tbuckley/cabot-search huggingface dataset:
Evaluation of a multimodal strategy to accelerate drug evaluations in early-stage metastatic prostate cancer.
Authors: Matthew O'Shaughnessy, Sean Matthew McBride, Hebert Alberto Vargas, Karim A. Touijer, Michael J. Morris, Daniel Costin Danila, Vincent Paul Laudone, Bernard H. Bochner, Joel Sheinfeld, MinYuen Teo, Erica Simone Dayan, Lawrence P. Bellomo, Daniel Sjoberg, Glenn Heller, Michael J. Zelefsky, James Andrew Eastham, Peter T. Scardino, Howard I. Scher
Journal: Journal of Clinical Oncology (2017)

187 Background: The paradigm of first testing systemic treatments in advanced disease followed by development in earlier disease states and finally large-scale trials evaluating whether the approach, in combination with local therapy, can prevent or delay the time-to-event measures of disease progression or death in patients with “high-risk” tumors is no longer practical now that 6 life-prolonging systemic therapies in metastatic castration-resistant prostate cancer are available. New strategies are needed to rapidly evaluate and prioritize regimens for large-scale phase 3 testing. Methods: We conducted a pilot study of twenty men with oligometastatic M1a (extrapelvic nodal disease) or M1b (bone disease) at diagnosis. All sites of disease were treated using a multimodal approach that included androgen deprivation (ADT), radical prostatectomy plus pelvic lymphadenectomy (retroperitoneal lymphadenectomy in the presence of clinically positive retroperitoneal nodes), and stereotactic body radiotherapy to osseous disease and/or the primary site. ADT was discontinued in responding patients. Outcomes of each treatment were assessed sequentially. The primary endpoint of “no evidence of disease” (NED) was defined by an undetectable PSA with noncastrate levels of testosterone at 20 months. Results: Each treatment modality contributed to the outcome: 95% of the cohort achieved an undetectable PSA with multimodal treatment, including 25% of patients after ADT alone and an additional 50% and 20% after surgery and radiotherapy, respectively. Overall, 20% of patients (95% confidence interval 3-38%) achieved the primary endpoint, which persisted for 5, 6, 27+, and 46+ months. All patients meeting the primary endpoint had been classified with M1b disease at presentation. Conclusions: Treatment directed at all sites can eliminate detectable disease in selected patients with metastatic prostate cancer. A multimodal treatment strategy inclusive of the NED endpoint for patients who present with disease that is beyond the limits of curability by any single modality should be considered to enable the evaluation of new approaches in order to prioritize large-scale testing in early stages of advanced disease.
Prognostic role of promoter hypermethylation of death-associated protein (DAP) kinase and p16 genes in early-stage non-small cell lung cancer
Authors: C. Lu, I. Wistuba, X. Zhou, B. N. Bekele, J. B. Putnam, A. Correa, L. Mao
Journal: Journal of Clinical Oncology (2006)

7216 Background: Promoter hypermethylation is an epigenetic mechanism of gene silencing commonly observed in malignancies. Prior studies suggest that hypermethylation of DAP kinase and p16, genes involved in apoptosis and cell cycle regulation, respectively, are associated with poorer survival in NSCLC patients. In this study we investigate the prognostic role of DAP kinase and p16 promoter hypermethylation in a large cohort of early-stage NSCLC patients. Methods: Pathologic stage I and II NSCLC patients who underwent complete surgical resection between 1/97 and 12/01 at our institution and did not receive adjuvant therapy were identified. Formalin-fixed, paraffin-embedded tissue blocks were retrieved, and p16 and DAP kinase promoter methylation status was determined by methylation specific PCR. Two-sided statistical analyses were performed to determine associations between methylation status, clinicopathologic characteristics, and survival. Results: DAP kinase and p16 methylation status was observed in 36.3% (97 of 267) and 36.4% (95 of 261) cases, respectively. Subject characteristics: 55% female, 77% former/current smokers, 81% stage I, 19% stage II, 61% adenocarcinoma, 29% squamous carcinoma, 63% performance status (PS) 0, 37% PS 1,93% &lt; 5% weight loss. Recurrent NSCLC and death occurred in 21.3% and 38% of cases, respectively. No significant associations were observed between DAP kinase methylation status and subject characteristics. P16 methylation was associated with moderate/high grade (p = 0.03). A higher frequency of p16 methylation was observed in ever vs never smokers (39% vs 28%, p = 0.17). Preliminary analyses do not demonstrate significant associations between methylation status and overall survival (p16 p = 0.13; DAP kinase p = 0.56) or disease-free survival (p16 p = 0.36; DAP kinase p = 0.71). Conclusions: In this relatively large cohort of early-stage NSCLC patients, we did not detect significant associations between p16 and DAP kinase promoter methylation and clinical outcome. Further subset analyses stratified by gender and histology will be performed. The prognostic role of these biomarkers in NSCLC remains unclear. No significant financial relationships to disclose.
Actigraphy measured sleep disruption as a predictor of survival in advanced breast cancer.
Authors: Oxana Palesh, Arianna Aldridge Gerry, Jamie M. Zeitzer, Cheryl Koopman, Booil Jo, Eric Neri, Bita Nouriani, David Spiegel
Journal: Journal of Clinical Oncology (2013)

