tbuckley/cabot-search huggingface dataset:
Time to castration-resistance and docetaxel outcomes in metastatic prostate cancer.
Authors: Lamia Aljundi, Nichole Miller, Andrew Taylor, Jonathan Hung, Clara Hwang
Journal: Journal of Clinical Oncology (2016)

e16519 Background: Castration resistant prostate cancer (CRPC) continues to present a challenge for oncologists. There is renewed interest in the use of docetaxel in advanced prostate cancer; however, a significant portion of patients do not respond and eventually all patients develop resistance. Androgen receptor (AR) variants have been hypothesized to be a common resistance mechanism to both androgen deprivation therapy (ADT) and docetaxel. We thus proposed that initial response to ADT might predict future response to docetaxel. Methods: A set of Cox regressions was computed to investigate the time to progression while on ADT and other factors on time to progression and overall survival while on docetaxel. Hazard ratios and p-values for each factor were calculated. Patients were stratified according to their time to progression while on ADT into three groups by tertiles. Rapid progressors were patients who progressed within less than a year while on ADT, intermediate progressors progressed within 1 and 2.6 years and slow progressors progressed after more than 2.6 years. Survival for each of these three categories was plotted using the Kaplan-Meier method and differences were assessed with the log-rank test. Results: Time to prostate specific antigen (PSA) progression while on ADT predicted future docetaxel response (HR = 0.8, p = 0.03) in univariate analysis. A difference in time to PSA progression was noted between rapid and fast progressors on ADT (p = 0.009, log-rank test). Overall survival for rapidly progressing patients was significantly inferior to intermediate and slow progressors (p = < 0.001, log-rank). However, multivariate analysis did not meet criteria for statistical significance between time to progression while on ADT and time to progression while on docetaxel (p = 0.062). Conclusions: Although time to CRPC was correlated with docetaxel outcomes, the relationship was not statistically significant on multivariate analysis. Further research is required to identify molecular characteristics in patients with CRPC that will predict response and outcomes with more precision.
Effects of training and competition on the sleep of elite athletes: a systematic review and meta-analysis
Authors: Spencer Stuart Haines Roberts, Wei-Peng Teo, Stuart Anthony Warmington
Journal: British Journal of Sports Medicine (2018)

Objectives To characterise the sleep of elite athletes and to identify factors associated with training and competition that negatively affect sleep. Design Prognosis systematic review. Data sources Three databases (PubMed, SCOPUS and SPORTDiscus) were searched from inception to 26 February 2018. Eligibility criteria for selecting studies Included studies objectively reported total sleep time (TST) and/or sleep efficiency (SE) in elite athletes. Studies were required to be observational or to include an observational trial. Results Fifty-four studies were included. During training, many studies reported athletes were unable to achieve TST (n=23/41) and/or SE (n=16/37) recommendations. On the night of competition, most studies reported athletes were unable to achieve TST (n=14/18) and/or SE (n=10/16) recommendations. TST was shorter (60 min) the night of competition compared with previous nights. SE was lower (1%) the night of competition compared with the previous night. TST was shorter the night of night competition (start ≥18:00; 80 min) and day competition (20 min) compared with the previous night. SE was lower (3%–4%) the night of night competition but unchanged the night of day competition compared with previous nights. Early morning training (start &lt;07:00), increases in training load (&gt;25%), late night/early morning travel departure times, eastward air travel and altitude ascent impaired sleep. Conclusion Athletes were often unable to achieve sleep recommendations during training or competition periods. Sleep was impaired the night of competition compared with previous nights. Early morning training, increases in training load, travel departure times, jet lag and altitude can impair athletes’ sleep. PROSPERO registration number CRD42017074367.
Circulating tumor microemboli as a prognostic factor for locally advanced or metastatic solid tumors.
