tbuckley/cabot-search huggingface dataset:
A pilot study of docetaxel and carboplatin for treatment of patients with mCRPC containing biallelic inactivation of genes in the <i>BRCA1/2</i> pathway.
Authors: Heather H. Cheng, Makayla DeJong, Evan Y. Yu, Roman Gulati, Matthew Rettig, Celestia S. Higano, Peter Nelson, Colin C. Pritchard, Robert B. Montgomery
Journal: Journal of Clinical Oncology (2020)

127 Background: Despite new treatments, metastatic castration resistant prostate cancer (mCRPC) remains ultimately lethal. Upwards of 25% of mCRPC tumors have alterations in homologous recombination DNA repair (HRD) genes, most frequently BRCA2. Retrospective data suggest addition of the DNA damaging agent carboplatin to standard docetaxel for patients with mCRPC whose tumors have biallelic inactivation of BRCA2 may be effective. Methods: In this prospective, pilot single-arm phase 2 study, we assess response to the combination of docetaxel 60mg/m 2 and carboplatin AUC 5 IV q21 days in patients with mCRPC whose tumors have evidence of biallelic inactivation of BRCA1, BRCA2 or ATM and have progressed after any prior treatment, including prior docetaxel and/or PARP inhibitor (PARPi). The primary endpoint is rate of ≥50% PSA decline from baseline (PSA 50 ). With H0 of PSA 50 of 26%, 14 patients will provide 80% power to conclude H1 of PSA 50 of 60% based on Simon's 2-stage design with 1-sided α = 5%. Secondary endpoints include PSA 30 , response duration, time to progression and correlative studies. Biallelic inactivation of other HRD-related genes were included at investigators’ discretion. Results: The study opened in Jan 2016 and has enrolled 8/14 (57%) of patients plus 5 patients with other HRD-related genes. 6/13 (46%) treated pts had grade 3 expected AEs, and no grade 4-5 AEs were observed. To date, 7/8 (88%) of pts with biallelic inactivation of BRCA1, BRCA2 and ATM (Table) and 10/13 (77%) of all pts achieved a PSA 50 (other HRD-related genes include CDK12, CHD1, MRE11A and PALB2). Updated results will be reported at final presentation. Conclusions: Addition of carboplatin to docetaxel appears to be well-tolerated and effective for patients with mCRPC whose tumors have biallelic inactivation in selected HRD genes such as BRCA2, including those with prior treatment with PARP inhibitor. Clinical trial information: NCT02598895. [Table: see text]
Erratum to ‘When not to start antibiotics: avoiding antibiotic overuse in the intensive care unit’ [Clin Microbiol Infect 26 (1) (January 2020) 35–40]
Authors: K.J. Denny, J. De Waele, K.B. Laupland, P.N.A. Harris, J. Lipman
Journal: Clinical Microbiology and Infection (2020)
Therapeutic Switch from Omalizumab to Mepolizumab in Patients with Uncontrolled Severe Eosinophilic Asthma: Treatment Effect by ACQ and SGRQ Quartiles
Authors: Kenneth Chapman, Bradley Chipps, Xavier Muñoz, Gilles Devouassoux, Miguel Bergna, Steven Smith, Frank Albers, Robert Price, Jay Azmi, Dmitri Galkin, Mark Liu
Journal: Journal of Allergy and Clinical Immunology (2020)
Impact of histology and toxicities on outcomes of patients with muscle invasive bladder cancer receiving neoadjuvant chemotherapy.
Authors: Catherine Curran, Gregory Russell Pond, Andres Acosta, Amin Nassar, Sarah Abou Alaiwi, Matthew D. Ingham, Mark A. Preston, Graeme S. Steele, Kerry L. Kilbridge, Bradley Alexander McGregor, Matthew Mossanen, Guru Sonpavde
Journal: Journal of Clinical Oncology (2020)

