tbuckley/cabot-search huggingface dataset:
Predictors of surgery types after neoadjuvant therapy for advanced stage breast cancer.
Authors: Jamila Alazhri, Tulay Koru-Sengul, Feng Miao, Stacey L. Tannenbaum, Margaret M Byrne, Hattan Alghamdi, Dido Franceschi, Eli Avisar
Journal: Journal of Clinical Oncology (2014)

1034 Background: Despite the established guidelines for breast cancer treatment, there is still variability in surgical treatment after neoadjuvant therapy among women with large breast tumors, leading to variability in the outcome. Our objective was to identify possible predictors of the type of surgical treatment; mastectomy versus breast conserving surgery (BCS) in women with T3/T4 breast cancer who received neoadjuvant therapy. Methods: Population-based Florida Cancer Registry and U.S. Census from 1996 to 2009 were linked to select women diagnosed with T3/T4 breast cancer who then received neoadjuvant therapy followed by BCS or mastectomy. A multivariable logistic regression model was used to identify significant predictors of type of surgery by including sociodemographic characteristics (race, ethnicity, socioeconomic status, age, marital status, urban/rural residency), tumor characteristics (ER/PR status, histology, grade, SEER stage, regional nodes positivity), treatment facilities (hospital volume, teaching/non-teaching), comorbidities and type of neoadjuvant therapy. Adjusted odds ratios (OR) and 95% confidence intervals (95%CI) were calculated. Type-I error rate was set to 5%. Statistical analyses were performed with SAS v9.3. Results: Out of 1,056 patients treated with neoadjuvant therapy for T3/T4 breast cancer, 107 (10%) had BCS and 949 (90%) had mastectomy. After adjusting for the aforementioned characteristics, Hispanic patients were more likely to have mastectomy (OR=3.50; 95%CI:1.38-8.84; p=0.008) than BCS. Compared to localized SEER stage, regional stage with direct extension (OR=3.24; 95%CI:1.60-6.54; p=0.001), regional direct extension and nodes (OR=4.35; 95%CI:1.72-11.03; p=0.002) and distant stage (OR=4.44; 95%CI:1.81-10.88; p=0.001) were significantly more likely to have mastectomy than BCS. Patients who received hormonal neoadjuvant therapy only (OR=0.29; 95%CI:0.12-0.68; p=0.004) were less likely to undergo mastectomy compared to patients receiving both chemo/hormonal therapy. Conclusions: Our study suggests that Hispanic ethnicity, advanced SEER stage, and type of neoadjuvant therapy are significant predictors of mastectomy after neoadjuvant therapy.
A multicenter observational study comparing physician-assessed febrile neutropenia (FN) risk and prediction-model severe neutropenia (SN) or FN risk in patients (pts) with nonmyeloid malignancies.
Authors: Gary H. Lyman, David C. Dale, Jason C. Legg, Phuong Khanh H. Morrow, Sadie Whittaker, Jeffrey Crawford
Journal: Journal of Clinical Oncology (2014)

9607 Background: A prediction model was previously developed that estimates the risk of SN or FN during the first cycle of chemotherapy (ctx) based on pt characteristics, disease characteristics, and the myelotoxicity of the ctx regimen (Lyman, 2011). Methods: This prospective, multicenter, observational study (124 community-based oncologists; 944 pts) was directed at investigating the relationship between physician-assessed FN risk and prediction-model SN or FN risk. The subjects of this study were the physicians, not the pts. Pts were included if they were ≥ 18 years old, newly diagnosed, and candidates for initiating an NCCN intermediate (10%–20%) FN risk ctx regimen. Physicians entered clinical data about the pts into a database and made a clinical prediction of FN risk. Physician-assessed FN risk was then compared to prediction-model SN or FN risk. Physicians were blinded to the data elements collected by the model and the risk predicted by the model. No outcome data were collected. Results: Physicians were hematologists/oncologists (79.8%), oncologists (18.5%), and gynecologists/oncologists (1.6%). Median (Q1, Q3) years of clinical experience was 12.0 (6.5, 20.0). Pts were 65.5% women, median (Q1, Q3) age was 62.0 (53.0, 70.0) years, and the most common tumor types were breast (38.6%), colorectal (27.4%), and NSCLC (12.2%). Correlation estimates (approximate 95% CI) for physician-assessed FN risk and prediction-model SN or FN risk were 0.194 (0.000, 0.373) for NHL, 0.166 (0.027, 0.298) for breast, 0.130 (–0.068, 0.318) for colorectal, 0.121 (–0.134, 0.362) for NSCLC, 0.008 (–0.309, 0.323) for SCLC, and –0.050 (–0.483, 0.403) for ovarian. Correlation between risk estimates was highest for physicians with 8–17 years of clinical experience, oncologists, and those working in clinical settings with > 4 physicians. Conclusions: The lack of correlation between physician-assessed FN risk and prediction-model SN or FN risk suggests that community oncologists would benefit from use of a standardized and systematic approach to assess FN risk among pts receiving intermediate-risk ctx regimens.
