tbuckley/cabot-search huggingface dataset:
Challenges for sustainable end-stage kidney disease care in low-middle-income countries: the problem of the workforce
Authors: Charles R. Swanepoel, Mignon I. McCulloch, Georgi Abraham, Jo-Ann Donner, Mona N. Alrukhaimi, Peter G. Blake, Sakarn Bunnag, Stefaan Claus, Gavin Dreyer, Mohammad A. Ghnaimat, Fuad M. Ibhais, Adrian Liew, Marla McKnight, Yewondwossen Tadesse Mengistu, Saraladevi Naicker, Abdou Niang, Gregorio T. Obrador, Jeffrey Perl, Harun Ur Rashid, Marcello Tonelli, Kriang Tungsanga, Tushar Vachharajani, Elena Zakharova, Carlos Zuniga, Fredric O. Finkelstein
Journal: Kidney International Supplements (2020)
Long-Term Outcomes of Anticoagulation for Bioprosthetic Valve Thrombosis
Authors: Ioana Petrescu, Alexander C. Egbe, Filip Ionescu, Vuyisile T. Nkomo, Kevin L. Greason, Cristina Pislaru, Patricia A. Pellikka, Heidi M. Connolly, Sorin V. Pislaru
Journal: Journal of the American College of Cardiology (2020)
Clinical characteristics and treatment adherence among men with testicular germ cell tumors: Real-world data from a referral center in Mexico.
Authors: Carlos Eduardo Salazar-Mejía, Omar Zayas-Villanueva, Adriana González Gutiérrez, Rolando Jacob Martinez, ABRAHAM GUERRA CEPEDA, Blanca Otilia Wimer-Castillo, Héctor Alejandro Rodríguez-Calvillo, Lourdes Paola Chapa-Montalvo, Brenda Alejandra Samaniego-Sáenz, David Hernández-Barajas, Oscar Vidal-Gutiérrez
Journal: Journal of Clinical Oncology (2020)

393 Background: Notwithstanding excellent oncological outcomes reported by pivotal trials in patients with testicular germ cell tumors (TGCT), adherence to medical treatment and follow-up remains a major issue in developing countries. Studies that describe the clinical characteristics and treatment adherence of Mexican men with TGCT are lacking. Methods: We performed a retrospective analysis of all men with newly diagnosed TGCT treated at an oncology referral center in Northeast Mexico from 2014 to 2018. Results: In the analysis, 195 patients were included. Median age at diagnosis was 28 years; median time from diagnosis to first evaluation by an oncologist was 26 days. Distribution according to the laterality of the primary tumor was right, 56%; left, 43%; and bilateral, 1%. There were 14 oncological emergencies at presentation; the most frequent was choriocarcinoma syndrome, described in 5 patients. Thirty-five percent of cases were seminomatous germ cell tumors (SGCT) and 65% nonseminomatous germ cell tumors (NSGCT). The clinical stages at diagnosis were I, 36%; IS, 8%; II, 18%; and III, 38%. After risk stratification according to the International Germ Cell Cancer Collaborative Group (IGCCCG), 90% of SGCT had a good risk and 10% an intermediate risk. In NSGCT, the risk distribution was 65, 10, and 25% for good, intermediate, and poor-risk disease, respectively. After proposing treatment, the adherence rate was 81%. Of the total, 58% were lost to medical follow-up with a median time of adherence of 11.5 months. Conclusions: Despite coverage by the Mexican public health insurance system “Seguro Popular”, treatment adherence and medical follow-up abandonment is a problem among men with TGCT, which could negatively impact their prognosis. Measures must be implemented to optimize adherence in this group of patients.
Quality of Life—The Appendix
Authors: Edward H. Livingston
Journal: JAMA Surgery (2020)

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Outcomes of men with ductal prostate cancer undergoing definitive therapy for localized disease.
