tbuckley/cabot-search huggingface dataset:
Risk for dose-limiting chemotherapy-induced peripheral neuropathy in black women with breast cancer.
Authors: Rebecca M Speck, John T Farrar, Mary D Sammel, Jun J Mao, Margaret G Stineman, Sean Hennessy, Angela DeMichele
Journal: Journal of Clinical Oncology (2013)

6560 Background: Chemotherapy induced peripheral neuropathy (CIPN) is a potentially dose-limiting toxicity. Recent data from early stage breast cancer clinical trials has suggested that black women are at increased risk for CIPN. We examined whether black race was a risk factor for dose-limiting CIPN events in a general academic practice. Methods: This retrospective cohort study included 260 women, (27.3% black) that received neoadjuvant or adjuvant paclitaxel for non-metastatic breast cancer. The primary outcome was a dose-limiting (DL) event (dose delay, dose reduction, or treatment discontinuation) attributed to CIPN (DL-CIPN). Cox proportional hazards models were used to analyze patient level and treatment level factors related to DL-CIPN. Survival time was represented by cumulative dose in milligrams of paclitaxel received. The final model included independent risk factors (p&lt;0.05) of DL-CIPN and confounders that when adjusted for altered the crude estimate by 10% or more. Results: There were 39 DL-CIPN events; 5 were excluded from analyses for being a subsequent event. For the 34 DL-CIPN events, the median cumulative dose received at time of DL-CIPN event was 925 mg (range=256-1520 mg), which differed significantly (p&lt;0.001) from the 188 women who had no dose-limiting event of any cause (median=1272, range=928-2136 mg). Black race was the only statistically significant independent risk factor for DL-CIPN. Compared to whites, black women had a greater than two-fold increased risk of DL-CIPN (HR=2.29, 95%CI=1.17-4.50). After adjusting for oncologist, menopausal status, obesity (BMI≥30), and regimen (80mg/m 2 weekly for 12 cycles vs. 175mg/m 2 bi-weekly for 4 cycles) the risk of DL-CIPN for blacks compared to whites was HR=3.35 (95%CI=1.54-7.28). Conclusions: Our findings contribute to the growing body of evidence that black race is associated with CIPN symptom onset and severity. Efforts to elucidate mechanisms, increase clinicians’ awareness of the greater susceptibility of black women to CIPN, and the development of symptom management strategies, effective in ensuring adequate adherence to chemotherapy, are crucial.
AHL 2011: A Lysa randomized phase III study of a treatment driven by early PET response compared to a standard treatment in patients with Ann Arbor stage III-IV or high-risk IIB Hodgkin lymphoma.
Authors: Rene-Olivier Casasnovas, Michel Meignan, Oumedaly Reman, Isabelle Gaillard, Aspasia Stamatoullas, Pauline Brice, Gilles A. Salles, Reda Bouabdallah, Serge Bologna, Emmanuelle Nicolas-Virelizier, Franck Morschhauser, Maud Janvier, Marc Andre, Alina Berriolo-Riedinger, Alexandra Traverse-Glehen, Veronique Edeline, Peggy Dartigues, Marie Parrens, Nicolas Mounier, Christophe Ferme
Journal: Journal of Clinical Oncology (2013)