Usefulness of <i>Streptococcus pneumoniae</i> urinary antigen test recommended in the management of community-acquired pneumonia in cancer patients.
Authors: Paul Louis Woerther, Sami Antoun, Arif Alibay, Sylvie Khan, Bertrand Gachot, Elisabeth Chachaty, Mario Di Palma, Mansouriah Merad
Journal: Journal of Clinical Oncology (2014)

e20679 Background Febrile dyspnea is one of the most frequent causes of emergency department (ED) visits by cancer patients (pts). International guidelines advocate for the use of pneumococcal urinary antigen test (PUAT) in pts with moderate to severe community-acquired pneumonia. In our ED this test is frequently prescribed. However, its usefulness in cancer pts has so far not been specifically evaluated. We thus performed a retrospective study to describe cases where the PUAT positivity was helpful for the diagnosis or for the treatment of pneumococcal pneumonia Methods: From January 2009 to October 2013, we conducted an observational retrospective study in the ED of a tertiary care cancer hospital. All pts with febrile dyspnea associated with a positive PUAT were included. Clinical, biological, and radiographic data were analysed. Results: PUAT was positive in 39 of the 1061 performed. Underlying diseases were: hematological malignancies for 6/39 (15%) pts and solid tumors for 33 (85%). The more frequent site of cancers were lung (14/33,) and head and neck (7/33,). Most of the patients had metastatic disease (23/33,). Apyrexia (<38°C) was observed in 9/39 (23%) of the pts, 4/39 (10%) had neutropenia (< 500 PMN/mm3). Median C reactive Protein level was 188 mg/L and 15/39 of them presented a PaO2<90 mmHg. Chest X-ray showed bilateral foci in 11/39 of the cases. S. pneumoniaewas cultured form respiratory sputum and blood cultures in respectively 7/14 (50%) and 4/30 (13%) of the pts,. Extended-spectrum cephalosporin was used as empirical treatment in 22/39 (56%). The final diagnosis was pneumococcal pneumonia in 27/39 (69%) of the pts. However, broad-spectrum beta-lactam treatment was changed for amoxicillin or amoxicillin-clavulanate in only 8/39 pts. Overall cost of PUAT was $20,000. Conclusions: In our study, PUAT was positive in only 3.7% of the pts with febrile dyspneaand and had only a moderate impact on antibiotic treatment adjustment. This was mainly due to the fear of severe forms in immuno compromised cancer pts. Finally, PUAT should be reserved to ambulatory patients with mild CAP to allow etiological diagnosis and oral amoxicillin treatment
RNA-sequencing of residual triple-negative breast cancers after neoadjuvant chemotherapy compared to matched pretreatment biopsies from the Hoosier Oncology Group trial BRE09-146.