Authors: Marcelo Corassa, Marcello Ferretti Fanelli, Thiago Bueno Oliveira, Celso Lopes Mello, Marcelo Calil Machado Netto, Ulisses Ribaldo Nicolau, Alexcia Camila Braun, Emne Ali Abdallah, Daniel Garcia, Virgilio Sousa Silva, Luiz Paulo Kowalski, Vanessa da Silva Alves, Ludmilla T.D. Chinen
Journal: Journal of Clinical Oncology (2016)

e23067 Background: Much is currently known about the role of circulating tumor cells (CTC) in diverse types of cancer. CTCs in metastatic (m) colorectal (CRC), breast and prostate cancers determine worst prognosis and survival. Little is studied, however, regarding Circulating Tumor Microemboli (CTM), defined as clusters of 3 or more cancer cells detected in peripheral blood. The objective is to characterize the presence of CTM in mCRC and locally advanced head and neck squamous cell carcinoma (LAHNSCC), including its influence on survival and implications in treatment. Methods: In two different ongoing projects, 98 patients positive for CTCs were separately and prospectively enrolled, one cohort for mCRC (54 patients) and another for LAHNSCC (44 patients). CTCs and CTM were detected by ISET (Isolation by Size of Epithelial Tumor Cells, Rarecells, France). The analysis included frequencies, demographic characterization and survival variables, including PFS and OS (for combined and individual groups), with PFS as primary endpoint. The PFS and OS were calculated based on the date of first CTC collection and first progression after collection (PFS) or death (OS). Results: The presence of CTM was demonstrated as a significant independent factor for worst prognosis for PFS and OS in LAHNSCC. Median time for PFS in LAHNSCC was 16.97 vs 7.73 months (p = 0,02) comparing CTM negative and CTM positive patients, respectively. The difference was confirmed for OS (p = 0.03), although median was not reached for both groups, with robust separation in survival curves. In mCRC, PFS (20.1 x 13.9 months; p = 0.55) and OS (64.5 x 49,8 months; p = 0,31) were both greater for CTM negative patients, however, without statistical significance. The same was demonstrated for the combined group (mCRC and LAHNSCC patients), (PFS 14.1 x 9.9 months – p = 0.10; OS 70.8 x 53.9 months – p = 0.20). Conclusions: CTM presence is a prognostic factor for PFS and OS in LAHNSCC, determining significant worst outcomes and decreased survival. For mCRC and the combined groups CTM was not demonstrated as a prognostic factor, however decreased non-significant survival was seen for CTM patients in both groups, warranting the hypothesis for worst outcomes for the presence of CTM.
TCT-59 Outcomes of Catheter-Directed Thrombolysis versus Standard Medical Therapy in Patients Admitted to Intensive Care Units with Submassive Pulmonary Embolism
Authors: Stephen D'Auria, Andrew Althouse, Floyd Thoma, Michael Sharbaugh, Jeffrey McKibben, Robert Maholic, Efthymios Avgerinos, Belinda Rivera-Lebron, Catalin Toma
Journal: Journal of the American College of Cardiology (2018)
Deep sequencing of metastatic cutaneous basal cell and squamous cell carcinomas to reveal distinctive genomic profiles and new routes to targeted therapies.