540 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) extends survival in muscle invasive bladder cancer (MIBC) patients (pts). Pathologic complete response (pCR) is associated with survival. We conducted a retrospective study to examine the prognostic impact of other variables including histologic subtype, location, multifocality, margins, size of tumor and toxicities. Methods: Pts who underwent RC at Dana-Farber for MIBC stage T2-T4N0-1 were studied. Data were collected for demographics, clinical and pathologic variables. Descriptive stats were reported, and Cox proportional hazards regression analyses were conducted to examine the association with recurrence-free survival (RFS) and overall survival (OS). Results: From 2002 to 2018, 150 patients were available. The median age was 66 (range 36-89) and 102 (68%) were male. MVAC/dose dense MVAC, GC and other non-standard regimens were given in 42 (28%), 85 (56.7%) and 23 (15.3%) pts, respectively. The 2-yr RFS was 63.6%, the 5-yr OS was 68.7% and pCR occurred in 38 pts (25.3%). Multivariable analysis identified pure urothelial carcinoma in the residual tumor and absence of pathologic response to be associated with poor RFS and OS. Positive margins were associated with poor RFS, while grade ≥3 toxicities were associated with poor OS. Conclusions: Pure urothelial carcinoma histology was associated with worse RFS and OS following RC after NAC for MIBC, suggesting molecular studies may be useful in these cases. The association of severe toxicities with poor OS suggests that optimal pt selection for NAC and early recognition of toxicities is important.[Table: see text]
Translation and functional roles of circular RNAs in human cancer
Authors: Ming Lei, Guantao Zheng, Qianqian Ning, Junnian Zheng, Dong Dong
Journal: Molecular Cancer (2020)

Abstract Circular RNAs (circRNAs) are a new class of non-coding RNAs formed by covalently closed loops through backsplicing. Recent methodologies have enabled in-depth characterization of circRNAs for identification and potential functions. CircRNAs play important roles in various biological functions as microRNA sponges, transcriptional regulators and combining with RNA binding proteins. Recent studies indicated that some cytoplasmic circRNAs can be effectively translated into detectable peptides, which enlightened us on the importance of circRNAs in cellular physiology function. Internal Ribosome Entry site (IRES)- and N 6 -methyladenosines (m 6 A)-mediated cap-independent translation initiation have been suggested to be potential mechanism for circRNA translation. To date, several translated circRNAs have been uncovered to play pivotal roles in human cancers. In this review, we introduced the properties and functions of circRNAs, and characterized the possible mechanism of translation initiation and complexity of the translation ability of circRNAs. We summarized the emerging functions of circRNA-encoded proteins in human cancer. The works on circRNA translation will open a hidden human proteome, and enhance us to understand the importance of circRNAs in human cancer, which has been poorly explored so far.
Reduction of HbA1c in patients with type 2 diabetes following duodenal mucosal resurfacing: could other factors be at play?
Authors: Michael P Johnston, Ryan Malcolm Buchanan, Janisha Patel, Nadeem Tehami
Journal: Gut (2020)

We were interested to read the recent article by van Baar and colleagues that described an open-label phase II trial of endoscopic duodenal mucosal resurfacing (DMR) in the management of patients with type 2 diabetes mellitus (T2DM).1 van Baar and colleagues demonstrated improvements in a number of parameters, most impressive of which was the reduction in haemoglobin A1c (HbA1c) at 12 months. It is intriguing to consider what the underlying mechanisms might be for this observed improvement in glycaemic control in patients with T2DM, what confounders might be at play and how these might inform the design of future sham-controlled studies.

For example, the investigators comment that the initial weight loss ~2.3 kg observed in …
Defining the monocyte subset transcriptional signature associated with progression during androgen-target therapy in prostate cancer patients.
Authors: Karen Angelica Cavassani, Sungyong You, Rebecca Meza, Chintda Santiskulvong, Helen Goodridge, Edwin M. Posadas
Journal: Journal of Clinical Oncology (2020)

157 Background: Myeloid-derived circulating monocytes are emerging as cells of interest in cancer biology. The role of circulating monocytes in human Prostate Cancer (PCa) is poorly understood. Here we asked what is the association of monocyte-specific subsets and their transcriptional signatures with PCa progression during (AR)-target therapy. Methods: Single-cell RNAseq analysis were performed in blood monocytes from 4 patients at two specific time points over their clinical, course: T1)responding to next generation androgen receptor signaling inhibitors (e.g. abiraterone or enzalutamide) as reflected by a decline in serum PSA and/or radiographic response, and T2)progressing through treatment as detected by increases in the serum PSA concentration and/or radiographic signs of progression .PBMC were subjected to Ficoll-purification, and FACS sorted to exclude dead cells and cells expressing B- and T- lineage markers. Samples were then pooled using a BD™ Single-Cell Multiplexing Kit. The samples for scRNA-seq analysis included monocytes defined as classical CD14 ++ CD16 − , intermediate CD14 + CD16 + , and non-classical CD14 low/- CD16 +++ . Results: We have observed nine (9) transcriptionally-defined clusters.Clusters 0, 1, 4, 5, and 8 mapped closely to that of classical monocytes with high expression of CD14and low expression of FCG3RA (CD16). Clusters 2 and 3 mapped closely to that of NK cells with high expression of FCG3RA(CD16) and KLRB1(CD161), and clusters 6 and 7 corresponded to CD14 low FCG3RA high SIGLEC10 + monocytes. Importantly, our preliminary data revealed a decrease in the percentage of cells in clusters 2 and 6 and an increase in the percentage of cells in cluster 4 in progressing patients (T2). At the transcriptional level, the three main clusters (classical, non-classical, NK-like) were distinguished by 32, 33, and 72 genes, respectively. Our preliminary findings show that progression was associated with several innate immune transcripts while cytotoxic genes were associated with response to Enzalutamide. Conclusions: These data suggest that monocytes transcriptional signature may be reshaped by PCa. Further study of monocytes in PCa progression are warranted.
Who is a bone-predominant patient to maximize clinical benefits of radium-223 dichloride?
Authors: Kohei Hashimoto, Yasuhide Miyoshi, Tetsuya Shindo, Naotaka Nishiyama, Shintaro Miyamoto, Takeshi Maehana, Manabu Okada, Masahiro Yanase, Ryuichi Kato, Hiroshi Hotta, Yasuharu Kunishima, Atsushi Takahashi, Hiroshi Kitamura, Hiroji Uemura, Naoya Masumori, Ko Kobayashi, Toshiaki Tanaka
Journal: Journal of Clinical Oncology (2020)

