tbuckley/cabot-search huggingface dataset:
Prostate-specific antigen (PSA) measurements' association with metastasis and mortality in patients with nmCRPC (non-metastatic castration resistant prostate cancer).
Authors: Sophia Li, Zhijie Ding, Jennifer H Lin, Ajay S. Behl, Chris Pericone, Siddhant Deshmukh, Brian Macomson, Neal D. Shore
Journal: Journal of Clinical Oncology (2018)

e17058 Background: Real world data regarding the progression of patients with nmCRPC is limited. This study assessed association of PSA doubling time (PSADT) over disease follow-up with risk for metastasis and mortality. Methods: This retrospective study included men ≥18 years of age from the Optum de-identified electronic health record database (1/1/2007 – 3/31/2016). nmCRPC was defined as a prostate cancer (PC) diagnosis, 2 rising PSA levels ≥1 week apart (index date as 2nd PSA rise), testosterone < 50 ng/dL (post-PC diagnosis), and no ICD-9/10 code or therapy indicating metastasis. PSADT was calculated using PSAs at and post index date until the earliest of metastasis or mortality development or end of follow-up. Cox proportional hazard regression was used to assess metastasis and mortality risk by PSADT groups, adjusted for log-transformed baseline PSA at index date and other confounders. The mortality risk model also included time to metastasis. Results: In total, 1,005 patients were included; mean age at index date was 77 years. During a median follow-up of 22 months, 547 men developed metastasis and 428 died. The median time to metastasis and mortality was 20 and 38 months. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of metastases of men with PSADT ≤2.5, 2.5-5, 5-7.5 and 7.5-10 months relative to men with PSADT > 10 months were 3.1 (2.3-4.2), 2.6 (2.0-3.2), 2.1 (1.6-2.7) & 1.8 (1.3-2.3), and HRs (CIs) for the risk of death were 2.3 (1.6-3.5), 3.0 (2.3-4.0), 2.4 (1.8-3.2) & 1.4 (1.0-2.0) respectively. Baseline PSA was independently associated with risk for metastasis (HR = 1.3, 95% CI = 1.1-1.5) and mortality (HR = 1.5, 95% CI = 1.2-1.8). Men developing metastasis within 1 year had > 3-fold higher mortality risk (95% CI = 1.6-6.0) than men who remained metastasis free at year 3. Conclusions: With no ICD-9/10 codes for nmCRPC and infrequent recording of PSA levels, time to metastasis was shorter than previously reported. Baseline PSA and PSADT appear to independently predict metastasis and mortality in patients with nmCRPC. Time to metastasis may also serve as a surrogate for nmCRPC patient mortality.
Characterization of the different cell population in primary culture of breast tumor
Authors: B. Pattanayak, G. Herrera, I. Garrido-Cano, A. Adam-Artigues, E. Tormo, B. Pineda Merlo, P. Cabello, A. Lluch, P. Eroles
Journal: Annals of Oncology (2018)

Background: From decades' immortal cells have been used as a model system to study the mechanism of cancer, drug resistance and explore the potential efficacy of the anticancer drugs. However, the numerous study has been suggested that studying the immortal cancer has a backdrop to represent the drug resistance and heterogeneity of the tumor in the patients. So, Primary tumor cultures currently begin to constitute the golden standard to study the lacking things, which has to apply to study the mechanism of resistance and personalized therapy including in breast tumor. Methods: Initially, 10 breast tumors with different subtypes were obtained from patients, with their informed consent. They were freshly taken biopsy samples. The patient biopsies underwent an enzymatic digestion with (3 mg /ml collagenase and 5unit/ml dispase). After enzymatic digestion cells were grown in normal complete media with different growth factors and ROCK inhibitor. All cell lines were maintained until their passage (p15-p20). The cells were characterized with different antibodies by flow cytometry, different gene expression and protein expression were assessed by PCR and western blot. Results: Here we found that, after characterization of the 10 samples, the most subpopulations have the breast cancer stem cells properties (CD44+/CD24low) as well as cancer-associated fibroblast (CAFs) characteristics with the positive expression of CD 140a. In the gene level, we found that the mesenchymal marker (fibronectin) and an oncofetal gene i.e. SALL4 are overexpressed in almost all cells except in Luminal B her2+ subtype, as compared to MCF 10a (a non-tumorigenic epithelial cell line). Further, we are impending to correlate the expression of metastatic and tumorigenic targets in those individual patients with cell proliferation, invasion, migration and drug efficacy. Conclusions: The present study provided that the primary cell culture can be a better way to study the mechanism behind metastasis and drug resistance. It also contributes to the knowledge behind the cell heterogeneity and increases the drug's efficacy. Primary tumor cell lines have the potential to improve the effectiveness of conventional clinical approaches to treat cancer of individual patients. Legal entity responsible for the study: 1) INCLIVA Biomedical Research Institute 2) CIBERONC. Funding: CIBERONC. Disclosure: All authors have declared no conflicts of interest.
The meta analysis of pathological and long-term outcomes of laparoscopic vs. open surgery for rectal cancer.
Authors: Ke-Feng Ding, Jun Li, Yi-Bo Cai, Xiang-Xing Kong, Ying Yuan, Hai-Yan Chen
Journal: Journal of Clinical Oncology (2016)

