tbuckley/cabot-search huggingface dataset:
An implementation model to guide rural Malawian communities in the scaling-up of an effective HIV prevention programme: an implementation science study
Authors: Linda L McCreary, Diana Jere, Crystal Patil, Kathleen Norr
Journal: The Lancet Global Health (2019)

BackgroundScaling-up of evidence-based programmes for HIV prevention in areas of high prevalence is a global priority. Many implementation models exist, but a major barrier is the lack of implementation models that are straightforward enough for use by community volunteers who have little education or research experience. Our previous findings have shown the efficacy of a peer-group HIV-prevention programme in Malawi. Now, to shift ownership of this programme from researchers to rural community volunteers, we have adapted an existing implementation model to guide rural Malawi community members in implementation of this programme. Here we describe communities' use of this three-step (Prepare, Roll-out, Sustain) Community Implementation Model (CIM).MethodsWe brought together district health, political, and traditional leaders, who agreed to support implementation of the programme; coordinating committees were formed in each community to organise implementation. We conducted workshops to develop leaders' capacities for following the CIM. The committee tracks progress every 6 months, recording the number of benchmarks met from a list of 28. Using a hybrid stepped-wedge design, we simultaneously evaluated three communities' use of the CIM to guide the implementation processes.FindingsBy Jan 17, 2019, all three communities had successfully begun implementation using the three-step CIM. During the Prepare step, each community established a coordinating committee, which planned and selected volunteers who were trained as peer group leaders. During Roll-out, peer leaders offered the programme. Two communities have begun the Sustain step, making and carrying out plans to continue and expand the programme. These two communities at the Sustain step have developed capacities needed to keep the programme going. One has submitted a proposal to obtain funding from our project budget; they will soon apply for local funding. The number of benchmarks achieved have steadily increased in all three communities and are shared with local leaders. All three communities have been highly enthusiastic and successful in carrying out the implementation.InterpretationThe CIM is an effective and replicable model to guide future community implementations of this and other health promotion programmes. If the pattern of results seen from two of our three communities continue with the third community, we conclude that the model will support transfer of programme ownership from researchers to community members.FundingNational Institutes of Health/National Institute for Nursing Research R01NR015409 and R01 NR08058.
Predictive value of fibroblast growth factor receptor (FGFR) mutations and gene fusions on anti-PD-(L)1 treatment outcomes in patients (pts) with advanced urothelial cancer (UC).
Authors: Ademi E. Santiago-Walker, Fei Chen, Yohann Loriot, Arlene O. Siefker-Radtke, Libo Sun, Ramesh Sundaram, Peter De Porre, Kiran Patel, Ying Wan
Journal: Journal of Clinical Oncology (2019)