47 Background: Radium-223 dichloride (Ra-223) is used for patients with castration-resistant prostate cancer (CRPC) and bone metastasis (BM). However, some patients often have disease progression of non-BM during Ra-223 and may enable to receive no more other life-prolonging therapies. Thus, diagnostic uncertainty in bone-predominant CRPC yet needs to be determined. To maximize clinical benefits of Ra-223, we clarified how to identify patients with bone-predominant metastatic CRPC. Methods: This was a multi-center retrospective study. The 136 CRPC patients who received Ra-223 between 2012 and 2019 were reviewed. Patients without visceral metastasis and lymph node metastasis of more than 3 cm received Ra-223, 55kBq/kg, every 4 weeks for up to 6 cycles, and were required to continue androgen deprivation therapy alone. All patients were divided into 3 groups by the types of dynamic changes of BM compared to BM at diagnosis: i) only known lesions; ii) new progressive lesions; iii) de novo BM at CRPC. Time from initiation of Ra-223 to failure of subsequent treatment (time to FST), radiographic progression-free survival (rPFS) and overall survival (OS) were evaluated. Results: The median age was 76 years. Of all, 68% received all 6 planned cycles of Ra-223. Overall, PSA responses were observed in 26 (19%). During follow-up of 12 months, the median time of FST, rPFS and OS were 8.3, 10.6 and 16.4 months, respectively. The type of dynamic changes of BM (HR 3.65, p=0.004) and PSA doubling time (PSADT) just before Ra-223 (HR 4.35, p=0.006) were significantly associated with time to FST. The dynamic changes of BM combined with PSADT highlighted an optimal decision of Ra-223. Patients with only known lesions of BM had longer time to FST, better rPFS and OS regardless of PSADT. The same was true for patients with de novo or new progressive lesions of BM and a long PSADT. In contrast, patients with new progressive lesions of BM and PSADT&lt; 3 months were presumably more likely to have the risk of FST and progression of visceral metastasis. Conclusions: Our findings suggest that the risk assessment with the type of dynamic changes of BM and PSADT could determine an ideal patient for Ra-223.
Phase II trial of monoamine oxidase inhibitor phenelzine in biochemical recurrent prostate cancer.
Authors: Mitchell E. Gross, David B. Agus, Tanya B. Dorff, Jacek K. Pinski, David I. Quinn, Olga O. Castellanos, Patrick O. Gilmore, Jean Shih
Journal: Journal of Clinical Oncology (2020)

