tbuckley/cabot-search huggingface dataset:
Integration of multi-modality treatment planning for early stage breast cancer (BC) into Watson for Oncology, a Decision Support System: Seeing the forest and the trees.
Authors: Andrew David Seidman, Melissa Louise Pilewskie, Mark E. Robson, Joanne Frankel Kelvin, Marjorie Glass Zauderer, Andrew S. Epstein, Mark G. Kris, Julia Fu, Jeffrey Keesing, Aryeh Caroline, Mark Megerian, Thomas Eggebraaten, Robert DeLima, Marie Setnes, Kevin Barker, Ayca Gucalp
Journal: Journal of Clinical Oncology (2015)

e12042 Background: IBM Watson for Oncology (WFO), trained by Memorial Sloan Kettering (MSK) is designed to assist medical oncologists in making expert treatment decisions driven by key disease and patient-specific attributes. As previously reported, medical logic instilled by MSK and IBM Watson's machine learning on actual and manufactured MSK cases allow WFO to consider nuances not addressed by existing guidelines. Decision making for early stage BC extends beyond adjuvant systemic therapy, to encompass breast surgery (BS), radiation (RT), clinical genetics (CG), and fertility preservation (FP) issues. Oncologists are imperfect in applying these referrals, with potential for both over- and under-referral. Contemporary digital decision support tools do not yet integrate capabilities that ensure optimal multidisciplinary patient care. Methods: We utilized published evidence, guidelines, and MSK expertise in training WFO to recommend clinically indicated referrals to multidisciplinary specialists. We measured the frequency with which WFO prompted consultation to ensure optimal breast/axillary surgery, adjuvant RT, and CG or FP management, and the degree of its agreement with two MSK breast medical oncology specialists. Results: Across 103 de-identified historical stage I-III BC cases entered into WFO after primary surgery, WFO output had 98% agreement with MSK recommendations on RT referral; 94% on CG counseling; and 91% on FP counseling as detailed in Table 1. WFO recommended BS consultation in 8/8 manufactured cases where MSK recommended completion axillary surgery, but also in 7/12 where MSK did not. Conclusions: An expert-guided machine learning approach informed by published evidence and guidelines succeeds in generating multidisciplinary care plans for early stage BC. We continue to optimize WFO with additional training data and by focusing on natural language processing and the incorporation of patient preference. Rate (%) of WFO recommendation by subgroup. Referral Subgroup Patient Age Rate of WFO Recommendation FP Counseling All <=40 100 41-45 6 >45 0 CG Counseling HR+ and/or HER2+ <=50 98 >50 25 TNBC <=60 92 >60 67
<i>HLA-DRB1</i>*07:01 biomarker characterization of hepatotoxicity during lapatinib combination therapies in ALTTO.
Authors: Colin F. Spraggs, Laura Rae Parham, Liling Warren, Lisa Simone Williams, Linda P Briley, Dana Fraser, Zefei Jiang, Zeba Aziz, Zhongsheng Tong, Shun Devan Moodley, Ajay O. Mehta, Nicola Jackson, Julie Byrne, Michael Andersson, Masakazu Toi, Lyndsay Harris, Julie Gralow, Rocco Crescenzo, Alison A. Armour
Journal: Journal of Clinical Oncology (2015)

617 Background: ALTTO (NCT00490139) is a large adjuvant breast cancer (ABC) study evaluating lapatinib, alone and in combinations with trastuzumab and taxanes. Characterization of hepatic abnormalities during lapatinib treatment in ALTTO was conducted using the lapatinib hepatotoxicity risk biomarker HLA-DRB1*07:01. Methods: Germline DNA collection for HLA-DRB1 genotype determination was achieved for 76% (6323/8270) of ALTTO subjects. Association of HLA-DRB1*07:01 allele carriage with ALT elevation during study treatments was evaluated by case-control analysis of NCI CTC AE grade 3 ALT elevation ( > 5x ULN, ALT). Results: A higher incidence of ALT elevation (2-5%, n = 6194) was observed in the three lapatinib-containing treatment arms compared with the trastuzumab monotherapy arm (1%, n = 2076; p < 0.01). Also, ALT was higher when lapatinib