tbuckley/cabot-search huggingface dataset:
Benefits of physician orders for scope of treatment (POST) forms on end-of-life care in cancer patients: Insights from the West Virginia registry.
Authors: Mark W. Knestrick, Sandra L. Pedraza, Stacey Culp, Evan C. Falkenstine, Alvin Howard Moss
Journal: Journal of Clinical Oncology (2016)

10006 Background: The West Virginia POST form, a POLST Paradigm form (www.polst.org), converts patient preferences into medical orders and implements advance care planning for patients with advanced illness for whom their physicians would not be surprised if they died in the next year. Few studies have evaluated the benefits of POST forms to cancer patients. The objective of this study was to compare the outcomes from the use of POST forms versus advance directives (ADs) on end-of-life care quality metrics in cancer patients. Methods: A retrospective study of West Virginians who submitted POST forms or ADs to the West Virginia e-Directory Registry and died from cancer between 1/1/2011 and 6/30/2014. Results: Of patients in the West Virginia e-Directive Registry during the study period, 1129 patients were identified who died from cancer: 538 (47.7%) with ADs and 591 (52.3%) with POST forms. Of patients with POST forms, 323 (54.7%) were referred to hospice compared to 146 (27.1%) with ADs (p<.001). In-hospital death occurred in 163 (30.3%) of patients with ADs compared to only 66 (11.2%) of patients with POST forms; the unadjusted odds ratio for an out-of-hospital death for patients with POST forms compared to AD was 3.46 (p<.001). Of the 591 POST forms, 31 oncologists completed 82 (13.9%), 20 palliative care physicians completed 205 (34.7%), and 195 primary care physicians completed 304 (51.4%). Median time from POST form completion to death was only .95 months. Conclusions: Utilization of POST forms compared to advance directives in cancer patients is associated with a greater achievement of two quality metrics for end-of-life care: referral to hospice and out-of-hospital death. Oncologist use of the surprise question and earlier POST form discussions may contribute to higher quality end-of-life care for patients with advanced cancer.
miR-106b-5p, miR-17-5p to predict recurrence and progression in breast DCIS model based on TGFβ paradox.
Authors: Jieun Lee, Kwangil Yim, Dong-Min Kim, Young-Seok Song, Ahwon Lee
Journal: Journal of Clinical Oncology (2017)

e23019 Background: Ductal carcinoma in situ (DCIS) is a well-known precursor of invasive ductal carcinoma (IDC). Part of patients show disease recurrence as DCIS or IDC after local treatment, but there are no established markers for prediction of recurrence. Methods: Authors analyzed 30 patients diagnosed as pure DCIS, recurrent DCIS, and IDC progressed in DCIS background. miRNA was extracted from archival tissue, and hierarchical clustering of miRNA microarray was performed. We selected highly expressed miR-17-5p and miR-106b-5p as marker for recurrence of DCIS. Two miRNAs were transfected to MCF-12 and MCF-7 cell line. Cell proliferation assay and Western blot analysis was performed for analyzing the interaction between cell proliferation and TGFβ downstream pathway. Results: miR-106b-5p single and combined miR-106b-5p and miR-17-5p transfected MCF-12 cell line showed increased proliferation index compared to un-transfected cell line. In MCF-7, miR-106b and miR-17-5p transfected cell line showed inferior proliferation index compared to un-transfected cell line. Western blot analysis showed minimal increased expression of SMAD4, phosphorylated SMAD2 (pSMAD2) in miR-106b-5p and miR-17-5p transfected MCF-12 cell line. However, decreased expression of TGFBR2 and no interval change of SMAD4 and pSMAD2 was detected in miR-106b-5p and miR-17-5p transfected MCF-7 cell line. Conclusions: miR-106-5p, miR-17-5p showed increased expression in recurrent DCIS or IDC based on miRNA hierarchical microarray. miRNA transfected MCF-12 cell line showed increased proliferation index and activated TGFβ downstream pathway. miRNA transfection might have made normal cell line to pre-cancerous cell line and TGFβ pathway might have influenced to promote tumor proliferation, based on TGFβ paradox hypothesis.
Comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck.
Authors: Inge Tinhofer, Theresa Eder, Robert Konschak, Franziska Niehr, Korinna Jöhrens, Ulrich Keilholz, Volker Budach
Journal: Journal of Clinical Oncology (2017)

