tbuckley/cabot-search huggingface dataset:
Anaplastic features (AnaF) and DNA-damage repair pathway (DDR) mutations in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Vincent Chau, Ravi Amrit Madan, Marijo Bilusic, Lisa M. Cordes, Jennifer L. Marte, Helen Owens, Amy Hankin, James L. Gulley, Jung-Min Lee, William L. Dahut, Fatima Karzai
Journal: Journal of Clinical Oncology (2021)

92 Background: Anaplastic prostate cancer displays features of small-cell carcinoma, a type of neuroendocrine tumor. Treatments for anaplastic prostate cancer are based on small cell lung cancer regimens. Both AnaF and mutations in DDR pathways, including BRCA2 confer an aggressive phenotype. For patients (pts) with certain DDR mutations, olaparib (O) was recently FDA approved, and an ongoing study is evaluating whether the addition of durvalumab (D) confers additional benefit in mCRPC (NCT02484404). We evaluate a potential preliminary relationship between DDR mutations, treatment with D and O, and AnaF. Methods: This is a phase II study of O plus D in pts with mCRPC with disease that is amenable to biopsy. On-study core biopsies undergo mutational analysis. Prior treatment with enzalutamide (enza) and/or abiraterone (abi) is required. D is given at 1500 mg iv q28 days + O 300 mg tablets po q12 hours. The primary endpoint is PFS. Pts were categorized into those with and without AnaF as defined by Aparicio et al. (2013). AnaF include small-cell histology; exclusively visceral metastases; predominantly lytic bone metastases; bulky lymphadenopathy (≥5 cm) or high-grade (Gleason ≥8) mass in prostate/pelvis; low PSA (≤10 ng/mL) at initial presentation with high volume (≥20) bone metastases; neuroendocrine markers in histology or serum plus elevated LDH, malignant hypercalcemia, or elevated serum CEA; or short interval (≤6 months) to androgen-independent progression. Results: Of 55 pts accrued, 24 had prior abi and enza; 19 pts had prior taxane. Common adverse events include anemia, fatigue, and nausea. Also, 11 pts (20.0%) displayed clear AnaF (Table) and 43 pts lacked AnaF, including 8 (14.5%) with partial AnaF that did not meet the full criteria, 4 (7.3%) who likely did not have AnaF due to difficulty in quantifying disease burden, 29 (52.7%) who did not have AnaF, and 2 (3.6%) had unknown status. Four pts (36.4%) with clear AnaF had DDR aberrations, including 3 (27.3%) with BRCA2, 1 (9.1%) with both BRCA2 and CHEK2, and 1 (9.1%) with ATM. Conclusions: Pts with mCRPC with DDR mutations can also have AnaF. This preliminary data demonstrates that pts with anaplastic prostate cancer and pts with DDR mutations are two distinct populations with some degree of overlap. O+D is well-tolerated, and future studies should focus on finding optimal treatments for pts with AnaF without and without DDR mutations. Clinical trial information: NCT02484404. [Table: see text]
Preliminary analysis of a U.S. phase II study of the safety and tolerability of proxalutamide (GT0918) in subjects with mCRPC who had progressed on either abiraterone (Abi) or enzalutamide (Enza).