Authors: Weranja Kalana Bodhisiri Ranasinghe, Daniel D. Shapiro, Chad A. Reichard, Mohamed A Elsheshtawi, Yaw Nyame, Debasish Sundi, Jeffrey J. Tosoian, Lamont Wilkins, Ridwan Alam, Tharakeswara Bathala, Chad Tang, Ana Aparicio, Shi-Ming Tu, Nora Navone, Louis L. Pisters, Andrew J. Stephenson, Eric A. Klein, Mohamad E. Allaf, Brian Francis Chapin, John W. Davis
Journal: Journal of Clinical Oncology (2020)

350 Background: Ductal prostate adenocarcinoma (DAC) is an aggressive variant of prostate cancer (PC). We aimed to assess the outcomes of men with localized DAC undergoing radical prostatectomy (RP) or external beam radiotherapy (RTx) compared to acinar adenocarcinoma of the prostate (PAC) and investigate any difference between these treatment modalities. Methods: All patients presenting to our institution with localized DAC from January 2005 - November 2018 were compared to a pooled cohort of patients from 3 tertiary referral centers who underwent RP for Gleason 8 PC and a cohort of high risk PC patients who underwent RTx for PAC. Patient, tumor characteristics and outcome data were analyzed. Results: 257 men with DAC were identified and compared to 803 with PAC. 203 men with DAC and 729 men with PAC underwent RP while 54 men with DAC and 74 men with PAC underwent RTx. Men with DAC were older (65 vs 63 years and 70.5 vs 66 years) and had higher cT3/T4 stage (43% vs 2.8% and 44.5% vs 31.1%) in both groups, respectively (all p &lt;0.05). The median follow-up for men undergoing RP was 34 (range 0.9 to 177) months and 73.4 (range 0.6 – 224.2) months for men having RTx. Presence of DAC was an independent risk factor for metastases (HR 2.5 (95% CI 1.4- 4.8); p&lt;0.01) and death (HR 2.3 (95% CI 1.1 – 4.7); p=0.02) following RP. The 3- year overall survival (OS) rates for DAC and PAC in men undergoing RP were 93.3% vs 99.3% (p&lt;0.01). On adjusting for Gleason score, clinical T stage, PSA and age, DAC was also an independent risk factor for death (HR 6.1 (95% CI 1.7-22.2); p&lt;0.01) in men undergoing RTx with 5-year OS rates of 100% and 81.6% for DAC and PAC, respectively. There was no difference in the OS of men with DAC between RP and RTx. Conclusions: Men undergoing RP or RTx for localized DAC had worse outcomes compared to PAC, but no survival difference was seen between these treatment modalities. DAC behaves clinically differently than PAC. Further evaluation of the underlying biology and potential for specific targeted multimodality therapies in DAC is needed.
Association of positive Ki-67 and PD-L1 expressions in post neoadjvuant chemotherapy (NAC) radical cystectomy samples with lack of tumor downstaging (TD) and shorter overall survival (OS) in patients with muscle-invasive bladder cancer (MIBC).
Authors: Selene Rubino, Wade J. Sexton, Youngchul Kim, Junmin Zhou, Jasreman Dhilon, Philippe E. Spiess, Michael Adam Poch, Brandon J Manley, Roger Li, Julio M. Pow-Sang, Scott Michael Gilbert, Jingsong Zhang
Journal: Journal of Clinical Oncology (2020)

554 Background: Previous chart review studies have reported that adjuvant chemotherapy after NAC did not clearly increase OS in MIBC cases characterized by a lack of TD. There is an unmet need to develop biomarkers to guide adjuvant therapy for this patient population. High levels of expression of cell proliferation marker Ki-67 are associated with poor outcome in chemotherapy naïve bladder cancer. Expression of PD-L1 has been studied as a potential predictive biomarker for anti-PD1 or PD-L1 therapies in metastatic MIBC. We therefore studied Ki-67 and PD-L1 expression in post NAC radical cystectomy samples at Moffitt Cancer Center and correlate them with TD and OS. Methods: Tissue microarrays (TMAs) were constructed from 116 post NAC cystectomy samples. The expressions of Ki-67 were evaluated with immunohistochemistry (IHC) and considered positive if any of the cores per sample were stained positive for Ki-67. The Dako 22C3 assay was used for PD-L1 IHC and the combined positive score of 10 or above was considered positive for PD-L1. Results: The median survival of this cohort of 116 patients was 33.4 months (range: 1.13 -127 months). 40 patients (35%) had TD and 21 patients (18%) achieved pathological complete response. Using Cox regression for OS, positive Ki-67 expression in post NAC radical cystectomy sample was associated with poorer OS (hazard ratio=2.412, 95% CI:1.076-5.408, p=0.033), independent of the pathological N stage. Patients with Ki67/PD-L1 double-negative tumors had a significantly longer median OS of 98.2 months versus 29.9 and 26.9 months in PD-L1-/Ki67+ and PD-L1+/Ki67+ tumors respectively (Log-rank test, p=0.0361). Lack of TD was significantly associated with positive Ki-67 (P&lt;0.001) and positive PD-L1 (p=0.003) in the post NAC samples with a multi-variable logistic regression model. Conclusions: Positive Ki-67 and PD-L1 expressions in post NAC radical cystectomy samples were associated with inferior OS and absence of TD. Adjuvant anti-PD1 therapy either alone or in combination with chemotherapy would be indicated for this subset of patients.
