tbuckley/cabot-search huggingface dataset:
Proliferation pathway aberration frequencies in BRCA1- and BRCA2-mutated ovarian cancers.
Authors: Deborah A. Zajchowski, Hugh Salamon, Ken D. Yamaguchi
Journal: Journal of Clinical Oncology (2012)

5074 Background: Large-scale genomic analyses of high-grade, advanced-stage serous ovarian cancers by The Cancer Genome Atlas (TCGA) project revealed aberrations in genes comprising key proliferation and survival pathways (RB-E2F, RAS, PI3K) in the majority of tumors. Patients with germline BRCA1/2-mutations have more favorable prognoses than non-BRCA carriers, and recent work suggests that BRCA2 carriers do better than BRCA1. We hypothesized that concurrent proliferation pathway aberrations and BRCA1/2 mutations in tumors might play a role in patient outcome. Methods: Mutation, copy number, and clinical data for 309 TCGA-profiled serous ovarian tumors were downloaded from the MSKCC cBIO web portal. Each tumor was scored as aberrant for a pathway if any gene (RB: RB1, CDKN2A, CCND1, CCND2, E2F3, CCNE1; PI3K: PIK3CA, PTEN, AKT1, AKT2; RAS: KRAS, BRAF, NF1) in that pathway was mutated, amplified, or deleted. Results: 205 of 309 tumors had an aberration in at least one of these pathways. The frequency of pathway alteration differed significantly in BRCA1 (82%, 28/34), BRCA2 (52%, 17/33) and BRCA1/2 WT (66%, 160/242) tumors (BRCA1 vs. BRCA2: Fisher’s p= 0.0096). BRCA1 tumors more frequently contained alterations in multiple pathways than BRCA2 or WT tumors (41% vs. 24% or 25%, respectively). RB-E2F pathway alteration frequency was significantly different (BRCA1: 56%, BRCA2: 18%, WT: 43%, p=0.0043), but no significant differences in PI3K and RAS pathway aberration frequencies (BRCA1%: 41, 38; BRCA2%: 36, 27; WT% 28, 27), respectively, were observed. In agreement with the previous report, BRCA2 patients had significantly better overall survival (OS) than either BRCA1 or WT patients (median OS months for BRCA1: 35.9, BRCA2 45.4, BRCA1/2 WT 27.8; p=0.001). Presence of pathway alterations was not significantly associated with OS in BRCA1, BRCA2, or WT patients in this cohort. Conclusions: These results show a negative association between BRCA2 mutations and aberrations in key proliferation and survival pathways. Beyond BRCA1 and BRCA2 genetic mutations, the elevated frequency of pathway alteration in BRCA1 vs. BRCA2 tumors highlights differences that may be important for patient prognosis as well as therapy responses.
Impact of age on the feasibility and efficacy of neoadjuvant chemotherapy in patients with locally advanced gastroesophageal cancer: A retrospective pooled analysis of individual patient data.
Authors: Silvia Spörl, Salah-Eddin Al-Batran, Marcus Feith, Alexander Novotny, Florian Lordick, Peter C. Thuss-Patience, Bernhard Haller, Sylvie Lorenzen
Journal: Journal of Clinical Oncology (2014)

4063 Background: Neoadjuvant chemotherapy (neoCTx) improves the prognosis of patients (pts) with locally advanced esophagogastric adenocarcinoma (EGC), but its value is unknown in elderly patients (pts). Methods: Pts from 4 institutions who received neoCTx followed by surgery for EGC between 2000 and 2012 were analyzed. We compared the feasibility and outcome of neoCTx in pts aged ≥70 (cohort I) and their younger counterparts (cohort II). Results: Data were available for 460 pts among which 173 (37.6%) were ≥70 years. The median age in cohort 1 and 2 was 59 and 73 years, respectively. Older age was associated with an increased rate of comorbidities (66.0% vs. 42.1%, p<0,001). As compared to the younger, elderly pts were more likely to receive doublet instead of triplet neoCTx (64% vs 38%, p<0.001) and oxaliplatin- instead of cisplatin-based regimens (60% vs 32%, p<0.001). Of the 460 pts who started neoCTx, 83% and 90% in cohort I and II completed neoCTx without major alterations. Dose reductions to < 80% were necessary in 27% and 20% in cohort I and II (p=0.129). No significant difference was observed in the rate of ≥ grade 3 toxicities for cohort I and II (47% vs. 41%) and postoperative morbidity was also not different (24% vs. 28%). 60 day mortality for cohort I and II was 1.8% and 3.5%. After a median follow up of 30.4 months, median DFS in cohort I and II was 30 and 31 months, with a 3-years DFS of 48% and 46%, respectively. Median OS was 78 and 81 months, with a 3-year OS of 69% and 65%, respectively. On multivariate analysis, age was not significantly correlated with overall survival after adjustment for the rate of co-morbidities, gender and the number of neoCTx drugs applied (HR for age: 0.947; p=0.80). Conclusions: Despite slightly more adverse events and dose reductions, neoCTx is feasible in elderly pts with EGC. Elderly pts achieve comparable survival outcomes compared with their younger counterparts.