Authors: Nicholas J. Vogelzang, Richard Levin, Arash Rezazadeh, Chandler H. Park, Britt Haley Bolemon, Nashat Y. Gabrail, Zulfiqar A. Malik, Luke T. Nordquist, Ashley Ross, Phoebe Zhang, Karl Zhou
Journal: Journal of Clinical Oncology (2021)

99 Background: GT0918, an androgen receptor (AR) antagonist, is a new chemical entity with reduced drug accumulation in the CNS. In a phase I dose escalation trial (NCT02826772), GT0918 was well tolerated with some durable responses in mCRPC patients (pts) who had progressed on ≥2 lines of standard and experimental therapies. This Phase 2 was designed to study the safety and efficacy of GT0918 400 mg vs. 500 mg oral daily in mCRPC pts who had progressed on either Abi or Enza with or without prior docetaxel. Methods: Pts with histologically confirmed mCRPC who had progressed on either Abi or Enza with or without prior docetaxel were eligible and randomized to 400 mg or 500 mg of GT0918 administered once daily orally. Pts continued treatment with GT0918 at their assigned dose until disease progression, intolerable toxicities or withdrawal of consent. PSA and labs were checked monthly. Imaging scans (CT/MRI and bone scan), circulating tumor cells and cf-DNA/RNA were performed every 3 months. Results: 61 pts were enrolled at 9 US sites and randomized 1:1 to 400 mg (n = 31) or 500 mg (n = 30) daily dose. All pts had progressed on either Abi (n = 34) or Enza (n = 27). Most of the reported AEs related to GT0918 were grade 1 or 2 as per CTCAE v4.03, but 22 AEs (5.3%) were reported as grade ≥ 3, such as fatigue, increase ALT/AST, rhabdomyolysis, or muscle weakness. Some AEs were due to drug-drug interaction with lipid-lowering medications leading to early discontinuation (26.2%). As of 5 October 2020, twelve pts finished 6 cycles. Among them, three finished 12 cycles and remained on the treatment. Treatment duration showed more pts in the 400 mg cohort with stable disease (SD) on imaging (9/31 finished 6 cycles) compared to the 500 mg cohort (3/30 finished 6 cycles). Further, all three pts who finished 12 cycles had progressed on Abi indicating that GT0918 might be a good treatment option for pts who had progressed on Abi. Conclusions: Proxalutamide (GT0918) administrated orally once a day is well tolerated and resulted in SD in pts who had progressed on either Abi or Enza. The 400 mg/day will be considered as the recommended phase II dose for further clinical trials. GT0918 is warranted for pts failed either Abi or Enza. Clinical trial information: NCT03899467.
Angiogenic and T-effector subgroups identified by gene expression profiling (GEP) and propensity for PBRM1 and BAP1 alterations in clear cell renal cell carcinoma (ccRCC).
Authors: Pedro C. Barata, Shuchi Gulati, Andrew Elliott, Arpit Rao, Hans J. Hammers, David I. Quinn, Benjamin Adam Gartrell, Matthew R. Zibelman, Shuanzeng Wei, Daniel M. Geynisman, Tian Zhang, Sourat Darabi, Nancy Ann Dawson, Ralph J. Hauke, Kelsey Anne Poorman, Chadi Nabhan, Charles J. Ryan, Elisabeth I. Heath
Journal: Journal of Clinical Oncology (2021)

343 Background: With the emergence of multiple active treatment options in RCC, predictive biomarkers for optimal treatment selection are lacking. Gene expression data from IMmotion151 and Javelin Renal 101 clinical trials generated anti-angiogenic and immune signatures that warrant further validation. We aimed to describe the genomic and gene expression profiles in a multi-institutional database of patients with ccRCC, and its association with other biomarkers of interest. Methods: Whole transcriptome sequencing was performed for ccRCC patient samples submitted to a commercial CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ) from February 2019 to September 2020. Tumor GEP and hierarchical clustering based on the validated 66-gene signature (D’Costa et al, 2020) were used to identify patient subgroups. Samples from both primary tumors and metastatic sites were included. Results: A total of 316 patients with ccRCC, median age 62 (range 32-90), 71.8% men, were included. Tissue samples were obtained from primary tumor (46.5%), lung (12.3%), bone (9.5%), liver (4.7%) and other metastatic sites (27%). Gene expression analysis identified angiogenic, mixed and T-effector subgroups in 24.1%, 51.3% and 24.7%, respectively. Patients with angiogenic subgroup tumors compared to those with T-effector subgroup tumors were more likely to be older (63 versus 60 years, p=0.035), female (40.8% versus 16.7%, p=0.0009) and more frequently found in pancreatic/small bowel metastases (75% versus 12.5%, p=0.0103). Biomarkers of potential response to immunotherapy such as PD-L1 (p=0.0021), TMB (not significant), and dMMR/MSI-H status (not significant) were more frequent in the T-effector subgroup. PBRM1 mutations were more common in the angiogenic subgroup (62.0% vs 37.5%, p=0.0034) while BAP1 mutations were more common in the T-effector subgroup (18.6% versus 3.0%, p= 0.0035). Immune cell population abundance (e.g. NK cells, monocytes) and immune checkpoint gene expression (TIM-3, PD-L1, PD-L2, CTLA4) were also increased in the T-effector subgroup. Conclusions: Our hierarchical clustering results based on the 66-gene expression signature were concordant with results from prior studies. Patient subgroups identified by evaluation of angiogenic and T-effector signature scores exhibit significantly different mutations and immune profiles. These findings require prospective validation in future biomarker-selected clinical trials.