Systematic functional identification of cancer multi-drug resistance genes
Authors: Man-Tat Lau, Shila Ghazanfar, Ashleigh Parkin, Angela Chou, Jourdin R. Rouaen, Jamie B. Littleboy, Danielle Nessem, Thang M. Khuong, Damien Nevoltris, Peter Schofield, David Langley, Daniel Christ, Jean Yang, Marina Pajic, G. Gregory Neely
Journal: Genome biology (2020)

Abstract Background Drug resistance is a major obstacle in cancer therapy. To elucidate the genetic factors that regulate sensitivity to anti-cancer drugs, we performed CRISPR-Cas9 knockout screens for resistance to a spectrum of drugs. Results In addition to known drug targets and resistance mechanisms, this study revealed novel insights into drug mechanisms of action, including cellular transporters, drug target effectors, and genes involved in target-relevant pathways. Importantly, we identified ten multi-drug resistance genes, including an uncharacterized gene C1orf115 , which we named Required for Drug-induced Death 1 ( RDD1 ). Loss of RDD1 resulted in resistance to five anti-cancer drugs. Finally, targeting RDD1 leads to chemotherapy resistance in mice and low RDD1 expression is associated with poor prognosis in multiple cancers. Conclusions Together, we provide a functional landscape of resistance mechanisms to a broad range of chemotherapeutic drugs and highlight RDD1 as a new factor controlling multi-drug resistance. This information can guide personalized therapies or instruct rational drug combinations to minimize acquisition of resistance.
Characterizing patterns of disease progression in patients with genitourinary cancers treated with immune checkpoint inhibitors.
Authors: Vaibhav G. Patel, Qian Qin, George Mellgard, Anish B. Parikh, Bo Wang, Parissa Alerasool, Philip Garcia, Suraj Jaladanki, Amanda Leiter, Emily Carroll, Danielle Brooks, Jennifer Ben Shimol, Elliot Eisenberg, Emily J. Gallagher, Matt D. Galsky, William K. Oh, Che-Kai Tsao
Journal: Journal of Clinical Oncology (2020)

482 Background: Despite the widespread use of immune checkpoint inhibitors (ICIs), patterns of disease progression (POD) are poorly characterized. We aim to define these characteristics in patients (pts) with advanced urothelial carcinoma (UC) and renal cell carcinoma (RCC) treated with ICIs. Methods: We retrospectively reviewed charts of pts with advanced UC and RCC who received at least 2 ICI doses at our institution from 12/1/10 – 10/31/18. Demographics, medical history, ICI course, toxicity, and outcomes were recorded. Characteristics at the time of radiographic POD including location of metastases (mets), symptoms (sx), and hospitalization details were collected. Fisher’s exact test was used to study differences in pts with and without hospitalization at POD. Results: Of the 71 pts identified (UC N=53; RCC N=18), 59 pts had POD. At POD, 19 (32.2%) pts had new sites of disease involvement, while the remaining pts (N=40, 67.8%) had progression only at previously known sites of disease. Fourty-six (78.0%) pts had sx at POD: 1 sx (N=19, 32.2%), 2 sx (N=13, 22.0%), 3+ sx (N=14, 23.7%). Pain was the most common sx at POD (N=32, 54.2%), followed by loss of energy (N=18, 30.5%), and loss of appetite (N=14, 23.7%). Twenty-five (42.4%) pts were hospitalized at POD, most commonly for sepsis (N=8, 32%). No clinical factors were identified to predict for pts being hospitalized at POD. Conclusions: In our review of GU cancer patients on ICIs, a large proportion of pts reported clinical sx at POD, pain being the most frequent. Furthermore, a substantial number of pts were hospitalized at POD, most commonly for sepsis. Thus, further studies are warranted to confirm these findings, and potentially identify strategies to optimize patients’ quality-of-life and reduce rates of hospitalizations at the time of POD on ICIs.