6059 Background: Recent next-generation sequencing (NGS) studies revealed a wide mutational spectrum in SCCHN. However, little is known about spatial intratumoral heterogeneity and temporal clonal evolution. Precise understanding of the genomic architecture of primary and recurrent/metastatic (R/M) tumors will be crucial for the development of personalized treatment and molecular biomarkers. Methods: In this pilot study, paired tumor samples (primary, R/M lesions) from 10 patients with locally advanced SCCHN who progressed after concurrent chemoradiation (CTRX) were included. Mutational profiling was performed by NGS targeting the exonic regions of 327 genes. Only somatic mutant variants with a difference of ≥0.15 in allele frequency (AF) between primary and R/M tumors were considered for further analysis. Results: Median time to progression was 6.2 months (range: 2.5-30.2). Overall, the difference in mutational patterns of primary and R/M tissue was very small. On average, one mutant variant (range: 0-2) was selectively detected in only one of the paired samples or differed in AF for ≥0.15. Nonetheless, clonal selection of mutant variants previously linked to disease progression was observed in 8 of 10 cases. In line with their gain of function, an increase in AF of TP53 missense mutations (R175H, R248Q) in the recurrent tumor - suggestive of the selection of treatment-resistant mutant TP53 subclones - was observed in two patients. Further variants with increased mutant AF in recurrent tumors were found in ADCY2, CDKN2A, FGFR3, MET, NOTCH1, PIK3CA and TGFBR2. Conclusions: We here provide first evidence that treatment-induced clonal selection after CRTX frequently occurs in SCCHN but is limited to only few gene alterations associated with an aggressive phenotype. This result is surprising given CRTX being a DNA-damaging regimen with inherent risk of de-novo mutagenesis and abundant time for clonal tumor evolution. Further investigations of spatial intratumoral heterogeneity and clonal evolution in larger patient cohorts are required for improving our understanding of treatment resistance and disease progression in SCCHN.
Disease-Free and Overall Survival Among Patients With Operable HER2-Positive Breast Cancer Treated With Sequential vs Concurrent Chemotherapy
Authors: Aman U. Buzdar, Vera J. Suman, Funda Meric-Bernstam, Ann Marilyn Leitch, Matthew J. Ellis, Judy C. Boughey, Gary W. Unzeitig, Melanie E. Royce, Kelly K. Hunt
Journal: JAMA Oncology (2018)

<h3>Importance</h3> Pathologic complete response rate (pCR), the primary end point of the ACOSOG (American College of Surgeons Oncology Group) Z1041 (Alliance) trial, and disease-free survival (DFS) and overall survival (OS) in women with operable HER2-positive breast cancer are similar between treatment regimens. <h3>Objective</h3> To assess DFS and OS for patients treated with sequential vs concurrent anthracycline plus trastuzumab. <h3>Design, Setting, and Participants</h3> Phase 3 randomized clinical trial conducted at 36 centers in the continental United States and Puerto Rico. Women 18 years or older with invasive operable HER2-positive breast cancer were enrolled from September 15, 2007, to December 15, 2011, and randomized to 1 of 2 treatment arms. The analysis data set was locked on October 15, 2017, and analysis was completed on December 15, 2017. <h3>Interventions</h3> Patients randomized to arm 1 received 500 mg/m<sup>2</sup>of fluorouracil, 75 mg/m<sup>2</sup>of epirubicin, and 500 mg/m<sup>2</sup>of cyclophosphamide (FEC) every 3 weeks for 12 weeks followed by the combination of 80 mg/m<sup>2</sup>of paclitaxel and 2 mg/kg (except initial dose of 4 mg/kg) of trastuzumab weekly for 12 weeks. Patients randomized to arm 2 received the same combination of paclitaxel with trastuzumab weekly for 12 weeks followed by FEC every 3 weeks with weekly trastuzumab for 12 weeks. Women with hormone receptor–positive disease received endocrine therapy, and radiotherapy was delivered at physician discretion. <h3>Main Outcomes and Measures</h3> The primary outcomes were DFS and OS and pCR in the breast and nodes. <h3>Results</h3> Two hundred eighty-two women with HER2-positive breast cancer were enrolled in the trial, and 2 withdrew consent before treatment. Among the remaining 280 women, the median age was 50 years (range, 28-76 years), 232 (82.9%) were white, 29 (10.3%) were black, 8 (2.9%) were Asian, 4 (1.4%) were American Indian or Alaskan Native, and 7 (2.5%) did not report race/ethnicity. There were 22 disease events in arm 1 and 27 in arm 2. Disease-free survival rates did not differ with respect to treatment arm (stratified log-rank<i>P</i> = .96; stratified hazard ratio [HR] [arm 2 to arm 1], 1.02; 95% CI, 0.56-1.83). Overall survival did not differ with respect to treatment arm (stratified log-rank<i>P</i> = .73; stratified HR [arm 2 to arm 1], 1.17; 95% CI, 0.48-2.88). <h3>Conclusions and Relevance</h3> Across a median follow-up of 5.1 years (range, 26 days to 6.2 years), pCR, DFS, and OS did not differ with respect to sequential or concurrent administration of FEC with trastuzumab. <h3>Trial Registration</h3> ClinicalTrials.gov identifier:NCT00513292
Safety and tolerability of cancer drugs studied in phase 3 randomized controlled trials (RCTs) over the last decade.
Authors: Domen Ribnikar, Hadar Goldvaser, Alberto Ocana, Arnoud J. Templeton, Bostjan Seruga, Eitan Amir
Journal: Journal of Clinical Oncology (2018)