A TLR9-dependent checkpoint governs B cell responses to DNA-containing antigens
Authors: Vishal J. Sindhava, Michael A. Oropallo, Krishna Moody, Martin Naradikian, Lauren E. Higdon, Lin Zhou, Arpita Myles, Nathaniel Green, Kerstin Nündel, William Stohl, Amanda M. Schmidt, Wei Cao, Stephanie Dorta-Estremera, Taku Kambayashi, Ann Marshak-Rothstein, Michael P. Cancro
Journal: Journal of Clinical Investigation (2017)

Mature B cell pools retain a substantial proportion of polyreactive and self-reactive clonotypes, suggesting that activation checkpoints exist to reduce the initiation of autoreactive B cell responses. Here, we have described a relationship among the B cell receptor (BCR), TLR9, and cytokine signals that regulate B cell responses to DNA-containing antigens. In both mouse and human B cells, BCR ligands that deliver a TLR9 agonist induce an initial proliferative burst that is followed by apoptotic death. The latter mechanism involves p38-dependent G1 cell-cycle arrest and subsequent intrinsic mitochondrial apoptosis and is shared by all preimmune murine B cell subsets and CD27- human B cells. Survival or costimulatory signals rescue B cells from this fate, but the outcome varies depending on the signals involved. B lymphocyte stimulator (BLyS) engenders survival and antibody secretion, whereas CD40 costimulation with IL-21 or IFN-γ promotes a T-bet+ B cell phenotype. Finally, in vivo immunization studies revealed that when protein antigens are conjugated with DNA, the humoral immune response is blunted and acquires features associated with T-bet+ B cell differentiation. We propose that this mechanism integrating BCR, TLR9, and cytokine signals provides a peripheral checkpoint for DNA-containing antigens that, if circumvented by survival and differentiative cues, yields B cells with the autoimmune-associated T-bet+ phenotype.
Genetic polymorphism in the<i> miR-196a</i> as a prognostic biomarker for early breast cancer.
Authors: Yee Soo Chae, Jong Gwang Kim, Sang Kyun Sohn, Byung Woog Kang, Soo Jung Lee, Jongwon Seo
Journal: Journal of Clinical Oncology (2014)

e22058 Background: MicroRNAs (miRNA) may play important roles in tumorigenesis by regulating the expression of proto-oncogenes or tumor suppressor genes. Single nucleotide polymorphisms (SNPs) in miRNA-coding genes and miRNA binding site genes may affect miRNA-mediated gene regulation, thereby contributing to the susceptibility or prognosis of cancer. Accordingly, the present study analyzed SNPs located in miRNA and miRNA-binding sites of various genes and their impact on the prognosis for patients with early breast cancer by altering the miRNA binding efficiency. Methods: 452 consecutive patients with curative resection were enrolled. Three SNPs (rs11614913, rs3746444, and rs1044129 of miR-196a, miR-499a, and miR-367, respectively) were selected using an in silico analysis of several miRNA databases and the HapMap database. The SNP genotyping was performed using a Sequenom MassARRAY. Results: The median age of all the patients was 48 years, and 283 (62.6%) had ER/PR-positive EBC, 86 (19.0 %) had HER2-overexpressed EBC, and 77 (17.0 %) had triple-negative EBC. The pathologic stages after surgical resection were as follows: stage I (n=174, 38.5%), stage IIA (n=168, 37.2%), stage IIB (n=54, 11.9%), and stage IIIA (n=56, 12.4%). During the median follow-up of 6.9 (range 0.37 -19.93) years, 67 (14.8%) relapses and 55 (12.2%) deaths occurred. Among the 3 polymorphisms, miR-196ars11614913T>C was significantly associated with DFS and distant DFS (DDFS) when adjusted for age, histologic grade, receptor status, and pathologic stage. In particular, the prognostic impact of rs11614913 was limited to the hormone receptor-expressed subtype, where the patients bearing the CC genotype showed worse survival in terms of RFS and DDFS compared with the patients with the TT or TC genotype as a recessive model (hazard ratio [HR] = 2.610 and P=0.003 for PFS; HR=2.730 and P=0.013 for DDFS). Moreover, there were no statistical differences in the patient and tumor characteristics between the genotypes of rs11614913. Conclusions: The current study provides evidence that the miR-196a rs11614913T>C polymorphism is a possible prognostic biomarker for patients with HR-expressed early breast cancer.