Authors: Jeffrey S. Ross, Laurie M Gay, Martin C Mihm, Rami N Al-Rohil, Ashley J Tarasen, J. Andrew Carlson, Adrienne Johnson, Julia Andrea Elvin, Jo-Anne Vergilio, Siraj Mahamed Ali, James Suh, Prasanth Ganesan, Filip Janku, Daniel D. Karp, Vivek Subbiah, Vincent A. Miller, Philip J. Stephens
Journal: Journal of Clinical Oncology (2016)

9522 Background: Although cutaneous cBCC and cSCC are the most frequent primary human cancers, primary treatment is nearly always curative, and metastatic disease (mcBCC and mcSCC) rarely develops. Methods: Comprehensive genomic profiling (CGP) of 315 cancer genes was applied to 50ng of DNA on 60 mcBCC and 122 mcSCC for evaluation of all classes of genomic alterations (GA). Clinically relevant genomic alterations (CRGA) were defined as those identifying anti-cancer drugs on the market or in registered clinical trials. Results: GA in mcBCC and mcSCC are shown in the Table. Age and gender frequencies were similar in both tumors. Both mcBCC and mcSCC had high mutational load, high TP53 mutation frequency, similar mean GA and CRGA per sample and UV light associated DNA damage signals in all cases indicating possible benefit for immunotherapies. mcSCC featured more cell cycle dysregulations (CDKN2A loss) and NOTCH1 GA. mcBCC had more sHH pathway alterations including PTCH1 primary GA and SMO GA associated with vismodegib resistance. Patient responses to targeted therapies will be presented. Conclusions: CGP of mcBCC and mcSCC reveals significant differences in driver alteration frequencies Although distant metastases requiring systemic treatment are rare in mcBCC and mcSCC, the high incidence of these primary tumors results in a significant numbers of patients seeking novel therapies. CGP shows significant promise for uncovering the tumor biology and directing new routes to targeted therapies for these cutaneous malignancies. Gene mcBCC mcSCC Significance Age in years 66.3 64.9 NS Gender 28% female/72% male 17% female/83% male NS GA/Sample 7.4 9.2 NS CRGA/Sample 3.5 2.5 NS TP53 79% 85% NS PTCH1 32% 11% P=0.0008 CDKN2A 16% 62% P<0.0001 hTERT 33% 20% NS ARID1A 18% 4% P=0.0036 SMO 17% 0% P<0.0001 NOTCH1 12% 43% P<0.0001 ERBB2 10% 6% NS PIK3CA 8% 6% NS BRCA2 2% 10% NS MLL2 18% 27% NS
Characteristics of ponatinib (PON) therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) patients (pts) in real-world (RW) clinical practice compared to the PACE trial.
Authors: Michael J. Mauro, Lisa McGarry, Mo Yang, Stephanie Lustgarten, Hui Huang
Journal: Journal of Clinical Oncology (2016)

e18514 Background: The pivotal trial (PACE) studied the use of PON in adult pts with refractory Ph+ ALL and formed the basis of approval of PON. Prescribing data tracked by the specialty pharmacy exclusively responsible for distribution of PON in the US is available from Jan’14 onward. Comparison of the earlier PACE clinical trial vs RW data can examine similarities and differences between pt characteristics, regimens and duration of therapy (DOT) evolving over time. Methods: We compared PACE data, which enrolled pts Sep’10 – Oct’11 to RW data for Ph+ ALL pts starting treatment Jan’14 – Dec’15. RW data came from referring physicians, pharmacy intake forms and dispensing records. Data on co-prescribing were available for a small subset of pts. Pt characteristics and dosing were compared using non-parametric tests; average daily dose was calculated, including therapy gaps as “zero” dose. DOT was assessed using Kaplan-Meier techniques and proportional hazard regression. Results: PACE enrolled 32 Ph+ ALL pts; 274 US RW Ph+ ALL pts started treatment with PON over a 2-yr period. Characteristics of PACE vs RW pts, including age (median 61.5 vs 55.5 yrs; p = 0.589) and % male (63% vs 58%; p = 0.600) were similar. All PACE pts received 45 mg as their initial dose; in the RW 50% initially received 45 mg, 41% 30 mg, and 9% 15 mg. Average dose was higher in PACE vs RW (39.1 vs 27.3 mg/day; p < .001). PACE permitted monotherapy with PON whereas combination therapy appears to be used commonly in RW practice. Median time on therapy was 2.7 mo in PACE vs 5.5 mo in RW pts (p < 0.001), and nearly 50% of RW pts remained on therapy after 6 mo, vs < 20% in PACE (Table). Conclusions: RW Ph+ ALL pts appear similar to those enrolled in PACE. Median DOT was significantly longer for RW pts than for PACE, with nearly one-half of RW pts remaining on therapy at 6 mo. Longer median DOT may be related to lower dose intensity and use of combination therapy in RW clinical practice. Further study of RW use of PON in Ph+ ALL is needed. Clinical trial information: NCT01207440.Time on therapy in PACE vs RW Ph+ ALL pts. Population (n) 6mo 12mo 18mo 24mo Hazard ratio [CI] (p-value) PACE (32) 18.8% 12.5% 3.1% 3.1% 0.573 [0.390 – 0.841] RW (274) 48.2% 21.2% 9.5% -- (0.004)
Final results of a phase 3 study of comparing paclitaxel plus 5-fluorouracil versus cisplatin plus 5-fluorouracil in chemoradiotherapy for locally advanced esophageal carcinoma (ESO-Shanghai 1).
