not recommended.
TCT-519 A Comprehensive Meta-analysis of Randomized Controlled Trials Comparing Drug-Eluting Stents with Bare-Metal Stents in Saphenous Vein Graft Interventions
Authors: Kirstin Hesterberg, Pooja Jagadish, Asra Butt, Khalid Najib, Aradhana Pathak, Samuel Latham
Journal: Journal of the American College of Cardiology (2018)
Efficacy comparison of pazopanib and trabectedin vs standard chemotherapy in second line treatment of patients with metastatic soft tissue sarcomas: Experience from countries with limited resources.
Authors: Anes Pasic, Luka Simetic, Davorin Herceg, Timur Ceric, Elma Kapisazovic, Semir Beslija
Journal: Journal of Clinical Oncology (2018)

e23555 Background: Soft tissue sarcomas (STS) are rare tumors with more than 50 histologic subtypes. Treatment outcomes for patients with STS has improved over the past few decades mostly due to the adoption of a multidisciplinary approach, but still patients with advanced disease have a poor prognosis.Our study compared efficacy of novel sarcoma therapies - pazopanib and trabectedin vs standard chemotherapy, after failure to anthracycline based therapy,in patients with metastatic STS, Methods: In the period between 2014 and 2017 we made a retrospective analysis of 80 patients treated in Clinical Centre University of Sarajevo and University Hospital Centre Zagreb for metastatic STS. All patients received antracycline based therapy as a first line therapy. Patients were grouped in two cohorts. Patients in first cohort received pazopanib and/or trabectedin as a 2nd line treatment. In second cohort patients were treated with standard chemotherapy protocols. Efficacy was assessed in terms of RR(response rate) and PFS(progression free survival). Results: For patients treated with pazopanib PFS in 2nd line therapy was 4.6 months and for trabectidine group 6.15 months. Patients receiving standard chemotherapy as a 2nd line treatment had PFS of 2.0 months. Conclusions: Doxorubicin monotherapy is currently the only standard option for the first-line treatment of STS. For second-line and subsequent lines of treatment, there is no standard therapy. Results of our study confirmed superior efficacy of novel therapies pazopanib and trabectedin over standard chemotherapy. Our results are in correlation with results of pivotal trials (PALETTE and ET743-SAR-3007 trial) for pazopanib and trabectedin. Future clinical trials should adress issues such as sequential therapy, identification of biomarkers and the use of immunotherapy in sarcoma treatment.Clinical studies exploring efficacy of novel drugs in specific histologies are needed.
Autoimmune genetic variants as germline biomarkers of response in melanoma immunotherapy treatment.
Authors: Vylyny Chat, Robert Ferguson, Danny Simpson, Esther Kazlow, Rebecca Lax, Una Moran, Melissa Wilson, Anna C. Pavlick, Ryan J. Sullivan, Keith Flaherty, Iman Osman, Jeffrey S. Weber, Tomas Kirchhoff
Journal: Journal of Clinical Oncology (2018)