e15039 Background: The non-inferiority of laparoscopic surgery (LS) for rectal cancer remains controversial. This study aimed to compare pathological and long-term outcomes of LS and open surgery (OS). Methods: We searched eligible randomized clinical trials (RCTs), published between Jan 1990 and Nov 2015, to compare LS and OS for rectal cancer. For dichotomous and continuous variables, the outcomes were summarized as odds ratios (ORs) and weighted mean differences (WMDs) respectively. The combined survival outcomes were expressed as hazard ratios (HRs). Subgroup analysis was conducted for patients underwent total mesorectal excision (TME). The PRISMA statement was complied. Results: Fifteen RCTs enrolling 4112 patients were included. The patients’ baseline characteristics of two groups were similar. The incomplete resection of mesorectal fascia was significantly more common in LS patients (OR, 1.49). There were no significant differences in circumferential resection margin (CRM) involvement, number of lymph nodes harvested, distal resection margin clearance. The TME subgroup analysis showed a higher rate of CRM involvement in LS group (OR, 1.56). The disease free survival and overall survival were equivalent. The inferior pathological results were led by the latest trials of ALaCaRT and ACOSOGZ6051, which had not reported the long-term results. Conclusions: This study demonstrated that laparoscopic rectal cancer resection related with the inferiority for pathological outcomes, especially in patients received TME. More long-term results of RCTs are mandatory to evaluate the safety of LS for rectal cancer. Meta-analysis results of pathological and long-term outcomes. Outcomes Overall Analysis Subgroup Analysis (TME) Number (LS/OS) OR, WMD or HR (95% CI) P Number (LS/OS) OR, WMD or HR (95% CI) P Incomplete Mesorectal Fascia 1348/989 1.49 (1.17,1.90) 0.001 682/ 658 1.52 (1.14,2.03) 0.004 CRM Involvement 1780/ 1377 1.22 (0.92,1.61) 0.17 840/ 818 1.56 (1.03,2.38) 0.04 Disease Free Survival 1348/880 0.94 (0.83,1.08) 0.39 343/ 338 0.97 (0.79,1.19) 0.78 Overall Survival 1517/ 1054 0.90 (0.80,1.02) 0.11 512/ 512 0.99 (0.84,1.16) 0.89 I 2 value of above outcomes were 0 % indicating no heterogeneity.
Identification of novel intra-genic deletions of <i>CTNNB1</i> gene in WT desmoid-type fibromatosis.
Authors: Milena Urbini, Annalisa Astolfi, Paola Collini, Valentina Indio, Antonino Belfiore, Nicholas Paielli, Federica Perrone, Giuseppe Tarantino, Elena Palassini, Marco Fiore, Andrea Pession, Silvia Stacchiotti, Maria A. Pantaleo, Alessandro Gronchi, Chiara Colombo
Journal: Journal of Clinical Oncology (2018)