9532 Background: Sleep disruption, prevalent in cancer patients and survivors, is associated with disrupted hormonal circadian rhythms and poor quality of life. Previous studies in cancer patients and survivors have pointed out the association between poor sleep and faster disease progression. However, until now these studies have been limited by their retrospective or correlational design, providing little resolution of the question of whether sleep disruption accelerates disease progression or whether disease progression dysregulates sleep, or whether a third factor might underlie the association between sleep dysregulation and disease progression. This study aimed to clarify this relationship by using a longitudinal research design to examine whether sleep disruption assessed at baseline predicts survival in women with metastatic breast cancer. Methods: We examined sleep quality and duration in 97 women diagnosed with metastatic breast cancer (mean age=54.6, SD=9.8) via wrist-worn actigraphy for 3 days and sleep diaries. Sleep quality was operationalized as poor sleep efficiency (the ratio of total asleep time to total time in bed * 100%). Results: As hypothesized, poor sleep efficiency was found to predict shorter survival (Hazard Ratio (HR), 0.96, 95% CI, 0.93 to 0.98, p&lt;0.001) over 6 years. This relationship remained significant (HR, 0.94, CI, 0.91 to 0.97, p&lt;.001) even after controlling for other known prognostic factors (age, ER status, cancer treatment, metastatic spread, cortisol levels, and depression). Conclusions: Our findings show that sleep dysregulation is a clear and significant independent prognostic factor for disease progression in metastatic breast cancer. Further research is needed to determine whether treating sleep disruption with cognitive behavioral therapy or medication can improve survival in metastatic breast cancer. Funded by P01AG018784, R01CA118867, K07CA132916.
Does routine symptom screening with the Edmonton Symptom Assessment System (ESAS) decrease emergency department visits in breast cancer patients undergoing adjuvant chemotherapy?
Authors: Lisa Catherine Barbera, Rinku Sutradhar, Doris Howell, Clare Atzema, Jonathan Sussman, Hsien Seow, Craig Earle, Deborah Jane Dudgeon, Amna Husain, Ying Liu, Monika K Krzyzanowska
Journal: Journal of Clinical Oncology (2014)

6514 Background: In 2007 the provincial cancer agency in Ontario, Canada initiated a wide scale program to screen for symptoms in the cancer population using the Edmonton Symptom Assessment Scale (ESAS). The purpose of this study is to evaluate the impact of screening with ESAS on emergency department (ED) visit rates in women with breast cancer receiving adjuvant chemotherapy (CT). Methods: This retrospective cohort study used linked administrative health care data from across the province of Ontario, Canada. The cohort included all women aged ≥18 who were diagnosed with stage I-III breast cancer between January 2007 and December 2009 and received adjuvant CT within 6 months of diagnosis. Using a recurrent event model to adjust for covariates, we examined the association of screening with ESAS at a clinic visit on the ED visit rate. Results: 8,359 women were included. Approximately one third were screened with ≥1 ESAS during their chemotherapy. The rate of ED visits was 35% lower among patients screened with ESAS compared to those not screened. For each additional ESAS assessment there was a 19% decreased rate of ED visits. Conclusions: Our results demonstrate that screening with ESAS is associated with decreased ED visits. To our knowledge this is the first report on the effectiveness of routinely documenting patient-reported symptoms on ED visits, in a real world setting. Adjusted model results showing relative rate (RR) of ED visits for exposure to ESAS during chemotherapy either as a dichotomous or continuous variable (also adjusted for region and number of clinic visits). Variable Value Adjusted ESAS (Y/N) ESAS (Continuous) RR LCL UCL RR LCL UCL Age Continuous 1.00 1.00 1.00 1.00 1.00 1.00 Income quintile 1 1.04 0.97 1.11 1.04 0.97 1.11 2 1.03 0.97 1.10 1.03 0.97 1.10 3 1.04 0.97 1.10 1.04 0.97 1.10 4 1.02 0.96 1.08 1.02 0.96 1.08 5 1 1 Charlson 0 1 1 1 1.04 0.97 1.11 1.04 0.97 1.12 Stage I 1 1 II 1.02 0.96 1.07 1.02 0.96 1.07 II 1.06 0.99 1.13 1.05 0.99 1.13 Unknown 1.12 1.01 1.24 1.12 1.01 1.23 Docetaxol regimen Yes 1.41 1.32 1.51 1.40 1.31 1.50 No 1 1 ESAS exposure Yes 0.65 0.61 0.70 - - - No continuous - - - 0.81 0.77 0.84 Abbreivations: LCL, lower confidence limit; UCL, upper confidence limit.
Time to Endovascular Thrombectomy for Acute Stroke
Authors: Akash P. Kansagra
Journal: JAMA (2017)

