tbuckley/cabot-search huggingface dataset:
Prospective linkage of clinical trial and administrative databases: Acceptability to patients and research ethics boards.
Authors: Annette E. Hay, Michael Crump, Pamela Skrabek, Matthew C. Cheung, Kuljit Grewal, Waleed Sabry, Haji I. Chalchal, Ismail Sharif, Guy Cantin, Michel Pavic, Jennifer Snyder, Mike Broekhoven, Marina Djurfeldt, Lois E. Shepherd, Ralph M. Meyer, Bingshu E. Chen, Joseph L. Pater
Journal: Journal of Clinical Oncology (2018)

e18692 Background: Health service and clinical trial research are typically separate. Benefits to merging data from both sources include potential improved long-term follow-up of patients treated on clinical trials. Patient identifiers, not routinely collected by clinical trial sponsors in Canada, are key to enable linkage of an individual’s records. Concerns about privacy have made it difficult to collect this information but previous research has shown that patients would be willing to provide identifying information. Methods: The Canadian Cancer Trials Group LY12 phase III trial in aggressive lymphoma, evaluating salvage therapy before and maintenance rituximab after autologous stem cell transplantation, forms the population basis for this study. Through protocol amendment, all individuals in Canada who remain alive are invited to participate. Those willing are asked to provide their name, date of birth, sex at birth, provincial health insurance number and postal code along with consent for future follow-up through linkage with their administrative records in Statistics Canada and provincial cancer registries. Results: Of the 16 Research Ethics Boards (REBs) across Canada asked to review the protocol amendment, 14 (89%) approved representing all 9 provinces in which the study was open. Following consideration, two of the REBs in the province of Quebec refused to approve sponsor access to patient identifying information because of small patient numbers at their institutions. Among the 86 participants at centres with REB approval who have so far been invited to enroll in the long-term follow-up study, 79 (92%) have consented, providing identifiers and permission for future data linkage; 7 (8%) have declined. Eleven patients could not be contacted. Patient acceptability rates vary across centres, being 100% at several institutions. The consent process is ongoing with additional individuals yet to be approached. Conclusions: The higher than anticipated rate of REB approval and patient acceptance rates consistent with previous research encourages further exploration of this approach to long-term follow-up. Clinical trial information: NCT00078949.
Peripheral blood T-cell functional assay as a predictive biomarker of immune-therapy of metastatic melanoma.
Authors: Harsh V Parmar, Nitya Chakraborty, Upendra P. Hegde
Journal: Journal of Clinical Oncology (2018)

e21593 Background: Activating effector T cell by inhibitory checkpoint blockade improves survival in metastatic melanoma (MM). Examining tumor infiltrating lymphocytes as predictive T cell biomarker are promising but have technical limitations. We report the results of peripheral blood (PB) derived T cell assays examining proliferation and regulation, and correlate them with patient (pt) survival at 6, 12 and 24 months (mts) during immune therapy. Methods: PB derived T lymphocytes of MM pts was analyzed on an IRB approved research protocol. Mart-1 specific T cells were isolated from PB and their expansion was quantified in response to MART-1 epitope presented by autologous mononuclear cell derived antigen presenting cell ex-vivo - cytotoxic T cell assay (CTL). We also quantified CD4+CD25+ natural regulatory T cells (nTreg) from PB using flow cytometry and isolated CD4+CD25+ nTreg and CD4+CD25- T cells using magnetic bead separation technique. We stimulated CD4+CD25- T cells with anti CD3 antibody in a proliferative assay and used CD4+CD25+ nTreg cells to suppress proliferation. The results were described as suppression or no suppression of CD4+CD25- T cells by nTreg. Additionally, CD4+CD25- T cells were polarized in Th1 and Th2 conditions and stimulated to examine cytokine generation (Th1 vs. Th2). Results: PB was obtained from 19 MM pts. MART-1 specific T cell effector responses were recorded in HLA-A2 positive pts. The nTreg cells in PB averaged between 4-10%. Suppression of proliferation by nTreg of CD4+CD25-T cells in response to anti CD3 antibody was seen in 10 pts while it was absent in 9. Suppressive activity of nTreg correlated with 60, 50, 30% survival at 6, 12 and 24 mts respectively compared to 100, 100 and 70% survival at 6,12 and 24 mts respectively in pts without suppression. No correlation was found between MART-1 specific T cells, CTL assay, and Th1 vs Th2 cytokines and survival. Conclusions: PB CD4+CD25+ nTreg activity interferes with immune therapy of MM and can be reliably studied as a potential predictive biomarker. Our study is limited by small size and needs validation in larger studies.
Phase III randomized study of elective nodal irradiation plus erlotinib combined with chemotherapy for esophageal squamous cell carcinoma.
Authors: Shi Xiu Wu, Honglei Luo, Lvhua Wang, Xuebang Zhang, Bing Xia, Congying Xie, Ming Chen, Conghua Xie, Xiuhua Bian, Wei Hu, Anping Zheng, Jiancheng Li, Duojie Li, Ruifei Xie, Gang Li
Journal: Journal of Clinical Oncology (2016)

