tbuckley/cabot-search huggingface dataset:
The effect of abiraterone acetate treatment on CREB and the development of abiraterone acetate resistance in prostate cancer cells.
Authors: Wenting Pan, Zhouwei Zhang, Hannah Kimball, Fangfang Qiu, Gwo-Shu Mary Lee, Toni K. Choueiri, Philip W. Kantoff
Journal: Journal of Clinical Oncology (2020)

177 Background: The androgen receptor (AR) remains an essential target in castration resistant prostate cancer (CRPC). Abiraterone acetate (AA), an inhibitor of CYP17A1, is an FDA approved drug for metastatic CRPC. AA can also be converted to the more active metabolite 4-abiraterone in vivo, which blocks multiple steroidogenic enzymes and antagonizes AR. However, not all patients respond to AA and AA resistance ultimately develops in those patients who initially respond. Methods: We established several AA resistant prostate cancer cell lines and performed a comprehensive study of mechanisms involved in the development of AA resistance. The AA-resistant cell lines are phenotypically stable with aggressive invasive features. By RNA-seq and phospho-kinase array screening, we found that the cAMP response element-CRE binding protein 1 (CREB1) is activated in AA resistant cell lines. Results: Over-expression of the wild type CREB1 or treatment with Forskolin desensitizes the cellular response to AA, while over-expressing the mutated CREB1 (S133A, an essential kinase site) did not significantly affect cell sensitivity to AA. Blocking pCREB1 with the CREB inhibitor increased the sensitivity of AA resistant cell lines to AA. The activation of pCREB1 in AA resistant cell lines may potentially activate the CBP/p300 complex. Our data demonstrated that treatment with a low dose of AA strongly synergistic the efficacy of CBP/p300 inhibitors in prostate cancer cell lines. Taken together, we found that AA treatment activates CREB1 and pCREB1 may interact with the CBP/p300 complex, leading to global gene expression alterations, which subsequently result in the development of drug resistance. Conclusions: Our study indicates that AR-targeted treatment potentially fosters de novo genetic and epigenetic alterations associated with progression. A more effective AR-targeted treatment for CRPC may be developed by considering low doses of multiple targets involved in the development of resistance pathways.
Association of KRT20 and KRT5 with response to neoadjuvant chemotherapy in patients diagnosed with muscle invasive bladder cancer.
Authors: Florian Roghmann, Moritz Reike, Ralph Wirtz, Maximilian Kriegmair, Philipp Erben, Karl Tully, Veronika Weyerer, Markus Eckstein, Arndt Hartmann, Felix Wezel, Christian Bolenz, Andrea Tannapfel, Joachim Noldus, Hendrik Juette
Journal: Journal of Clinical Oncology (2020)

562 Background: Patients with muscle-invasive bladder cancer (MIBC) that underwent neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) show improved overall survival. Those with a pathological complete response (pCR) usually have the best prognosis. In the literature, improved response to NAC has been associated with basal tumor characteristics in MIBC so far. The aim of the present study was to examine the association of luminal (KRT20) and basal (KRT5) mRNA expression patterns at transurethral resection (TUR) with pCR at RC after NAC in a contemporary cohort of consecutive MIBC patients. Methods: Clinical Data and formalin fixed paraffin embedded tumor tissue samples from TUR and RC of 49 patients with MIBC were retrospectively analyzed. Using RT-PCR KRT20 and KRT5 mRNA expression were measured in 40-∆Ct values and normalized against the control gene CALM2. Statistical analyses comprised nonparametric and chi 2 testing, partition models and spearman correlation analyses. Results: The study cohort had a median age of 63 years and consisted of 38/49 (78%) males. After NAC, 17/49 (35%) patients had cPR. Using partition models, we found that patients with high-KRT20 (≥39.5 ∆C t ) had a higher chance of pCR (57% vs. 26%, p=0.04). Using a cutoff for KRT5 at &lt;38.1 ∆C t within the subgroup of patients with low-KRT20 (&lt;39.5 ∆C t , n=35), we found poorest response among low-KRT20/low-KRT5 compared to low-KRT20/high-KRT5 and high-KRT20 (13% vs. 37% vs. 57%, p=0.29), respectively. For low-KRT20/low-KRT5, low-KRT20/high-KRT5 and high-KRT20 median KRT5 was 34.8 vs. 39.5 vs. 34.1 ∆C t ( p=0.001) and median KRT20 was 37.9 vs. 32.9 vs. 40.1 ∆C t ,( p=0.001), respectively. Conclusions: Patients with MIBC showing high expression of KRT20 were more likely to show pCR at RC after NAC. Moreover, we were able to identify a high risk group of patients with lowKRT20/lowKRT5 that was less likely to achieve pCR at RC after NAC. Our findings are contradicting previous studies and need further verification in larger cohorts. However, our results might be useful for treatment stratification in MIBC patients.