Polymorphisms in CXCR3 ligands predict early CXCL9 recovery and severe chronic GVHD
Authors: Hao Dai, Sivaramakrishna P. Rachakonda, Olaf Penack, Igor W. Blau, Olga Blau, Aleksandar Radujkovic, Carsten Müller-Tidow, Peter Dreger, Rajiv Kumar, Thomas Luft
Journal: Blood Cancer Journal (2021)

Abstract Chronic graft-versus-host disease (cGVHD) is a major cause of mortality and morbidity after allogeneic stem cell transplantation (alloSCT). The individual risk of severe cGVHD remains difficult to predict and may involve CXCR3 ligands. This study investigated the role of single-nucleotide polymorphisms (SNPs) of CXCL4, CXCL9, CXCL10, and CXCL11, and their day +28 serum levels, in cGVHD pathogenesis. Eighteen CXCR3 and CXCL4, CXCL9–11 SNPs as well as peri-transplant CXCL9–11 serum levels were analyzed in 688 patients without (training cohort; n = 287) or with statin-based endothelial protection cohort ( n = 401). Clinical outcomes were correlated to serum levels and SNP status. Significant polymorphisms were further analyzed by luciferase reporter assays. Findings were validated in an independent cohort ( n = 202). A combined genetic risk comprising four CXCR3 ligand SNPs was significantly associated with increased risk of severe cGVHD in both training cohort (hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.33–4.64, P = 0.004) and validation cohort (HR 2.95, 95% CI 1.56–5.58, P = 0.001). In reporter assays, significantly reduced suppressive effects of calcineurin inhibitors in constructs with variant alleles of rs884304 ( P &lt; 0.001) and rs884004 ( P &lt; 0.001) were observed. CXCL9 serum levels at day +28 after alloSCT correlated with both genetic risk and risk of severe cGVHD (HR 1.38, 95% CI 1.10–1.73, P = 0.006). This study identifies patients with high genetic risk to develop severe cGVHD.
Peri-operative morbidity and mortality in a modern series of patients treated with cytoreductive nephrectomy (CN) at five centers.