Open-Label Follow-Up of the PEPITES Study (PEOPLE) to Evaluate the Long-Term Efficacy and Safety of Epicutaneous Peanut Immunotherapy in Peanut-Allergic Children
Authors: David Fleischer, Gordon Sussman, Kirsten Beyer, Jonathan Hourihane, Roxanne Oriel, Lara Ford, Wayne Shreffler, Dianne Campbell, Todd Green, Robin Mukherjee, Philippe Begin
Journal: Journal of Allergy and Clinical Immunology (2020)
The CD33 splice isoform lacking exon 2 as therapeutic target in human acute myeloid leukemia
Authors: Colin D. Godwin, George S. Laszlo, Brent L. Wood, Colin E. Correnti, Olivia M. Bates, Eliotte E. Garling, Zhengwei J. Mao, Mary E. Beddoe, Margaret C. Lunn, Olivier Humbert, Hans-Peter Kiem, Roland B. Walter
Journal: Leukemia (2020)
Maintenance sunitinib (MS) or observation (O) in metastatic pancreatic adenocarcinoma (MPA): Clinical and translational results of a phase II randomized trial (NCT00967603).
Authors: Michele Reni, Stefano Cereda, Michele Milella, Anna Novarino, Alessandro Passardi, Andrea Mambrini, Giuseppe Di Lucca, Laura Ferrari, Carmen Belli, Marco Danova, Francesca Bergamo, Enrico Franceschi, Bianca Rovati, Clara Fugazza, Domenica Ceraulo, Eugenio Villa
Journal: Journal of Clinical Oncology (2012)

4017 Background: Combination chemotherapy (CT) prolonged progression-free survival at 6 months (PFS6) of patients (pts) with MPA from &lt;20% with gemcitabine (GEM) to &gt;50%. To prolong CT over 6 months has unproven benefit and is hampered by cumulative toxicity. This open-label, randomised, multi-centre phase II trial explored the role of MS in pts with MPA without progressive disease (PD) after CT, using an O group as calibration arm. The role of circulating endothelial cells (CEC) as biomarker of MS activity was explored. Methods: Adult pts with pathologic diagnosis of MPA, performance status (PS) &gt;50%, without radiological PD or CA19.9 raise &gt;20% after 6 months of CT were stratified based on PS and previous CT and randomized to O (arm A) or MS at 37.5 mg daily until PD or a maximum of 6 months (arm B). Primary endpoint was PFS6. Sample size (H0 10%; H1 30%; a .10; b .10) was 26 pts per arm and MS had to be considered of interest with &gt;5 pts PFS6. CEC were evaluated by flow cytofluorometry on a baseline peripheral blood sample. Results: 56 pts (29 arm A; 27 arm B) were enrolled. One arm B pt had kidney cancer and was excluded. Pts characteristics were (A/B): median age 64/61 years; median PS 90/100; median CA19.9 45/32; previous CT: GEM 3/3; combination CT 26/22. Main grade 3-4 toxicity in arm B was 15% neutropenia; 12% thrombocytopenia and hand-foot syndrome, 8% diarrhea. Second line CT was given to 76% of pts in both arms. One arm A (3%) and 6 arm B pts (23%; p=.01) were PFS6; 2y overall survival (OS) was 4% and 25% (p=.09). Blood sample for CEC analysis was available for 46 of 55 pts (84%). In arm A, median PFS was longer for pts with CEC number &lt;30 (lower terzile group) when compared to &gt;30 (2.9 versus 1.9 months; p.08). MS significantly increased PFS in CEC &gt;30 group (3.4 months; p=.01). No PFS difference between arms was observed in &lt;30 group (2.3 months). Conclusions: This is the first randomized trial on maintenance therapy in MPA. In arm B, the primary endpoint was fulfilled and 2y OS was remarkably high, suggesting that MS may have a role in pts with MPA. The number of CEC may be useful to predict benefit from MS.