419 Background: FGFR alterations have been shown to be associated with immunologically “cold” UC tumors with low immune marker expression and T cell infiltrate, a poorly receptive environment for immune checkpoint inhibitors. Using a real world matched clinical and genomic dataset of pts with advanced UC, we explored their predictive value in pts receiving anti-PD-(L)1 therapy. Methods: The Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB) contained full clinical and treatment information and molecular data on a cohort of pts with confirmed advanced UC. The populations of interest are FGFR+ and FGFR- patients determined by the presence or absence of a prespecified panel of FGFR2/3 mutations and fusions. Overall survival (OS), measured from the start of anti-PD-(L)1 therapy, was analyzed using Kaplan-Meier estimation and Cox proportional hazards models adjusted for left truncation (delayed entry model). Results: 118 pts ( FGFR+ n = 26, FGFR- n = 92) treated with anti-PD-(L)1 therapy for advanced UC were assessed for OS. Median OS for FGFR+ pts who received any line of anti-PD-(L)1 therapy (n = 26) was 3.1 mo vs 6.1 mo for FGFR- pts (n = 92) (hazard ratio [HR] 1.33, 95% CI 0.78-2.26, p = 0.30). For first-line anti-PD-(L)1 therapy, median OS in FGFR+ pts (n = 12) was 4.7 mo vs 11.3 mo for FGFR- pts (n = 28) (HR 1.94, 95% CI: 0.78-4.82, p = 0.15); median OS in second-line were 3.1 mo (n = 12) vs 6.1 mo (n = 47), respectively (HR 1.17, 95% CI 0.53-2.59, p = 0.70). Per multivariate analysis, FGFR+ status appears to be associated with poorer OS in pts treated with any line of anti-PD-(L)1 therapy (HR 1.25, 95% CI 0.71-2.21, p = 0.43). Conclusions: These real-world data suggest that FGFR+ pts following anti-PD-(L)1 therapy for advanced UC may be associated with a trend in poorer overall survival outcome compared with FGFR- pts. These findings are in alignment with treatment history data from BLC2001 (Siefker-Radtke A, et al. ASCO-GU 2018), which showed low response rates to prior anti-PD-(L)1 therapies among FGFR+ pts.
Longitudinal Analysis Reveals Early Development of Three MPER-Directed Neutralizing Antibody Lineages from an HIV-1-Infected Individual
Authors: Shelly J. Krebs, Young D. Kwon, Chaim A. Schramm, William H. Law, Gina Donofrio, Kenneth H. Zhou, Syna Gift, Vincent Dussupt, Ivelin S. Georgiev, Sebastian Schätzle, Jonathan R. McDaniel, Yen-Ting Lai, Mallika Sastry, Baoshan Zhang, Marissa C. Jarosinski, Amy Ransier, Agnes L. Chenine, Mangaiarkarasi Asokan, Robert T. Bailer, Meera Bose, Alberto Cagigi, Evan M. Cale, Gwo-Yu Chuang, Samuel Darko, Jefferson I. Driscoll, Aliaksandr Druz, Jason Gorman, Farida Laboune, Mark K. Louder, Krisha McKee, Letzibeth Mendez, M. Anthony Moody, Anne Marie O’Sullivan, Christopher Owen, Dongjun Peng, Reda Rawi, Eric Sanders-Buell, Chen-Hsiang Shen, Andrea R. Shiakolas, Tyler Stephens, Yaroslav Tsybovsky, Courtney Tucker, Raffaello Verardi, Keyun Wang, Jing Zhou, Tongqing Zhou, George Georgiou, S. Munir Alam, Barton F. Haynes, Morgane Rolland, Gary R. Matyas, Victoria R. Polonis, Adrian B. McDermott, Daniel C. Douek, Lawrence Shapiro, Sodsai Tovanabutra, Nelson L. Michael, John R. Mascola, Merlin L. Robb, Peter D. Kwong, Nicole A. Doria-Rose
Journal: Immunity (2019)
Management of Patients With Atrial Fibrillation
Authors: Andrew D. Beaser, Adam S. Cifu
Journal: JAMA (2019)

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The genetic variation observed in <i>BRCA</i> 1/2 + families.
Authors: Rachael Brandt, Ellie Jeanette DelGiacco, Cristina Nixon, Elizabeth Chao, Jill S Dolinsky, Virginia Speare, Jamie Mushlin, Ned Z. Carp, Theresa W. McHugh
Journal: Journal of Clinical Oncology (2015)

e12511 Background: While BRCA1 and BRCA2 are high penetrance genes accounting for a significant proportion of hereditary breast and ovarian cancers (HBOC), many other genes have been associated with increased risks of both cancers. Multigene panel tests have recently emerged to analyze multiple genes simultaneously. Although multigene panels were initially proposed for use in families with hereditary cancer patterns testing negative for BRCA 1/2, commercialization combined with updates in professional guidelines have led to increased utilization of multigene panels as a 1st-tier test for HBOC. However, the possible utility of multigene tests in families with known BRCA1/2 mutations has not previously been investigated. Methods: All BRCA 1/2 positive pedigrees obtained in a suburban hospital genetics program over a 15 year period were reviewed retrospectively. Pedigrees with a complex presentation of cancers, such as competing diagnoses, syndrome specific cancers present in two or more branches of a family, or the presence of a phenocopy, were considered eligible for this IRB-approved study. Consented individuals were offered a multiplex next generation sequencing panel analyzing 23 genes associated with breast, ovarian and other cancers. Results: Of 77 BRCA positive eligible individuals, 16 from 15 unrelated families enrolled. A second pathogenic mutation was identified in 5 of 15 (33%) families in the following genes: MUTYH (3), RAD51D, and ATM. Five variants of unknown significance were detected in 4 additional families in the PMS2 (2), PALB2, PTEN, and MSH6 genes. Conclusions: Though a small cohort, these results highlight the utility of reviewing BRCA1/2 positive pedigrees for features supporting further testing. Identifying other mutations may modify BRCA-associated risks, which could impact medical management/risk assessment of probands and/or residual cancer risks in relatives who don’t harbor the familial BRCA mutation. Also, further studies in BRCA positive families may add important data for variant classification. This study highlights the need to uncover the prevalence of digenic HBOC mutations in large cohorts of BRCA1/2 positive families with complex histories and the impact of multiple mutations on cancer risk and medical management.
Persistence of platinum in semen of cisplatin-treated survivors of advanced testicular cancer.
Authors: Eoghan Ruadh Malone, Jeremy Howard Lewin, Lisa Wang, Susan Lau, Robert James Hamilton, Aaron Richard Hansen, Keith Jarvi, Wenjiang Zhang, Eric Xueyu Chen, Philippe L. Bedard
Journal: Journal of Clinical Oncology (2020)