Establishing a New Mastocytosis Registry in Canada
Authors: Mahdi Hassan, Elena Netchiporouk, Sofianne Gabrielli, Greg Shand, Elinor Simons, Barbara Miedzybrodzki, Fatemeh Jafarian, Shawna Lechner-Rumpel, Sharon Baum, Shoshana Greenberger, Moshe Ben-Shoshan
Journal: Journal of Allergy and Clinical Immunology (2020)
David Oliver: Allow nurses to use their professional judgment
Authors: David Oliver
Journal: BMJ (2020)

In January the Nursing and Midwifery Council (NMC) suspended a nurse's registration for 12 months because she'd decided not to commence cardiopulmonary resuscitation (CPR) in an elderly, dying care home resident. 1 2An earlier panel had heard evidence that the resident was "waxy, yellow and almost cold" when the nurse decided not to initiate CPR or call paramedics. 3The NMC concluded that the nursing profession had been brought into disrepute, the nurse's fitness to practise impaired, and her patient put at risk of harm.The nurse had the option to appeal the decision.
<i>NF2</i> mutation-driven renal cell carcinomas (RCC): A comprehensive genomic profiling (CGP) study.
Authors: Evgeny Yakirevich, Carmen Perrino, Andrea Necchi, Petros Grivas, Gennady Bratslavsky, Oleg Shapiro, Joseph Jacob, Ethan Sokol, Jo-Anne Vergilio, Keith Killian, Douglas I. Lin, Shakti H. Ramkissoon, Eric Allan Severson, Jon Chung, Brian Michael Alexander, Julia Andrea Elvin, Alexa Betzig Schrock, Natalie Danziger, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2020)

726 Background: NF2 genomic alterations (GA) have been associated with aggressive behavior in RCC. Methods: FFPE tissues from 1,386 clear cell (ccRCC), 307 papillary (pRCC), 72 chromophobe (chRCC), 145 sarcomatoid (sRCC), 54 collecting duct (cdRCC),37 medullary (medRCC) and 134 unclassified (nosRCC) underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and MSI was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: 140 (7%) RCC featured NF2 GA which were predominantly short variant (SV) mutations. Gender and age were similar with male preponderance in all histologic subtypes. NF2 GA frequency was highest in cdRCC (20%) and sRCC (19%) and lowest in ccRCC (3%). The medRCC at 5% NF2 GA and chRCC at 0% NF2 GA were not further evaluated. VHL and PBRM1 GA were significantly more frequent in NF2 altered ccRCC than all other RCC (P &lt; 0.001). Other mTOR pathway GA were uncommon. Potentially targetable kinase GA in NF2-mutated RCC included BRAF (2% of ccRCC), EGFR (3% of pRCC), ERBB3 (4% of sRCC) and PIK3CA (9% of cdRCC). No NF2 mutated RCC featured MSI -high status and both TMB and PD-L1 expression levels were extremely low in all subsets with exception of high PD-L1 staining in sRCC tumors. Conclusions: cdRCC, sRCC, pRCC and nosRCC are enriched in NF2 GA. Low PBRM1 GA, TMB and MSI- high predict resistance to immunotherapy in NF2 mutated RCC although the high PD-L1 expression in sRCC is noteworthy.[Table: see text]
Relationship between hyperphosphatemia with infigratinib (BGJ398) and efficacy in <i>FGFR3</i>-altered advanced/metastatic urothelial carcinoma (aUC).
