tbuckley/cabot-search huggingface dataset:
Basic molecular and cell biology: Gene regulation
Authors: DS Latchman
Journal: BMJ (1992)

Redwood City, California: Scientific Press, 1987. 9 Pauker SP, Pauker SG. Prenatal diagnosis: a directive approach to genetic counselling using decision analysis. YaleJ BwlMed 1977;50:275-89. 10 Bingham P, Lilford RJ. Management of the selected term breech presentation: assessment of the risks of selected vaginal delivery versus Cesarean section for all cases. Obstet Gynecol 1987;69:965-78. 11 Hillner BE, Smith TJ. Efficacy and cost effectiveness of adjuvant chemo? therapy in node negative breast cancer. N EnglJ Med 1991 ,324:160-8. 12 Klein K, Pauker SG. Recurrent deep venous thrombosis in pregnancy: analysis of the risks and benefits of anticoagulation. Med Decision Making 1981;1:181-202. 13 Elstein AS, Holzman GB, Ravitch MM, Metheny WA, Holmes MM, Hoppe RB, el al. Comparison of physicians decisions regarding estrogen replace? ment for menopausal women and decisions derived from a decision analytic model. Am J Med 1986;80:246-58. 14 Feldman GB, Freiman JA. Prophylactic caesarean section at term? N EnglJ Med 1985,312:1264-7. 15 Weinstein MC, Pliskin JS, Stason WB. Coronary artery bypass surgery; decision and policy analysis. In: Bunker JP, Barnes BA, Mosteller E, eds. Costs, benefits and risks of surgery. Oxford: Oxford University Press, 1977. 16 Tompkins RK, Burnes DC, Cable WE. An analysis of the cost effectiveness o? pharyngitis management and acute rheumatic fever prevention. Ann Intern Med 1977;86:481-92. 17 Neutra R. Indications for the surgical treatment ol suspected acute appendi? citis. A cost effectiveness approach. In: Bunker JP, Barnes BA, Mosteller E, eds. Costs, benefits and risks of surgery. Oxford: Oxford University Press, 1977. 18 Neuhauser D, Lewicki AM. What do we gain from the sixth stool guaic? N' EnglJ Med \975;293:226-S. 19 Van Crevel H, Habbema JDF, Braakman R. Decision analysis of the management of incidental intracranial saccular aneurysms. Neurology 1986; 36:1335-9.
Fertility counseling in young adult patients with cancer.
Authors: Sonia Evelyn Reichert, Sadie Sanchez, Jen Kolb, Amir S. Steinberg, Randall F. Holcombe, Elizabeth Garland, Janice Lynn Gabrilove
Journal: Journal of Clinical Oncology (2013)

e20570 Background: In 2008, 450,000 US cancer survivors were of reproductive age (18-45 years). Currently, oncologists receive little training about fertility preservation and counseling for patients. In 2006, the American Society of Clinical Oncology (ASCO) recommended oncologists “discuss the possibility of infertility during their reproductive years prior to chemotherapy.” This study aimed to evaluate adherence to these guidelines and determine if a chemotherapy consent form increased compliance. Methods: At a tertiary care center in New York on April 23, 2012, a specialized chemotherapy consent form, including a fertility risk statement and checkbox, was implemented. A retrospective chart review was conducted 250 days before April 23, 2012 (pre group) and 250 days after April 23, 2012 (post group). This study included patients 18-45 years old with a new malignant diagnosis who received fertility altering therapy. Patients with a prognosis less than 12 months were excludedfrom the study. Data collected included demographics, documentation of fertility discussions, presence of a signed chemotherapy consent form and the use of a fertility risk checkbox prior to initiation of treatment. Results: Of 645 new patient visits, 80 in the pre-group and 53 in the post-group met the inclusion criteria. The mean age (SD) for the pre and post groups was 35.6 (±6.7) and 36.8 (±6.7) respectively. Thirty-five (43.8%) patients had documented fertility counseling in the pre group compared to 16 (30.1%) in the post group. A Cochran–Mantel–Haenszel test determined that these 2 groups were not statistically different (p = 0.250). In the post group, 5 (12.8%) patients had both documented fertility counseling and a consent form; and only 3 (7.6%) patients had evidence of documented counseling, a consent form and the fertility risk box checked. Conclusions: Fertility counseling was documented in less than half of cancer patients for whom this procedure is recommended. The introduction of a specialized chemotherapy consent form did not improve the rates of documented fertility counseling. Further exploration is needed to identify the barriers to fertility counseling and identify the best resources and tools for providers to ensure compliance with ASCO guidelines.