94 Background: Monoamine oxidase A (MAOA) influences prostate cancer growth and metastasis in pre-clinical models. We examined effects of phenelzine (a monoamine oxidase inhibitor) in patients with biochemical recurrent castrate-sensitive prostate cancer. Methods: An open-label single arm clinical trial enrolled subjects with biochemical recurrent prostate cancer defined by: PSA ≥ 0.4 ng/ml (post-prostatectomy) or PSA ≥ 2 ng/ml above nadir (post-radiation therapy); no evidence of metastasis on imaging; and normal androgen levels. Subjects received phenelzine 30 mg orally twice daily. Mood symptoms were assessed with the hospital anxiety depression score (HADS) questionnaire. The primary endpoint was the proportion of patients who achieved a PSA decline of ≥50% from baseline. Results: Characteristics of the 20 eligible patients enrolled included: mean ± SD age 66.9 ± 4.8 years and PSA 4.7 ± 5.8 ng/dl. Maximal PSA declines ≥ 30% and ≥ 50% were observed in 25% (n=5/20) and 10% (n=2/20) of subjects, respectively. At 12 weeks, 17 subjects remained on treatment with PSA declines ≥ 30% and ≥ 50% of 24% (n=4/17) and 6% (n=1/17), respectively. Common toxicities observed included dizziness (grade 1 = 45%, grade 2= 35%), hypertension (grade ≥ 2 =30%), and edema (grade 1=25%, grade 2=10%). There was 1 episode of grade 4 hypertension (cycle 4) and 2 episodes of grade 3 syncope (cycle 12 and cycle 14) requiring treatment discontinuation. HADS questionnaires demonstrated a significant decrease in anxiety with no change in depressive symptoms on treatment. Conclusions: Phenelzine demonstrated efficacy in patients with biochemical recurrent castrate sensitive prostate cancer. Most treatment related toxicities were mild, but rare significant and reversible cardiovascular toxicities were observed. Therapies directed at MAOA may represent a new avenue for treatment in patients with recurrent prostate cancer. Clinical trial information: NCT02217709.
The impact of race and insurance status on survival of prostate cancer patients.
Authors: Trevanne Rose Matthews Hew, Jason Desmond Hew, Hardik Satish Chhatrala, Ian Tfirn, Meet Kadakia, Shiva Gautam, Dat C. Pham
Journal: Journal of Clinical Oncology (2020)

233 Background: While prostate cancer mortality has declined in the in the general population, it remains high in African Americans. The aim of our study is to determine whether race and insurance type affect treatment outcomes in prostate cancer patients at our institution. Methods: A retrospective chart analysis between 2012 and 2017 of 2763 prostate cancer patients was done at our institution. We collected data on age, race, stage, insurance, treatment history, date of diagnosis, Gleason score, date of death. The healthcare insurance information was categorized into Medicare with and without supplement, VA, Medicaid, no insurance/self- pay, City Contract and private. City Contract is the city sponsored health care access for person with low income living in the Duval County. Univariate and multivariate chi square analysis with odd ratio was performed, 95 % confident intervals were evaluated with P value &lt; 0.05. Results: African Americans were 2.93 times more likely to experience death than Caucasians (Odds Ratio, OR, 1.79-4.78, 95 % CI). Both Private and VA insurance were more likely to have a lower stage of prostate cancer compared to City Contract (0.53 times, 0.30-0.93, and 0.411 times, OR 0.23-0.84 95 % CI respectively). African Americans were significantly more likely to have a more advanced cancer stage when compared to Caucasians (1.85 times, 1.49 -2.29 95 % CI). Every insurance type was significantly less likely to undergo surgery compared to City Contract. All except Medicaid, were more likely to undergo radiation compared to City Contract. African Americans are more likely to undergo surgery (2.68 times, 2.01-3.56, 95% CI) and were less likely to have radiation or chemotherapy when compared Caucasians (0.25 times, 0.20-0.31 95% CI). Conclusions: Disparities in race and insurance type can affect the stage at presentation, type of treatment received and survival.[Table: see text]
Long-term Outcomes Associated With Total Arterial Revascularization vs Non–Total Arterial Revascularization
Authors: Rodolfo V. Rocha, Derrick Y. Tam, Reena Karkhanis, Xuesong Wang, Peter C. Austin, Dennis T. Ko, Mario Gaudino, Alistair Royse, Stephen E. Fremes
Journal: JAMA Cardiology (2020)