Adenosine receptor blockade with ciforadenant +/- atezolizumab in advanced metastatic castration-resistant prostate cancer (mCRPC).
Authors: Lauren Christine Harshman, Michael Chu, Saby George, Brett Gordon Maxwell Hughes, Bradley Curtis Carthon, Lawrence Fong, Jaime R. Merchan, Long Kwei, Andrew N. Hotson, Mehrdad Mobasher, Richard A. Miller
Journal: Journal of Clinical Oncology (2020)

129 Background: Adenosine, generated by the ectonucleotidase CD73, mediates immunosuppression within the tumor microenvironment by triggering adenosine 2A receptors (A2AR) on immune cells. Tumor CD73 expression may be prognostic in prostate cancer. We evaluated the clinical activity of adenosine blockade using A2AR antagonist, ciforadenant, with or without the anti-PDL-1 antibody, atezolizumab (atezo), in advanced mCRPC patients (pts) in an ongoing phase 1 trial. Methods: Eligibility required measurable disease and up to 5 prior systemic therapies. Prior anti- PD-(L)1 was allowed. Ciforadenant was administered orally BID as monotherapy at 50-200mg or 100mg in combination with atezo 840mg IV Q 2 weeks (wks). Safety and efficacy were evaluated by CTCAE4, RECIST1.1 and PCWG2. Serum was obtained for measurement of cytokines. Results: Of 33 enrolled pts, 10 received ciforadenant monotherapy and 23 in combination with atezo. As of 10/21/19, 14 pts are evaluable for response and described further. Median prior therapies is 3 (range 2-6) with median follow-up 10.8 (4-33) wks. Metastatic burden included 4 node only, 2 bone plus node, and 8 visceral metastases. Five pts experienced tumor regression: 2 ciforadenant monotherapy (tumor reductions 12%, 17%); and 3 combination (tumor reductions 4%, 27%, 42%). The pt with a partial response had PSA decline from 98 ng/mL to &lt;1. Eight pts had stable disease (SD) for a clinical benefit rate (SD + PR) of 8/14 (57%). Median duration of disease control was 24 wks. Study treatment was well tolerated with two Gr3/4 adverse events (AEs) of fatigue (1) and anorexia (1). The most common Gr1/2 AEs were fatigue and nausea. Serum TNFα levels increased by 4-8 wks on therapy in 12/13 pts. Baseline levels of soluble VCAM-1, which has been implicated in metastatic spread/more aggressive disease, were higher in pts with tumor regression (771 ± 109 ng/mL, n=4) than pts with tumor growth (544 ± 62 ng/mL, n=5, p&lt;0.05). Conclusions: Results from this phase 1 study show mCRPC can be sensitive to A2AR blockade with ciforadenant. Cytokine changes provide evidence of treatment-induced inflammatory response, which may predict efficacy. Data on all 33 enrolled pts will be presented. Clinical trial information: NCT02655822.
Elevated circulating CCL2 in prostate cancer patients.