Validation of a clinical trial accrual predictive model.
Authors: Wendy R. Tate, Lee D. Cranmer
Journal: Journal of Clinical Oncology (2015)

6535 Background: The costly and extensive process to drug approval highlights the need to streamline the drug pipeline process. We previously reported a novel predictive model with the outcome of anticipated accrual to be used when considering a prospective clinical trial at our center. Here, we present the results of the validation study. Methods: Eligible studies include treatment and supportive care intervention studies permanently closed to accrual between 10/2013 and 01/2015 at our center. Data abstracted from the clinical trials management system (OnCore, Forte Systems, Madison, WI) included: use of investigational drug, disease management team (DMT), use of local IRB, local start date, DMT accrual prediction value, actual total accrual, and clinicaltrials.gov (NCT) number. Abstracted from clinicaltrials.gov were protocol-specific data: number of national sites, national enrollment goal, national start date, and national date of expected primary endpoint completion. Studies were run through the model and actual accrual plotted against predicted accrual. Actual, team- and model-predicted subjects accrued; percent of trials meeting cut-off values; and model sensitivity and specificity were calculated. Results: Sixty-one trials met study inclusion criteria. Total accrual was 373 subjects (mean: 6.1±17.2); 16 (26.2%) studies had zero accrual, 23 (37.7%) accrued 88.7% of the total subjects. The model predicted accrual of 513 subjects (138% of actual) versus the DMT predicted accrual of 1111 subjects (298% of actual). The model correctly predicted whether a study would accrue 4+ subjects 75% of the time. Twenty-seven studies (44.3%) correlated perfectly at the category level. Model sensitivity is 70%; specificity is 78%. For the 17 studies not correctly categorized using a cutoff of four, nine (60%) would have been incorrectly opened (predicted 4+, < 4 accrued) and six (40%) would have incorrectly not opened (predicted < 4, 4+ accrued). Conclusions: The identified national and local factors to predict clinical trial accrual at our center are valid, showing it to be an accurate, quick and valuable metric in assessing trial success as well as planning resource allocation. Further research includes national expansion of the model to cancer centers.
Vancomycin treatment is a risk factor for vancomycin-nonsusceptible Staphylococcus capitis sepsis in preterm neonates
Authors: Marine Butin, Jean-Philippe Rasigade, F. Subtil, Patricia Martins-Simões, C. Pralong, A.-M. Freydière, François Vandenesch, S. Tigaud, J.-C. Picaud, Frédéric Laurent
Journal: Clinical Microbiology and Infection (2017)
Certification and role of local pathologists for diffuse large B-cell lymphoma (DLBCL) subtyping and eligibility determination in the phase II PYRAMID study.
