tbuckley/cabot-search huggingface dataset:
Plasma circulating tumor DNA (ctDNA) based clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Manish Kohli, Winston Tan, Tiantian Zheng, Amy Wang, Yelia Huo, Carlos Montesinos, Calvin Wong, Pan Du, Shidong Jia, Jianjun Yu
Journal: Journal of Clinical Oncology (2020)

160 Background: mCRPC is a heterogeneous disease state with variable survival and molecular markers that define survival continue to be determined. We applied a 120 gene panel based targeted next-gen sequencing (NGS) approach to probe plasma ctDNA based outcomes for survival. Methods: mCRPC chemo-naive patients (pts) were enrolled in a prospective study and plasma cell free DNA (cfDNA) extracted. ctDNA fractions estimated based on somatic variants. NGS of plasma cfDNA was performed using HiSeq X Ten on a panel of 120 genes (PredicineLDT). Clinical and molecular prognostic factors were determined for overall survival (OS). Cox proportional hazard regression was used to estimate hazard ratios (HR) at the univariate level and only significant associations included in multivariate analysis (significance at P&lt;0.05). Results: 96 mCRPC pts were enrolled. 17/96 pts failed NGS QC. Median cfDNA, ctDNA yields for 79/96 pts are provided in Table. Median follow up for study cohort was 92.5 months (mon) (Range:62.3-109.6); median survival time was 25.9 mon (95% CI:19.9, 31.4) and 72/79 pts had died. TMPRSS2-ERG fusion was detected in 18/79 pts. Significant alterations associated with OS are listed in Table. 49/59 pts underwent subsequent docetaxel chemo. In chemo treated pts significant copy number alterations predictive of survival included AR amplification (p=0.01, HR=2.0, 95% CI[1.2, 3.5], RB1 loss (p=3.20E-06, HR=5.0, 95% CI[2.4, 10.6], PTEN(p=0.009, HR=2.6, 95% CI[1.2, 5.4]), CDH1(p=0.001, HR=4.3, 95% CI[1.6, 11.4]). Conclusions: ctDNA yield in mCRPC state was the most significant prognostic factor for survival, Several specific plasma genomic perturbations were observed topredict docetaxel efficacy and need further evaluation.[Table: see text]
Programmatic versus personalised approaches to managing the global epidemic of multidrug-resistant tuberculosis
Authors: Jeremiah Muhwa Chakaya, Ben Marais, Philipp du Cros, Francine Ntoumi, Sayoki Mfinanga, Nathan Kapata, Seyed Ehtesham Hasnain, Ruvandhi Nathavitharana, Alimuddin Zumla
Journal: The Lancet Respiratory Medicine (2020)
Characteristics of radiation-associated bladder cancer compared to primary bladder cancer
Authors: Sybil Sha, Edward Christopher Dee, Brandon Arvin Virgil Mahal, Kent William Mouw, Paul L. Nguyen, Vinayak Muralidhar
Journal: Journal of Clinical Oncology (2020)

582 Background: Radiation-associated muscle-invasive bladder cancer (RA-MIBC) has been suggested to represent a more aggressive disease variant compared to primary (non-radiation associated) MIBC. We sought to characterize the presentation, patterns of care, and outcomes of RA-MIBC compared to primary MIBC. Methods: We identified 60,117 patients diagnosed with non-metastatic or metastatic MIBC between 1988 and 2015 using the Surveillance, Epidemiology, and End Results (SEER) database and stratified patients based on whether radiation had been administered to a pelvic primary prior to the development of bladder cancer. We used logistic regression to compare rates of chemotherapy, surgery, or radiation for patients with RA-MIBC compared to primary MIBC. We used Fine-Gray competing risks regression to compare adjusted bladder cancer-specific mortality (BCSM) for RA-MIBC and primary MIBC. Results: There were 1,093 patients with RA-MIBC and 59,024 patients with primary MIBC. Patients with RA-MIBC were older compared to patients with primary MIBC (mean age 77.4 years vs 72.4 years, p &lt; 0.001) and more likely to be male (86.8% vs 73.3%, p&lt;0.001). RA-MIBCs were more likely to be high-grade (57.5% vs 47.6%, p&lt;0.001), more likely to have T4 disease at diagnosis (21.0% vs 17.3%, p&lt;0.001), and less likely to be node-positive (4.2% vs 8.1%, p &lt; 0.001). In terms of treatment, non-metastatic primary MIBC patients were more likely to undergo radiation (14.0% vs 3.1%, p&lt;0.001) as well as radiation with cystectomy (1.9% vs 0.8%, p&lt;0.001) compared to those with RA-MIBC. Median survival was significantly shorter for patients with RA-MIBC (13 mo. vs 19 mo.; p&lt;0.001). Conclusions: RA-MIBCs tend to present with higher grade and higher stage disease and are less likely to receive curative treatment. Even when adjusting for stage, grade, and receipt of treatment, patients with RA-MIBC have worse survival compared to those with primary MIBC. These findings raise the possibility that RA-MIBC represents a biologically more aggressive disease compared to primary MIBC. Future research is needed to better understand biological differences between RA-MIBC and primary MIBC and develop improved therapeutics for radiation-associated cancers.