TPS8615 Background: ABVD is the most widely chemotherapy regimen used as standard treatment of advanced Hodgkin lymphoma (HL). The escalated BEACOPP (BEAesc) regimen which delivers more drugs at higher dose intensity was shown to improve patient’s PFS but not OS when compared to ABVD (Federico M, 2009; Viviani S, 2011; Carde P, 2012). The better efficiency of BEAesc is associated to a marked immediate hematologic toxicity and a higher risk of secondary myelodysplasia/leukemia. Also, the gonadal toxicity which is a real concern in young women, is quite higher when using BEAesc. So, to better manage HL treatment we need to identify early responding patients able to benefit from a strategy of dose intensity decrease after upfront BEAesc, without impairing the disease control. PET performed after 2 cycles of chemotherapy (PET2) might identify such a population suitable for receiving ABVD after 2 cycles of upfront BEAesc, and was implemented in the present study. Methods: The AHL 2011 trial (NCT01358747) was designed to test in 16 to 60 years old HL patients with Ann Arbor stage III, IV or high risk IIB, a treatment strategy driven by PET after 2 cycles of BEACOPPesc, delivering 4 cycles of ABVD for PET2 negative patients and 4 cycles of BEAesc for PET2 positive patients, compared to a treatment not monitored by PET, delivering the best BEAesc schedule consisting in 6 cycles of this regimen (Engert A, 2012). A baseline PET is mandatory before treatment and PET2 are centrally reviewed within 48 hours and interpreted according to Deauville criteria. The allocation of treatment in the experimental arm is based on the PET2 central review result. PFS is the primary endpoint of the study with an hypothesis of non-inferiority of the experimental arm with a margin of 10% (85% 5y-PFS in the control arm vs &gt;75% in the experimental arm). With a 6-year of accrual period, inclusion of 405 patients in each arm would have 80% power to detect a HR of 1.77 using a one-sided log rank test with significance level of 0.025. The trial started in May 2011 and to date, 385 patients have been enrolled. The DSMC reviewed the trial in November 2012 and suggested that the trial continue as planned. Clinical trial information: NCT01358747.
Lynch syndrome testing in ethnically diverse patients: Mutation spectrum and performance of prediction models.
Authors: Y. Nancy You, Eduardo Vilar Sanchez, Rebecca Slack, George J. Chang, Sa Thi Nguyen Nguyen, Amanda Cuddy, Swapnil Khose, William Wisniewski, Sarah A. Bannon, Maureen M. Mork, Patrick M. Lynch, Miguel A. Rodriguez-Bigas
Journal: Journal of Clinical Oncology (2013)

1546 Background: Lynch syndrome (LS) is characterized by deficiency in DNA mismatch repair (MMR). Several models can predict the probability of MMR gene mutations, but all were derived from populations in Northern Europe and America. We aimed to characterize MMR mutations and to evaluate the performance of 4 models (Leiden, MMR predict , MMR pro , and PREMM 1,2,6 ) in an ethnically diverse high-risk population. Methods: Mutation and pedigree data from 387 distinct probands tested for germline MMR mutations at a single center between 2003-2012 were analyzed. Mutation testing was triggered by suggestive tumor microsatellite results and/or clinical/family history. Race/ethnicity was self-reported: 84 (22%) were ethnically-diverse (African American, 19; Hispanic, 29; Asian/Arabic, 34; and other, 2) and 303 (78%) were white. Area under the receiver operating curve (AUC) for all 4 models was analyzed by logistic regression. Results: Pathogenic mutations were detected in 152 patients (39%; MLH1 in 37, MSH2/EPCAM in 84, MSH6 in 21, and PMS2 in 10). The detection rate was significantly lower in ethnically-diverse patients when compared to white patients (30 vs. 42%; p=0.04). The mutation frequency of the major MMR genes MLH1 and MSH2 differed, although the overall mutation distribution did not reach statistical significance (MLH1, 40 vs. 22%; MSH2: 36 vs. 59%; MSH6: 20 vs. 13%; and PMS2: 4 vs. 7%; p=0.10 vs. white). The Leiden, MMR predict , MMR pro , and PREMM 1,2,6 models trended toward inferior discrimination for the ethnically diverse patients, with AUCs of 0.63, 0.64, 0.63, and 0.66 respectively (vs. AUCs of 0.71, 0.69, 0.72, and 0.76 for white patients), but the difference was not statistically significant(p=0.11, 0.17, 0.09, and 0.08, respectively). Adjusting for family size did not significantly alter results. Conclusions: In ethnically-diverse patients, the overall detection rate for pathogenic MMR mutations is significantly lower, with associated differences in mutation frequencies and in predictive model performance. We caution against relying solely on predictive scores, as high-risk ethnically-diverse patients without an identified mutation may deserve to be followed as clinical LS patients.
Overcoming the barriers to early-phase clinical trials (EPCT): Increasing EPCT minority accrual.
Authors: Steven D. Weitman, Amelie G. Ramirez, Patricia Chalela, Edgar Munoz, Brad H. Pollock
Journal: Journal of Clinical Oncology (2012)