Authors: Milan Radovich, Bradley Allen Hancock, Jeffrey Peter Solzak, Rutuja Atale, Sunil S. Badve, Kathy D. Miller, Bryan Paul Schneider
Journal: Journal of Clinical Oncology (2014)

1002 Background: Residual disease after neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients entails a high risk of disease recurrence. We investigated the transcriptomes of residual disease versus matched pre-treatment biopsies from a post-neoadjuvant TNBC trial to understand mechanisms of treatment resistance and to identify potential therapeutic interventions. Methods: RNA-sequencing of 44 TNBC tumors with high tumor cellularity (22 matched pre- and post-neoadjuvant specimens) was performed using the Ion Proton Next Generation Sequencer. RNA-seq data was aligned to the genome followed by expression and network analysis. Results: Statistical analysis resulted in 1,022 genes differentially expressed between matched pre- and post-neoadjuvant chemotherapy samples (p<0.01). Pathway analysis identified significant down-regulation of immune genes (P<1x10-5), which correlated with histologic observation of the depletion of lymphocytic cells in the post-neoadjuvant specimens (p=0.018). To identify novel therapeutic modalities, we employed upstream regulator analysis which predicts transcriptional regulators that are activated based on differentially expressed genes. Our top activated regulator in post-neoadjuvant specimens is MAPK1 (p=1.13x10-4), a key component of the MEK/ERK pathway. To further identify novel markers of residual disease, we analyzed for precursor microRNAs. Differential expression identified significant up-regulation of our top hit, miR-663B (P=2x10-4, Fold-Change=3.4) in residual disease tumors. Conclusions: RNA-seq and histology identified significant depletion of immune cells in residual disease, which has been previously associated with poor prognosis in breast cancer. We further identified a highly activated MAPK1 network, suggesting the potential use of MEK/ERK inhibitors in clinical trials for this population. Lastly, we identified a novel clinical biomarker, miR-663B, which is known to mediate in vitro TNBC resistance to doxorubicin, cyclophosphamide, and docetaxel.
Mouse models to study cancer stem cells in osteosarcoma.
Authors: Nino Carlo Rainusso, Lyazat Kurenbekova, Lawrence Donehower, Jeffrey Rosen, Jason Todd Yustein
Journal: Journal of Clinical Oncology (2014)

10543 Background: Osteosarcoma (OS) is the most common malignant bone tumor in children and young adults. Many patients suffer disease recurrence and eventually die from metastatic disease that has spread to the lungs. Clearly, more research is needed to understand the biology and molecular mechanisms driving OS metastasis and chemoresistance. The identification of cancer stem cells (CSCs) in solid tumor malignancies, mainly carcinomas and brain tumors, has expanded our knowledge about tumor heterogeneity and its role in tumorigenesis, metastasis and therapy resistance. However, similar research accomplishments have not been established in sarcomas. Methods: We performed our experiments aimed to identify OS stem cells using two distinct mouse models: a genetically engineered mouse model that carries an osteoblast-specific p53 mutation and a syngenic (DLM8 tumor cells orthotopically injected in C3H mice) mouse model. Results: We observed that murine tumor cells obtained from freshly isolated tumors developed sphere-like structures (sarcospheres). Sarcophere forming capacity was significantly increased in tumor cells obtained from metastatic lesions. We found that both OS models contain ALDH Hi (stem-like) cells. The high expression of ALDH ranged from 0.7 to 17%. Further analysis showed that distal metastases contained up to 10 times more ALDH Hi cells than the primary bone tumors. Moreover, we performed microarray analysis of primary bone tumors, pulmonary nodules and CSCs in both primary and metastatic sites, and found that 159 genes were differently expressed between bone and metastatic lung OS tumors. Our preliminary data showed that genes involved in the biologic processes of bone development, mesenchymal differentiation and skeletal morphogenesis were enriched in ALDH Hi cells in primary bone tumors, and genes involved in immune response, inflammatory response and cytokines/chemotaxis were up-regulated in ALDH Hi cells in metastatic tumors. Conclusions: We have identified putative OS stem cells in two immunocompetent mouse models of metastatic OS. Our preliminary data have shown that CSC content seems to be increased in metastases.