Authors: Jonathan W. Said, James Andrew Reeves, Ian Flinn, Anil Tulpule, Robert Leon Robles, Christopher Flowers, Nicholas J. DiBella, Kathryn S. Kolibaba, Parameswaran Venugopal, Tatjana Kolevska, Sven De Vos, David L. Jaye, Dixie Esseltine, George Mulligan, Maria Margarita Corvez, John R. Eckardt, Bryan Brockman, Isagani M. Chico, John Leonard, Steven Kussick
Journal: Journal of Clinical Oncology (2013)

8559 Background: The role of local pathologists in promoting patient (pt) accrual and evaluating eligibility criteria involving a complicated immunohistochemical (IHC) algorithm has rarely been investigated. The phase II PYRAMID trial (NCT00931918) is assessing R-CHOP ± bortezomib for newly diagnosed pts with non-germinal-center B-cell (non-GCB) subtype DLBCL. In this trial, local pathologists were encouraged to perform DLBCL subtyping at the point of biopsy, identify suitable pts for the trial, and facilitate accrual. Methods: Determination of GCB vs non-GCB subtype is per the Hans method, an algorithm based on IHC for CD10, BCL-6, and IRF4/MUM1. In stage 1, pathologists demonstrated IHC subtyping proficiency by evaluating a tissue microarray (TMA) of 12 DLBCL cases; those with ≥80% of samples in agreement with central lab results were certified for determining trial eligibility. In stage 2, to broaden participation, pathologist certification occurred via teleconference outlining trial eligibility criteria, tissue subtyping requirements, and determining pathologists’ experience with the Hans method. Results: 182 pathologists have been certified for local subtyping, 50 via TMA and 132 by teleconference. 66/88 active study sites have ≥1 certified pathologist. Only 1 of the 10 top enrolling sites lacks a certified pathologist. 52% (84/162) of pts have been enrolled based on local pathologist subtyping prior to central lab confirmation. Discordance with central lab results occurred in 9/84 cases (11%). Enrollment rates pre- and post-local pathologist certification were 0.053 and 0.096 pts/site/month; an improvement of 81%. Trial accrual correlates with the presence of a certified local pathologist (p=0.0026). The rate of ineligible GCB cases sent for central lab testing was lower from sites with a certified pathologist (23% [69/299 cases] vs 38% [40/106 cases] for sites without). Conclusions: Engagement of local pathologists in trials requiring pathology selection can significantly improve accrual. This study demonstrates the effectiveness of various training modalities in improving selection by local pathologists using a complex IHC algorithm. Clinical trial information: NCT00931918.
Converting borderline-resectable, locally-advanced esophageal carcinoma to resectability with neoadjuvant chemoradiotherapy.
Authors: Zachary D. Horne, Weijing Sun, Michael K. Gibson, Arjun Pennathur, James D. Luketich, Brian J Karlovits, Dwight Earl Heron, Joel S. Greenberger
Journal: Journal of Clinical Oncology (2017)

160 Background: Treatment of T3-4/N+ esophageal cancer is challenging. Outcomes are suboptimal and patterns of care are not well defined for borderline-resectable esophageal cancer (BREC). We present our institutional experience using preoperative chemoradiotherapy (CRT) in the management of BREC. Methods: We identified 67 patients with T3-4/N+ BREC who were treated with concurrent CRT between 2009 and 2014. Survival was calculated with Kaplan-Meier curves and cohort comparisons were made with log-rank test and Cox regression. Results: We treated 67 patients (81% males, median age 61 years, and KPS of 80), primarily with T3N2 disease. Median follow-up was 16 months. The most common CRT regimen was 58.8Gy in 28 fractions with carboplatin and paclitaxel. Median survival was 16.5 months. Forty two (62.7%) patients underwent minimally invasive Ivor-Lewis esophagectomy within 100 days of CRT. Resected patients had a median survival of 30.6 vs. 6.4 months without surgery (p&lt;.001). Pathologic complete response and pN0 was 30.0% and 59.5%, respectively. Acute grade 3+ toxicity was seen in 34.3% and late grade 3+ toxicity in 49.3%. Three patients (4.5%) died during CRT or before surgery. Predictors of overall survival (OS) on univariate analysis included age, KPS, male gender, absence of radiographic progression and surgical resection (all p&lt;.05). Surgery remained significant on multivariate analysis (HR 0.215 [95%CI .114-.408, p&lt;.001]). For resected patients, survival was predicted by positive margins, pathologic N stage, and number of positive nodes (all p&lt;.05). The only predictor of OS on multivariate analysis was pathologic N stage, with actuarial 1- and 2-year OS for pN0 vs. pN+ of 96.2%/73.1% vs 53.3%/40.0% (p=.001). pN+ patients receiving adjuvant chemotherapy (53.3%) had improved survival of 26.7 vs 8.3 months without (p=.023). Conclusions: Preoperative CRT enabled a significant proportion of patients with BREC to proceed with a potentially curative resection. Further investigation with careful patient selection is warranted in incorporating a trimodality strategy to optimize outcomes and better define a treatment algorithm for this complex cohort of patients.