6588 Background: Data suggest that newly approved cancer drugs have worse safety and tolerability profiles than older drugs used as control groups in trials. However, less is known about the toxicity profile of cancer drugs studied in unselected phase 3 clinical trials including those not resulting in regulatory approval. Methods: We searched clinicaltrials.gov to identify phase 3 RCTs evaluating experimental drugs in patients with metastatic breast, colorectal, lung and prostate cancer. We included all RCTs completed between 1 January 2005 and 31 October 2016. Odds ratios (OR) and 95% CI were computed for the following safety and tolerability end points: toxic death, treatment discontinuation without progression and commonly reported grade 3-4 adverse events (AEs). Data were then pooled in a meta-analysis using RevMan 5.3 software. Results: The analysis included 143 RCTs comprising 88,603 patients. 75% of the trials evaluated targeted therapies (including endocrine and immunotherapy). Compared to control groups, experimental drugs were associated with higher odds of toxic death (OR, 1.14; 95% CI, 1.03-1.27), treatment discontinuation without progression (OR, 1.64; 95% CI, 1.56-1.71) and grade 3-4 AEs (see Table). Conclusions: New cancer drugs studied in phase 3 RCTs are associated with worse safety and tolerability profiles compared to standard therapies when reported by investigators and have increased treatment-related mortality. Cancer patients considering enrollment on phase 3 trials should be aware of these risks. Toxicity OR 95% CI p % of trials with significantly higher odds in the experimental arm % of trials with significantly lower odds in the experimental arm Toxic death 1.14 1.03-1.27 0.02 5 0 Treatment discontinuation 1.64 1.56-1.71 < 0.001 46 7 Anemia 1.15 0.96-1.38 0.13 14 11 Neutropenia 1.09 0.86-1.39 0.47 28 25 Thrombocytopenia 2.04 1.46-2.85 < 0.001 16 2 Diarrhea 1.97 1.59-2.42 < 0.001 33 5 Vomiting 1.19 1.01-1.41 0.04 8 3 Stomatitis 2.44 1.69-3.51 < 0.001 25 4 Hypertension 2.63 1.93-3.60 < 0.001 42 4 Cardiac 1.46 1.19-1.78 < 0.001 9 0 Fatigue/asthenia 1.30 1.16-1.46 < 0.001 24 5 Skin 3.58 2.53-5.07 < 0.001 43 8 Dyspnea 1.04 0.91-1.19 0.52 6 2 Neuropathy 1.14 0.66-1.96 0.65 11 11
Carotid body tumors in Japan: A multi-institutional study.
Authors: Kiyoto Shiga, Aya Ikeda, Daisuke Saitoh, Katsunori Katagiri, Shin-ichi Oikawa
Journal: Journal of Clinical Oncology (2017)

e17574 Background: Carotid body tumor (CBT) is thought to be a rare disease derived from carotid body paraganglion cells. It is well known that this tumor is related to some hereditary tendencies that linked to such as SDH gene mutations. CBTs have rich vascular contents and capsules supplied by many feeding arteries. When we head and neck surgeons perform resection sugery, we sometimes encounter much blood loss or injuries of carotid arteries. There has been no study to reveal the characteristic features of CBT patients in Japan because of lack of registration and survey system for them. Methods: We attempted to analyze CBT patients all over Japan by integrating information of CBT patients from institutions which had head and neck surgeries. Results: 399 patients were referred to 112 institutes for past 20 years. Among these patients, 150 were registered to our study. There were 87 female and 63 male patients and their mean and median age were 48.0 years old and 49 years old, respectively, ranging from 8 to 78 years old. Eighteen patients had family history of paragangliomas. 15 patients had bilateral CBTs. Among 94 patients who underwent surgery to remove CBT, 23 patients had tumors classified as Shamblin type I, 59 as type II and 12 as type III. Mean operation time of the surgery and the mean amount of blood loss were calculated to compare. Angiography revealed that most frequent feeding artery of these CBTs was ascending pharyngeal artery followed by superior thyroid artery and occipital artery. Preoperative embolization of these arteries was effective to reduce the blood loss but operation time in Shamblin type I and II tumors. Conclusions: Further investigation will be needed to clarify gene mutations for hereditary paragangliomas including CBTs in Japan.
Pan-cancer genomic features of <i>PIK3CA/PTEN</i> and clinical response to everolimus in Chinese population.
Authors: Guoling Lin, Zhang Xiao Chen, Yong Li, Yunsheng Qin, Zhen Lv, Tao Xiang, Yingcheng Lin, Cheng Zou, William Lewis, Honglin Guo, Jinwei Hu, Aodi Wang, Ming Yao
Journal: Journal of Clinical Oncology (2018)