Outcomes of biliary stents in advanced pancreatic cancer in the era of improved systemic therapy.
Authors: Wungki Park, Pavan Kumar Mankal, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2014)

e15233 Background: In advanced pancreatic cancer (PC) patients (pts), different types of biliary stents are used to address biliary obstruction. Since 2010, a new standard of care for good performance status pts has emerged, FOLFIRNINOX (FOL). In this more active systemic therapy era, our hypothesis is that biliary stent patency may be improved with longer re-stent interval, fewer stent-related complications, and lower re-admission rates. Methods: Retrospectively, we identified patients who were diagnosed with advanced PC from 1/1/2006 - 6/30/2007, gemcitabine (G) era, and compared to 1/1/2011 - 6/30/2012, FOL era. Pts with a prior Whipple surgery and neoadjuvant therapy were excluded. Chart review was performed and information on age, gender, diagnosis, stage, treatment, biliary stents, clinical course, and complications was procured. Descriptive statistics and t-test comparisons were performed. Results: N= 127 pts identified, N= 70 in G (median 68.5 years) and N= 57 in FOL (median 63.5 years), were included in our analysis. Overall, the average interval between initial and the second stent was significantly shorter in plastic than metal stent group (3.8 vs. 6.6 months p=0.043). Interestingly, this trend persisted in FOL (2.3 vs. 7.1, p= 0.002), but not in G. There were no statistical differences for the average number of stents over disease course between G and FOL (1.81 vs. 1.7, p=0.49), and for the re-stent rate, 33% in G and 30% in FOL. The complications comparing G and FOL included stenosis/obstruction, N= 20 vs. 11, migration N= 4 vs. 1, cholangitis N= 21 vs. 21, and pancreatitis N= 1 vs. 2. There was a trend to an increased number stent-related hospitalizations, 0.49 vs. 0.74 ( p=0.21), and an increased length of hospitalization 2.5 vs. 4.4 days(p=0.069) for G vs FOL. Conclusions: In FOL era, the average of re-stent interval for metal was significantly longer than plastic. However, comparing G vs. FOL, the rates of serious complications (i.e. cholangitis, pancreatitis) were slightly higher with longer hospital stay in FOL, albeit with a slightly lower re-stent rate, possibly related to improved therapy efficacy.
Thinking About Schizophrenia in an Era of Genomic Medicine
Authors: Daniel R. Weinberger
Journal: American Journal of Psychiatry (2019)

Genetic discoveries about human brain development and neuropsychiatric syndromes have changed the landscape of psychiatric research. The genotyping of hundreds of thousands of individuals has identified many hundreds of genomic regions that are associated with psychiatric diagnoses, and progress is being made in uncovering the specific genes that underlie these statistical associations, although most are still undetermined. While there are great expectations that such genetic discoveries will lead to novel treatments based on fundamental mechanisms of illness, there are important caveats. Individual risk-associated common variants explain only a tiny fraction of individual liability. The degree to which common risk variants represent "core" pathogenic insights is controversial. Individuals with rare and more penetrant risk variants are often intellectually disabled, which raises epistemological questions about classification. In clinical research, the application of polygenic risk scores—the cumulative sum of associated alleles in an individual genome—to prediction models of environmental influences and outcome is gaining enthusiasm because these scores explain more liability, but predictions are small and not yet actionable for individuals. Psychiatry is intertwined with genomic medicine, and our understanding of what we call schizophrenia and the possibilities of improving the lives of affected individuals have never seemed more promising. Yet the research challenges are daunting; psychiatric syndromes ultimately reflect how the brain mishandles environmental information, which at the systems level is far "downstream" of the effect of genes in cells.