5056 Background: Cisplatin is highly curative treatment for testicular cancer. Most survivors develop azoospermia immediately after cisplatin with recovery expected in 50% at 2 years and 80% at 5 years. Platinum is a heavy metal that can be detected at low levels in serum many years after treatment, however, it is not known whether platinum also persists in semen and if platinum persistence in semen is associated with impaired fertility. Methods: Testicular cancer survivors previously treated with cisplatin were enrolled, relapsed disease treated with salvage chemotherapy was excluded. Semen samples were collected to assess semen quality. Repeat semen collections were performed if azoo- or oligospermia was noted. Serum and semen Platinum levels were determined using HPLC-tandem mass spectrometry. DNA Fragmentation Index (DFI) was measured. Results: From 11/2017 to 12/2019, 38 pts (median age 32 years; range: 19-52; median BSA 2.03; range: 1.81-2.61) were enrolled, 31 were treated with 3 cycles of Bleomycin, Etoposide, Cisplatin. Median cumulative cisplatin dose was 300 mg/m 2 (range: 274-404). Median serum platinum concentration was 0.1 ng/mL (range: 0-22.6) at a median of 11 months (range 0.5-36) post treatment completion. Median semen platinum concentration was 0.5 ng/mL (range: 0.2-28.7) at a median of 14 months (range: 1.3-40) post treatment completion. Semen platinum levels were higher in semen than in blood drawn at the same time (p = 0.03). Semen platinum levels were associated with time from last cisplatin dosing (r = -0.34; p = 0.09) but not cumulative cisplatin dose (r = -0.10, p = 0.63). Sperm concentration was correlated with time from last cisplatin dosing (r = 0.58, p &lt; 0.001) but not with semen platinum level (r = -0.15, p = 0.46). DFI was associated with time from last cisplatin dosing (r = 0.55, p = 0.08) but not with semen platinum level (r = -0.32, p = 0.33). In 4 pts with serial semen samples available, semen platinum level decreased with time, sperm concentration and motility increased. Conclusions: Platinum can be detected in semen in long-term testicular cancer survivors at higher levels than matched blood samples. Our preliminary findings may have important implications for reproductive health of survivors of advanced testicular cancer, further studies are needed to assess the relationship between platinum persistence in semen and recovery of fertility post chemotherapy.
Comprehensive multiplatform biomarker analysis of 212 anal squamous cell carcinomas.
Authors: Patrick McKay Boland, Jue Wang, David Arguello, Sherri Z. Millis, Zoran Gatalica, Sandeep K. Reddy, Joshua E. Meyer, Thorvardur Ragnar Halfdanarson
Journal: Journal of Clinical Oncology (2015)

3519 Background: Squamous cell anal carcinoma is a rare, HPV-associated malignancy accounting for 2% of digestive system cancers. Usually these malignancies are detected early and successfully managed with chemoradiation. Uncommonly, these cancers recur or present with metastases. In this setting, cisplatin and 5-fluorouracil represent the only endorsed regimens. Beyond standard therapy, few therapeutic options exist. The purpose of this study is to identify other novel, potential targets and therapeutic options for this disease, utilizing a multiplatform approach. Methods: 212 squamous cell anal carcinoma specimenswere tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (CISH or FISH). Tissue from a metastatic site was submitted in 80.2% of the cases. Documentation of positive HPV or HIV status was provided in six cases. Results: IHC overexpression was noted in MRP1 (97.6%, 81/83), EGFR (89.7%, 35/39), TOPO1 (68.3%, 123/180), MGMT (67.2%, 125/186), and PTEN (46.9%, 90/192). EGFR and HER2 were amplified (ISH) in 7.4% (5/68) and 1.8% (2/111) of cases. High mutation rates were seen in biomarkers associated with the PIK3CA/Akt pathway: PIK3CA (26.8%, 26/97), FBXW7 (11.8%, 8/68), PTEN (3.1%, 2/64), and Akt1 (1.5%, 1/68). PIK3CA exon 9 mutations were detected in 75% of all PIK3CA mutations. KRAS mutations were rare (1.8%, 2/111). Point mutations in other genes were also identified, including a few co-occurring mutations. Conclusions: Multiplatform tumor profiling identified several potential targets. Protein expression aberrations identified potential treatment options not routinely considered. Mutations in PIK3CA, Akt1, and FBXW7 and PTEN loss indicate potential for targeting the PI3 kinase pathway. Targeting the ErbB-family receptors, namely with anti-EGFR agents or newer generation pan-HER inhibitors, may represent another option, given EGFR and HER2 amplification as well as EGFR overexpression. Differences in anal carcinomas whose etiology is of viral origin may present different treatment options based on the driver mutations.
Abstract P6-01-05: Detection of HER2 positive tumor cells using functionalized iron oxide nanoparticles
Authors: FZ Bischoff, K Mathieu, J Vargas, L Pang, AM Kulp, A Dewing, X Liu, RC Bast, J Hazle, M Zhang
Journal: Cancer Research (2019)