The treatment continuum of panitumumab, cetuximab, and bevacizumab in 1st through 3rd line by KRAS, NRAS, and BRAF mutation status among mCRC patients treated at community cancer centers in the United States.
Authors: Kimberly Lowe, Kristina Hool, George Kafatos, Michael Anthony Kelsh, Tamer Garawin
Journal: Journal of Clinical Oncology (2017)

638 Background: Our objective was to use real world data to evaluate of the treatment continuum of bevacizumab (Bmab), cetuximab (Cmab), panitumumab (Pmab) or no biologics across 1 st , 2 nd , and 3 rd lines among metastatic colorectal cancer (mCRC) patients who were treated at community cancer centers in the United States. This objective was applied separately to patients with confirmed KRAS, NRAS, or BRAF wild-type (WT) or mutation (MUT) status, as well as patient who did not receive biomarker testing (UNK). Methods: This descriptive study utilized data from the Oncology Services Comprehensive Electronic Records (OSCER) database. It included 5,446 (2,064 WT, 1,807 MUT, and 1,575 UNK) patients diagnosed with mCRC between 1/1/2011 and 8/31/2015. Patients were stratified into the following mutually-exclusive categories in 1 st , 2 nd line, and 3 rd line: Pmab only, Cmab only, Bmab only, or no biologic. Patients who survived and continued therapy were followed through the lines of therapy. Results: 23.8% of WT, 36.3% of MUT and 49.5% of UNK patients did not receive a biologic in 1 st line. There were 1,003 WT patients who were treated with Bmab in 1 st . Of those, n=587 (58.5%) survived and elected to continue treatment in 2 nd line as follows: n=221 (37.6%) continued with Bmab, n=216 (36.8%) initiated Cmab, n=65 (11.1%) initiated Pmab, and n=85 (14.5%) received no biologic in 2 nd line. Of the 221 WT patients who received Bmab in 1 st and 2 nd line, n=129 (58.4%) survived and initiated 3 rd line treatment, of which n=20 (15.5%) received Bmab in 3 rd line. There were 127/2,604 (4.9%) WT patients who were treated with Pmab in 1 st line. Of those 127 patients, n=46 (36.2%) survived and elected to continue treatment in 2 nd line as follows: n=11 (29.3%) continued treatment with Pmab in 2 nd line, while n=14 (30.4%) initiated treatment with Bmab, n=4 (8.7%) initiated treatment with Cmab, and n=16 (36.4%) did not receive a biologic in 2 nd line. Conclusions: A small proportion of patients continued treatment with the same biologic throughout subsequent lines of therapy. Many patients were not treated with a biologic in any line, even if they were confirmed WT.
Palliative chemotherapy and travel distance impacts hospice referral in patients with stage IV pancreatic cancer.