Vismodegib for advanced basal cell carcinoma: Duration of response after vismodegib discontinuation and response to vismodegib retreatment upon disease progression.
Authors: Aleksandar Sekulic, John D. Hainsworth, Karl D. Lewis, Anthony E. Oro, Anja Gesierich, Laurent Mortier, Luc Dirix, Stephen Bernard, Brigitte Dreno, Dedee F. Murrell, Sarah Williams, Jeannie Hou, David Christopher Fisher, Axel Hauschild
Journal: Journal of Clinical Oncology (2014)

9081 Background: Vismodegib (VISMO) (Erivedge) is a first-in-class Hedgehog pathway inhibitor (HPI) approved for advanced basal cell carcinoma (aBCC). In the ERIVANCE trial, VISMO-treated patients (pts) demonstrated objective response rates (ORRs) by independent review of 30% in metastatic BCC (mBCC; n=33) and 43% in locally advanced BCC (laBCC; n=63). ORRs by investigator (INV) review were 45% (mBCC) and 60% (laBCC). Treatment on VISMO may be prolonged, and a number of pts discontinued treatment prior to progression on therapy. Here we provide results from a survey designed to assess durability of response in laBCC pts from ERIVANCE who discontinued VISMO while experiencing a response or stable disease (SD). We also determined whether they responded to retreatment with VISMO. Methods: As of May 28, 2012, we identified 13 pts who did not have progressive disease (PD) at the time of study discontinuation and were still alive and available for follow-up.In Oct 2012, a survey was sent to INVs to determine pt outcome (disease status and additional treatments) based on the most recent pt assessment. Results: Of the 13 pts identified, 11 had stopped VISMO with an INV assessment of response; 2 had SD. Reasons for discontinuation were pt decision (n=7), adverse event (n=4), and physician decision (n=2).The INV or the referring dermatologist assessed 12 pts within ≤7 months of Oct 2012; 1 pt visited a primary care physician in January 2009. 6 of 13 pts remain progression free. For the other 7 pts with PD, duration of treatment-free interval ranged from 89 to ~725 days. 5 pts were treated with excision and/or Mohs surgery and 2 were retreated with VISMO. Best responses in the 2 pts retreated with VISMO were SD and unconfirmed partial response. Overall, 8 of 13 pts did not have PD for >1 year after discontinuation of VISMO. Conclusions: VISMO discontinuation after achieving tumor stabilization did not lead to rapid tumor recurrence; pts may maintain response for >1 year. Among pts who experience PD after discontinuation, additional treatment (Mohs or surgery) may be possible. Pts who discontinue VISMO prior to disease progression may benefit from retreatment upon progression. Clinical trial information: NCT00833417.
Neo-tAnGo science: A translational study of PAM 50 sub-typing in sequential fresh tissue samples during neoadjuvant chemotherapy.