4048 Background: The addition of anti-EGFR therapy to chemoradiotherpay in the treatment of unresectable esophageal squamous cell carcinoma (ESCC) is not well defined, as well as the role of elective nodal irradiation (ENI). This phase III trial was designed to determine whether the addition of erlotinib and/or ENI to concurrent conventional chemoradiotherapy containing cisplatin/paclitaxel (CP) improved survival. Methods: This study was a 2x2 factorial design, with erlotinib and ENI as factors. We randomized Chinese patients with ESCC to: (A) ENI/CP/erlotinib; (B) ENI/CP; (C) conventional-field irradiation (CFI)/CP/erlotinib; (D) CFI/CP. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival, local-regional failure rate, and toxicity. Three hundred and forty-four patients and 242 events were needed for 85% power to detect a hazard ratio (HR) of 0.76 (2-year OS rate from 35% to 45% for each factor) if no interaction between the two factors was observed. Results: From December 2007 to December 2014, 352 patients were recruited. Median follow-up was 16.5 months for all patients at this analysis. There were no significant interactions between the two factors of ENI and erlotinib (P = 0.999). Two-year OS rate and median OS was 54% and 35.4 months for ENI (A+B) versus 42% and 20.5 months for CFI (C+D; HR = 0.69; 95% CI, 0.52 to 0.91; P = 0.008), respectively. Two-year OS rate and median OS was 52% and 24.9 months for erlotinib (A+C) versus 44% and 20.9 months for control (B+D; HR = 0.77; 95% CI, 0.57 to 1.00; P = 0.049), respectively. Patients treated with ENI plus erlotinib (A) achieved a 2-year OS rate of 58% and a median OS of 47.2 months. Hematologic toxicities grade 3 or above were the most common adverse events. Erlotinib was associated with a higher rate of all-grade rash events. Conclusions: Compared with conventional chemoradiotherapy, the addition of either ENI or erlotinib significantly improved survival among Chinese patients with ESCC, with the best of benefits in those treated with ENI plus erlotinib. The incidence rates of adverse-event were acceptable in this study. Clinical trial information: NCT00686114.
Key drivers of physician decision-making in utilizing next generation sequencing results to guide cancer therapy.
Authors: Digant Gupta, Susan Zook, Hannah Kuhah, Arezoo Nazari, Kim Kramer, Pamela A. Crilley, Bradford A. Tan, Theodore Pollock, Glen J. Weiss, Donald Peter Braun, Maurie Markman
Journal: Journal of Clinical Oncology (2016)