Authors: Jennifer Michelle Duff, Ryan M. Thomas
Journal: Journal of Clinical Oncology (2017)

490 Background: Despite advances in chemotherapy (CTx), the prognosis for metastatic pancreatic ductal adenocarcinoma (mPDAC) is poor and while hospice is known to improve end-of-life care, referrals are often placed close to death. This may be due to accessibility issues or misconceptions that referral implies abandonment. We hypothesized that utilization of palliative CTx and travel distance to the treatment center impacts hospice referral patterns. Methods: Patients with histologically confirmed or radiographically presumed mPDAC as their initial diagnosis were retrospectively identified in a Veterans Administration Medical Center (VAMC) from 2005-2014. Demographic and clinical data were collected according to timing of hospice referral. Results: Fifty-eight mPDAC patients were identified with a median age of 63yr of which 57 (98.3%) were male. Palliative CTx was used in 26 (44.8%) patients with 32 (55.2%) not treated due to poor performance status (n = 18; 56.3%) or patient refusal (n = 14; 43.8%). Of the 52 (89.7%) patients referred to hospice, the median time from diagnosis to referral and referral to death was 2.4wk (Interquartile Range [IQR] 14.9) and 3.1wk (IQR 6.5), respectively. The median time to hospice referral was 18.7wk for patients treated with CTx vs 1.4wk for those who did not undergo therapy (p &lt; 0.001). The median distance from residence to the VAMC was 58.5mi (IQR 77). Subset analysis for those living &gt; 60mi vs &lt; 60mi to the VAMC, the median time to hospice referral was 1.7wk vs 4.7wk, respectively (p = 0.1). With no significant differences between groups in age, sex, race, or disease burden, univariate analysis demonstrated that those referred to hospice &gt; 2.4wk from diagnosis more often received CTx (p &lt; 0.001) and lived &gt; 60mi from the treatment center (p = 0.05). Conclusions: The majority of patients with mPDAC were enrolled in hospice and while travel distance trended to shorter time to referral, this was not significant. However, receipt of palliative chemotherapy did delay referral and those with this delay lived farther from the hospital. These data suggest that physicians delay hospice care in patients who are able to tolerate treatment and travel long distance to receive it.
IKZF1 (IKAROS) deletions as a prognostic marker in BCR-ABL1 positive acute lymphoblastic leukemia patients: A GIMEMA ALL WP Report
Authors: I. Iacobucci, C. Storlazzi, A. Lonetti, A. Ferrari, M. Messina, D. Cilloni, C. Papayannidis, M. Baccarani, R. Foà, G. Martinelli
Journal: Journal of Clinical Oncology (2009)

11005 Expression of BCR-ABL1 in hematopoietic stem cells can alone induce a chronic myeloid leukemia (CML) but cooperating oncogenic lesions are required for the generation of a blastic leukemia. To identify oncogenic sub-microscopic lesions that cooperate with BCR-ABL1 to induce ALL, by high resolution single nucleotide polymorphism (SNP) arrays (250K NspI and SNP 6.0, Affymetrix) we studied 106 patients (pts) with de novo adult BCR-ABL1-positive ALL. The most frequent somatic copy number alteration was deletion on 7p12 of IKZF1 (68/106, 64%), which encodes the transcription factor Ikaros required for the earliest stages of lymphoid lineage commitment. We characterized and mapped all breakpoints in IKZF1 gene to recognize that two major deletions occur: the first one characterized by loss of exons 4–7 (44%) and due to breakpoints in introns 3 and 7; the second one characterized by removal of exons 2–7 (19%) and due to a variable pattern of breakpoints in introns 1 and 7. In two pts we had both Δ2–7 and Δ4–7 deletions and in one we identified a deletion of all IKZF1 gene and part of GRB10. A variable number of nucleotides (patient-specific) were inserted at the conjunction and maintained with fidelity at the time of relapse. Gene expression profiling analysis of pts with IKZF1 deletion vs wild-type pts identified a unique signature characterized by a down-regulation of genes involved in pre-B-cell differentiation (e.g. VPREB1, VPREB3, IGLL3, BLK), demonstrating that genomic IKZF1 alterations have a strong impact on trascriptoma and contribute to an impaired B-cell differentiation. Univariate analysis showed that the IKZF1 deletion is a negative prognostic marker influencing the cumulative incidence of relapse (10.1 months for pts with deletion vs 56.1 months for wild-type pts, p=0.0103) and disease-free survival (DFS) (10.1 months vs 32.1 months, respectively, p=0.0229). The negative prognostic impact of the IKZF1 deletion on DFS was also confirmed by multivariate analysis (p=0.0445). In conclusion, deletion of IKZF1 is an important event in the development of BCR-ABL1 B-progenitor ALL which significantly influences clinical outcome. Supported by European LeukemiaNet, AIL, AIRC, FIRB 2006, Strategico di Ateneo, GIMEMA Onlus. No significant financial relationships to disclose.