Authors: Yun Chen, Jingjun Ye, Zhengfei Zhu, Weixin Zhao, Ling Li, Min Fan, Chaoyang Wu, Huarong Tang, Gang Xu, Qin Lin, Jiancheng Li, Yi Xia, Yunhai Li, Jialiang Zhou, Kuaile Zhao
Journal: Journal of Clinical Oncology (2018)

4053 Background: Concurrent chemoradiotherapy (CCR) with cisplatin plus 5-Fu (PF) regimen is a standard modality for locally advanced esophageal squamous cell carcinoma (ESCC) patients. This trial aimed to assess the efficacy and safety of the paclitaxel plus 5-Fu (TF) regimen versus PF regimen in CCR for ESCC patients. Methods: ESCC patients presenting with stage IIa to IVa were enrolled in a prospective multicenter phase 3 study. Patients were randomized to either TF or PF group. Patients in TF group were treated with 5 cycles of weekly TF (5-Fu 300 mg/m2, civ 96h plus paclitaxel 50 mg/m2, d1) in CCR followed by 2 cycles of monthly TF (5-FU 1800 mg/m2, civ 72h, plus paclitaxel 175 mg/m2 d1) in consolidation chemotherapy. Patients in PF group were treated with 2 cycles of CCR followed by 2 cycles of consolidation chemotherapy with PF (cisplatin 25 mg/m2/d, d1-3, plus 5-Fu 1800 mg/m2, civ 72h, q28d). The radiotherapy dose was 61.2 Gy delivered in 34 fractions. The primary end-point was the 3-yr OS. Results: 436 ESCC patients (217 assigned to TF group and 219 assigned to PF group) in 6 centers were recruited between April 2012 and July 2015. Median follow-up of patients who survived was 44.6 months [IQR 29.3–72.0]. The 3-yr OS was 57% in TF group and 51% in PF group (HR 0.91; 95% CI 0.69-1.18; P = 0.46). No significant differences were recorded in 3-yr DPFS or 3-yr LPFS between TF and PF groups (44.3% vs. 45.3% and 48.8% vs. 49.8%, respectively). TF group had a significant higher incidence of acute Grade 3/4 leukopenia (31.3% vs. 18.3%), dermatitis (5.1% vs. 1.4%), and pneumonitis (9.7% vs. 3.2%), and significant lower incidence of anemia (0.5% vs. 3.2%), thrombocytopenia (0.5% vs. 13.7%), fatigue (6.9% vs. 19.6%), anorexia (1.4% vs. 14.6%), nausea (1.4% vs. 14.2%), and vomiting (2.3% vs. 18.3%) than PF group (P < 0.05). There were 3 (1.4%) patients in TF group died of acute pneumonitis, 1 (0.5%) patient in TF group and 2 (0.9%) patients in PF group died of delayed pneumonitis. Conclusions: TF might be an option used in CCR in ESCC patients with a different type of side effects compared with PF, although it did not significantly prolong OS. Clinical trial information: NCT01591135.