Authors: Helena Margaret Earl, Suet-Feung Chin, Mark Dunning, Mahesh Iddawela, Oscar Rueda, Roslin Russell, Linda Jones, A-L Vallier, Luke Hughes-Davies, Jean Abraham, Steve Chan, Anthony Skene, Kim Benstead, Christopher J. Gallagher, Nicholas Murray, Diana Ritchie, Janet A. Dunn, Louise Hiller, Elena Provenzano, Carlos Caldas
Journal: Journal of Clinical Oncology (2013)

1015 Background: Neo-tAnGo was an NCRI UK neoadjuvant breast cancer study testing the addition of gemcitabine to anthracycline and taxane-based treatment and also the sequencing of chemotherapy. In a translational substudy, sequential fresh tissue was analysed for PAM 50 subgroups. Methods: Neo-tAnGo recruited 831 patients. 162 patients were consented for Neo-tAnGo Science, for 3 additional fresh tissue samples to be taken at diagnosis (diag), mid-chemotherapy (CT) and end-CT. Standard methodology was used for PAM 50 subtyping. Results: Fresh tissue samples at diag were received from 123 patients (pts). 45 pts (37%) had 2 additional samples provided (at mid- and end-CT). 57 pts (46%) had 1 additional sample provided (34 at mid-CT, 23 at end-CT). PAM 50 subtyping at diag was as follows: 31 (25%) BASAL; 30 (24%) HER2; 39 (32%) LUM B; 13 (11%) LUM A; 10 (8%) NORMAL-like. Pathological complete response rates (pCR: no disease in breast or axillary nodes, n = 121 pts) differed between PAM 50 subtype at diag (p = 0.04): BASAL 11/31 (35%); HER2 8/30 (27%); LUM B 3/37 (8%); LUM A 1/13 (8%); NORMAL-like 3/10 (30%). Of the 94 pts who were not PAM50 NORMAL-like at diag and had 2+ samples, 42 (45%) ‘shifted to NORMAL-like’. This was associated with slightly higher pCR rates (24% vs 15% who didn’t ‘shift to NORMAL-like’, p = 0.44) and borderline significantly higher rates of pCR or minimal residual disease (MRD: &lt;10% residual scattered tumour cells) (48% vs. 27% who didn’t ‘shift to NORMAL-like’, p = 0.06). In the 102 pts with 2+ samples, 58 pts (57%) showed a shift to a better prognosis PAM 50 subtype after CT (Group (Gp) 1), 37 (36%) showed no change (Gp 2) and 7 (7%) a shift to a worse prognosis subtype (Gp 3). pCR rates were 26% Gp1, 14% Gp2 and 0% Gp3 (p = 0.05). pCR/MRD rates were 48% Gp1, 22% Gp2 and 0% Gp3 (p = 0.001). Conclusions: PAM 50 subtype at diagnosis correlates with pCR to neoadjuvant chemotherapy. Shift to a better prognosis PAM 50 group during neoadjuvant chemotherapy was demonstrated in 57% of pts and was significantly correlated with higher pCR and pCR/MRD rates. Clinical trial information: 78234870.
KEYNOTE-177: Randomized phase III study of pembrolizumab versus investigator-choice chemotherapy for mismatch repair-deficient or microsatellite instability-high metastatic colorectal carcinoma.