e16566 Background: Increasing minority accrual is critical to the development of novel cancer therapeutics. Without adequate minority representation in EPCT, researchers cannot assess differential effects among groups nor ensure the generalizability of trial results. Little is known about cultural factors that impact the decision to participate in EPCT among Hispanics. Methods: The goals of this research were to identify cultural, economic and environmental barriers to EPCT accrual and potential interventions to reduce these barriers. Two surveys were conducted. One survey was with 114 oncologists and one with 100 cancer patients (50 who were enrolled in an EPCT and 50 who never participated). Results: The top four logistical barriers stated by oncologists were all related to the extra work and time of recruiting and referring patients: referring patients is extra work (63%), too much paperwork (57%), too complex of procedures (57%) and excessive details of protocols (50%). Significant differences between clinical trial and non-clinical trial participants were found for two barriers in the decision-making process [lack of knowledge about available trials (88% and 94%), and lack of understanding about trial processes and purpose due to medical jargon (82% and 90%)]. Non-clinical trial participants gave higher importance to four barriers related to attitudes and beliefs [fear of being a guinea pig (80%), fear that the experiment is more important than the patient (76%), distrust in the medical system (72%), and fear of sacrificing QoL (72%)]. Non-participants in EPCT tended to have less education, lower income, and were Hispanic. In addition, two-thirds (68%) of non-participants considered language as a major barrier. Conclusions: Oncologists would be more likely to refer patients for EPCT if they are aware of the studies, feel confident with their patients, trust the research team, see benefit for their patients, and have an easy way to refer patients. The results of this study may have implications in terms of message development for groups traditionally underrepresented, which may require language appropriate materials, more visual materials with lower reading levels, and with more precise economic information.
Next-generation sequencing (NGS) in relapsed/refractory triple-negative breast cancer (TNBC) in Israel.
Authors: Noa Ben-Baruch, Tamar Peretz-Yablonski, Georgeta Fried, Moshe J. Inbar, Yousef Samih, Victoria Neiman, Bella Nisenbaum, Karen Drumea, Neil Friedman, Rony Weitzen, Tamar Safra, Lior Soussan-Gutman, Addie Dvir, Phil Stephens, Kai Wang, Vincent A. Miller, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2014)

1028 Background: Relapsed/metastatic TNBC is an aggressive form of the disease that typically responds initially to chemotherapy, but eventually progresses in the majority of patients (pts). We hypothesized that a comprehensive NGS assay (FoundationOne) could identify novel therapy targets not routinely interrogated in TNBC pts. Methods: Hybridization capture of 3,769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to ≥ 50 ng of DNA extracted from 26 TNBC FFPE specimens and sequenced to high, uniform coverage. Genomic alterations (GA) including base substitutions, small indels, copy number alterations, and select gene fusions, were characterized and reported for each pt sample. Actionable GAs were defined as those identifying anti-cancer targeted therapies on the market or in registered clinical trials. Results: The 26 TNBC pts had a mean age of 49.6 yrs (range, 28-74). All 26 tumors were ER-/PR-/HER2- on routine slide-based testing. Samples used for NGS originated from breast (42%), lymph nodes and axilla (23%), chest wall and muscle (12%), skin (8%) and serous effusion (4%). All 26 cases harbored ≥1 GA, with a total of 113 GAs and a mean of 4.35 GAs per tumor. The most frequent currently unactionable GAs were TP53 (21, 81%) and MYC (8, 31%). Twenty two cases (85%) harbored ≥1 actionable GA; mean, 2.73 actionable GAs per tumor. The most common actionable GAs were PIK3CA (7, 27%), MCL1 (4,15%), PTEN (3,12%), BRCA1 (3,12%), and BRCA2 (2,8%). One pt (4%) had ALK amplification. Activating ERBB2 point mutations not detectable by IHC/FISH, potentially targetable with anti-HER2 therapies were identified in 2 pts; EGFR amplifications, potentially treatable with anti-EGFR TKI were identified in 2 pts (1 pt had both of these GAs). One pt with ERBB2mutation received neratinib monotherapy and one pt with EGFR amplification received capecitabine plus cetuximab; both had partial response lasting 8+ months. Conclusions: For TNBC, comprehensive genomic profiling can identify a significant number of actionable GAs not currently tested for in routine practice. Results point to the potential of MTOR, anti-HER2, and anti-EGFR targeted therapies for a significant subset of pts.
Sequential ipilimumab (Ipi) versus best supportive care (BSC) following first-line chemotherapy (Ctx) in patients (pts) with unresectable locally advanced or metastatic gastric or gastro-esophageal junction (GEJ) cancer: A randomized, open-label, two-arm, phase II trial (CA184-162) of immunotherapy as a maintenance concept.
Authors: Markus Hermann Moehler, Yeul Hong Kim, Iain B. Tan, Agnes Balogh, Teresa Kong Sanchez, Yung-Jue Bang
Journal: Journal of Clinical Oncology (2013)