Phase I development of a weekly dosing schedule for the oral taxane tesetaxel.
Authors: Amy Lang, Muralidhar Beeram, Anthony W. Tolcher, Kyriakos P. Papadopoulos, Ronald Drengler, Lon S. Smith, Alex Amaya, Kelly Barnhurst, Loretta Itri, Amita Patnaik
Journal: Journal of Clinical Oncology (2012)

2555 Background: Tesetaxel (TST) has anticancer activity in patients (pts) with metastatic breast cancer (MBC) and gastric cancer when administered orally once every 3 weeks (Q3W). This drug is not a Pgp substrate, does not cause hypersensitivity reactions, and may be associated with less neurotoxicity. The maximally tolerated dose (MTD) on the Q3W schedule is 27 mg/m 2 , and neutropenia is dose-limiting. Since taxane activity may be schedule-dependent, we conducted a weekly, dose-ranging, and PK evaluation of TST. Methods: Eligibility: advanced solid tumors; ECOG PS 0-2; adequate organ function. TST was given once weekly for 3 weeks in a 28-day cycle, beginning at a total flat dose of 25 mg/cycle with progressive increases in total dose up to 75 mg/cycle. Subsequently, dosing was converted to a weight-based regimen at weekly doses of 12.5, 15, and 17.5 mg/m 2 (i.e., total per cycle dose up to 52.5 mg/m 2 ). Serial plasma samples were assayed by HPLC. Results: 26 pts were treated in 8 dose cohorts. The MTD was 15 mg/m 2 /wk (total cycle dose, 45 mg/m 2 ). With repeated cycles, constitutional symptoms (fatigue and anorexia) rather than neutropenia proved dose-limiting at 17.5 mg/m 2 /wk. Only 1 pt (at 12.5 mg/m 2 /wk) developed grade 3 neutropenia; no other episodes of Grade 3-4 myelotoxicity were observed. One pt with MBC (who had progressed after 2 prior taxane regimens) achieved a PR; 1 pt with prostate cancer has maintained prolonged reduction of PSA (&gt; 57%). PK analyses showed low but progressive increases in trough TST concentrations (0.4–4.6 nmol/mL) 7 days after each succeeding dose, which was consistent with the prolonged T½ of this drug (~180 hrs). There was no substantial drug accumulation over multiple cycles. Conclusions: Weekly oral TST is safe, provides long-term low-level drug exposure, and increases the total delivered dose over 12 wks by 25%. Interestingly, this regimen is not associated with significant myelosuppression. Thus, weekly TST dosing provides a highly convenient, “dose-dense”, taxane regimen that is not associated with neutropenia, which should facilitate its integration into multiple chemotherapy regimens. An ongoing study is evaluating efficacy of weekly TST dosing in MBC.
Risk factors for readmission in patients admitted for febrile neutropenia.