A phase I study of guadecitabine (SGI-110) plus cisplatin in patients with platinum refractory germ cell tumors.
Authors: Costantine Albany, Michael J. Spinella, Nabil Adra, Nasser H. Hanna, Lawrence Einhorn
Journal: Journal of Clinical Oncology (2020)

408 Background: Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. Platinum-refractory germ cell tumors (GCT) showed significant DNA hypermethylation compared to platinum sensitive tumors. In preclinical studies, GCT were extremely sensitive to low dose decitabine which restored sensitivity to cisplatin in cell lines. We aimed to assess the safety and clinical activity of guadecitabine in combination with cisplatin in patients with platinum-refractory GCT. Methods: In this open-label, phase 1 study, patients with GCT refractory to or had relapsed after platinum-based treatment were treated with subcutaneous (SQ) guadecitabine, once-daily for 5 consecutive days, followed by cisplatin on day 8 with growth factor support (GFS) in a 28-day treatment cycle. A modified toxicity probability interval (mTPI) dose-escalation design was used in which we treated patients with guadecitabine doses of 30-45 mg/m 2 plus cisplatin 100 mg/m2 up to 6 cycles until progression or intolerable toxicity. The primary objective was to assess safety and tolerability of the combination, determine the maximum tolerated dose (MTD). Secondary objective was objective response rate (ORR). Results: Fourteen patients with incurable disease were enrolled. Primary site were testis 11, mediastinum 2, and ovarian 1. All progressed after at least 2 lines of standard of care chemotherapy including HDCT. Dose-limiting toxicities were neutropenic fever. Most common toxicities were neutropenia (82% any grade), thrombocytopenia (42%), anemia (33%), neutropenic fever (8%), and diarrhea (8%). The maximum tolerated dose of guadecitabine was 30 mg/m 2 x 5 days and cisplatin 100 mg/m 2 . We observed 2/14 complete response lasting more than 6 months, 2 partial response and 1 stable disease. ORR 28.5%. Conclusions: We report the first study of chemo-priming with epigenetic therapy in GCT. Guadecitabine 30 mg/m 2 x 5 days and cisplatin 100 mg/m 2 with GFS was safe and tolerable and showed promising activity with 4/14 responses in this highly treatment refractory patient population. Clinical trial information: NCT02429466.
Risk of pregnancy-related venous thromboembolism and obstetrical complications in women with inherited type I antithrombin deficiency: a retrospective, single-centre, cohort study
Authors: Maria Abbattista, Francesca Gianniello, Cristina Novembrino, Marigrazia Clerici, Andrea Artoni, Paolo Bucciarelli, Marco Capecchi, Flora Peyvandi, Ida Martinelli
Journal: The Lancet Haematology (2020)
Real-world evidence of the impact of prior antibiotic exposure on immune checkpoint inhibitor outcomes in patients with metastatic urothelial cancer.