e18101 Background: Next-generation sequencing (NGS) has led to a rapid and substantial increase in the understanding of cancer molecular biology. However, for NGS to successfully impact treatment decisions, it is critical to identify factors that influence the physician decision-making (PDM) process while interpreting the NGS results. Methods: We evaluated 2 independent series of patients (pts) who underwent NGS genomic profiling at our institution in Feb-2014 and Feb-2015 and subsequent PDM for 6 months for each. An actionable genomic alteration was defined as an alteration linked to an FDA approved drug in either the same tumor or a different tumor as defined by the commercial NGS test. Physicians were interviewed for their reasons for not utilizing the NGS results to guide further treatment. Results: The table compares the 2 pt groups with regard to baseline characteristics and key NGS metrics. Majority of the tumors were colorectal, lung, breast, head & neck and urological for both groups. For both groups, the top primary reasons for ordering the NGS testing were no response to standard 1st line therapy, potential use in the future, rapidly advancing metastatic disease, and no known accepted standard therapy. There was no statistically significant difference in the proportion of pts with actionable alterations and proportion treated based on NGS results between the 2 groups. The primary reasons for not following the NGS report guidance during the subsequent 6 months from receipt of report were pt too sick, pt still having standard therapy, and not enough evidence for targeted therapy. Conclusions: The influence of NGS-testing on PDM in cancer remains a controversial topic. Our study reports a stable impact rate of approximately15-20% for employing NGS-directed suggestions over a 1 year period. Addressing factors influencing PDM is critical to enhance the relevance of NGS testing in oncology. Feb 2014 (n = 146) Feb 2015 (n = 99) P Mean age (yrs) 54.7 53.8 0.49 Mean turn-around time to NGS report (days) 15.4 15 0.64 Female N (%) 87 (59.6) 65 (65.7) 0.34 N (%) of total cases with actionable alterations 105 (72%) 72 (72.7%) 0.67 N (%) of cases with actionable alterations treated based on NGS report 17 (16.2%) 15 (20.8%) 0.27
Differential outcomes in patients with uncommon EGFR exon 19 mutations.
Authors: Tyler Stewart, Anna Truini, Michelle DeVeaux, Daniel Zelterman, Zenta Walther, Anna Wurtz, Scott N. Gettinger, Katerina A. Politi, Sarah B. Goldberg
Journal: Journal of Clinical Oncology (2018)

9056 Background: Exon 19 deletions (ex19 dels) account for ~50% of EGFR-mutant NSCLCs. The E746_A750 ex19 del accounts for 75% of these cases. Two frequent uncommon ex19 dels are L747_P753 > S and L747_A750 > P. Studies have largely grouped outcomes of ex19 dels together despite mutational differences. We previously demonstrated in vitro that erlotinib and osimertinib suppress phosphorylation of EGFR (pEGFR) in the E746_A750 and L747_P753 > S mutants, but do not effectively suppress pEGFR in the L747_A750 > P mutant, whereas afatinib suppresses pEGFR in all 3 mutant types. Here we investigate the clinical outcomes in patients (pts) with various EGFR ex19 dels treated with erlotinib. Methods: We assessed progression free survival (PFS), duration on treatment (DOT) and overall survival (OS) in pts with EGFR exon 19 dels (E746_A750, L747_P753 > S or L747_A750 > P) who received erlotinib as first-line therapy for advanced disease. Primary resistance was defined as progression on first scan after initiation of therapy. Results: 32 pts met criteria: 24 with the common E746_A750 mutation, and 4 each with the L747_P753 > S and L747_A750 > P mutations. Patients with the L747_A750 > P mutation demonstrated significantly worse PFS, DOT and OS than those with the E746_A750 and L747_P753 > S mutations (see Table). There was no difference between the E746_A750 and L747_P753 > S groups. Two of four pts with L747_A750 > P mutations demonstrated primary resistance to erlotinib, whereas no pts with E746_A750 or L747_P753 > S mutations exhibited primary resistance. Conclusions: This study shows differential clinical outcome to EGFR-directed therapy within EGFR ex19 del tumors, specifically that pts with ex19 del L747_A750 > P have inferior outcomes versus those with E746_A750 or L747_P753 > S when treated with erlotinib. Understanding outcomes with other EGFR inhibitors based on the specific EGFR del 19 mutation present may allow for more precise treatment that results in superior patient outcomes. Outcomes by EGFR Exon 19 Mutations (Months) E746_A750 (n = 24) L747_P753 > S (n = 4) L747_A750 > P (n = 4) p-value PFS 11.7 13.1 4.1 0.0003 DOT 14.8 14.3 5.9 0.0001 OS 47.0 36.4 14.1 0.0031
Feasibility of a self-funded model to provide breast cancer services to uninsured women in New York City.
Authors: Janice Zaballero, Emeline Aviki, Kayla Abderholden, Stephen Matthew Schleicher, Julia Anne Smith
Journal: Journal of Clinical Oncology (2018)