e24283 Background: PI3K/mTOR signaling pathway plays a central role in cancer biology. Previously studies had shown that mTOR inhibitors might be a promising therapeutic approach in patients (pts) with PIK3CA/PTEN mutations. Pan-cancer study about characteristics of PIK3CA/PTEN variations in Chinese population had not been fully evaluated. Methods: FFPE tumor and matched blood samples of 515 Chinese pts including 317 males and 198 females with a median age of 58 years were collected for NGS based 450-gene panel assay. The whole cohort included 314 lung adenocarcinomas (ADC), 128 colorectal carcinomas (CRC) and 73 hepatocellular carcinomas (HCC). Genomic alterations including single base substitutions, short and long insertions/deletions, copy number variations, gene rearrangements in selected genes were assessed. Results: PIK3CA variations were detected in 8.7% of Chinese cancer pts, in which the hotspot mutations included E542, E545 and H1047 accounted for 71.1%. PTEN variations were detected in 4.5% of the pts, whereas 6 pts had both PIK3CA and PTEN mutations. The rates of PIK3CA/PTEN variations in CRC, ADC and HCC were 23.4%, 8.6% and 6.7%, respectively. Compared with TCGA dataset, more PIK3CA/PTEN alterations were ovserved in Chinese CRC patients than Western ones (23.4% vs 12.1%), but similar frequency in ADC (8.6% vs 6.1%) and HCC (6.7% vs 7.1%). In CRC patients with PIK3CA/PTEN mutations, 63.3% and 53.3% of them were found possessing mutations in KRAS and APC respectively. 14 pts with PIK3CA or PTEN alterations including 8 NSCLC, 3 cholangiocarcinoma, 1 lung neuroendocrine carcinoma, 1 soft tissue sarcoma and 1 osteosarcoma had been treated with Everolimus. Two pts (both NSCLC) achieved partial response (PR), and 9 pts showed stable disease (SD), resulting in a disease control rate (DCR) of 78%. Conclusions: Our study revealed the pan-cancer genomic profile differed in different cancer types, more PIK3CA/PTEN mutated in Chinese CRC pts than western population. The retrospective analysis of efficacy of everolimus monotherapy in a small cohort of pts with PIK3CA/PTEN alterations across various cancers showed DCR of 78%, which indicated the regimen was effective in PI3K/mTOR pathway activated solid tumors.
Abstract 12221: Impact of Serum Uric Acid on Mortality in Heart Failure With Preserved Ejection Fraction
Authors: Takeshi Shimizu, Akiomi Yoshihisa, Mai Takiguchi, Shunsuke Miura, Akihiko Sato, Yuichi Nakamura, Hiroyuki Yamauchi, Takashi Owada, Satoshi Abe, Satoshi Suzuki, Masayoshi Oikawa, Takayoshi Yamaki, Koichi Sugimoto, Hiroyuki Kunii, Kazuhiko Nakazato, Hitoshi Suzuki, Shu-ichi Saitoh, Yasuchika Takeishi
Journal: Circulation (2015)