Authors: Jean H. Hoffman-Censits, Lauren Christine Harshman, Meredith Metcalf, Sarah Abou Alaiwi, Craig S. Meyer, Erru Yang, Sacha Satram, Sarika Ogale, Kathleene Faber, Esprit Ma
Journal: Journal of Clinical Oncology (2020)

452 Background: Prior research suggests that systemic antibiotic (ABX) exposure may impact gut microbiome and potentially result in suboptimal immune checkpoint inhibitor (ICI) treatment outcomes. A recent real-world analysis demonstrated that cumulative ABX exposure was associated with poorer outcomes across multiple tumor types independent of known prognostic clinical factors. Given the paucity of real-world data, we set out to evaluate the association of prior ABX exposure with ICI treatment outcomes among patients with metastatic urothelial cancer (mUC). Methods: This was a retrospective analysis using Truven Health MarketScan Commercial, Medicare Supplemental, and Coordination of Benefits (Medicare) databases. Patients with mUC, ≥18 years old, who received first line (1L) ICI therapy between 1/1/2016 and 12/31/2018 were analyzed. Prior ABX exposure was defined as any use in the 90 days prior to 1L ICI therapy initiation. Time to treatment discontinuation was used as a proxy to quantify ICI treatment outcomes. Results: Among the 304 ICI treated patients, 128 (42%) had ABX exposure within 90 days prior to ICI initiation. Statistically significant differences in baseline co-morbidities and urinary tract infections (36% vs. 17%; p&lt;0.001) were observed between patients with vs. without ABX exposure. The median time to treatment discontinuation was shorter for patients with ABX exposure (7.9 months) vs. without (9.3 months). In adjusted regression analysis, there was no statistically significant difference in time to treatment discontinuation between patients with vs. without ABX exposure (p=0.95). These findings were consistent in a sensitivity analysis looking at ABX exposure 30 and 60 days prior to 1L ICI initiation. Conclusions: In this real-world analysis of patients with mUC, those with ABX exposure within 90 days prior to 1L ICI initiation demonstrated similar outcomes to those without ABX exposure. While there was a shorter time to treatment discontinuation in the patients with vs. without ABX exposure, findings were not statistically significant. Further research is warranted to investigate the impact of concomitant ABX use on ICI outcomes.
MAGNIMS consensus recommendations on the use of brain and spinal cord atrophy measures in clinical practice
Authors: Jaume Sastre-Garriga, Deborah Pareto, Marco Battaglini, Maria A Rocca, Olga Ciccarelli, Christian Enzinger, Jens Wuerfel, Maria P Sormani, Frederik Barkhof, Tarek A Yousry, Nicola De Stefano, Mar Tintoré, Massimo Filippi, Claudio Gasperini, Ludwig Kappos, Jordi Río, Jette Frederiksen, Jackie Palace, Hugo Vrenken, Xavier Montalban, Àlex Rovira
Journal: Nature Reviews Neurology (2020)

Abstract Early evaluation of treatment response and prediction of disease evolution are key issues in the management of people with multiple sclerosis (MS). In the past 20 years, MRI has become the most useful paraclinical tool in both situations and is used clinically to assess the inflammatory component of the disease, particularly the presence and evolution of focal lesions — the pathological hallmark of MS. However, diffuse neurodegenerative processes that are at least partly independent of inflammatory mechanisms can develop early in people with MS and are closely related to disability. The effects of these neurodegenerative processes at a macroscopic level can be quantified by estimation of brain and spinal cord atrophy with MRI. MRI measurements of atrophy in MS have also been proposed as a complementary approach to lesion assessment to facilitate the prediction of clinical outcomes and to assess treatment responses. In this Consensus statement, the Magnetic Resonance Imaging in MS (MAGNIMS) study group critically review the application of brain and spinal cord atrophy in clinical practice in the management of MS, considering the role of atrophy measures in prognosis and treatment monitoring and the barriers to clinical use of these measures. On the basis of this review, the group makes consensus statements and recommendations for future research.