Authors: Yung Lyou, Petros Grivas, Jonathan E. Rosenberg, Jean H. Hoffman-Censits, David I. Quinn, Daniel Peter Petrylak, Matt D. Galsky, Ulka N. Vaishampayan, Ugo De Giorgi, Sumati Gupta, Howard A. Burris, Jessica Rearden, Yining Ye, Hao Wang, Susan Moran, Siamak Daneshmand, Dean F. Bajorin, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2020)

576 Background: Infigratinib (BGJ398) is a potent and selective FGFR1–3 inhibitor with significant clinical activity in aUC bearing FGFR3 alterations. A common adverse event is hyperphosphatemia, a class effect associated with FGFR1 inhibition. We sought to better understand the relationship between hyperphosphatemia and response to infigratinib in patients with aUC. Methods: Eligible patients had aUC with activating FGFR3 mutations/fusions and had received prior platinum-based chemotherapy, unless contraindicated. Patients received infigratinib 125 mg orally daily (3w on/1w off) until disease progression or unacceptable toxicity. Calcium and phosphate levels within normal limits were required at enrollment. Efficacy was assessed by overall response rate (ORR) and disease control rate (DCR) based on RECIST 1.0 criteria. All patients received prophylaxis with the oral phosphate binder sevelamer. Hyperphosphatemia was defined as serum phosphorous &gt;5.5 mg/dL, consistent with the threshold for action in the protocol. Results: Of the 67 patients enrolled, 48 (71.6%) had hyperphosphatemia on ≥1 post-baseline lab test. Efficacy findings in patients with vs without hyperphosphatemia were: ORR 33.3% (95% CI 20.4–48.4) vs 5.3% (95% CI 0.1–26.0), mPFS 4.9 months (95% CI 3.65–5.98) vs 1.84 months (95% CI 1.28–3.48), and mOS 8.74 months (95% CI 5.72–13.67) vs 7.62 months (95% CI 2.53–15.57). Median treatment length was 4.1 vs 1.4 months and mDOR was 5.0 vs 3.7 months for patients with vs without hyperphosphatemia, respectively. A landmark analysis at the 1-month mark was performed, and hyperphosphatemia (Y/N) was determined based on lab tests within the first month. The differences in efficacy outcomes were still observed. Conclusions: Hyperphosphatemia is a well-described class effect and pharmacodynamic biomarker of FGFR inhibitors, including infigratinib, and is generally reversible/easily managed with diet and phosphate binders. Our data support prior observations with FGFR inhibitors, suggesting that hyperphosphatemia is associated with treatment response and is not negatively associated with treatment length. Clinical trial information: NCT01004224.
Prospective trial of nivolumab (Nivo) plus radium-223 (RA) in metastatic castration-resistant prostate cancer (mCRPC) evaluating circulating tumor DNA (ctDNA) levels as a biomarker of response.