and taxane were administered concurrently. HLA-DRB1*07:01 carriage frequency was enriched in lapatinib-treated ALT cases compared with controls (OR 6.5, 95% CI 4.6-9.3, p = 2x10-26, n = 4568), with overall negative and positive ALT risk predictive values for the HLA allele of 98.6% and 8.7%, respectively. The HLA association was weaker when concurrent taxane was administered to lapatinib-treated patients, suggesting an ALT risk independent of HLA-DRB1*07:01 carriage. Homozygous and heterozygous HLA-DRB1*07:01 genotype carriers exhibited different ALT elevation risk during lapatinib treatment of 12.1% (n = 67) and 8.5% (n = 965), both higher than the risk for non-carriers (1.4%, n = 3586). Furthermore, homozygous carriers exhibited greater severity with significantly higher maximum ALT elevations. ALT elevation risk was significantly correlated with geographic differences in HLA-DRB1*07:01 carriage frequency. Conclusions: Whilst efficacy of lapatinib plus trastuzumab was not sufficiently improved over trastuzumab alone to support a treatment indication for ABC, the present data provide robust lapatinib ALT risk estimates for HLA-DRB1*07:01 allele carriage that may discriminate causality and support safety management during the use of lapatinib combinations for treatment of metastatic breast cancer globally. Funding: GlaxoSmithKline. Clinical trial information: NCT00490139.
Somatic mutation spectrum of non-small cell lung cancers (NSCLCs) from African Americans (AAs).
Authors: Philip Edward Lammers, Velmalia Matthews-Smith, Ya-Lin Yun, Yumei Pan, Snjezana Zaja-Milatovic, Amy Sullivan, Rosana Eisenberg, Adriana Gonzalez, Yu Shyr, Steven N. Wolff, Ann G. Schwartz, William Pao, David Paul Carbone
Journal: Journal of Clinical Oncology (2012)

6038 Background: In the AA population, previous studies have presented conflicting data on the frequency of EGFR mutations (Reinersman JTO 2011;Leidner JCO 2009), while frequencies of other gene mutations and translocations, including anaplastic lymphoma kinase (ALK), have not been described. Methods: 161 archival FFPE tumor specimens from self reported AA patients with any stage NSCLC from 1997-2010 were collected from 3 sites in Tennessee (132 samples) and one site in Michigan (29 samples). Samples were evaluated for known recurrent driver mutations in EGFR, KRAS, BRAF, NRAS, AKT1, PI3KCA, PTEN, HER-2, MEK1 by standard SNaPshot/sizing assays, and translocations in ALK by FISH. Clinical data was collected on 119 patients. Chi-square was used to compare the frequency of mutations in subgroups and Kaplan-Meier and log rank were used to calculate and compare PFS between groups. Results: 5.0% of tumors had EGFR mutations, 14.9% had KRAS mutations, 0.6% had a BRAF, AKT1, PI3KCA, or HER2 mutation, and 0% had NRAS, PTEN, or MEK1 mutations. Of 35 ‘pan-negative’ non-squamous specimens, 0 had ALK translocations. PFS was the same in those with and without KRAS mutation (p=0.74) and showed a trend towards improvement in those with EGFR mutation (p=0.08). The frequency of EGFR mutations was higher in samples from Detroit versus those from Tennessee (17% vs 2.3%, p&lt;0.01), as was the frequency of adenocarcinoma (62% vs 44%, p&lt;0.05). The frequency of EGFR mutations in never smokers was higher in the samples from Detroit versus Tennessee (83% vs 7.1%, p&lt;0.01). Conclusions: In the largest tumor mutational profiling study of NSCLC from AAs to date, EGFR mutations occurred less frequently than would be expected from a North American population. We noted a regional difference, with fewer EGFR mutations in Tennessee than in Michigan, a finding that may have been the result of more adenocarcinoma samples from Michigan. The rates of other mutations and translocations including ALK were low. While lung cancer tumors should continue to undergo routine molecular testing to prioritize therapy, future comprehensive genotyping efforts should focus on identifying novel driver mutations in this population. Funding: 5RC1CA162260 R01CA060691 R01CA87895.