Innate Immune Signaling in Nonalcoholic Fatty Liver Disease and Cardiovascular Diseases
Authors: Jingjing Cai, Meng Xu, Xiaojing Zhang, Hongliang Li
Journal: Annual Review of Pathology Mechanisms of Disease (2018)

The physiological significance of innate immune signaling lies primarily in its role in host defense against invading pathogens. It is becoming increasingly clear that innate immune signaling also modulates the development of metabolic diseases, especially nonalcoholic fatty liver disease and cardiovascular diseases, which are characterized by chronic, low-grade inflammation due to a disarrangement of innate immune signaling. Notably, recent studies indicate that in addition to regulating canonical innate immune-mediated inflammatory responses (or immune-dependent signaling-induced responses), molecules of the innate immune system regulate pathophysiological responses in multiple organs during metabolic disturbances (termed immune-independent signaling-induced responses), including the disruption of metabolic homeostasis, tissue repair, and cell survival. In addition, emerging evidence from the study of immunometabolism indicates that the systemic metabolic status may have profound effects on cellular immune function and phenotypes through the alteration of cell-intrinsic metabolism. We summarize how the innate immune system interacts with metabolic disturbances to trigger immune-dependent and immune-independent pathogenesis in the context of nonalcoholic fatty liver disease, as representative of metabolic diseases, and cardiovascular diseases.
Effect of comorbidities on outcomes in colorectal cancer (CRC) survivors.
Authors: Colleen A Cuthbert, Brenda R Hemmelgarn, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2018)

10055 Background: The effect of comorbidities on outcomes in cancer survivors has not been evaluated in detail, but this can inform survivorship care. We aimed to evaluate comorbid medical conditions, causes of death (COD), and the effect of these conditions on survival among CRC survivors in a Canadian province. Methods: A population-based cohort study using administrative data. Patients were diagnosed with stage I-III CRC from 2004 to 2015. ICD-10 codes were used to categorize COD. CRC patients were divided into 5 mutually exclusive comorbid groups: cardiovascular disease (CVD), diabetes (DM), both cardiovascular disease and diabetes (CVD+DM), other comorbidities (OC), and no comorbidities. Kaplan Meier and Cox proportional hazards models were used to evaluate survival, adjusting for age, cancer stage, and treatment. Results: We evaluated 12,265 patients. Median age 67.3(range 18-104) years, 56.2% men, 61.8% colon cancer, 38.8% stage III disease, and 36.8% Charlson comorbidity index ≥1. There were 1153 (9.4%), 1711(13.9)%, 515(4.2%), and 1141(9.3%) patients in the CVD, DM, CVD+DM and OC groups, respectively. Mean follow-up was 3.8 years. Median overall survival (mOS) was 8.6 (CI 8.3-8.9) years in the entire cohort. Among those who died (N = 3964), 51.2% and 39.3% were due to CRC and other causes, respectively. CVD was a common non-CRC COD (17.1%). In comparison to those with no comorbidities, patients with CVD+DM fared the worst (mOS 3.3 [2.8-3.7] years; adjusted HR for death, 2.27, 95% CI 2.0-2.6, p < 0.001) (see Table). For stage III disease, the percentage receiving curative intent (surgery + adjuvant) treatment was different (p < .001) across groups (31.7% in CVD+DM, 37.6% in CVD, 66.7% in DM, and 57.4% in OC). Conclusions: Specific comorbid medical conditions are associated with increased risk of death from CRC and non-CRC causes. Undertreatment was associated with comorbidity profile and may be a driver of worse CRC survival in these patients. Engagement of primary care and other specialty providers earlier in the survivorship trajectory is warranted. Group mOS HR (95% CI) P value No comorbidities 10.8 yrs referent CVD 4.2 yrs 1.98 (1.7-2.1) < .001 DM 7.3 yrs 1.33 (1.2-1.5) < .001 CVD+DM 3.3 yrs 2.27 (2.0-2.6) < .001 OC 6.0 yrs 1.61 (1.5-1.8) < .001
Genomic landscape of small cell carcinoma of the breast (SCCB) contrasted to small cell carcinoma of the lung (SCLC).