lncRNA JPX/miR-33a-5p/Twist1 axis regulates tumorigenesis and metastasis of lung cancer by activating Wnt/β-catenin signaling
Authors: Jinchang Pan, Shuai Fang, Haihua Tian, Chengwei Zhou, Xiaodong Zhao, Hui Tian, Jinxian He, Weiyu Shen, Xiaodan Meng, Xiaofeng Jin, Zhaohui Gong
Journal: Molecular Cancer (2020)

MicroRNAs (miRNAs) and Twist1-induced epithelial-mesenchymal transition (EMT) in cancer cell dissemination are well established, but the involvement of long noncoding RNAs (lncRNAs) in Twist1-mediated signaling remains largely unknown.RT-qPCR and western blotting were conducted to detect the expression levels of lncRNA JPX and Twist1 in lung cancer cell lines and tissues. The impact of JPX on Twist1 expression, cell growth, invasion, apoptosis, and in vivo tumor growth were investigated in lung cancer cells by western blotting, rescue experiments, colony formation assay, flow cytometry, and xenograft animal experiment.We observed that lncRNA JPX was upregulated in lung cancer metastatic tissues and was closely correlated with tumor size and an advanced stage. Functionally, JPX promoted lung cancer cell proliferation in vitro and facilitated lung tumor growth in vivo. Additionally, JPX upregulated Twist1 by competitively sponging miR-33a-5p and subsequently induced EMT and lung cancer cell invasion. Interestingly, JPX and Twist1 were coordinately upregulated in lung cancer tissues and cells. Mechanically, the JPX/miR-33a-5p/Twist1 axis participated in EMT progression by activating Wnt/β-catenin signaling.These findings suggest that lncRNA JPX, a mediator of Twist1 signaling, could predispose lung cancer cells to metastasis and may serve as a potential target for targeted therapy.
Phase I experience with rogaratinib in patients (pts) with urothelial carcinoma (UC) selected based on <i>FGFR</i> mRNA overexpression.
Authors: Emmanuelle Kempf, Nicolas Penel, Christophe Tournigand, Pablo Gajate, Daniel Shao-Weng Tan, Philippe Cassier, Lucia Nogova, Richard Cathomas, Martin Schostak, Andreas Janitzky, Martin Wermke, Cyrus Sayehli, Alejandro Navarro, Se Hoon Park, Ana-Maria Piciu, Sebastian Bender, Hendrik Nogai, Peter Ellinghaus, Markus Joerger, Martin H. Schuler
Journal: Journal of Clinical Oncology (2020)

527 Background: Aberrant activation of the fibroblast growth factor receptor (FGFR) pathway is implicated in many cancers, including UC. In a recent Phase I dose-escalation study, rogaratinib, an oral pan-FGFR1-4 inhibitor, demonstrated favorable efficacy and safety in pts with solid cancers selected based on FGFR1-3 mRNA overexpression. We report results from the Phase I expansion cohort with rogaratinib in pts with UC selected by FGFR1-3 mRNA overexpression and/or FGFR3-activating mutations (NCT01976741). Methods: Pts with advanced/metastatic UC were screened for FGFR1-3 mRNA overexpression using RNA in situ hybridization (RNAscope) and NanoString assay in fresh or archival tumor samples. Pts received rogaratinib 800 mg po BID continuously. Tumor response and safety were assessed. Results: 74 pts with UC were treated with rogaratinib; 73.0% were male, median age was 66 years (range 45-85), and 93.2% had stage IV disease. Rogaratinib was well tolerated, with adverse events being mostly mild or moderate. The most common treatment-emergent adverse events (TEAEs) are shown in the Table. The most common drug-related TEAEs (any grade) were diarrhea (52.7%), increased blood phosphorus (41.9%), and decreased appetite and dry mouth (31.1% each). No ocular toxicities were reported. Increased blood creatinine and acute kidney injury (AKI), regardless of relatedness, were reported in 16.2% and 2.7% of pts, respectively; 1 case of AKI was confirmed as acute tubular necrosis. Of 72 evaluable pts, 15 (20.8%) achieved an objective response; complete and partial responses were observed in 1 (1.4%) and 14 (19.4%) pts, respectively. Stable disease was achieved by 34 pts (47.2%), with a disease control rate of 68.1%. Conclusions: Rogaratinib demonstrated a favorable safety and efficacy profile in pts with tumor FGFR1-3 mRNA-positive UC. TEAEs observed in &gt;25% of pts. Clinical trial information: NCT01976741. [Table: see text]
Dosimetry of 177Lu-PSMA-617 for the treatment of metastatic castration-resistant prostate cancer: A sub-study of the VISION trial.