The optimal conduits for coronary artery bypass grafting (CABG) remain controversial in multivessel coronary artery disease.To compare the long-term clinical outcomes of total arterial revascularization (TAR) vs non-TAR (CABG with at least 1 arterial and 1 saphenous vein graft) in a multicenter population-based study.This multicenter population-based cohort study using propensity score matching took place from October 2008 to March 2017 in Ontario, Canada, with a mean and maximum follow-up of 4.6 and 9.0 years, respectively. Individuals with primary isolated CABG were identified, with at least 1 arterial graft. Exclusion criteria were individuals from out of province and younger than 18 years. Patients undergoing a cardiac reoperation or those in cardiogenic shock were also excluded because these conditions would potentially bias the surgeon toward not performing TAR. Analysis began April 2019.Total arterial revascularization.Primary outcome was time to first event of a composite of death, myocardial infarction, stroke, or repeated revascularization (major adverse cardiac and cerebrovascular events). Secondary outcomes included the individual components of the primary outcome.Of 49 404 individuals with primary isolated CABG, 2433 (4.9%) received TAR, with the total number of bypasses being 2, 3, and 4 or more vessels in 1521 (62.5%), 865 (35.6%), and 47 individuals (1.9%), respectively. The mean (SD) age was 61.2 (10.4) years and 1983 (81.5%) were men. After propensity score matching, 2132 patient pairs were formed, with equal total number of bypasses (mean [SD], 2.4 [0.5]) but with more arterial grafts in the TAR group (mean [SD], 2.4 [0.5] vs 1.2 [0.4]; P < .01). In-hospital death (15 [0.7%] vs 21 [1.0%]; P = .32) did not differ between TAR vs non-TAR groups after propensity score matching. Throughout 8 years, TAR was associated with improved freedom from major adverse cardiac and cerebrovascular events (hazard ratio, 0.78; 95% CI, 0.68-0.89), death (hazard ratio, 0.80; 95% CI, 0.66-0.97), and myocardial infarction (hazard ratio, 0.69; 95% CI, 0.51-0.92). There was no difference in stroke and repeated revascularization.Total arterial revascularization was associated with improved long-term freedom from major adverse cardiac and cerebrovascular events, death, and myocardial infarction and may be the procedure of choice for patients with reasonable life expectancy requiring CABG.
Abstract 14568: Outcomes of Acute Type A Aortic Dissection in Patients Aged 45 Years and Younger: Influence of Etiologic Factors
Authors: Naoyuki Kimuira, Kei Aizawa, Koji Kawahito, Ryo Itagaki, Atsushi Yamaguchi, Yoshio Misawa, Matthias Siepe, Martin Czerny, Friedhelm Beyersdorf, Fabian A Kari, Bartosz Rylski
Journal: Circulation (2017)

Introduction: Etiologic factors vary in patients aged <45 years who suffer acute type A aortic dissection (ATAAD); hypertension (HT), Marfan syndrome (MFS), familial thoracic aortic aneurysm/dissec...
Copy number amplification of androgen receptor in cell-free DNA is a potential prognostic factor in patients with CRPC.
Authors: Itsuto Hamano, Shingo Hatakeyama, Tohru Yoneyama, Yuichiro Suzuki, Hayato Yamamoto, Atsushi Imai, Takahiro Yoneyama, Yasuhiro Hashimoto, Chikara Ohyama
Journal: Journal of Clinical Oncology (2020)

180 Background: A circulating cell-free DNA (cfDNA) has been suggested as a potential biomarker for castration-resistant prostate cancer (CRPC). However, clinical implication of the parameters in cfDNA remains unclear. We aimed to investigate the impact of copy number variation (CNV) of androgen-receptor amplification (AR-amp) in cfDNA on prognosis in patients with CRPC. Methods: We retrospectively evaluated AR-amp in cfDNA in 154 patients with prostate cancer between April 2018 and September 2019. We compared AR-amp between the patients with CRPC and non-CRPC. An optimal cutoff point was defined using receiver operating characteristic (ROC) curve. The effect of AR-amp on prognosis was evaluated between the CRPC patients with AR-amp high and low. Results: The median age and initial PSA was 75 years and 34 ng/mL, respectively. The number of patients with abiraterone acetate, enzalutamide, docetaxel, cabazitaxel was 24, 15, 21, and 2, respectively. No significant association was observed between the AR-amp and serum prostate-specific antigen (PSA) level at AR-amp measurement. Of 154, 73 (47%) patients developed to CRPC. The AR-amp was significantly higher in the patients with CRPC than that in the non-CRPC (1.07 vs. 0.97, respectively, P&lt;0.001). The cutoff value of AR-amp was defined 1.16 with area under the ROC curve of 0.672. Overall survival was significantly shorter in the patients with AR-amp low (≤1.16, n=46) than that with AR-amp high (&gt;1.16, n=27) (8.9 vs. 9.6 months, respectively, P &lt; 0.001). The AR-amp was not significantly different between the pre- and post-docetaxel status in patients with CRPC. Conclusions: AR-amp in cfDNA might be a potential biomarker for poor prognosis in patients with CRPC who were treated with life-prolonging therapies.
17P Assessment of the Intratumoral Heterogeneity in Metastatic Breast Cancer (Mbc) Through the Analysis of the Frequency of Pik3Ca Mutant Alleles
Authors: L. De Mattos-Arruda, J. Cortes, A. Sánchez-Pla, C. Aura, V. Ortega, J. Jimenez, C. Saura, J. Tabernero, J. Seoane, A. Vivancos
Journal: Annals of Oncology (2012)