Abstract Background: Iron oxide nanoparticles (NPs) have been used for a variety of in-vivo and ex-vivo applications within the biomedical sciences. Moreover, when intended for clinical in-vivo applications, NPs need to meet rigorous requirements to ensure safety as well as bio-functionality including blood circulation time and specificity for cellular targets. PrecisonMRX® NPs are extensively characterized superparamagnetic NPs composed of a 25nm magnetite cores that are currently employed in a variety of in-vivo applications including non-invasive/in vivo diagnosis of cancer, Magnetic Particle Imaging, MRI, and magnetic hyperthermia. Objective: Here we report on the extensive pre-clinical development and functionality of antibody (Herceptin)-conjugated NPs for in-vivo and ex-vivo detection of HER2+ tumor cells by Magnetic Relaxometry (MRX). Results: We observed: 1) specific binding and detection of HER2 positive tumor cells in-vitro; 2) specific detection of HER2+ tumors in mice; 3) binding and amplitude of magnetic signal to be proportional to the level of HER2 expression in-vitro and in-vivo; 4) the nanoconstruct remains stable in circulation; 5) the particles do not induce a pro-inflammatory response nor activate complement; 6) the particles are biodegradable; and do not induce acute or delayed signs of morbidity in mice. Conclusion: Precision MRX® nanoparticles offer great clinical promise including the in- vivo detection of tumor cells by magnetic relaxometry. Given the stability and safety of these NPs, our pre-clinical results support progressing to clinical testing. A first-in human ex-vivo clinical research study design and strategy will be discussed. Citation Format: Bischoff FZ, Mathieu K, Vargas J, Pang L, Kulp AM, Dewing A, Liu X, Bast RC, Hazle J, Zhang M. Detection of HER2 positive tumor cells using functionalized iron oxide nanoparticles [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-01-05.
Increasing adipose burden in young men with metastatic testicular cancer following front-line cytotoxic chemotherapy.
Authors: Karan Kumar Arora, Caroline Kato, Kunnal Batra, Michael Russell Mullane, Thomas E. Lad, Viraj A. Master, Sarah P. Psutka
Journal: Journal of Clinical Oncology (2019)

525 Background: Exposure to cytotoxic chemotherapy (CC) has been observed to be associated with significant changes in body composition, namely marked lean muscle mass losses, with implications for treatment-related toxicity and oncologic outcomes. However, prior studies predominately include elderly patients who, a priori, are at risk for sarcopenia or severe skeletal muscle deficiency. To date, the impact of CC on body composition in young men with testicular cancer remains undefined. Methods: A retrospective analysis of 19 patients with metastatic testicular cancer treated with CC was performed (2015-17). Lumbar skeletal muscle index (SMI), visceral (VAI), subcutaneous (SCAI), and intramuscular adipose (IMAI) indices (cm 2 /m 2 ), as well as fat-free mass (FFM, kg) and fat mass (FM, kg) were calculated using cross-sectional soft tissue area measurements on pre- and post-CC computed tomography (CT) axial scans and compared using paired Wilcoxon Signed Rank Tests. Results: Median age was 29 years. According to the NHANES FMI-based classification, 5 (26.3%), 9 (47.4%), 4 (21.1%), and 1 (5.3%) patients had normal, excess, class I, and class II obesity, respectively. Median pre- and post-CC BMI was 27.7 vs. 29.6 kg/m 2 (p = 0.03). Median pre- and post-CC SMI, VAI, SAI, and IAI were 63.5 vs 57.8 (p = 0.14), 19.9 vs 30.8 (p = 0.01), 47.9 vs 58.2 (p = 0.03), and 3.0 vs 5.2 (p = 0.002), respectively. Median muscle density pre- and post-CC were 47.0 vs 43.6 HU (p = 0.002). Pre- and post-chemotherapy FFM were 21.5 vs 19.5 kg, representing an overall median loss of 2.8%, (IQR -10.1, +4.7; Range -49.5 - +16.3; p = 0.14). Conversely, pre- and post-CC FM were 6.6 vs 7.5 kg, representing an overall median gain of 13.3% (IQR -3.3, +17.0; -24.9 - +50; p = 0.01). Median time between imaging assessments was 121 days. Specific median measures of adiposity each increased significantly, such that VIA increased by 29% (p = 0.01), SCAI increased by 39.7% (p = 0.03), and IMIA increased by 39.7% (p = 0.002). Conclusions: While lean muscularity remained stable, we observed significant increases in total body adipose mass with decreased muscle density in this consecutive case series of testicular cancer patients following CC.
Disease burden and outcome in metastatic hormone sensitive prostate cancer (mHSPC).
Authors: Laurence Albiges, Wanling Xie, Yu-Hui Chen, Jean-Marie Boher, Loana Bueno Valenca, Brandon David Bernard, Stephane Culine, Muriel Habibian, Michael Anthony Carducci, Robert S. DiPaola, Glenn Liu, Mark Pomerantz, Mari Nakabayashi, Philip W. Kantoff, Karim Fizazi, Gwenaelle Gravis, Christopher Sweeney
Journal: Journal of Clinical Oncology (2015)