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A nonrandomized phase II study of dose-dense paclitaxel and cyclophosphamide (PC) in early-stage breast cancer (EBC).
Authors: Kailash Mosalpuria, Ryan C. Ramaekers, Mehmet Sitki Copur, Kenneth H. Cowan, Mary Mailliard, Elizabeth Lyden, Wajeeha Razaq, Elizabeth C. Reed
Journal: Journal of Clinical Oncology (2014)

e11588 Background: Docetaxel, cyclophosphamide has less cardiotoxicity and improved disease-free and overall survival (OS) compared to doxorubicin, cyclophosphamide (AC) in EBC. However, dose-dense (DD) AC followed by paclitaxel (P) showed better OS compared to AC-P every (q) 3 weeks (wks). We proposed that DD PC would optimize dosing with little cardiac and hematologic toxicity. Methods: Patients (pts) with stage I or II BC received P (175 mg/m2), C (600 mg/m2) and pegfilgrastim dose (2-6 mg) q 2 wks for 6 cycles after surgical resection. Pts with Her2/neu and/or hormone receptor positive (+) BC also got trastuzumab (TTM) and hormone therapy, respectively (resp). Echocardiograms were done baseline and q 3 months in all pts. Sample size was based on a 10% and 5% incidence of febrile neutropenia (FNP) and decline in cardiac output (CO), resp. Results: Pts, n=102, median age, 58 years (range34-80) with BC (75% ER +, 67% PR+, 21% Her2/neu +, 20% triple negative, 51% grade 3,52% Stage II, and 69% node-negative ) receiving ≥ 1 cycle PC completed 573 of 612 planned cycles. Twelve pts (12%) received < 6 cycles for neuropathy-4 pts, hives/angioedema, infusion reaction, elevated SGOT, GI bleed, bone pain, fever, hyperglycemia, and social reasons-1 pt. Incidence of grade≥ 3 FNP and neurotoxicity was 4% and 9%, resp. One pt had decreased LVEF CO while on TTM alone. The estimated 1 year BC specific RFS and OS is 100% and 99% resp after a median follow-up of 2.2 years. One patient developed AML 8 months after diagnosis of primary breast cancer and died. A BRCA1 positive patient (ER > 90%, PR 80%, Her2/neu negative, Ki 67 > 50%) developed metastatic carcinoma thought to be of GI vs endometrial primary (positive for focal CDX2 and CK7; negative for ER, PR, CK 5/6, calretinin, TTF-1, napsin, mammaglobin, GCDDP-15) 16 months after initial diagnosis of breast cancer. Conclusions: Dose dense PC supported by pegfilgrastim resulted in a low incidence of grade ≥ 3 cardio and myelo-toxicity with a few dose delay/reductions. Clinical trial information: NCT01106898.
Do patients and doctors have the same conversation about colorectal cancer screening?
Authors: James Austin Talcott, Maureen Bezuhly, Jessica Herzstein, Michael P. Osborne, Kelly Cassano, Manjeet Chadha
Journal: Journal of Clinical Oncology (2017)