6558 Background: Despite access-expanding mandates in the ACA, approximately 30% of New York State residents remain uninsured. Most safety net programs provide services only to patients who qualify for Medicaid, leaving a large percentage of women without access to affordable breast cancer screening and diagnostics. In response, we developed Breast Treatment Task Force (BTTF) to provide these services to uninsured patients earning $23,760 - $47,520 annually (200%-400% FPL). Methods: We surveyed imaging centers located in New York City to determine unused imaging capacity. BTTF then negotiated reduced rates for breast imaging services at these sites. We developed referral networks composed of community organizations including Planned Parenthood. We raised nearly $400,000 through philanthropy to fund operations. We collected demographics for all patients, and patient satisfaction was assessed through surveys administered after receiving services. Results: We identified 24 imaging centers with unused capacity totaling 20,000 screening exams and diagnostic procedures. In 2017, BTTF facilitated care for 646 patients in the form of 409 screening exams and 832 diagnostic procedures. Average wait time from abnormal mammogram to diagnostic procedure was less than six days. The median age of BTTF patients was 40, and the majority were from minority backgrounds (34% Asian, 32% Hispanic, and 19% African-American). Median annual income per patient was approximately $30,000, and 61% of patients were employed. Attendance rates for diagnostic services and patient satisfaction rates were each 99% (versus industry averages of 60% and 67%, respectively). Nine patients were newly diagnosed with cancer. Since 2007, BTTF has delivered $16 million in medical services with an annual budget of under $400,000. Conclusions: BTTF constructed two networks: 1) network of private imaging centers willing to donate a significant portion of unused capacity and 2) network of large community referral partners to identify low-income patients. This model offers an example of how to successfully provide important breast cancer screening and diagnostic services to non-Medicaid-eligible women who cannot afford health insurance.
Outcomes of patients (pts) with disease recurrence after treatment for locally advanced non-small cell lung cancer (LANSCLC) detected by routine follow-up (f/u) CT scans vs. symptom (sx) driven evaluation.
Authors: Joseph Nicholas Bodor, Josephine Louella Feliciano, Soren Bentzen, Martin J. Edelman
Journal: Journal of Clinical Oncology (2016)