11577 Background: Desmoid-type fibromatosis (DT) are characterized by molecular alterations of CTNNB1 or APC genes. These abnormalities have been described in ∼85% of DT using Sanger sequencing. Recently, whole-exome sequencing allowed to detect molecular aberrations in CTNNB1 or APC in approximately 95% of DT. In order to characterized the true WT DT, we performed this study on DT WT Sanger-sequenced samples. Methods: Deep sequencing of CTNNB1 and of APC was performed using TruSeq Custom Amplicon Low Input kit (Illumina) on 11 WT FFPE DT samples from patients treated with surgery. Whole Exome sequencing (WES) was performed using Nextseq500 (Illumina, CA) sequencer. Mutations were validated through Sanger sequencing, and expression of CTNNB1 mutated alleles was evaluated through RT-PCR. Results: APC mutation was found in 2 cases, while low-frequency CTNNB1 mutations were discovered in 5 samples (45%) (mean of 16% reads) and 4 cases remained WT. WES was performed in 6 cases (3 CTNNB1 WT and 3 with low frequency mutations). Through in-depth analysis of reads spanning exon 3 of CTNNB1, 2 large intra-genic deletions were detected in 2 cases, one carrying also a T41A low frequency mutation. Both deletions were approximatively of 190bp and led to the loss of the T41 codon hotspot of mutation. In one case, the deletion led to the loss of the second half of exon 3 and part of intron 3, in the other it involved part of intron 2 and the 5’ part of exon 3 losing the splicing acceptor site. We demonstrated that even if the acceptor splicing site was lost, the deleted allele of CTNNB1 was expressed, with the retention of 32 bp of intron 2 in the mature mRNA. Moreover, we demonstrated that, at mRNA level, low frequency T41A mutated allele was the prevalent isoform expressed with respect to the WT allele. The importance of these molecular alterations in the natural history of DT needs further investigations. Conclusions: A minority of DT is WT for either CTNNB1, APC or any other gene involved in the WNT pathway. In this subgroup novel and hard to be detected molecular deletions of CTNNB1 were discovered, contributing to explain a portion of the allegedly WT DT cases.
Abstract 12139: Calpain Inhibition Attenuates Contractile Dysfunction Induced by Cardiac Dyssynchrony
Authors: Clifford R Greyson, Shuyu Ye, Li Lu, Gregory G Schwartz, John S Walker
Journal: Circulation (2015)

Introduction: Cardiac dyssynchrony confers poor prognosis in heart failure, but whether dyssynchrony is merely a marker for contractile dysfunction, or actively contributes to it, is uncertain. In vivo, dyssynchrony causes local muscle lengthening during electrical activation. In skeletal muscle, forced lengthening during contraction (LEN-CON) activates the calcium sensitive protease calpain and causes contractile dysfunction and sarcomere disorganization. Hypothesis: Calpain inhibition attenuates contractile dysfunction and sarcomere disorganization in cardiac muscle subjected to LEN-CON. Methods: Rat right ventricular trabeculae (cross sectional area 0.06±.04 mm 2 ) at fixed diastolic length L 0 were paced at 1 Hz for 1 hr and allowed to shorten against normal load (50% initial isometric force F 0 , CONTROL n=4), or forced to lengthen to 110% L 0 during each contraction without (UNTREATED n=12) or with (TREATED n=14) calpain inhibitor (calpeptin 1 μM). After 1 hr, isometric force was remeasured (F 1Hr ), and sarcomere length, length dispersion and organization in trabeculae fixed in diastole at L 0 and stained for α-actinin were quantified by Fourier power spectrum analysis of digitally deconvolved photomicrographs. Results: In CONTROL, isometric force was unchanged after 1 hr (F 1Hr /F 0 94±18%, mean±SD). In UNTREATED, 1 hr LEN-CON caused dysfunction (F 1Hr /F 0 50±9%, p&lt;.001 vs CONTROL). In TREATED, dysfunction from LEN-CON was attenuated (F 1Hr /F 0 63±16%, p=.02 vs UNTREATED). Sarcomere length after LEN-CON was similar in UNTREATED and TREATED (2.21±.20 vs 2.12±.09 μm, p=NS), but TREATED showed less length dispersion and better preserved sarcomere organization (FIG) by Fourier analysis (p&lt;.05). Conclusions: Lengthening contraction causes dysfunction and sarcomere disorganization in cardiac muscle, at least in part through calpain activation. Calpain inhibition may have potential to ameliorate contractile dysfunction due to dyssynchrony in vivo.
TCT-282 Unstable Coronary Microvascular Physiology - The Critical Relationship of Patency and Perfusion Pressure Assessed by Controlled Flow Infusion
Authors: Esther Gerteis, Robert Schwartz, Martin Rothman, Jonathan Schwartz, Oliver Bludau, Jon Hoem, Nikola Cesarovic, Mareike Gastl, Blathnaid Feldman
Journal: Journal of the American College of Cardiology (2018)
Clinicopathologic features of ‘best’ and ‘worst’ responders to PD1/PDL1 checkpoint inhibitors (CPIs) in non-small-cell lung cancer (NSCLC).
Authors: Dawn Michelle Stults, Shelby Condello, Melissa Moore, David R. Spigel, Melissa Lynne Johnson
Journal: Journal of Clinical Oncology (2016)