Authors: Benjamin Louis Maughan, Roberto Nussenzveig, Umang Swami, Sumati Gupta, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2020)

TPS267 Background: RA is a calcium-mimetic radiopharmaceutical emitter of alpha particles that has been approved for treatment of mCRPC. Radiation plus checkpoint inhibitors has demonstrated promising efficacy in previous clinical trials (PMID 27466265, 23535954). Alteration to PD-1 expression has been observed with radium-223, suggesting potential synergy with Nivo (PMID 29137877). ctDNA concentration may accurately reflect overall tumor burden and response to immune therapy. ctDNA testing after 6 weeks of therapy predicts efficacy of immunotherapy in patients with metastatic NSCLC and urothelial carcinoma (PMID 30093454) and metastatic gastric cancer (PMID 30013197). Reduction of ctDNA correlated with both radiographic progression free survival (rPFS) and overall survival. We hypothesize that RA + Nivo will be safe and decrease ctDNA, which may predict response to therapy earlier than conventional scans. Methods: This is a single-arm phase I/II investigator initiated trial (NCT04109729). Primary objectives: 1) Safety, 2) Change in ctDNA after 6 weeks treatment compared to baseline. Secondary objectives: 1) PSA-PFS; 2) PSA 50% response rate; 3) Time to skeletal related event; 4) Bone metabolism marker response. Inclusion criteria: symptomatic bone metastasis, mCRPC, adequate hematopoiesis. Exclusion criteria: visceral metastasis, history of autoimmune disease and current use of immune suppression therapy. A total of 36 patients will be enrolled. Cycles are 28 days. ctDNA concentration will be measured using GuardantOMNI research platform which evaluates 500 genes. Treatment: RA (55 kBq/kg IV) monotherapy lead in for two cycles followed by RA plus Nivo (480mg IV) for an additional 4 cycles. Nivo monotherapy then continues for up to 2 years. ctDNA collected prior to combination therapy and 6 weeks after. Restaging scans done every 2 cycles while on radium-223 and every 3 cycles while on nivolumab. Clinical trial information: NCT04109729.
Food diversity but not the time of solid food introduction reduces risk of childhood atopic diseases: Birth cohort from a developing Asian country
Authors: Thanaporn Ratchataswan, Pantipa Chatchatee, Thiratest Leesutipornchai, Thansinee Saetae, Wanlapa Weerapakorn, Stephen Kerr, Narissara Suratannon
Journal: Journal of Allergy and Clinical Immunology (2020)
Comparative quality of life in patients randomized contemporaneously to docetaxel or abiraterone in the STAMPEDE trial.
Authors: Hannah L. Rush, Adrian David Cook, Christopher D. Brawley, Laura Murphy, Archie Macnair, Robin Millman, Gerhardt Attard, Noel Clarke, Alicia K. Morgans, Simon Chowdhury, Duncan C. Gilbert, David P. Dearnaley, Matthew R. Sydes, Nicholas D. James, Ruth E. Langley, Mahesh K. B. Parmar
Journal: Journal of Clinical Oncology (2020)

14 Background: Docetaxel (DOC) and abiraterone (ABI) both improve overall survival (OS) in men with locally advanced or metastatic hormone-sensitive prostate cancer (HSPC) but no head to head trials compare the 2 agents. STAMPEDE, a multi-arm multi-stage platform trial, recruited patients (pts) to treatments including DOC or ABI between Nov-11 and Mar-13. There was no evidence OS differed between DOC or ABI, thus quality of life (QOL) may increasingly inform treatment options. Methods: QOL scores were analysed in pts contemporaneously randomised to receive DOC or ABI, in addition to standard of care treatment. Self-assessment QOL questionnaires EORTC QLQ C30 and PR25 were completed during treatment and follow-up. These analyses focus on average global QOL over the first 2 years after randomisation, using repeated measures analysis, plus cross-sectional analyses at 3, 6, 12 and 24 months. A score difference of ≥4 points was pre-defined as clinically meaningful. Results: 173 men randomised to DOC and 342 men randomised to ABI participated in the QOL sub-study and contributed to this analysis. Baseline characteristics and proportion of missing data were similar between groups. Baseline global QOL scores were similar (mean (sd): DOC 77.8 (20) and ABI 78.0 (19.3)). Average global QOL over 2 years was higher in pts randomised to ABI than DOC, although the difference was statistically significant it did not meet the pre-defined clinical parameter (+3.9, 95%CI 0.6 to 7.1, p=0.021). Cross-sectional analyses showed clinically meaningful superior QOL in the ABI group at 3 and 6 months (+6.6, 95%CI 2.6 to 10.7, p=0.001; +8.0, 95%CI 3.6 to 12.3, p&lt;0.001), but not at 1 or 2 years (+1.3, 95%CI -3.0 to 5.6, p=0.545; +4.5, 95%CI -0.25 to 9.2, p=0.063). An exploratory analysis indicated average QOL for pts with metastatic disease (n=207) was better in the ABI group (+4.44, 95%CI 0.2 to 8.6, p=0.036). Conclusion: Global QOL was significantly higher in the first 2 years of treatment for the ABI group compared to the DOC group, though did not meet the pre-defined clinically meaningful threshold. The majority of difference was seen in the first year of treatment. This should be considered when discussing treatment options with pts. Clinical trial information: NCT00268476.