3079 Background: Immune checkpoint inhibition (ICI) has improved clinical outcomes for metastatic melanoma patients. However, ~ 60% of patients do not respond to ICI and 65-80% experience immune-related adverse events (irAEs). Currently, the personalized biomarkers predicting ICI efficacy or toxicity are limited. Given the link between immunotherapy, irAEs and autoimmunity, we investigated if the baseline genetic susceptibility to multiple autoimmune diseases can modulate clinical efficacy of ICI. Methods: By performing a comprehensive search of autoimmune genome wide association studies, we identified 25 SNPs, each associated with at least 3 autoimmune diseases. Using the Agena MassArray, we genotyped 25 SNPs in 389 Caucasian metastatic melanoma patients receiving ICI treatment (N = 214 anti-CTLA4, N = 175 anti-PD1) at one of our collaborative centers. Multivariate logistic regression adjusting for age at treatment and gender was used to test for association of germline variants with ICI efficacy. Results: We identified two variants previously associated with multiple autoimmune diseases that may predict ICI efficacy: rs1893217 in PTPN2 (OR = 0.35; 95%CI = 0.17-0.73; p = 0.005) and rs17388568 in the IL2, IL21 cluster (OR = 3.28; 95%CI = 1.62-6.64; p = 0.0009) were associated with clinical benefits in anti-CTLA4 and anti-PD1 ICI, respectively. These variants predict efficacy in opposite direction - rs1893217 was associated with anti-CTLA4 treatment resistance while rs17388568 was associated with anti-PD1 response sensitivity. Conclusions: Our study reports two autoimmune germline variants as potential biomarkers of anti-CTLA4 or anti-PD1 ICI efficacy in melanoma and suggests that underlying genetic susceptibility to autoimmunity may play an important role during ICI treatments. rs1893217 in PTPN2, involved in cytokine signaling, has been associated with colitis, celiac disease, inflammatory bowel, rheumatoid arthritis and type 1 diabetes. Similarly, rs17388568 was mapped to important immune-related genes (IL2, IL21 and ADAD1) and associated with allergy, colitis and type 1 diabetes. Additional genetic and functional validation of these findings is underway in a large collaborative setting.
Presence of genetic aberrations in patients with brain metastases from non-small cell lung cancer (NSCLC) and clinical outcomes.
Authors: Robert H. Press, Xinyan Zhang, Richard John Cassidy, Matthew Jeffrey Ferris, Jim Zhong, Conor Ernst Steuer, Rathi Narayana Pillai, Taofeek Kunle Owonikoko, Suresh S. Ramalingam, Pretesh R Patel, Walter John Curran, Hui-Kuo George Shu, Gabriel Sica, Kristin Ann Higgins
Journal: Journal of Clinical Oncology (2017)

e20604 Background: Historically, survival in patients (pts) with NSCLC brain metastases (BM) is poor, however, improved systemic therapies are now available including targeted therapies and immunotherapy. We sought to evaluate the prevalence of genetic alterations in pts with BM from non-squamous (NS) lung cancer, and to determine clinical outcomes in the modern era. Methods: With IRB approval, pts with BM from NS-NSCLC from 1/2010-1/2016 with genetic testing were captured and retrospectively reviewed. Snapshot genotyping was performed prior to 1/2014, after which Next Generation Sequencing was utilized, along with FISH lung cancer panel. Genes examined included: EGFR, ALK, RET, ROS1, TP53, KRAS, NRAS, MET, PTEN, BRAF, FBXW7, MAP2K1, APC, PIK3CA, CTNNB1, and SMAD4. Univariable and multivariable analysis (MVA) were utilized to assess factors associated with overall survival (OS). Results: 92 pts were included. Median number of BM was 4 (range 1-45). Median age was 64 (32-90 years). 59.8% were male. 38% received targeted therapy, 11% received immunotherapy, and 70% received conventional chemotherapy. 52.2% and 47.8% received whole brain radiotherapy and stereotactic radiosurgery, respectively. Median OS from first brain radiotherapy (RT) was 10.7 months (0.1-56.4). EGFR mutation, ALK fusion, ROS1 rearrangement, and RET rearrangement occurred in 27.5%, 5.2%, 1.7%, and 0% of pts. EGFR L858 and EGFR T790 mutations occurred in 19.2% and 2.7% of all pts. TP53, KRAS, and NRAS mutations occurred in 63.9%, 28.8% and 7% of pts. All other mutations had an incidence of less than 3%. On MVA, targeted therapy (HR 0.43 95% CI 0.22-0.86), immunotherapy (HR 0.04 95% CI 0.01-0.3), surgical resection (HR 0.38 95% CI 0.18-0.81), and ECOG performance status (0.23 95% CI 0.1-0.54) were associated with improved OS. No specific genetic aberration, RT modality, or number of BM was associated with OS. Conclusions: In pts with BM from NS-NSCLC, the most common molecular aberrations include TP53, EGFR, and KRAS mutations. Treatment with brain RT and modern systemic therapies yields a median survival greater than ten months. The use of targeted therapy or immunotherapy was associated with increased OS.