Abstract P119: High Stress Reasons for Immigration Affect Diabetes Risk, Body Size and Behavior: The Africans in America Study
Authors: Sara M Briker, J Damascene Kabakambira, Rafeal L Baker, Christopher W DuBose, Lilian S Mabundo, Francine Thomas, Stephanie T Chung, Anne E Sumner
Journal: Circulation (2018)

Introduction: Leaving Africa to live in the United States is stressful. Due to oversecretion of glucocortoids and catecholamines, stress has biologic consequences. No data exists on whether Africans who come to America for reasons associated with high stress have a higher rate of conditions such as obesity, diabetes and hypertension than Africans who come for low stress reasons. Goals: Working with the Africans in America cohort and using allostatic load score (ALS) to measure biologic stress, our objectives were to (a) rank by ALS the 5 most common reasons for immigration (work, study, asylum/refugee, family unification and lottery); (b) divide the cohort in to 2 groups: high stress (combining the individuals with the 3 reasons with the highest ALS) and low stress (combining the individuals with the lowest ALS); (c) compare body size, visceral adipose tissue (VAT), glucose, BP, sleep duration and smoking in Africans with high and low stress. Methods: OGTT and abdominal CT scans were performed in 114 African immigrants (68% male, age 41±10, range22-62y) born in subSaharan Africa but living in Washington, DC. Results: Ranked from highest to lowest, ALS for each reason for immigration was: work 3.18±1.71; asylum/refugee 2.68±1.46; study 2.66±1.88; family 1.77±1.27; lottery 1.60±1.27. Hence, high stress reasons for immigration were: work, asylum/refugee and study. Low stress reasons were: family and lottery. ALS in high vs. low stress reasons for immigration were: 2.81±1.74 vs. 1.72±1.25, P&lt;0.01. BP did not vary by group. However, Africans with high stress had a higher BMI, more VAT and hyperglycemia than Africans with low stress (Table). Africans with high stress also had a greater tendency to sleep &lt;7h per night and smoke (Table). Conclusions: High stress reasons for immigration include work, asylum/refugee and study. As obesity, hyperglycemia, and behaviors such as decreased sleep duration and smoking are associated with high stress reasons for immigration, medical histories when possible should include reason for immigration.
Higher Number of Cycles of Cytarabine Consolidation Improves Outcomes in Elderly AML Patients
Authors: Asha Ricciuti, Mounzer Agha, Anastasios Raptis, Jing-Zhou Hou, Rafic Farah, Robert L. Redner, Alison R. Sehgal, Kathleen A. Dorritie, James M. Rossetti, Yongli Shuai, Daniel Normolle, Rahim Remtulla, Shawn Tahata, Michael Boyiadzis, Annie Im
Journal: Blood (2018)
Absolute bioavailability, mass balance, elimination route, and metabolite profile of the selective oral MEK1/2 inhibitor pimasertib in cancer patients.
Authors: Giorgio Massimini, Istvan Udvaros, Elmar Wimmer, Oliver von Richter, Andreas Johne
Journal: Journal of Clinical Oncology (2014)

e13552 Background: The MAPK signaling pathway is aberrantly upregulated in cancer. Pimasertib is a selective, uncompetitive MEK1/2 inhibitor with potent activity in human melanoma cells and xenografts harboring MAPK pathway mutations. Pimasertib is currently being developed in NRAS mutant melanoma and in combination with the PI3K inhibitor SAR 245409 and the HDM-2 inhibitor SAR 405838. This trial characterized the basic pharmacokinetics (PK) of pimasertib in cancer patients (pts). Methods: Six male pts with solid tumors refractory to standard therapy or for whom no effective standard therapy was available were enrolled into this trial. Exclusion criteria included ECOG PS >1. Primary trial objectives were determination of the absolute bioavailability, PK, mass balance, elimination route(s), and metabolite profile of pimasertib. In part A of the trial, pts received a 60 mg oral dose of unlabeled pimasertib followed by an intravenous (IV) tracer dose of [14C]pimasertib 2 µg (equaling 9 kBq) as a bolus injection, one hour after the oral dose, on Day 1. On Day 8, all pts received 60 mg unlabeled pimasertib capsules spiked with 2.6 MBq of [14C]pimasertib. Pts received 60 mg oral unlabeled pimasertib twice daily from Day 3 to Day 21 and subsequent 21 day cycles in part B. Results: Following IV administration, [14C]pimasertib exhibited a total body clearance (CL) of 61.7 L/h (CV: 47.6%) and a volume of distribution (Vz) of 310 L (CV: 40.5%). Pimasertib was completely absorbed at a 60 mg dose with an absolute bioavailability (f) of 0.985 (90% CI: 0.82–1.18). A total of 85.1% of the [14C] dose was recovered in excreta. Total radioactivity was mainly excreted into urine (52.8%) and feces (30.7%). Pimasertib was extensively metabolized. Only 5% and 1% of the dose was recovered as unchanged drug in feces and urine, respectively. Two major circulating metabolites were identified in plasma, a phosphoethanolamine conjugate (MSC2521347) and a carboxylic acid (MSC2359570). Conclusions: Pimasertib showed a favorable PK profile after oral and IV dosing. Availability of pimasertib PK data will facilitate future development of combination therapies. Clinical trial information: NCT01713036.