8515 Background: At least 75% of pts with LANSCLC relapse despite treatment with curative intent. Pts with recurrent NSCLC may benefit from further treatment. An optimal follow-up strategy, particularly in terms of the timing of CT chest scanning, has not yet been defined. Methods: A retrospective review was performed on pts who had undergone definitive treatment (chemotherapy + radiotherapy +/- surgery) for LANSCLC (stage IIIa,b 7th ed). Standard f/u was q 3mo CT chest x 1 y, q 4mo x 2 y, q 6 mo x 1 y and then annually. We evaluated whether outcome was dependent upon how progression was diagnosed (f/u or sx) as well as the pattern of recurrence: local relapse (LR) or systemic. If systemic, we evaluated whether there were single (SM) or multiple sites (MM) of metastasis. Survival was determined with Kaplan-Meier curves and compared by log rank. Results: 311 patients with LANSCLC were treated between 01/01/2000 and 2/28/2015, of which 167 pts relapsed and there were adequate records. 99 progressions were detected by f/u and 68 by sx. The median time to progression was 11.5 mo vs. 9.6 mo (p = 0.186); OS for f/u vs. sx was 7.5 mo vs. 6.4 mo (p = 0.843). When evaluating pts with LR or MM, f/u pts had a trend towards better OS than sx pts (10.3 mo vs. 4.7 mo, p = 0.141; 5.0 mo vs. 2.9 mo, p = 0.135, respectively). SM pts had longer OS than those with LR or MM (12.7 mo vs. 8.5 mo vs. 3.7 mo, p < 0.001). Conclusions: Our findings suggest that, in the case of CT chest scans, symptom-driven evaluation may not adversely affect survival. Routine f/u (n = 99) Sx directed (n = 68) p-value Stage: IIIa/IIIb 46/53 30/38 0.765 Sex : M/F 48/51 33/35 0.995 Median Age at Initial Diagnosis 61 57 0.244 Race: White/AA 51/48 41/24 0.144 Pattern (%): LR/SM/MM 56/12/32 29/38/32 < 0.001 Median TTP in months (min, max) LR 12.3 (2.9, 163.5) 11.1 (3.3, 81.1) 0.908 SM 5.4 (2.4, 38.6) 8.0 (2.9, 27.0) 0.396 MM 11.9 (3.0, 68.4) 8.1 (1.6, 26.8) 0.318 Median OS in months LR 10.3 4.7 0.141 SM 7.5 12.7 0.412 MM 5.0 2.9 0.135
Cochrane director says his sacking was flawed and came after “show trial”
Authors: Nigel Hawkes
Journal: BMJ (2018)

The head of the Nordic Cochrane Centre, Peter Gotzsche, has said that his dismissal from Cochrane’s board was the outcome of a “show trial” where the verdict was prefabricated and the process flawed.

In a statement defending himself, Gotzsche sheds new light on an affair that has divided a highly respected organisation whose reviews influence care across the medical spectrum.

Gotzsche was expelled from the Cochrane board on 13 September after a board meeting (from which he was excluded) voted by a majority of one to oust him.1 Four of his supporters subsequently resigned their board positions, and those that remained agreed a statement that was read to the Cochrane annual colloquium this week in Edinburgh by the organisation’s co-chair, Martin Burton.2

What the statement did not make clear is exactly what Gotzsche did to warrant his expulsion. Burton referred to “repeated bad behaviour over many years” but legal reasons and reasons of privacy, he …
Pumping blood with self-reliance and cooperation
Authors: M. Luisa Iruela-Arispe
Journal: The Journal of Experimental Medicine (2018)

In this issue of JEM, Singhal et al. (https://doi.org/10.1084/jem.20180008) explore the cellular mechanisms involved in endothelial cell regeneration in the liver. Using a combination of myeloablative and nonmyeloablative approaches, the authors found that repair of the endothelium is mediated by endothelial cells themselves, but when injured, endothelial cells enlist myeloid counterparts that aid in vascular repair.
Association of early reduction in circulating tumor DNA (ctDNA) with improved progression-free survival (PFS) and overall survival (OS) of patients (pts) with urothelial bladder cancer (UBC) treated with durvalumab (D).
Authors: Michael Kuziora, Brandon W. Higgs, Philip Z. Brohawn, Rajiv Raja, Carlos Bais, Koustubh Ranade
Journal: Journal of Clinical Oncology (2017)