e20658 Background: CPIs have led to improved survival and response duration for patients (pts) with NSCLC. Tumor PDL1 expression using IHC is a method for predicting benefit from CPIs, but more reliable biomarkers are needed. Other clinicopathologic features for predicting benefit have been suggested, including heavy smoking history, high mutation burden, and exposure to radiation (RT). Here we report a retrospective analysis of pts with NSCLC treated with CPI monotherapy. Methods: We sought to identify clinical and molecular characteristics associated with benefit from CPI treatment (tx) in a database of pts with NSCLC treated in the community from March, 2013 through October, 2014. We identified pts with a highly favorable (HFR, ‘best’) response to CPI tx as those having partial response to tx (per RECIST 1.1) or duration of tx > 1 year; and pts with unfavorable responses (UFR, ‘worst’) as those whom came off CPI tx due to progressive disease at the first disease evaluation after ≥ 3 doses of tx. Next-Generation Sequencing (NGS) results were assessed where available. Results: As of Sept 2015, 152 pts were treated with CPI (median time on tx 117 days (range 1-849)). 28 pts were classified in the HFR cohort; 29 pts in the UFR cohort. Baseline characteristics including age, gender, smoking history, and RT exposure were similar between cohorts (Table). NGS revealed similar numbers of genomic alterations (GA)/variants of unknown significance (VUS) between HFR and UFR cohorts. Driver oncogenes were noted in both groups (2 EGFR mutations in the HFR group and 3 ALK rearrangements in the UFR group) as well as individual outliers-including one pt with 42 GA and 134 VUS who remains on tx for 2.5+ years. Conclusions: In this analysis, there was no clear clinical or molecular differences identified between two groups of pts with distinct responses to CPI tx. Additional work is needed to identify predictive factors for response to immunotherapy. HFR N = 28 UFR N = 29 Median Age 67 (53-86) 63 (50-88) Male 20 21 Female 8 8 Smoking History (median pack years) 46 (0 -135) 40 (0 - 0.92) 0 - 20 9 7 > 20 19 22 Prior RT exposure 13 19 No RT exposure 15 10 # GA by NGS (median) 3.5 5.5 # of total mutation burden (GA+VUS) (median) 12 12
Inflammation, Superadded Inflammation, and Out-of-Proportion Inflammation in Atherosclerosis
Authors: Jagat Narula, Eloisa Arbustini
Journal: JAMA Cardiology (2018)

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Resolving diagnostic uncertainty in bone-predominant metastases in cancer of unknown primary (CUP) using the 92-gene assay.
Authors: Kanwal Pratap Singh Raghav, Graham M. Poage, Catherine A. Schnabel, Gauri R. Varadhachary
Journal: Journal of Clinical Oncology (2018)

12064 Background: Bone-predominant metastases in patients (pts) with CUP pose diagnostic challenges in pathologic analyses, which may delay optimal therapy. The 92-gene assay is a validated gene expression profiling (GEP)–based cancer classifier with high accuracy in limited tissue. This study evaluated performance and clinical utility of the 92-gene assay in bone biopsies from bone-predominant CUP. Methods: A correlative database integrating 92-gene assay (CancerTYPE ID) results and de-identified patient data was developed under an IRB-approved protocol for 26,594 cases where the assay was performed in routine care. Database was queried using biopsy site of bone/skeletal designation (rib, pelvis, vertebrae, sacrum, femur). Descriptive statistics and Chi-square analyses were used. Results: 7% (n = 1834) of cases were bone specimens. With an analytical success rate of 70%, a molecular diagnosis was made in 94% cases, among which pancreaticobiliary (Pb; 19%), NSCLC (14%), and kidney (8.3%) were most frequently classified tumors. Kidney, sarcoma, liver, salivary gland, and thyroid were more prevalent with bone biopsies (all p< 0.05), while neuroendocrine, intestine, ovary, and endometrium were more frequent with non-bone cases (all p< 0.05). In Pb subtypes, gallbladder showed a higher proportion of bone cases (p< 0.001) compared to cholangiocarcinoma and pancreas. Higher frequency of immune-responsive tumor types was observed in bone vs non-bone biopsies (44% vs 35%), with kidney and liver predictions 2-3x more frequent in bone samples (p< 0.0001). Conclusions: The 92-gene assay is effective for molecular diagnosis in bone-predominant CUP. In this large cohort of bone biopsies, tumor type results matched previously reported frequencies of CUP putative primaries. A notable subset of bone-predominant CUP was identified as having a molecular diagnosis with an FDA-approved indication for immunotherapy. These results indicate a promising avenue for a GEP classifier to identify immune-responsive CUP subsets. Given the limited nature of bone samples, tissue-sparing GEP assay should be considered early in the diagnostic workup to direct biomarker testing and treatment selection.
Personalized periodontal treatment for the tobacco‐ and alcohol‐using patient
Authors: Mark I. Ryder, Elizabeth T. Couch, Benjamin W. Chaffee
Journal: Periodontology 2000 (2018)