TPS4151 Background: First-line systemic CTX is standard-of-care for advanced gastric cancer. However, most pts relapse or have severe adverse events (AEs), creating a need for new therapies with better benefit/risk and toxicity profiles. Endogenous immune activity against tumor cells has been demonstrated in the human gastric cancer tumor microenvironment, supporting a role for immunotherapy. As a new maintenance concept, sequential administration of immunotherapy may prolong clinical benefit of first-line CTX before disease progression (PD). Ipi, a fully human monoclonal antibody which binds CTLA-4, augments the antitumor immune response. Ipi improved overall survival (OS) in patients with advanced melanoma with AEs managed using product-specific treatment guidelines.This global (32 sites among 10 countries), multicenter, randomized, open-label, phase II trial (ClinicalTrials.gov identifier NCT01585987) will compare the efficacy of Ipi and BSC after first-line CTX. Methods: Pts with good performance status (0 or 1) and histologically confirmed, unresectable locally advanced or metastatic gastric or GEJ cancer without PD after first-line CTX with a fluoropyrimidine (F) and platinum (P) doublet will be eligible. Pts with radiological evidence of brain metastases, autoimmune/immune-mediated disease, inadequate hematologic, renal, and hepatic function, or are HER2+ will be ineligible. Pts will be randomized to Ipi (4 doses [10 mg/kg, IV Q3W], followed by Q12W) until confirmed immune-related PD or unacceptable toxicity, or to BSC (continuing F used in lead-in CTX or no active systemic therapy). The primary objective is to compare immune-related progression-free survival (PFS): immune-related response criteria were derived from World Health Organization (WHO) criteria to better capture Ipi response patterns. Secondary objectives are to compare PFS per mWHO criteria and OS, and estimate immune-related best overall response rate. The study is planned to randomize 114 pts. Clinical trial information: NCT01585987.
Phase II study of dovitinib in first-line metastatic or nonresectable primary adrenocortical carcinoma (ACC): SOGUG study 2011-03.
Authors: Paula Jimenez, Marta Guix, Nuria Lainez Milagro, Luis Leon Mateos, Maria Jose Mendez Vidal, Miguel Angel Climent Duran, Jesus Garcia-Donas
Journal: Journal of Clinical Oncology (2012)

TPS4688 Background: Dovitinib is a novel targeted therapy, that has proven to inhibit, among other tyrosin kinases, the fibroblast growth factor receptor (FGFR). Since this pathway has been proposed to play a major role in ACC, we aim to test the clinical efficacy of dovitinib in this tumor. Methods: An open label phase II trial has been designed in patients with advanced non-resectable ACC. The objective will be to obtain at least a 15% response rate according to RECIST criteria. Taking as a basis the two-stage Gehan model, 15 patients would need to be included in the first stage to demonstrate a treatment efficacy of at least 15%. Sample size calculation was done based on the following parameters, probability of Type I error α = 0.05, power of the test (1 - β) = 0.8. Main inclusion criteria are advanced non-resectable disease and no prior therapy (other than mitotane). Dovitinib scheduled dose matches currently employed standard in the drug development (500mg daily for 5 days then 2 days off) for 6 months. If clinical benefit is obtained longer treatment will be allowed for particular patients. Since this is an extremely unfrequent disease 7 institutions, members of the SOGUG (Spanish Oncology Genitourinary Group), will participate. The active support of a big collaborative group will guarantee candidate patients to be refereed to such institutions. Starting January 26 th 2012 recruitment is scheduled to last around 12 months. A translational research, including whole exome analysis, will be performed in order to improve our scarce knowledge of ACC.
Transformation diffusion reconstruction of three-dimensional histology volumes from two-dimensional image stacks
Authors: Ramón Casero, Urszula Siedlecka, Elizabeth S. Jones, Lena Gruscheski, Matthew Gibb, Jürgen E. Schneider, Peter Kohl, Vicente Grau
Journal: Medical Image Analysis (2017)