Choosing the right level of analysis: Stereotypes shape social reality via collective action
Authors: Ben M. Tappin, Ryan T. McKay, Dominic Abrams
Journal: Behavioral and Brain Sciences (2017)

Abstract In his 2012 book Jussim argues that the self-fulfilling prophecy and expectancy effects of descriptive stereotypes are not potent shapers of social reality. However, his conclusion that descriptive stereotypes per se do not shape social reality is premature and overly reductionist. We review evidence that suggests descriptive stereotypes do have a substantial influence on social reality, by virtue of their influence on collective action.
Single-center experience with pegfilgrastim (P) and lenograstim (L) in nonmetastatic breast cancer (NMBC) patients (pts) during adjuvant FEC100 or sequential FEC100 plus DOCETAXEL100 (D100).
Authors: ANSELMO PAPA, Luigi Rossi, Davide Caruso, Federica Tomao, Giulia Rinaldi, Eleonora Zaccarelli, Erika Giordani, Monica Verrico, Martina Strudel, Gian Paolo Spinelli, Carlo Capalbo, Giuseppe Lo Russo, Salvatore Evangelista, Fabio Ricci, Francesca Perrone-Congedi, Loredana Bianchi, Valeria Stati, Alessandra Anna Prete, Silverio Tomao
Journal: Journal of Clinical Oncology (2014)

e12005 Background: Neutropenia (N) is a common chemotherapy (CT) related adverse event and febrile N (FN) often requires hospitalization, being associated with morbidity and mortality. Primary prophylaxis with G-CSF is a common strategy to avoid the onset of FN. Methods: Retrospectively, we evaluated efficacy and safety of daily injections of L (263 μg) from day 5 to 9 (5 total injections) compared with a single injection of P (6 mg) on day 2 in 55 NMBC pts (median age 55 years) during 6 cycles of FEC100 (group A) or 3 cycles of FEC100 followed by further 3 cycles of D100 (group B). Incidence of N, FN and bone pain (BP) (NRS >7) were evaluated. In group A: 35 pts (median age 54 years) received 6 cycles of FEC100. At every cycle, 17 pts received L, while 18 pts one dose of P. In group B: 20 pts (median age 55.5 years) underwent 3 cycles of FEC100 plus 3 of D100. At every cycle, 12 and 8 pts received L and P, respectively. Results: In overall population incidence of N-G3/G4 was 54.5%. In group A: G3/G4-N was 50% and 58% in P and L arm, respectively. One case of FN occurred in P arm. During first cycle, incidence of G3/G4-N was 33% and 41% in P and L arms, respectively; no G3/G4-N occurred during the last cycle. Incidence of BP was 11% in both arms. CT reduction occurred in 50% and 29% in P and L arm, respectively. In group B: G3/G4-N was 25% in P arm and 83% in L arm. No case of FN occurred in both arms. During first cycle, incidence of G3/G4-N was 0% in P and 50% in L arm; while during last cycle no G3/G4-N occurred in the P arm and 25% in L arm. 37% and 50% of pts experienced BP in P and L arm, respectively. CT dose reductions were necessary in 50% of P arm and 58% of L arm. Conclusions: P showed an higher efficacy than L for preventing G3/G4-N in both groups, also in the first cycle, even if the only FN occurred in a patient who was assuming P. There was a higher frequency of BP for L arm in FEC100-D100. In pts assuming FEC100 incidence of CT dose reduction was higher in P arm, while those assuming FEC100-D100 the incidence was higher in L arm.