Authors: Ashanda Rosetta Patrice Esdaille, Jose A. Karam, Philippe E. Spiess, Jay D. Raman, Daniel D. Shapiro, Pranav Sharma, Wade J. Sexton, Logan Zemp, Alyssa Bilotta, Glenn O. Allen, Surena F. Matin, Christopher G. Wood, Edwin J Abel
Journal: Journal of Clinical Oncology (2021)

268 Background: For metastatic renal cell cancer (mRCC) patients considering cytoreductive nephrectomy (CN), perioperative morbidity is important to discuss but few contemporary multi-institutional data are available. The objective of this study is to describe factors associated with perioperative outcomes in a modern multi-institutional cohort of patients treated with cytoreductive nephrectomy. Methods: Data for perioperative complications was recorded for patients treated with CN at 5 centers from 2005-2019. Postoperative complications within 90 days were categorized using Clavien- Dindo system. Univariate and multivariable analysis was used to evaluate for associations with complications and 90-day mortality. Factors evaluated included receipt of pre-surgical systemic therapy, ECOG performance status (PS), Charlson comorbidity index (CCI), concurrent IVC thrombectomy, age, and surgical approach (open vs. laparoscopic/robotic). Results: Perioperative outcomes were evaluated in 937 consecutive patients treated with CN at 5 institutions from 2005-2019. Median age at surgery was 61 years (IQR 53-68) and median tumor diameter was 9.8cm (IQR 7-12).Venous thrombus was present in 406/937 (43.3%) patients overall including 65/406 (16%) patients for whom IVC thrombus extended above the hepatic veins. Open and laparoscopic/robotic approach was used in 715 (76.3%) and 290 (23.4%) patients. The median ECOG PS was 1 (IQR 0-1) and median CCI was 1 (IQR 0-2). Pre-surgical systemic therapy was given to 243 (25.9%) patients prior to CN. The median length of hospital stay was 5 days (IQR 4-7) and 429 (34.6%) received blood transfusion. Median length of stay was 3.0 (IQR 2-4) for laparoscopic/robotic approach and 6 days (IQR 4-8) for patients with IVC thrombectomy. Hospital readmission within 30 days was identified in 112 (9.0%) patients. A total of 93/937 (9.9%) patients had major (≥Clavien 3) complications identified within 90 days postoperatively. On multivariable analysis, IVC thrombectomy was associated with higher risk of major complications OR 1.95 (95% CI 1.2-3.1), p = 0.006. Pre-surgical systemic therapy, ECOG PS, CCI, age and surgical approach were not associated with major complications (p = 0.09-0.85). Perioperative mortality was 12/937 (1.3%) at 30 days and 51/937 (6.7%) at 90 days. After multivariable analysis, pre-surgical systemic therapy, ECOG PS, CCI, age, and IVC thrombectomy were not associated with perioperative mortality (p = 0.1-0.85). Conclusions: Cytoreductive nephrectomy is associated with major complications for 10% of patients and 1% mortality at 30 days. Pre-surgical systemic therapy was not associated with increased risk of complications or mortality.
Safety and Efficacy: Clinical Experience of Venetoclax in Combination With Hypomethylating Agents in Both Newly Diagnosed and Relapsed/Refractory Advanced Myeloid Malignancies
Authors: Jonathan Feld, Douglas Tremblay, Mikaela Dougherty, Tina Czaplinska, Gillian Sanchez, Claudia Brady, Marina Kremyanskaya, Michal Bar-Natan, Alla Keyzner, Bridget K. Marcellino, Janice Gabrilove, Shyamala C. Navada, Lewis R. Silverman, Siraj M. El Jamal, John Mascarenhas, Alan H. Shih
Journal: HemaSphere (2021)

Hypomethylating agents (HMAs) in combination with venetoclax have been widely adopted as the standard of care for patients who cannot tolerate induction chemotherapy and for patients who have relapsed/refractory (R/R) acute myeloid leukemia (AML). This study retrospectively analyzed the outcomes of all patients with AML (n = 65) or myelodysplastic syndrome (n = 7) who received the combination of HMA and venetoclax at our institution. Outcomes measured included complete remission (CR) and CR with incomplete hematologic recovery (CRi) rates, duration of response (DOR), and overall survival (OS). Patient mutational profiles and transfusion requirements were also assessed. Of 26 newly diagnosed AML patients, the CR/CRi rate was 53.8%. The median DOR and OS were 6.9 months and not reached, respectively. Of 39 R/R AML patients, the CR/CRi rate was 38.5%. The median DOR and OS were both 8.1 months. Responders to HMA and venetoclax were enriched for TET2 , IDH1 , and IDH2 mutations, while nonresponders were associated with FLT3 and RAS mutations. Adaptive resistance was observed through various mechanisms including acquired RAS pathway mutations. Of transfusion-dependent patients, 12.2% and 15.2% achieved red blood cell (RBC) and platelet transfusion independence, respectively, while 44.8% and 35.1% of RBC and platelet transfusion independent patients, respectively, became transfusion dependent. In total 59.1% of patients developed a ≥grade 3 infection and 46.5% neutropenic fever. HMA + venetoclax can lead to impressive response rates with moderately durable remissions and survival. However, the benefits of this combination are diminished by the significant toxicities from infection, persistent cytopenias, and transfusion requirements.