Authors: Justin Lin, Amanda Caress, Farzana Ahmed, Nicole Taylor, Yixuan Gong, William K. Oh
Journal: Journal of Clinical Oncology (2020)

201 Background: Monocyte chemoattractant protein 1 (CCL2 or MCP-1), a chemokine secreted by monocytic cells, is critical in recruiting T reg and MDSCs into the tumor microenvironment and in regulating prostate cancer (PCa) migration and proliferation. In this study, we examined circulating CCL2 levels in healthy vs PCa patients and used an in vitro coculture model to identify the source of the elevated CCL2. Methods: Serum CCL2 concentrations were evaluated via ELISA in 59 patients (19 health controls, 20 “treatment naïve” PCa, 20 mCRPC). Monocytic leukemia cells (U937) were either directly cocultured with PC3 PCa cell line or cultured in the PC3 conditioned medium (CM). The induction of CCL2 mRNA in the cultures was examined by qPCR. The secretion of CCL2 into cell culture supernatants was evaluated via human cytokine array. Neutralizing antibodies to several overexpressed inflammatory cytokines in PC3 cells were added into the PC3 CM to evaluate the contribution of these inflammatory cytokines to CCL2 induction. Results: Circulating CCL2 concentrations were significantly higher in prostate cancer patient serum compared to control patient serum (p=4.4e-6) (Table). To understand the potential source of elevated CCL2, we grew U937 and PC3 in coculture and evaluated with qPCR, revealing that while CCL2 was not expressed in PC3 cells, it was expressed at very low levels in U937 cells. Interestingly, coculture of PC3 with U937 increased CCL2 mRNA expression by over 10-fold, and the result was confirmed at protein levels by human cytokine array. Our results also indicated that IL-6 and GM-SCF were the two major cytokines released by PCa cells to induce CCL2 mRNA in U937 cells and MEK and JAK-STAT signaling were crucial for CCL2 induction. Conclusions: Prostate cancer cells induce CCL2 secretion from monocytes in an IL-6 and GM-CSF dependent manner. Given the critical role of CCL2 in mediating immunosuppressive tumor microenvironments, our study highlighted the CCL2 Concentrations in PCa vs Healthy Serum.[Table: see text]
Hepatitis B protein HBx binds the DLEU2 lncRNA to sustain cccDNA and host cancer-related gene transcription
Authors: Debora Salerno, Letizia Chiodo, Vincenzo Alfano, Oceane Floriot, Grazia Cottone, Alexia Paturel, Matteo Pallocca, Marie-Laure Plissonnier, Safaa Jeddari, Laura Belloni, Mirjam Zeisel, Massimo Levrero, Francesca Guerrieri
Journal: Gut (2020)

Objective The HBV HBx regulatory protein is required for transcription from the covalently closed circular DNA (cccDNA) minichromosome and affects the epigenetic control of both viral and host cellular chromatin. Design We explored, in relevant cellular models of HBV replication, the functional consequences of HBx interaction with DLEU2, a long non-coding RNA (lncRNA) expressed in the liver and increased in human hepatocellular carcinoma (HCC), in the regulation of host target genes and the HBV cccDNA. Results We show that HBx binds the promoter region, enhances the transcription and induces the accumulation of DLEU2 in infected hepatocytes. We found that nuclear DLEU2 directly binds HBx and the histone methyltransferase enhancer of zeste homolog 2 (EZH2), the catalytic active subunit of the polycomb repressor complex 2 (PRC2) complex. Computational modelling and biochemical evidence suggest that HBx and EZH2 share two preferential binding sites in DLEU2 intron 1. HBx and DLEU2 co-recruitment on the cccDNA displaces EZH2 from the viral chromatin to boost transcription and viral replication. DLEU2-HBx association with target host promoters relieves EZH2 repression and leads to the transcriptional activation of a subset of EZH2/PRC2 target genes in HBV-infected cells and HBV-related HCCs. Conclusions Our results highlight the ability of HBx to bind RNA to impact on the epigenetic control of both viral cccDNA and host genes and provide a new key to understand the role of DLEU2 and EZH2 overexpression in HBV-related HCCs and HBx contribution to hepatocytes transformation.
Air Pollution Is Associated With Increased Sinus Tissue Eosinophilia In Chronic Rhinosinusitis
Authors: Leena Padhye, Jennifer Kish, Christopher Codispoti, Mary Tobin, Phillip LoSavio, Donyea Moore, Pete Batra, Gregory Miller, Mahboobeh Mahdavinia
Journal: Journal of Allergy and Clinical Immunology (2020)