Influence of food on the pharmacokinetics (PK) of panobinostat (LBH589), an orally active histone deacetylase inhibitor, in patients with advanced cancer
Authors: L. Lewis, R. Frank, U. B. Dandamudi, J. Gallagher, L. Zhao, M. Woo, S. Hirawat, G. I. Shapiro
Journal: Journal of Clinical Oncology (2009)

2550 Background: The effect of food on the bioavailability and PK of panobinostat (PAN) are of considerable importance in allowing appropriate dosing of chronic oral cancer therapy. Methods: Patients (pts) with advanced cancer received 20 mg PAN twice a week of a 21-day cycle and were randomized to receive 1 of 6 treatment sequences where PAN PK was evaluated weekly under fasting, high fat and normal breakfast. Serial blood samples were collected for PAN PK evaluations on Days 1, 8, and 15. Plasma PAN concentrations were measured by LC-MS-MS. PK parameters were estimated by using non-compartmental analysis. Results: A total of 34 patients were evaluated. PAN was generally well tolerated with no significant lab, ECG, or other safety concerns. No residual PAN concentrations were detected in pre-dose samples on Days 8 and 15. Meal conditions and PAN PK parameters expressed as either mean (CV%) or median [range] or ratio are described in the Table . The overall exposure and inter-patient variability (CV 59%) remained unchanged with or without food, whereas C max was transiently reduced (&lt;45%) by food. Although tumor response was not the main objective, a pt with recurrent RCC, following sunitinib and sorafenib treatment, has achieved a PR after ∼6 cycles of PAN and is continued on study. Conclusions: Since the overall extent of absorption and variability was not changed due to food, PAN administration with or without food is unlikely to significantly impact systemic PAN exposure in cancer patients. PAN can be administered without regards to food in future studies. [Table: see text] [Table: see text]
Outcomes and survival in nonbilharzial pure squamous cell bladder cancer in patients undergoing curative radical cystectomy.
Authors: Janet Baack Kukreja, Nourhan Ismaeel, Neema Navai, Ashish M. Kamat, Colin P.N. Dinney, Jay Bakul Shah
Journal: Journal of Clinical Oncology (2017)

363 Background: Pure squamous cell cancer of the bladder is uncommon in the United States. Because squamous cell bladder cancer is rare, there are no large studies with details on optimal preoperative neoadjuvant therapies and long-term outcomes. To improve the overall knowledge of the disease this study sought to provide a contemporary update in a single center cohort. Methods: A retrospective cohort study was performed. 57 patients had a radical cystectomy (RC) for pure nonbilharzialsquamous cell bladder cancer between 1995 and 2015. Demographics, risk factors for squamous cell bladder cancer, pathology, and outcomes were reviewed and compared with descriptive statistics. Advanced disease was defined as ≥ T3/T4 disease and any positive lymph node metastasis. Logistic regression was used to identify predictors of overall survival (OS), disease specific survival (DSS) and recurrence free survival (RFS). Kaplan-Meier curves were used for survival prediction. Results: With a median follow up of 24 months (IQR 9.7-131.8 months), 12 (21.4%) had a recurrence. The median time to recurrence was 15.5 months (IQR 5.0-20.0 months). Recurrence was most common in the pelvis, n = 5(62.5%). 20 had neoadjuvant chemotherapy (NAC), 16 of which it was combined with external beam radiation (XRT). 50.8% of patients had advanced pathology. 5-year OS was 59.7%. To predict RFS all of the following were adjusted for: age, stage, advanced pathology, nonbilharzialsquamous cell risk factors, lymphovascular invasion, and number of lymph nodes removed at RC. Predictors of RFS were combined NAC and XRT, pathologic T-stage, advanced disease (p = &lt; 0.01, p = 0.02 and p = 0.02, respectively). Predictors of DSS were pathologic T-stage and node positive disease (p = 0.04 and &lt; 0.01, respectively). OS was best predicted by clinical stage, p &lt; 0.001. Conclusions: The combination of NAC and preoperative XRT may provide a RFS advantage in nonbilharzialsquamous cell bladder cancer. Those with clinically advanced disease continue to have a poor prognosis. However, OS does seem to have an improved prognosis compared to previous reports.