Authors: Luis A. Diaz, Dung T. Le, Takayuki Yoshino, Thierry Andre, Johanna C. Bendell, Minori Koshiji, Yinghua Zhang, S. Peter Kang, Baohoang Lam, Dirk Jäger
Journal: Journal of Clinical Oncology (2017)

TPS815 Background: A subset of colorectal carcinomas (CRCs) are characterized by mismatch repair (MMR) deficiency resulting in microsatellite instability (MSI). MSI-high tumors contain high levels of lymphocyte infiltrates and express the PD-1 immune checkpoint receptor and its ligand, PD-L1. In the phase 2 KEYNOTE-016 study, the anti–PD-1 antibody pembrolizumab demonstrated antitumor activity against MMR-deficient tumors in patients with treatment-refractory metastatic CRC. KEYNOTE-177 (ClinicalTrials.gov, NCT02563002) is an international, randomized, open-label, phase 3 study of pembrolizumab versus standard-of-care (SOC) chemotherapy in first-line MMR-deficient or MSI-high metastatic CRC. Methods: Key eligibility criteria include age ≥18 years, confirmed MSI-high or MMR-deficient metastatic CRC, ECOG PS 0-1, no active autoimmune disease or brain metastases, and no prior therapy for metastatic disease. ~270 patients will be randomly assigned 1:1 to receive either pembrolizumab 200 mg every 3 weeks or investigator's choice of SOC chemotherapy (mFOLFOX6 or FOLFIRI alone or in combination with bevacizumab or cetuximab, chosen before randomization). Treatment is to continue until progressive disease (PD), unacceptable toxicity, patient/investigator decision, or completion of 35 cycles (pembrolizumab only). Response is to be assessed every 9 weeks per RECIST v1.1 by central imaging vendor review and per RECIST adapted for immunotherapy response patterns. Eligible patients may continue pembrolizumab beyond initial RECIST-defined progression. Patients in the SOC arm who have PD and meet crossover criteria may be eligible to receive pembrolizumab for up to 17 treatment cycles. AEs are to be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. Patients are to be followed up for survival every 9 weeks. The primary end point is PFS per RECIST v1.1; key secondary end points include OS and ORR. Enrollment in KEYNOTE-177 is ongoing. Clinical trial information: NCT02563002.
Preclinical studies with neratinib in triple-negative breast cancer.
Authors: Maeve Mullooly, Neil A. O'Brien, Dylan Conklin, Richard S. Finn, Dennis J. Slamon, John Crown, Norma O'Donovan, Patricia M. McGowan, Michael J. Duffy
Journal: Journal of Clinical Oncology (2013)

1054 Background: Currently, one of the most urgent problems in breast cancer therapeutics is the validation of targeted therapy for triple-negative breast cancer (TNBC). Neratinib is an irreversible small molecule inhibitor that targets the kinase activity of EGFR, HER2 and HER4. As one of these targets, EGFR, is expressed at high levels in a subset of TNBC, we hypothesised that neratinib is a potential treatment for at least some patients with TNBC. Methods: The antiproliferative effects of neratinib were investigated in a panel of 35 breast cancer cells lines including 9 luminal, 12 HER2-positive and 14 triple-negative (TN). Baseline levels of total HER proteins were determined using flow cytometry. Results: IC 50 values for neratinib across the panel of breast cancer cell lines ranged from &lt; 0.001 - 1.9 µM. HER2-positive cell lines were significantly more sensitive to neratinib than HER2-negative cells (p = 0.008, Student’s t-test). For the 14 TN cell lines, IC 50 values ranged from 0.03 – 1.9 µM. TN cell lines defined as basal-type A were significantly more sensitive to neratinib than those designated basal-type B (p = 0.02, Student’s t-test). Treatment with neratinib resulted in a reduction in HER-family signalling as detected by decreased Akt and ERK phosphorylation. Consistent with the finding that basal type A TN cells were more sensitive to neratinib than type B, significantly higher levels of EGFR expression were found in the A subtype compared to the B subtype (p = 0.02, Student’s t-test). To determine a possible predictive marker of response for neratinib, levels of all 4 HER proteins were related to response in the basal A subgroup. Baseline levels of HER3 expression were found to correlate significantly with response to neratinib (p = 0.02, r = -0.875, n = 7, Spearman), i.e., cell lines with the highest levels of HER3 expression had the lowest IC 50 values within this cohort. Conclusions: Our results suggest that neratinib is a potential novel therapeutic option for patients with basal A type triple negative breast cancer. HER3 may act as a predictive marker of response for this subgroup of patients. Acknowledgements: The authors thank SFI for funding MTCI (SRC award, 08/SRC/B1410 to MTCI) and an SFI Short Term Travel Fellowship to MM, for funding this work.