Traditional histology is the gold standard for tissue studies, but it is intrinsically reliant on two-dimensional (2D) images. Study of volumetric tissue samples such as whole hearts produces a stack of misaligned and distorted 2D images that need to be reconstructed to recover a congruent volume with the original sample's shape. In this paper, we develop a mathematical framework called Transformation Diffusion (TD) for stack alignment refinement as a solution to the heat diffusion equation. This general framework does not require contour segmentation, is independent of the registration method used, and is trivially parallelizable. After the first stack sweep, we also replace registration operations by operations in the space of transformations, several orders of magnitude faster and less memory-consuming. Implementing TD with operations in the space of transformations produces our Transformation Diffusion Reconstruction (TDR) algorithm, applicable to general transformations that are closed under inversion and composition. In particular, we provide formulas for translation and affine transformations. We also propose an Approximated TDR (ATDR) algorithm that extends the same principles to tensor-product B-spline transformations. Using TDR and ATDR, we reconstruct a full mouse heart at pixel size 0.92µm×0.92µm, cut 10µm thick, spaced 20µm (84G). Our algorithms employ only local information from transformations between neighboring slices, but the TD framework allows theoretical analysis of the refinement as applying a global Gaussian low-pass filter to the unknown stack misalignments. We also show that reconstruction without an external reference produces large shape artifacts in a cardiac specimen while still optimizing slice-to-slice alignment. To overcome this problem, we use a pre-cutting blockface imaging process previously developed by our group that takes advantage of Brewster's angle and a polarizer to capture the outline of only the topmost layer of wax in the block containing embedded tissue for histological sectioning.
Adverse event-related costs for breast cancer treatment among Medicaid patients.
Authors: Debra E Irwin, Anthony Masaquel, Stephen Johnston, Brian Barnett
Journal: Journal of Clinical Oncology (2015)

e17798 Background: Existing treatments for breast cancer (BC) are effective; however, patients often experience adverse events (AEs). The healthcare cost related to AEs in a Medicaid population is relatively unknown. Methods: A retrospective cohort study using a multi-state Medicaid insurance claims database (2006-2013) was conducted in women with a BC diagnosis treated with biologic or chemotherapy. Data were stratified by disease status (metastatic or non-metastatic) and by line of therapy (first or prior exposure). Incidence and average monthly AE-related health care costs of AEs during a line of therapy were calculated. Multivariable models were fit to estimate adjusted total healthcare costs. Results: A sample of 3,861 BC patients met inclusion criteria; mean follow-up range: 149-229 days. The most common AE types were hematological (non-metastatic 50%; metastatic 66%), constitutional (non-metastatic 50%; metastatic 78%) and gastrointestinal (non-metastatic 39%; metastatic 59%). Hematological AEs incurred the highest average monthly AE-specific costs followed by gastrointestinal AEs and constitutional AEs. Adjusted total monthly healthcare costs increased with the number of AEs (non-metastatic: No AEs $5,078, 1-3 AEs $7,057, 4-6 AEs $9,077, 7+ AEs $11,587 [all p<0.01]; metastatic: No AEs $5,908, 1-3 AEs $13,731, 4-6 AEs $16,264, 7+ AEs $19,701 [all p<0.01]). Conclusions: Adverse events among BC patients treated with systemic therapy in a Medicaid population are associated with substantial economic burden. Therapies associated with a favorable AE profile may reduce costs and improve patient outcomes. Mean AE-specific healthcare costs (per patient per month). First Line Mean Prior Exposure Mean Non-Metastatic (n=2,203) (n=929) Hematological $1,342 $506 Gastrointestinal $560 $174 Constitutional $259 $182 Metastatic (n=270) (n=459) Hematological $1,521 $1,526 Gastrointestinal $881 $815 Constitutional $687 $858