Authors: Jens Kurth, Ken Herrmann, Matthias Eiber, Kambiz Rahbar, Martin Heuschkel, Michael Lassmann, Walter Jentzen, Daniela Chicco, Richard Messmann, A. Oliver Sartor, Michael J. Morris, Bernd J. Krause
Journal: Journal of Clinical Oncology (2020)

TPS265 Background: Prostate-specific membrane antigen-617 labelled with lutetium-177 ( 177 Lu-PSMA-617) is a promising treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) after treatment with taxane chemotherapy and a novel androgen axis inhibitor. The radiotherapeutic molecule has high PSMA binding affinity, prolonged tumor retention with a rapid kidney clearance, and high tumor-to-background ratio, delivering therapeutically relevant doses of radiation to prostate cancer lesions. A randomized, prospective phase 3 trial to assess the efficacy of 177 Lu-PSMA-617 in patients with progressive PSMA-positive mCRPC is ongoing (VISION trial, NCT03511664). However, as with other targeted radionuclide treatment modalities, there may be a risk of radiotoxicity to normal organs. Therefore, estimation of absorbed doses in these organs in a representative manner within the framework of such a study is essential. Methods: As a substudy of the VISION trial, extensive intratherapeutic dosimetry will be performed in a group of 30 patients at four participating German sites. Patients will undergo planar whole-body scintigraphy scans and single-photon emission computed tomography/computerized tomography (SPECT/CT) scans of the upper and lower abdomen at approximately 2, 24, and 48 hours, and 7 days after administration, along with blood sampling and urine collection. SPECT/CT data will be quantitatively reconstructed and a standardized calibration procedure of the imaging and measurement equipment used (SPECT/CT, dose calibrator, well counter) will be performed at all sites according to European Association of Nuclear Medicine (EANM) and Medical International Radiation Dose (MIRD) guidelines [1]. Organ masses will be measured for each patient using CT imaging, if accessible. Absorbed doses for kidneys, liver, spleen, salivary and lacrimal glands, and bone marrow, as well as prostate cancer lesions, will be calculated for each patient following international guidelines [2,3]. References: [1] Ljungberg M et al. J Nucl Med 2016;57:151–62. [2] Siegel JA et al. J Nucl Med 1999;40:37S–61S. [3] Hindorf C et al. Eur J Nucl Med Mol Imaging 2010;37:1238–50. Clinical trial information: NCT03511664.
Germline alterations in patients with testicular cancer.