The use of various forms of tobacco is one of the most important preventable risk factors for the incidence and progression of periodontal disease. Tobacco use negatively affects treatment outcomes for both periodontal diseases and conditions, and for dental implants. Tobacco-cessation programs can mitigate these adverse dental treatment outcomes and may be the most effective component of a personalized periodontal treatment approach. In addition, heavy alcohol consumption may exacerbate the adverse effects of tobacco use. In this review, the microbiology, host/inflammatory responses and genetic characteristics of the tobacco-using patient are presented as a framework to aid the practitioner in developing personalized treatment strategies for these patients. These personalized approaches can be used for patients who use a variety of tobacco products, including cigarettes, cigars, pipes, smokeless tobacco products, e-cigarettes and other tobacco forms, as well as patients who consume large amounts of alcohol. In addition, principles for developing personalized tobacco-cessation programs, using both traditional and newer motivational and pharmacological approaches, are presented.
Abstract 14124: A Marked Increase in Myocardial Oxidative Stress Associated With Sympathetic Hyperactivity is Related to Transient Myocardial Dysfunction in Patients With Takotsubo Cardiomyopathy
Authors: Takuma Nanno, Shigeki Kobayashi, Seiko Oda, Hironori Ishiguchi, Takeki Myoren, Yosuke Miyazaki, Takeshi Suetomi, Makoto Ono, Mamoru Mochizuki, Tetsuro Oda, Shinichi Okuda, Jutaro Yamada, Takayuki Okamura, Masafumi Yano
Journal: Circulation (2015)

Introduction: Sympathetic hyperactivity is considered as one of the most likely pathogenic mechanism in takotsubo cardiomyopathy (TC). However, little is known about the relationship between sympathetic hyperactivity and myocardial oxidative stress (OS). Hypothesis: We hypothesized that cardiac sympathetic hyperactivity was associated with cardiac myocardial OS, and OS related to transient myocardial dysfunction in patients with TC compared with acute anteroseptal myocardial infarction (AMI). Methods: In 8 TC patients and 8 AMI patients (NYHA 3), ECG, echocardiography, cardiac catheterization and serial measurements of plasma catecholamines, urinary (U) 8-hydroxy-2’-deoxyguanosine (8-OHdG) as a marker of OS and plasma CPK were performed for two weeks from onset. Results: Blood sampling from coronary sinus (CS) and aorta (Ao) at 1st day showed that norepinephrine (NE) levels and 8-OHdG level in CS were significantly higher than those in Ao and peripheral blood, indicating that an increase in myocardial OS was associated with cardiac sympathetic hyperactivity. NE levels in peripheral blood were peaked out at 1st day and 2-times higher in TC than in AMI within a week, while the max CPK value in TC was significantly lower than that in AMI. Dual scintigraphy of 201Tl and 123I-meta-iodobenzylguanidine was performed at 7th day showed that cardiac sympathetic nervous injury was much larger than myocardial perfusion damage in all TC patients. U-8OHdG level (ng/mg Cr; normal range:&lt;10.0) in TC was elevated in parallel with the profile of plasma NE level (1st day: 65.6±24.5, 4th day: 19.1±8.3, 7th day: 16.4±9.1), while it was decreased to almost normal range after percutaneous coronary intervention for left anterior descending artery in AMI (1st day: 24.3±13.8, 4th day: 9.8±3.4, 7th day: 12.3±2.7). Interestingly, difference in serum 8-OHdG levels (CS vs Ao) in TC increased proportionally with wall motion score (WMS) as an index of LV dysfunction (R=0.93, p&lt;0.001), while difference in serum NA levels (CA vs Ao) in TC did not. U-8OHdG level in TC was positively correlated with WMS at each day (1st day, 7th day). Conclusions: These findings suggest that myocardial OS induced by cardiac sympathetic hyperactivity may play a critical role in transient LV dysfunction in TC.