Impact of primary tumour location (PTL) on outcomes in patients (pts) with metastatic colorectal cancer (mCRC) undergoing first-line panitumumab (Pmab) + FOLFIRI treatment .
Authors: Meinolf Karthaus, Marc Van Den Eynde, Laurent Mineur, Josef Thaler, Reija Koukakis, Marloes Berkhout, Javier Gallego
Journal: Journal of Clinical Oncology (2018)

820 Background: Prognosis in pts with mCRC is affected by PTL; PTL may also affect the activity of the epidermal growth factor receptor inhibitor Pmab (+ FOLFIRI). Methods: In this phase II, single-arm study (NCT00508404), pts received first-line Pmab+FOLFIRI Q2W until disease progression (PD); primary endpoint: objective response rate (ORR). Analyses included pts with RAS wild-type (WT) mCRC (no mutations in KRAS/ NRAS exons 2, 3 and 4). Baseline demographics/disease characteristics were summarised by PTL and the effect of PTL on outcome was analysed. Early tumour shrinkage (ETS) was defined as a ≥30% reduction in the sum of the longest diameters of measurable target lesions at week 8. Depth of response (DpR) was the maximum % change from baseline to nadir in pts with shrinkage, or the change at PD in pts with no shrinkage. DpR was positive for shrinkage, negative for growth and zero for no change. Progression-free survival (PFS) was analysed by PTL and ETS status. There was no long-term follow-up of overall survival in this study. Results: PTL could be determined in 52/69 (75%) RAS WT pts; 45/52 (87%) had left (L)-sided disease. Pts with L- vs right (R)-sided disease were more likely to have BRAF WT mCRC (91% vs 71%), an ECOG performance status of 0 (56% vs 43%) and liver+other metastases (53% vs 29%). Pts with L- vs R-sided disease had longer median (95% CI) PFS (11.2 [7.6,17.0] vs 7.2 [1.1,19.1] months) and were more likely to experience ETS ≥30% (53% vs 29%). ORR (60% vs 57%), median (95% CI) duration of response (DoR; 13.2 [9.3,47.7] vs 14.3 [3.5,17.3] months), median DpR (61% vs 60%), and resection rates (any: 13% vs 14%; R0: 7% vs 14%) were similar for L- and R-sided pts. ETS ≥30% was associated with improved PFS irrespective of PTL (HR [95% CI] vs ETS &lt; 30%: 0.53 [0.22,1.29] on L; 0.35 [0.03,3.54] on R). Conclusions: These post-hoc data are in line with larger previous studies suggesting improved ETS/PFS with Pmab treatment in RAS WT left-sided mCRC; ORR, DoR and DpR were similar regardless of PTL. No formal conclusions can be drawn regarding the activity of Pmab+FOLFIRI in right-sided mCRC due to the small pt numbers, but ETS may also predict PFS benefit in right-sided disease. Clinical trial information: NCT00508404.