532 Background: Participant characteristics affect shared decision making. In a randomized trial of physician (MD) educational interventions to improve cancer screening guideline compliance, we studied patient (PT) and MD recall of discussions and how PT characteristics affected recall. We report the first results for colorectal cancer screening. Methods: In a cluster-randomized trial of educational supports for MDs, we are enrolling an age- (30-89 years) and sex-stratified sample of 216 PTs who underwent a physical examination at two urban hospitals, 18 for each of 12 primary care MDs. Screening guideline formatting (color-coding) and academic detailing were randomly assigned to MDs in a 2x2 design. Immediate post-encounter surveys recorded PT and MD recall of screening discussions and recommendations. Results: We report on the first 174 participants. They were diverse (63% white) and well educated (77% college degree). When MDs reported a colorectal screening discussion, 20% of PTs did not, and MDs had similar disagreement when PTs reported the discussion. Greater disagreement occurred on the MD recommendation: 15% of PTs disagreed when the MD reported screening was recommended, and 33% of MDs disagreed when their patients reported they had recommended it. Agreement between PTs and MDs on whether screening was recommended was fair (kappa = 0.33), and there was no agreement for PTs over 70 years (kappa = -0.15). When PTs under 50 or 75 and older differed from their MDs on screening recommendations, it was for screening not against (8 vs. 2). PTs reported more elements of shared decision making than MDs (data not shown). Conclusions: In a highly educated population of PTs and MDs surveyed immediately after their encounter, reports of whether colorectal screening was discussed, the shared decision making elements and the MD recommendation had important discrepancies, especially for older PTs. Clinical trial information: NCT02430948.
Early recurrence in glioblastoma.
Authors: Pamela Z. New, Bin S. Teh, Arnold Paulino
Journal: Journal of Clinical Oncology (2013)

e13032 Background: Current standard treatment for glioblastoma (GBM) consists of surgical resection, radiotherapy of 6000 cGy to the tumor bed and concomitant then adjuvant temozolomide (TMZ). Median survival on this regimen is 14 months. Early recurrence on imaging studies can be conflicted with treatment effect. Six patients are presented who recurred locally within 7 months of diagnosis despite optimal treatment, in an effort to determine molecular characteristics of patients with early progression. Methods: Three patients underwent gross total tumor resection, 3 underwent subtotal resection. All received IMRT totaling 6000 cGy with concomitant TMZ, followed by adjuvant TMZ. Ages ranged from 23 to 71, median 56. Time to radiographic recurrence was 3 to 7 months, median 4.8 months. There are 5 males and one female. Tumor methylation status and other markers are presented. Results: Three of the 6 patients were re-operated and pathology consistent with recurrent GBM. The remaining 3 progressed neurologically and by MRI scan. The O-6-methylguanine-DNA methyltransferase (MGMT) promoter gene of one tumor was unmethylated. This tumor specimen also expressed topoisomerase II; EGFR and EGFR VIII were negative. One tumor specimen expressed the BRAF V600e mutation. Both of these latter specimens expressed high levels of ERCC1, a DNA repair enzyme which would render these tumors unresponsive to platinum compounds. Conclusions: MGMT promoter methylation status may not be the only predicter of early recurrence. Exploring other biomarkers in more patients with glioblastoma at the time of surgery may assist in predicting true early progression verses pseudoprogression, an imaging challenge, in patients who may respond to different agents.
In vitro chemoresponse assay for patients with cervical cancer.
Authors: Giuseppe Del Priore, Perry Wayne Grigsby, Christine M. Gan, Todd D. Tillmanns
Journal: Journal of Clinical Oncology (2012)