Racial and sex differences in somatic mutations in bladder cancer patients: An analysis of the cBioPortal for Cancer Genomics.
Authors: Yaw A. Nyame, Kelsey K. Baker, Robert B. Montgomery, Petros Grivas, Mary Weber Redman, Jonathan L. Wright
Journal: Journal of Clinical Oncology (2020)

556 Background: Disparities in bladder cancer outcomes exist by race/ethnicity and sex. However, limited data exists on differences in tumor biology by race/ethnicity and sex. Methods: This is a retrospective analysis of non-synonymous mutational data from the cBioPortal open access platform. A total of eight unique cohorts were identified. The cohort was divided into groups by sex and race. Somatic mutations were selected from those with frequency &gt; 7% from TCGA and DNA damage repair (DDR) genes. Univariable analysis was performed using Student’s t-test and Fischer’s exact test. For those genes with significant differences, multivariate Cox regression analysis was performed, including a test for interaction for genes significantly associated with race or gender. Results: A total of 917 unique patients were identified from cBioPortal for this analysis. Median age for the cohort was 68 years (range: 25-98) and 227 (25%) were identified as female. The cohort was majority white (85%). TP53 (54% vs. 31%, p &lt; 0.001), ARID1A (29% vs. 7%, p &lt; 0.001), ERBB3 (12% vs. 3%, p = 0.01) and CDKN1A (8% vs 18%, p = 0.02) were differentially mutated in white tumors compared to non-white tumors. ERBB2 was more common among male (13%) compared to female (6%) patients in the cohort (p &lt; 0.01). There were no differences in DDR genes by race/ethnicity and sex. The median age for those with ERCC2 (70.4 vs. 66.8 years) and RAD51 (76.3 vs. 67.0 years) mutations was higher compared to those without the mutations, respectively. On multivariable analysis, ERCC2 (HR 0.45, 95% CI 0.25, 080), SPTAN1 (HR 0.50, 95% CI 0.29, 0.84), and EP300 (HR 0.60, 95% CI 0.39, 0.92) were associated with survival. There was a significant interaction between white race and CDKN1A in the survival analysis, with non-white patients with CKDN1A mutations having increased hazard for mortality (HR 3.1, 95% CI 1.14, 8.42). Conclusions: Somatic mutational differences existed by both race and gender in a large cohort of patients with bladder cancer. These findings are limited by poor representation of non-white patients and retrospective design; advocating for representative patient cohorts to assess tumor biology in bladder cancer disparities research.
Role of soft tissue metastases on tumor progression in castrate-resistant metastatic prostate cancer.