Authors: Brennan McCullar, Manjari Pandey, Felicia Hare, Kruti Patel, Matthew Stein, Melissa Crawley, George Yaghmour, Rebecca Feldman, Michael Gary Martin
Journal: Journal of Clinical Oncology (2016)

e23281 Background: SCCBis a rare, aggressive form of breast cancer that is associated with extremely poor outcomes (Hare 2015). In an effort to identify new treatment options, we utilized comprehensive genomic profiling to assess the potential for novel therapies in SCCB. Methods: Under an IRB approved protocol, we identified patients (pts) with SCCB and SCLC profiled by Caris Life Sciences between 2007-2015. Tumors were assessed with up to 21 IHC stains, in situ hybridization (ISH) of cMET, EGFR, HER2 and TOP2A, and next generation sequencing (NGS) as well as Sanger sequencing of 47 genes. Results: 19 patients with SCCB were identified, median age was 58 years (range 37-79) and 42% had metastatic disease at presentation; for comparison 58 pts with SCLC were identified (66 [36-86], 65% metastatic). By IHC 30% SCCB pts expressed ER, 15% expressed PR and 18% expressed androgen receptor; SCLC pts expressed ER 0%, PR 2%, AR 6%. SCCB and SCLC pts had similar patterns of other IHC expression (0% v 0% PDL1, 50% v 42% PD1, 80% v 95% TOP2A, respectively). All SCCB and SCLC pts were negative for HER2 and cMET amplification by ISH. NGS revealed TP53 mutations in 75% of patients both with SCCB and SCLC and PIK3CA mutations in 38% of SCCB pts but no SCLC pts (Fisher’s exact test p = 0.005, OR 0.02 [0.00-0.52]). No other mutations were found in SCCB pts and no other mutation occurred in over 10% of SCLC pts except RB1 in 20% (p = 0.31). Conclusions: SCCB is an aggressive tumor with few therapeutic options. Molecular profiling suggests many similarities between SCCB and SCLC with the exception an increased incidence of PIK3CA mutations in SCCB, which may have therapeutic implications.
The novel long non-coding RNA PANCR: A p53 activator and potential breast cancer biomarkers.
Authors: Yu Cao, Deliang Cao, Hongyan Ling
Journal: Journal of Clinical Oncology (2017)

e23016 Background: Long non-coding RNAs (LncRNAs) may serve as a biomarker and potential therapeutic target of cancers. Chromosome 16q22.1 is frequently deleted in breast cancer and may contribute to breast carcinogenesis by inactivation of tumor suppressor genes. This study characterized a new LncRNA tumor suppressor in this region, named p53 activating non-coding RNA (PANCR). This LncRNA consists of 1.5kb in length. Methods: Quantitative real-time PCR was used for examine the PANCR expression in breast cancer tissues. RNA-pull down and RNA-Immunopreicitation were used to analyze PANCR targeted protein. Results: Our data showed that PANCR was downregulated in breast cancer cell lines and tissues. In the breast cancer cell lines, PANCR expression appeared reversely correlated with cell malignancy, and in breast cancer tissues, PANCR was downregulated over 2 times in 31(62.0%) of 50 cases compared to adjacent normal breast tissues. In breast cancer cells MCF7 and immortalized human mammary epithelial cells MCF10A, ectopic expression of PANCR induced marked apoptosis, suppressing cell proliferation in culture and tumor growth in xenografts, but in contrast, shRNA–mediated silencing of PANCR promoted cell growth and proliferation. Mechanistic approaches revealed that in both MCF7 and MCF10A cell, PANCR activated p53 and upregulated pro-apoptotic proteins bid and bim and cell cycle inhibitors p21 waf/cip1 and p27 Kip1 . We further found that the PANCR binds to and activates p53 by dissociating the p53-MDM2 complex. We further characterized the functional domain of PANCR that interacts with p53. Conclusions: The LncRNA PANCR located in the deleted Chromosome 16q22.1 region is a novel intracellular p53 activator and tumor suppressor, which may be used as a target for cancer therapy through mimicking its binding domain and activation of p53.