Common genetic and clinical risk factors: Association with fatal prostate cancer in the Cohort of Swedish Men.
Authors: Minh-Phuong Huynh-Le, Roshan Karunamuni, Chun Chieh Fan, Wesley K Thompson, Kenneth Muir, Artitaya Lophatananon, Karen Tye, Alicja Wolk, Hakansson Niclas, Ian G. Mills, Ole A Andreassen, Anders M Dale, Tyler M Seibert, The PRACTICAL Consortium
Journal: Journal of Clinical Oncology (2021)

65 Background: Clinical variables (age, family history, and genetics) are commonly used for prostate cancer risk stratification. Recently, polygenic hazard scores (PHS46, PHS166) were validated as associated with age at prostate cancer diagnosis. While polygenic scores, including PHS, are associated with all prostate cancer and are not specific for fatal cancers, PHS46 was also associated with age at prostate cancer death. We evaluated if adding PHS to available clinical variables improves associations with prostate cancer death. Methods: Genotype and phenotype data were obtained from a nested case-control subset (n=3,279; 2,163 were diagnosed with prostate cancer, 278 died of prostate cancer) of the longitudinal, population-based Cohort of Swedish Men. PHS and clinical variables (family history, alcohol intake, smoking, heart disease, hypertension, diabetes history, and body mass index) were independently tested via univariable Cox proportional hazards models for association with age at prostate cancer death. Multivariable Cox models were constructed with clinical variables and PHS. Log-likelihood tests compared models. Results: Median age at last follow-up and at prostate cancer death were 78.0 (IQR: 72.3-84.1) and 81.4 (75.4-86.3) years, respectively. On univariable analysis, PHS46 (HR 3.41 [95% CI 2.78-4.17]), family history (HR 1.72 [1.46-2.03]), alcohol intake (HR 1.74 [1.40-2.15]), and diabetes (HR 0.53 [0.37-0.75]) were each associated with prostate cancer death. A multivariable clinical model including PHS46 improved associations for fatal disease ( p&lt;10 −15 ). On multivariable analysis, PHS46 (HR 2.45 [1.99-2.97]), family history (HR 1.73 [1.48-2.03]), alcohol intake (HR 1.45 [1.19-1.76]), and diabetes (HR 0.62 [0.42-0.90]) all remained associated with prostate cancer death. Similar results were found using the newer PHS166. Conclusions: PHS had the most robust association with fatal prostate cancer in a multivariable model with common clinical risk factors, including family history. Adding PHS to clinical variables may improve individualized prostate cancer risk stratification strategies.