Cryoablation of cT1 renal masses in the “healthy” patient: Early outcomes from Mayo Clinic.
Authors: Harras B. Zaid, Thomas D. Atwell, Grant Schmit, Stephen A. Boorjian, William P. Parker, John C. Cheville, Bradley C. Leibovich, Robert Houston Thompson
Journal: Journal of Clinical Oncology (2017)

433 Background: Current guidelines suggest that percutaneous thermal ablation (PTA) can be utilized in those with significant comorbidity who are unable to tolerate surgery (radical or partial nephrectomy). However, the use of PTA in healthy patients, who are otherwise candidates for surgery, has been limited. Here, we reviewed our institutional experience in healthy patients electing to undergo PTA, specifically cryoablation. Methods: We identified patients ≤65 years undergoing percutaneous cryoablation for solitary, non-metastatic renal masses &lt;7cm (cT1). We further limited our cohort to patients with an ASA score of 1 or 2, and in whom pre-operative eGFR was &gt;60. Clincopathologic characteristics and recurrence patterns (local recurrence within the kidney versus metastatic disease) were evaluated. Results: Between March 2003 and December 2015, 705 patients underwent cryoablation, of whom 43 (6.1%) were deemed to be “healthy”. Median age of this cohort was 57 years (IQR 52−62), with pre-ablation eGFR of 75.6 (IQR 69.0-86.3). Seven patients (16.3%) had a prior partial nephrectomy, and 5 (11.6%) had a solitary kidney. The majority (40, 93.0%) of ablated masses were cT1a, with 3 (7.0%) being cT1b. Median tumor size was 2.0 cm. 27 masses (63.7%) were biopsy-proven renal cell carcinoma (RCC) and 6 (13.6%) were benign; histology was unknown in 10 (22.7%). Follow-up imaging was available for 37 patients. Median radiological follow-up was 22 months (IQR 9-42), during which time 2 patients developed metastatic disease and 1 developed local recurrence; all events were in patients with biopsy-proven RCC. No patients died from RCC during this time period. Conclusions: In this single institution cohort of “healthier” patients with cT1 solitary renal masses, cryoablation offered reasonable short term oncologic control. While longer follow-up data are needed to evaluate for durability, cryoablation in healthy patients, particularly those with challenging surgical anatomy, warrants further study.
Is cigarette smoke associated with increased catabolism of gemcitabine in patients with advanced solid tumors?
Authors: Meaghan Working O'Malley, Stephanie Daignault, Patrick N. Healy, Lindsay A. Schmidt, Nithya Ramnath
Journal: Journal of Clinical Oncology (2012)

2602 Background: Cigarette smoking can accelerate chemotherapy metabolism and result in lower plasma concentrations of the chemotherapeutic agent. Reduced drug levels may lead to undertreatment in smokers and, conversely, increased treatment-related neutropenia in nonsmokers. Methods: An IRB-approved retrospective chart review was performed on 151 patients with solid tumor malignancies who received gemcitabine alone or in combination with oral chemotherapy agents from July 1, 2009 to June 30, 2011 at the University of Michigan. Using logistic regression, we compared toxicity, including neutropenia, and smoking history measured in pack-years in smokers vs. nonsmokers to ascertain whether cigarette smoking is an independent factor predictive of toxicity to gemcitabine. Results: Tumor types included breast (9.3%), lung (4.6%), pancreatobiliary (70.9%), or other/unknown primary (15.2%). Most patients had advanced disease (stage III-IV; 78.1%); specifically, of the pancreatobiliary cohort (PB; n=107), 77.6% patients had stage III-IV disease. Within the PB cohort, most patients were “ever” smokers as compared to “never” smokers (60.7% vs. 39.3%). Logistic regression of this cohort showed that current smokers had decreased CTC-AE grade 3-4 neutropenia vs. never smokers (OR 0.667; 95% CI [0.156-2.859]). This effect was more pronounced with higher pack-year history: smokers with &gt;50 pack-years had even less neutropenia as compared to never smokers (OR 0.333; 95% CI [0.065-1.699]). Further statistical analysis of subgroups was not performed due to small sample size. Conclusions: Smokers with pancreatobiliary malignancies receiving gemcitabine had less treatment-related neutropenia as compared to never smokers, a finding that was more pronounced as pack-years increased. Decreased toxicity, including neutropenia, may be due to increased metabolism and drug clearance as a result of smoking. This may lead to potential undertreatment of smokers and, conversely, increased treatment-related toxicity in never smokers. A prospective clinical trial is needed to further elucidate this correlation, and is currently being designed.