e15514 Background: Chemotherapy is used in cervical cancer as neoadjuvant, chemosensitization with radiation, and upon recurrence. This study reports the results of an in vitro chemoresponse assay (ChemoFx, Precision Therapeutics) in primary, metastatic, or recurrent cervical cancer. Methods: Between 8/8/06- 6/2/10, 557 tumor specimens were received and 353 (63%) were successfully assayed. Status (primary, metastatic or recurrent) and histology (squamous 58%; adenocarcinoma 20%; adenosquamous 6%; neuroendocrine 5%; and other12%) was confirmed in 273 for this report. Single agents tested included: carboplatin, cisplatin, paclitaxel, docetaxel, epirubicin, fluorouracil, 4-hydroxy ifosfamide, SN-38, topotecan, and vinorelbine. Doublets included carboplatin/paclitaxel (Carbo/Tax) and cisplatin/topotecan (Cis/Topo). Tumor response was determined from dose response curves and scored as responsive (R), intermediate response (IR), or nonresponsive (NR). Chemoresponse is reported as R+IR. Results: 273 tumor specimens were evaluable for response. Chemoresponse of primary cancers (n=151) to single agents was SN-38-75%; 4-hydroxy ifosfamide-71%; topotecan-62%; epirubicin-58%; and cisplatin-58%. Chemoresponse of primary tumors to doublets was 73%-carbo/Tax and 56%-Cis/Topo. Chemoresponse of metastatic cancers (n=66) to single agents was irinotecan-54%; ifosfamide-51%; epirubicin-44%; topotecan-41% and fluorouracil-40%. Chemoresponse of metastatic tumors to doublets was 53%-Carbo/Tax and 30%-Cis/Topo. Chemoresponse of recurrent cancers (n=56) to single agents was epirubicin-44%; ifosfamide-41%; vinorelbine-39%; paclitaxel-39%; and topotecan-36%. Chemoresponse of recurrent tumors to doublets was 46%-Carbo/Tax and 35%-Cis/Topo. Conclusions: In vitro chemoresponse analysis is feasible in cervical cancer. Overall chemoresponsiveness was greater in primary cancers (58%) than in recurrent cancers (35%); (p&lt;0.0001). Chemoresponse to single agent cisplatin was lower than most other single agents in all three patient groups. Since many recurrent patients have prior platinum exposure, a chemoresponse assay will have further study possibilities in this setting.
Skin biopsy polymerase chain reaction for rapid microbiological diagnosis in patients with purpura fulminans
Authors: T. de Risi-Pugliese, A. Servy, J.-W. Decousser, B. Nebbad, M. Desroches, P. Wolkenstein, N. de Prost, O. Chosidow
Journal: British Journal of Dermatology (2017)

Purpura fulminans (PF) is mostly caused by Neisseria meningitidis or Streptococcus pneumoniae. Prompt identification of the causative bacteria is essential, but cerebrospinal fluid (CSF) and blood cultures may lack sensitivity, mostly because of prior antibiotic administration, and be time-delayed. A skin biopsy of a purpuric lesion with N. meningitidis polymerase chain reaction (PCR) is now recommended by French guidelines, still, the usefulness of this tool remains debated in some countries, owing to the lack of high-level evidence.

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Tumor heterogeneity in anal cancer assessed with diffusion-weighted (DW) and T2-weighted MRI: Potential biomarker of treatment outcome.
Authors: Kasia M. Owczarczyk, Davide Prezzi, Muhammad Siddique, James Stirling, Gary J. R. Cook, Robert Glynne-Jones, Andrew M. Gaya, Martin Leslie, Vicky Goh
Journal: Journal of Clinical Oncology (2017)

617 Background: Despite advances in the management of anal squamous cell carcinoma (ASCC), roughly 25% of patients undergoing chemoradiotherapy (CRT) will experience a disease recurrence. Currently, there is no validated way to predict treatment failure and guidance on the timing of follow-up scans differs. This study was carried out to assess the role of statistical and fractal heterogeneity parameters from pre-treatment and early post-CRT T2- and diffusion-weighted MR in predicting disease outcome. Methods: Baseline and follow-up MR scans from patients with histologically proven non-metastatic ASCC undergoing radical CRT were included in this study. T2-W and DWI MR images were analyzed by two readers, blinded to clinical data. Statistical and fractal heterogeneity parameters were derived using in-house software. Results: 40 patients were included in the final analysis. Follow-up MRI scan was performed at a median of 15 weeks from the start of radiotherapy. 31/40 patients achieved a radiological complete response (CR) and a further 7/40 partial response (PR). Median follow-up was 34.5 months. During the course of follow-up, 12 patients experienced disease recurrence (30%). Radiological CR was not significantly associated with disease outcome. First order statistical heterogeneity analysis demonstrated a significantly lower ROI Skewness (median -0.05±0.49 vs 0.45±1.04 p=0.01) on baseline T2-W imaging as well as lower ROI Entropy (3.95±0.46 vs 4.45±0.49, p=0.01) and higher ROI Energy (0.07±0.03 vs 0.03±0.03, p=0.01) on follow-up T2-W imaging in subjects who experienced disease recurrence. In these patients T2-W Homogeneity derived from Grey-Level Co-occurrence Matrices (GLCM) was lower at baseline (0.41±0.12 vs 0.58 ±0.15 p=0.02) and associated with a higher T2-W Sum Average (median 35±7 vs median 29±7 p=0.01), whereas T2-W Contrast and ADC Correlation derived from GLCM were lower on follow-up imaging (30±11 vs 38 ±35, p=0.01 and 0.77±0.12 vs 0.88±0.12 p=0.04, respectively). Conclusions: First order statistical and fractal heterogeneity analysis of baseline and early post CRT MR scans in patients with ASCC might have a role in predicting long-term disease outcome.