5052 Background: Patients (Pts) with higher burden of mHSPC have shorter OS but there is no uniform definition of high (H) vs low (L) volume of disease (VD). Methods: Pts with mHSPC with known VD were analyzed [2 trials of ADT vs ADT + Docetaxel (D) and the Dana-Farber Cancer Institute Gelb center database of pts treated with ADT]. OS (95% CI) was calculated from randomisation for GETUG and E3805, and from initiation of ADT at the Gelb center, until death or censored at last follow-up. E3805 HVD defined as visceral metastases and/or 4 or more bone metastases (BM) with at least 1 beyond the pelvis/vertebrae. Results: 1,528 of 1,603 pts had data available to accurately categorize HVD/LVD. A gradient in outcome is noted for increasing BM burden. OS variability is seen in the 4-9 BM group and OS across the 3 cohorts. The E3805 composite definition consistently dichotomized the 5 groups (HR for HVD/LVD ≥ 2 for risk of death). Conclusions: A composite definition of HVD consistently dichotomized the 5 groups. Variability between cohorts may be due to different pts characteristics and CRPC therapy. GETUG 15 E 3805 Gelb Center Median follow up (yrs) 6.9 2.4 5.8 ADT N=193 ADT+DN=192 ADT N=393 ADT+DN=397 ADT N=428 Absence of localized treatment 75% 67% 73.0% 72.8% 43.9% Median OS (mos) Overall 46.5 (39.1-60.6) 60.9 (46.1-71.4) 44.0 (34.4-49.1) 57.6 (49.1-72.8) 58.4 (50.3-71.2) Visceral mets n=23 32.0 (23.2-66.9) n=28 27.1 (21.9-71.4) n=66 27.5 (19.8-42.3) n=57 49.2 (40.3-52.7) n=23 64.4 (21.6-NR) # of BM (no visceral mets) All n=137 46.1 (37.2-54.5) n=132 51.2 (39.8-70.5) n=326 47.3 (36.7-52.8) n=340 57.6 (48.8-72.8) n=283 53.1 (46.8-62.2) N<4 n=60 66.1 (40.9-NR) n=61 NR (60.9-NR) N/A N/A n=108 86.4 (68.8-104.8) [4-9] n=36 36.7 (30.1-62.2) n=43 42.5 29.9-70.5 n=101 34.4 (27.2-48.1) n=123 58.1 (38.4-72.8) n=40 79.8 (45.4-121.6) N≥10 n=50 30.4 (26.3-42.2) n=47 30.5 (21.1-46.1) n=75 38.0 (25.8-62.6) n=74 38.4 (25.6-57.6) n=112 44.4 (34.4-47.7) E3805-HVD n=91 35.1 (29.9-44.2) n=92 39.0 (28.0-52.6) n=250 32.2 (28.6-39.5) n=263 49.2 (38.4-58.1) n=156 48.6 (42.5-60.0) E3805-LVD n=102 NR (61.8-NR) n=100 83.1 (69.5-NR) n=143 NR (49.1-NR) n=134 NR (NR-NR) n=197 92.4 (71.2-149.8) Hazard Ratio (HVD/LVD) 2.5 (1.9-4.1) 2.8 (1.7-3.8) 2.96 (1.9-4.6) 2.4 (1.4-4.0) 2.1 (1.5-2.8)