Two randomized, placebo-controlled phase 3 studies of ruxolitinib (Rux) + capecitabine (C) in patients (pts) with advanced/metastatic pancreatic cancer (mPC) after failure/intolerance of first-line chemotherapy: JANUS 1 (J1) and JANUS 2 (J2).
Authors: Herbert Hurwitz, Eric Van Cutsem, Johanna C. Bendell, Manuel Hidalgo, Chung-Pin Li, Marcelo Garrido, Teresa Mercade Macarulla, Vaibhav Sahai, Ashwin Reddy Sama, Edward Greeno, Kenneth H. Yu, Chris Verslype, Fitzroy W. Dawkins, Christopher Walker, Jason Clark, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2017)

343 Background: The JAK-STAT pathway plays a role in the pathogenesis of PC. In a phase 2 study, the JAK1/2 inhibitor Rux + C improved OS vs C alone in mPC pts with evidence of systemic inflammation. Methods: In two phase 3 studies, advanced/mPC pts with only 1 prior chemotherapy regimen and C-reactive protein &gt; 10mg/L were randomized to 21-day cycles of Rux 15 mg BID + C 2000 mg/m 2 /d (day 1-14) vs placebo (Pb) BID + C 2000 mg/m 2 /d (day 1-14). The primary endpoint was OS. The studies were terminated early based on efficacy findings of a planned interim analysis for J1, with J2 enrollment incomplete. Results: 321 pts were randomized in J1 and 86 in J2. The median age was similar between groups (Rux + C vs Pb + C): J1, 68 vs 67 yrs; J2, 68 vs 69 yrs. The most common prior chemotherapy regimens were gemcitabine (gem) + nab-paclitaxel (J1: 50% vs 51%, J2: 42% vs 37%), gem alone (J1: 24% vs 21%, J2: 28% vs 33%). Median study treatment durations were 42 d for both Rux and Pb in J1; 40 d for Rux and 43 d for Pb in J2. Discontinuations were mainly due to disease progression (J1: 62% vs 65%, J2: 51% vs 58%), AEs (J1: 4% vs 10%, J2: 12% vs 12%) or death (J1: 8% vs 5%, J2: 7% vs 5%). Rux + C did not show a benefit over C alone in OS or PFS (see Table). Overall response rates were &lt; 5% in each treatment group (NS).The most common grade 3/4 non-hematologic AEs were abdominal pain (J1: 7% vs 14%; J2: 14% vs 5%), palmar-plantar erythrodysesthesia syndrome (J1: 7% vs 4%; J2: 0% vs 12%), pulmonary embolism (J1: 4% vs 3%; J2: 10% vs 5%), dyspnea (J1: 2% vs 2%; J2: 10% vs 2%) and vomiting (J1: 5% vs 5%; J2: 2% vs 12%). The most common new/worsening hematologic labs abnormalities of grade 3/4 included: anemia (J1: 20% vs 6%; J2: 11% vs 8%) and lymphopenia (J1: 17% vs 9%; J2: 16% vs 8%). Conclusions: When added to C, Rux was well tolerated but did not improve clinical outcomes in the second-line treatment of mPC pts. Clinical trial information: NCT02117479 and NCT02119663. [Table: see text]