Authors: Kathleen Ruchalski, Michael Douek, Steven Raman, Maitraya Patel, Antonio Gutierrez, Victor Sai, Benjamin D. Levine, Martin Allen-Auerbach, Pawan Gupta, Hyun J. Kim, Bianca Villegas, Jonathan Goldin
Journal: Journal of Clinical Oncology (2020)

214 Background: While visceral metastases in castrate resistant prostate cancer (mCRPC) are a negative prognostic factor, patients may still derive treatment benefits. Given varying anatomic sites of tumor may display differing treatment responses we investigated the role of soft tissue metastases in progressive disease (PD) by anatomic site. Methods: A retrospective review of anonymized patients enrolled in phase 3 clinical trials was performed. Patients were excluded if lacked Tc bone scan or CT chest, abdomen and pelvis (CT CAP) on trial. Subjects were included if they had soft tissue disease per RECIST 1.1. Bone disease was defined by automated BSLA criteria. All CT CAPs per clinical trial protocol were assessed by RECIST 1.1. Soft tissue PD was noted as target|nontarget lesion growth and/or presence of new lesions by anatomic site. Bone PD was defined by &gt;20% increase in BSLA score. Results: Of 322 total patients, 138 met criteria of soft tissue disease at baseline. Baseline anatomic sites of metastases per RECIST included: visceral (74, 53.6%), lymph node only (52, 37.7%) and soft tissue bone (12, 7.1%). PD occurred in 46 patients with baseline soft tissue disease; with PD first detected by BSLA (23, 16.7 %), RECIST (19, 13.8 %) or with PD occurring simultaneously by BSLA and RECIST (4, 2.9%). Of the 138 patients with baseline soft tissue disease, PD occurred by RECIST in 25 patients. This occurred due to worsening visceral (11, 68.8%), lymph node (4, 25.0%) or soft tissue bone (1, 6.3%) disease. PD by new lesions only occurred in 9 patients (36.0%), as a result of 77.8% visceral and 22.2% lymph node. Conclusions: In mCRPC with soft tissue disease at baseline, progression by BSLA bone score still accounts for a large portion of PD. Further analyses must be performed to better differentiate disease phenotypes amongst mCRPC with combined visceral/osseous disease.
Phase II trial of neoadjuvant chemohormonal therapy (NAC) in prostate cancer (PC) with response assessment using PSMA PET/MRI.
Authors: Christos Kyriakopoulos, Brian Johnson, Erika Heninger, Tariq A. Khemees, Alejandro Roldán-Alzate, Wei Huang, David J. Beebe, Hamid Emamekhoo, Shane A. Wells, David Frazier Jarrard, Steve Y. Cho, Joshua Michael Lang
Journal: Journal of Clinical Oncology (2020)

334 Background: Previous studies have shown that addition of docetaxel to androgen deprivation therapy (ADT) significantly improves progression-free survival (PFS) and overall survival (OS) in men with metastatic hormone-sensitive PC. Removal of the primary may also improve outcomes by reducing tumor self-seeding. We are conducting a phase II trial in men with PC to examine the feasibility of NAC, response using PSMA PET/MRI imaging and molecular mechanisms of resistance. Methods: This is an open-label, single-arm trial. Thirty patients with newly diagnosed very high risk localized, locally advanced or oligometastatic PC will receive ADT/docetaxel for three cycles before prostatectomy. The primary endpoint is rate of complete pathologic response. Key secondary objectives include PSA recurrence at month 12 after surgery. Exploratory objectives include tumor response and response heterogeneity in primary and metastatic tumors before and after treatment assessed by PSMA PET/MRI and evaluation of gene expression signatures in cancer cells, prostate stroma, bone marrow microenvironment and circulating tumor cells. Results: To date, 26 of 30 patients have enrolled and completed treatment. Mean age was 61 and mean PSA at time of diagnosis was 32.1 ng/dl. All patients had multi-focal prostate cancer with 23/26 patients with Gleason Grade Group 5. Metastatic disease by conventional imaging was identified in 6/26 patients (5 in lymph nodes [LN] and bone, 1 in LN only). Treatment was overall well tolerated. All patients had multi-focal primary prostate cancer detected on PSMA PET/MRI. All patients had a decline in PSMA PET SUV max in at least one intraprostatic lesion. Two patients had an increase in SUV max in at least one intraprostatic lesion that correlated with a resistant tumor focus on histopathology. Conclusions: NAC prior to surgery generates high rates of local tumor control with a heterogeneous response between foci. Primary resistance, identified by increasing PSMA PET SUV max, is uncommon, however incomplete responses were observed in nearly all patients, suggesting that more cycles of treatment would improve response. PSMA PET/MRI can be used to monitor response and resistance in PC. Clinical trial information: NCT03358563.