Authors: Justin Van Klein, Andrew J Gillis-Smith, Rebecca Slotkin, John Leonard Reagan
Journal: Journal of Clinical Oncology (2015)

e17733 Background: Febrile neutropenia (FN) is a common and serious complication among cancer patients, which often requires costly and hospital admissions and time away from home. In this study, we examined specific risk factors that may indicate a higher risk for 30 day readmission in FN patients. Methods: Patients with admission ANC < 1500 and fever (T > 100.3) who survived to discharge were studied retrospectively. Demographic, comorbidity and care related data were collected for each of these patients. The patients were divided into two groups: those with a readmission within 30 days of discharge and those without. Fisher exact and Student T-tests were used to compare the groups for statistical significance. Results: 141 patients from one urban and one sub-urban Rhode Island hospital met the study criteria, 51 of which had a 30 day readmission (rate = 36%). Significant factors increasing risk for readmission were found to be the presence of a hematologic malignancy, diabetes, more frequent prior admissions, administration of chemotherapy in the prior 6 months and a lack of inpatient antibiotics (Table). Conclusions: Patients admitted for FN with hematologic malignancies, diabetes, frequent prior admissions, recent chemotherapy or who received no inpatient antibiotics were found to be at increased risk for 30 day hospital readmission. These findings will allow clinicians to early identify FN patients at high risk for readmission. Future studies may then focus on these high risk patient populations to develop strategies to decrease their readmission rates. Select analysis of risk factors for 30 day readmission. Risk factor 30 day readmission (n=51) No readmission (n=90) p-value Cancer Diagnosis 94.1% 83.3% 0.07 Hematologic malignancy 74.5% 46.7% 0.012 Avg. ANC 380 389 0.989 Chemotherapy in prior 6 months 86% 68.1% 0.026 Avg. number of days since chemotherapy 16.7 15.5 0.97 Avg. MASCC 19.5 19.9 0.94 High risk admission (MASCC < 21) 52.9% 43.3% 0.296 Inpatient antibiotics given 92.2% 100% 0.016 Diabetes 27.5% 12.2% 0.037 COPD 11.8% 13.3% 1 Avg. number of admissions in prior 12 months 2.75 1.58 <0.01 Avg. number of outpatient oncology visits in prior 12 months 7.74 6.31 0.88 Follow up appointment scheduled 62.7% 61.1% 1
Activating transcription factor 3 is a target molecule linking hepatic steatosis to impaired glucose homeostasis
Authors: Ji Yeon Kim, Keon Jae Park, Joo-Yeon Hwang, Gyu Hee Kim, DaeYeon Lee, Yoo Jeong Lee, Eun Hyun Song, Min-Gyu Yoo, Bong-Jo Kim, Young Ho Suh, Gu Seob Roh, Bin Gao, Won Kim, Won-Ho Kim
Journal: Journal of Hepatology (2017)

Graphical abstractAbstractBackground & AimsNon-alcoholic fatty liver disease (NAFLD) contributes to impaired glucose tolerance, leading to type 2 diabetes (T2D); however, the precise mechanisms and target molecules that are involved remain unclear. Activating transcription factor 3 (ATF3) is associated with β-cell dysfunction that is induced by severe stress signals in T2D. We aimed to explore the exact functional role of ATF3 as a mechanistic link between hepatic steatosis and T2D development.MethodsZucker diabetic fatty (ZDF) rats were utilized for animal experiments. An in vivo-jetPEI siRNA delivery system against ATF3 was used for loss-of-function experiments. We analyzed the baseline cross-sectional data derived from the biopsy-proven NAFLD registry (n=322). Human sera and liver tissues were obtained from 43 patients with biopsy-proven NAFLD and from seven healthy participants.ResultsATF3 was highly expressed in the livers of ZDF rats and in human participants with NAFLD and/or T2D. Insulin resistance and hepatic steatosis were associated with increased ATF3 expression and decreased fatty acid oxidation via mitochondrial dysfunction and were attenuated by in vivo ATF3 silencing. Knockdown of ATF3 also ameliorated glucose intolerance, impaired insulin action, and inflammatory responses in ZDF rats. In patients with NAFLD and/or T2D, a significant positive correlation was observed between hepatic ATF3 expression and surrogate markers of T2D, mitochondrial dysfunction, and macrophage infiltration.ConclusionsIncreased hepatic ATF3 expression is closely associated with hepatic steatosis and incident T2D; therefore, ATF3 may serve as a potential therapeutic target for NAFLD and hepatic steatosis-induced T2D.Lay summaryHepatic activating transcription factor 3 (ATF3) may play an important role in oxidative stress-mediated hepatic steatosis and the development of type 2 diabetes (T2D) in a Zucker diabetic fatty (ZDF) rat model and in human patients with non-alcoholic fatty liver disease (NAFLD). Therefore, ATF3 may be a useful biomarker for predicting the progression of NAFLD and the development of T2D. Furthermore, given the significant association between hepatic ATF3 expression and both hepatic steatosis and impaired glucose homeostasis, in vivo ATF3 silencing may be a potential central strategy for preventing and managing NAFLD and T2D.