11538 Background: Mutation variant allele frequencies (VAFs) in ctDNA indicate the frequency of cancer clones harboring the specific variant in the primary lesion and metastases, thus providing a surrogate for tumor burden. We previously reported that early reduction in VAF in ctDNA was associated with improved survival on durvalumab in NSCLC subjects. Here we replicated this association in UBC pts treated with durvalumab. Methods: CP1108/NCT01693562 was a nonrandomized phase 1/2 trial evaluating D in pts with advanced UBC or other solid tumors. By 24OCT2016, 103 UBC pts received 10 mg/kg Q2W of D with median 8.4 mos follow up. A panel of 70 genes was assayed for DNA variants using the Guardant360 cancer panel in plasma ctDNA from 33 UBC pts pre-treatment and 29 pts pre and 6 wks on-treatment. The mean VAF pre or on treatment of patient single nucleotide variants (SNVs) and insertion/deletions was correlated with clinical outcomes. Objective response rate (ORR) was calculated according to RECIST v1.1 and a Cox proportional hazard ratio (HR) was calculated adjusting for baseline ECOG, sex, age, and smoking status. Results: Complete and partial responders (CR/PRs) showed a significant decrease (Δ = -2.4%, p = 0.02) in ctDNA mean VAF post-treatment with D (i.e. reduction in tumor burden) compared to an increase in mean VAF (i.e. increase in tumor burden) in progressive disease (PD) pts (Δ = +2.7%, p = 0.31). This correlation was also observed in total mutation count in CR/PR (Δ = -4.6, p = 0.003) compared to PD pts (Δ = +2.8, p = 0.44). Pts with a decrease in ctDNA VAF at week 6 had longer median PFS (9.3 mos, 95%CI = [3.0, not reached(NR)] and OS (median NR, 95% CI = [20.3,NR]) compared to those with an increase in VAF (median PFS = 1.4 mos, 95%CI = [1.3,NR];HR = 0.29; p = 0.05 and median OS = 8.2 mos, 95% CI = [2.3,NR]; HR = 0.12; adjusted p = 0.04). DCR was 85%/14% for pts with a decrease/increase in VAF (p = 0.002). Conclusions: CtDNA VAFs were reduced in responders but not non-responders after six wks of D. A decrease in VAFs 6 wks following treatment with D correlated with longer PFS and OS, suggesting utility as an early indicator of clinical benefit. Clinical trial information: NCT01693562.
Chest X-ray prior to thyroidectomy: Is it really needed?
Authors: Alexandra Mikhael, Rushad Patell, Gauri Bhuchar, Michael Tabet, James Bena, Shannon Morrison, Eren Berber, Ahmet Bahadir Ergin, Tobenna Igweonu Nwizu, Christian Nasr
Journal: Journal of Clinical Oncology (2016)

6092 Background: Chest X-ray (CXR) prior to thyroid surgery is routinely ordered despite the lack of evidence to establish its utility. Unnecessary testing would be adding medical, financial and personal expenses without benefit. This study aimed to determine the utility of preoperative CXR in patients undergoing thyroidectomy. Methods: 594 consecutive patients who underwent thyroidectomy at the Cleveland Clinic were included in the study. Patients without preoperative CXR were excluded Retrospective review was performed to collect data including demographics, CXR findings, anesthesia records and pathological data including cancer stage and presence of metastasis. Patients with findings on CXR were compared to those without, to see if there was any correlation with difficult intubation or stage of cancer. Results: 494 patients (83%) of patients reviewed had a preoperative CXR. 67% had cancer on surgical pathology. 56 % had at least one abnormality reported on the reading. Skeletal abnormalities (25%) were the most frequent abnormality reported followed by tracheal deviation (16%), cardiomegaly (12%), lung nodules (6%; 3% subcentimetric and 0.5% diffuse nodularity), emphysema (2%) and pleural effusion (1%). Of 78 patients with tracheal deviation on CXR only 5% had a difficult intubation during surgery. CXR was shown to impact management in 4%. Tracheal deviation was more commonly seen in non-cancer cases compared to cancer patients (27% vs. 12%, p < 0.001). Amongst patient with cancer a higher T stage ( ≥ 2) had higher proportions of tracheal deviation compared to T = 1 (17% vs. 8 %, p < 0.001). Although patients with metastatic cancer (n = 81) compared to other cancer patients had a higher proportion of any abnormality on CXR (57% vs. 44%, p = 0.045) there was no significant difference for tracheal deviation or lung nodules on CXR. Of patients with nodules on CXR (n = 29) only 14% patients were shown to have metastatic disease. Conclusions: The utility of preoperative CXR in patients undergoing thyroidectomy including for thyroid cancer is very limited. In the climate of value-based care, routine use of this modality may be considered redundant, and should be ordered only if otherwise clinically indicated.