Background: Serum uric acid is a predictor of cardiovascular mortality in heart failure with reduced ejection fraction. However, the impact of uric acid on heart failure with preserved ejection fraction (HFpEF) remains unclear. Here we investigated the association between hyperuricemia and mortality in HFpEF patients. Methods and Results: Consecutive 424 patients, who admitted to our hospital for decompensated heart failure and diagnosed as HFpEF, were divided into two groups based on presence of hyperuricemia (serum uric acid ≥ 7 mg/dl). We compared patient characteristics, cardio-ankle vascular index and cardio-pulmonary exercise test findings between the two groups. Furthermore, we prospectively followed cardiac and all-cause mortality. The hyperuricemia group (n=254), as compared with non-hyperuricemia group (n=170), had higher prevalence of male gender (55.5 vs. 41.7%, P=0.005), hypertension (79.9 vs. 69.4%, P=0.013), diabetes mellitus (38.5 vs. 26.4%, P=0.010) and use of diuretics (72.4 vs. 41.7%, P&lt;0.001). Furthermore, the hyperuricemia group had higher levels of B-type natriuretic peptide (112.3 vs. 71.4 pg/ml, P&lt;0.001), lower levels of estimated GFR (53.2 vs. 69.7 ml/min/1.73m 2 , P&lt;0.001), higher cardio-ankle vascular index (8.7 vs. 7.5, P&lt;0.001), lower peak VO 2 (14.9 vs. 17.9 ml/kg/min, P&lt;0.001) and higher VE/VCO 2 slope (34.9 vs. 31.9, P=0.02) compared with non-hyperuricemia group. In the follow up period (mean of 897 days), cardiac and all-cause mortalities were significantly higher in those with hyperuricemia (P=0.006 and P=0.004, respectively). In the multivariable Cox proportional hazard analyses after adjusting for confounding factors including chronic kidney disease and use of diuretics, hyperuricemia was an independent predictor of all-cause mortality (hazard ratio 1.98, P=0.039). Conclusion: Hyperuricemia is associated with arterial stiffness, impaired exercise capacity, and high mortality in HFpEF.
Maternal Immune Activation and Neuropsychiatric Illness: A Translational Research Perspective
Authors: Alan S. Brown, Urs Meyer
Journal: American Journal of Psychiatry (2018)

Epidemiologic studies, including prospective birth cohort investigations, have implicated maternal immune activation in the etiology of neuropsychiatric disorders. Maternal infectious pathogens and inflammation are plausible risk factors for these outcomes and have been associated with schizophrenia, autism spectrum disorder, and bipolar disorder. Concurrent with epidemiologic research are animal models of prenatal immune activation, which have documented behavioral, neurochemical, neuroanatomic, and neurophysiologic disruptions that mirror phenotypes observed in these neuropsychiatric disorders. Epidemiologic studies of maternal immune activation offer the advantage of directly evaluating human populations but are limited in their ability to uncover pathogenic mechanisms. Animal models, on the other hand, are limited in their generalizability to psychiatric disorders but have made significant strides toward discovering causal relationships and biological pathways between maternal immune activation and neuropsychiatric phenotypes. Incorporating these risk factors in reverse translational animal models of maternal immune activation has yielded a wealth of data supporting the predictive potential of epidemiologic studies. To further enhance the translatability between epidemiology and basic science, the authors propose a complementary approach that includes deconstructing neuropsychiatric outcomes of maternal immune activation into key pathophysiologically defined phenotypes that are identifiable in humans and animals and that evaluate the interspecies concordance regarding interactions between maternal immune activation and genetic and epigenetic factors, including processes involving intergenerational disease transmission. [AJP AT 175: Remembering Our Past As We Envision Our Future October 1857: The Pathology of Insanity J.C. Bucknill: "In the brain the state of inflammation itself either very quickly ceases or very soon causes death; but when it does cease it leaves behind it consequences which are frequently the causes of insanity, and the conditions of cerebral atrophy." (Am J Psychiatry 1857; 14:172-193 )].
Abstract 15854: Association of Low Endothelial Shear Stress With Coronary Microvascular Endothelial Dysfunction in Patients With Early Coronary Atherosclerosis
Authors: Gerasimos Siasos, Jaskanwal D Sara, Marina Zaromitidou, Kyoung H Park, Shi-Wei Yang, Ahmet Umit Coskun, Lilach O Lerman, Dimitris Fotiadis, Lampros Michalis, Michail Papafaklis, Kostas Stefanou, Charles Feldman, Amir Lerman, Peter H Stone
Journal: Circulation (2016)

Introduction: Coronary microvascular disease is related to higher risk of cardiovascular events in patients without significant epicardial stenosis. Hypothesis: Low endothelial shear stress (ESS) is associated with coronary microvascular endothelial dysfunction and high risk plaque characteristics in patients with early atherosclerosis. Methods: Fifty one subjects (age 53±10 y) with mild coronary atherosclerosis (diameter stenosis <40% throughout entire coronary arteries) were included. Coronary microvascular endothelial function was estimated using intracoronary acetylcholine infusion. Vascular profiling, using 2-plane coronary angiography and intravascular ultrasound, was used to reconstruct the 3-D anatomy of left anterior descending artery (LAD). Each reconstructed artery was divided into sequential 3mm segments and analyzed for the local ESS with computational fluid dynamics. Each segment was characterized by local predominant ESS values, including the average ESS and the lowest ESS in a 90° arc arou...