Secreted heat shock proteins control airway remodeling: Evidence from bronchial thermoplasty
Authors: Lei Fang, Junling Li, Eleni Papakonstantinou, Meropi Karakioulaki, Qingzhu Sun, Desiree Schumann, Michael Tamm, Daiana Stolz, Michael Roth
Journal: Journal of Allergy and Clinical Immunology (2021)
10P Emerging role of Telomeric repeat-containing RNA TERRA in hepatocellular carcinoma
Authors: M. Manganelli, I. Grossi, J. Corsi, K. Jurikovà, E. Cusanelli, V. D'Agostino, S. Molfino, G. Baiocchi, N. Portolani, A. Salvi, G. De Petro
Journal: Annals of Oncology (2021)
Treatment of Fibromyalgia in the 21st Century—Reply
Authors: Rodrigo Oliveira Mascarenhas, Mateus Bastos Souza, Vinicius Cunha Oliveira
Journal: JAMA Internal Medicine (2021)

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Abstract 416: IL-33 Reduces Cardiac Remodeling, Inhibits Myocardial Apoptosis and Improves Survival After Experimental Myocardial Infarction
Authors: Shoji Sanada, Vandna Handa, Daihiko Hakuno, Joseph Gannon, Catherine MacGillivray, Richard T Lee
Journal: Circulation (2007)

ST2 is an IL-1 receptor family protein with membrane-bound (ST2L) and soluble (sST2; extracellular portion of ST2L) isoforms. We have previously reported that serum sST2 predicts mortality in myoca...
Plasma cell-free DNA profiling of PI3K/Akt pathway aberrations in two multi-institutional independent metastatic castration-resistant prostate cancer (mCRPC) cohorts.
Authors: Edmond Michael Kwan, Chao Dai, Heidi Fettke, Christine Hauser, Patricia Bukczynska, Nicole Ng, Siavash Foroughi, Lisa-Jane K. Graham, Kate Lynette Mahon, Winston Tan, Amy Wang, Zhixin Zhao, Tiantian Zheng, Kemin Zhou, Jian-Jun Yu, Peter Du, Lisa Horvath, Shidong Jia, Manish Kohli, Arun Azad
Journal: Journal of Clinical Oncology (2021)

159 Background: Tumour tissue from metastatic castration-resistant prostate cancer (mCRPC) harbors frequent copy number variations (CNVs) in the phosphatidylinositol-3-kinase (PI3K)/Akt-signaling pathway. However, identifying CNVs in plasma cell-free DNA (cfDNA) has proven challenging. With emerging data supporting Akt inhibition in PTEN-deficient mCRPC, cfDNA assays for robustly identifying PI3K/Akt pathway aberrations including CNVs are urgently required. Methods: In this multi-institutional prospective biomarker study, we used the Predicine cfDNA assay, optimised for CNV detection, to perform targeted sequencing in 231 mCRPC patients in two independent cohorts (Australian, n = 78; US, n = 153). Kaplan-Meier survival estimates and multivariable Cox regression analysis were used to assess associations between genomic aberrations and progression-free survival (PFS) and overall survival (OS). Results: PTEN loss and PIK3CA gain were detected in 37% (85/231) and 17% (39/231) of patients, respectively. Poorer outcomes were observed in patients with PI3K/Akt pathway aberrations, including those with dual PTEN loss and PIK3CA gain (HR 2.3, 95% CI 1.2-4.4). Similarly, cumulative CNV burden in the PI3K/Akt and AR pathways (0 vs 1 vs ≥2 CNVs in Australian cohort: median OS 33.5 vs 17.2 vs 9.7 months, p&lt; 0.001; 0 vs 1 vs ≥2 CNVs in US cohort: median OS 35.5 vs 14.3 vs 9.2 months, p&lt; 0.001) was associated with significantly worse clinical outcomes. Notably, 21% (31/146) of PTEN-neutral patients harbored other alterations in the PI3K/Akt pathway. Conclusions: Our cfDNA assay readily detected PI3K/Akt pathway CNVs, with the prevalence of PTEN loss comparable to prior tissue sequencing studies. CNVs in the PI3K/Akt pathway were associated with deleterious clinical outcomes, especially when concurrent with AR gain. Additional PI3K/Akt pathway aberrations were found in approximately one-fifth of PTEN-neutral mCRPC. Collectively, our data demonstrate the potential utility of profiling cfDNA to facilitate and optimize patient selection for treatment with Akt inhibitors in mCRPC. [Table: see text]