Authors: Chethan Ramamurthy, Edward D. Esplin, Shan Yang, Michael Liss, Gail Elizabeth Tomlinson, Guru Sonpavde
Journal: Journal of Clinical Oncology (2020)

397 Background: There are limited data for the association of testis cancer (TC) with hereditary cancer genes. We report the prevalence of germline mutations among men with TC completing germline genetic testing through a large, commercial laboratory. Methods: We reviewed a de-identified dataset of men from across the USA with history of TC who underwent testing of 1 to 130 genes via massively parallel sequencing with customized capture bait-sets to analyze exonic regions, flanking intronic sequences, and copy number alterations. Pathogenic (P) and likely pathogenic (LP) were confirmed using orthogonal technology in accordance with Invitae standard operating practices. P/LP variants including single nucleotide variants/indels/copy number variants are reported. Fisher’s Exact test was used to analyze categorical variables. Results: The cohort of 250 men was 84% White/Caucasian. The median number of genes tested was 48. P/LP variants were found in 18% (n = 45) of subjects. P/LP variants occurred in several moderate to high penetrance genes, including CHEK2 (n = 10 [4.0%]), BRCA1/2 (n = 6 [2.4%]), ATM (n = 6 [2.4%]) and Lynch syndrome genes (n = 4 [1.6%]). Heterozygous MUTYH (n = 6) and NTHL1 (n = 1) mutations were also found. DNA damage repair (DDR) mutations were found in 14.8% (n = 37) of subjects. Of the 45 carriers, 18 (40%) had no other personal cancer history while 27 (60%) had an additional primary cancer, but there was no significant association between having another primary and risk of carrying a mutation (p = 0.253). CHEK2 was the single most frequently mutated gene, with 2 of the low penetrance I157T mutations identified, but 8 other higher penetrance variants, including 2 1100delC mutations. Conclusions: A high percentage of hereditary cancer gene mutations were found in testicular cancer patients, many which were not associated with a history of another malignancy. Several mutations were in high penetrance DDR genes such as BRCA1/2 and Lynch genes, which may also serve as actionable targets. CHEK2 mutations were common, supporting prior data suggesting an association with testicular cancer. Further multigene panel testing in unselected patients and the study of association with histologic subtype, race, stage and family history is warranted.
Pegilodecakin as monotherapy or in combination with anti-PD-1 or tyrosine kinase inhibitor in heavily pretreated patients with advanced renal cell carcinoma (RCC): Updated results from phase I/Ib IVY study.
Authors: Aung Naing, Kyriakos P. Papadopoulos, Deborah J.L. Wong, Raid Aljumaily, Annie Hung, Manuel Afable, Jong Seok Kim, David Ferry, Alexandra Drakaki, Johanna C. Bendell, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2020)

679 Background: Pegilodecakin (PEG), a pegylated recombinant human interleukin-10, has demonstrated clinical benefit and manageable toxicity in advanced RCC (Naing et al. 2016 JCO, Naing et al. 2019 Lancet Oncol). As part of the multi-arm (arm A to J) phase 1 IVY study, PEG alone (Part A) or in combination with pazopanib (Part G) or anti-PD-1 (pembrolizumab or nivolumab; Parts H+I) were investigated in heavily pretreated RCC patients (pts). Methods: In a phase 1/1b study which enrolled 353 pts in the US from 2013 to 2017, we analyzed treatment-related adverse events (TRAEs) graded by CTCAE v 4.02, tumor response by irRC, progression-free survival (PFS), and overall survival (OS) for all the advanced RCC pts who received PEG-containing treatment (n=66). Data cut-off was February 19, 2019. Results: Sixty six heavily pretreated RCC pts received PEG alone (n=24, 1-20 µg/kg), with pazopanib (n=4, 10µg/kg), with pembrolizumab (n=9, 10-20 µg/kg), or with nivolumab (n=29, 10-20 µg/kg). Most pts were male (70%), median age 62.5 years, initially diagnosed as stage IV (42%) with clear cell histology (64%), ECOG performance status of 1 (58%), and intermediate/poor (73%/14%) risk per IMDC category. Patients received a median number of 2 prior therapies. Most common grade 3/4 TRAEs were anemia (32%), thrombocytopenia (15%), and hypertriglyceridemia (14%). No pts died due to a TRAE. Median follow-up was 31.5 months. Conclusions: PEG alone or in combination with anti-PD-1 or pazopanib suggested some clinical activity with manageable toxicity in advanced RCC pts. These findings support further ongoing studies of PEG combinations in RCC pts. Clinical trial information: NCT02009449 .[Table: see text]
The Impact of Disease Perception and Psychosocial Factors on Medication Adherence in Asthmatic Adolescents
Authors: Preyanit Takkinsatian, Witchaya Srisuwatchari, Punchama Pacharn, Sasitorn Chantaratin, Sudarat Sirisakpanit, Orathai Piboonpocanun, Nualanong Visitsunthorn
Journal: Journal of Allergy and Clinical Immunology (2020)