tbuckley/cabot-search huggingface dataset:
Anastrozole has an Association between Degree of Estrogen Suppression and Outcomes in Early Breast Cancer and is a Ligand for Estrogen Receptor α
Authors: James N. Ingle, Junmei Cairns, Vera J. Suman, Lois E. Shepherd, Peter A. Fasching, Tanya L. Hoskin, Ravinder J. Singh, Zeruesenay Desta, Krishna R. Kalari, Matthew J. Ellis, Paul E. Goss, Bingshu E. Chen, Bernhard Volz, Poulami Barman, Erin E. Carlson, Tufia Haddad, Matthew P. Goetz, Barbara Goodnature, Matthew E. Cuellar, Michael A. Walters, Cristina Correia, Scott H. Kaufmann, Richard M. Weinshilboum, Liewei Wang
Journal: Clinical Cancer Research (2020)

To determine if the degree of estrogen suppression with aromatase inhibitors (AI: anastrozole, exemestane, letrozole) is associated with efficacy in early-stage breast cancer, and to examine for differences in the mechanism of action between the three AIs.Matched case-control studies [247 matched sets from MA.27 (anastrozole vs. exemestane) and PreFace (letrozole) trials] were undertaken to assess whether estrone (E1) or estradiol (E2) concentrations after 6 months of adjuvant therapy were associated with risk of an early breast cancer event (EBCE). Preclinical laboratory studies included luciferase activity, cell proliferation, radio-labeled ligand estrogen receptor binding, surface plasmon resonance ligand receptor binding, and nuclear magnetic resonance assays.Women with E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL after 6 months of AI treatment had a 2.2-fold increase in risk (P = 0.0005) of an EBCE, and in the anastrozole subgroup, the increase in risk of an EBCE was 3.0-fold (P = 0.001). Preclinical laboratory studies examined mechanisms of action in addition to aromatase inhibition and showed that only anastrozole could directly bind to estrogen receptor α (ERα), activate estrogen response element-dependent transcription, and stimulate growth of an aromatase-deficient CYP19A1-/- T47D breast cancer cell line.This matched case-control clinical study revealed that levels of estrone and estradiol above identified thresholds after 6 months of adjuvant anastrozole treatment were associated with increased risk of an EBCE. Preclinical laboratory studies revealed that anastrozole, but not exemestane or letrozole, is a ligand for ERα. These findings represent potential steps towards individualized anastrozole therapy.
A comparison of sipuleucel-T (sip-T) product parameters from two phase III studies: PROVENT in active surveillance prostate cancer and IMPACT in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Ashley Ross, Andrew J. Armstrong, Christopher M Pieczonka, James L. Bailen, Ronald F. Tutrone, Matthew R. Cooperberg, Christian P. Pavlovich, Joseph F. Renzulli, Heather Haynes, Nadeem Anwar Sheikh, Neal D. Shore
Journal: Journal of Clinical Oncology (2020)

321 Background: Sip-T is an FDA approved, autologous cellular immunotherapy for mCRPC, manufactured by activating peripheral blood mononuclear cells collected by apheresis and culturing them with PA2024 (PAP fused to human GM-CSF). Overall survival (OS) in mCRPC is positively correlated with key product parameters of sip-T: CD54 upregulation; CD54+ cell count; and total nucleated cell (TNC) count. Product parameters were amplified in men with earlier stage prostate cancer vs mCRPC, including increased T cell trafficking to the prostate (Fong L, JNCI 2014) and greater CD54 upregulation and larger immune responses (Antonarakis ES, Clin Can Res 2017). Methods: ProVENT (NCT03686683) will evaluate sip-T in men with Gleason grade 1/2 prostate adenocarcinoma receiving active surveillance (target, 450 men; randomized 2:1 to receiving sip-T or not). We evaluated apheresis and final key product parameters (CD54 upregulation; CD54+ cell count; and TNC count) for each infused product as well as cumulative values while also comparing with IMPACT (NCT00065442) study results. Results: This preliminary analysis describes data from the first 184 sip-T men in ProVENT. CD54 upregulation profiles were consistent between IMPACT and ProVent, peaking in week 2 products; however, values at each treatment week, and subsequently cumulative CD54 upregulation, were statistically significantly higher for ProVENT (P&lt;0.001 per comparison; Table). The number of CD54+ cells was significantly greater at each treatment for both incoming apheresis as well as the final product, including cumulative values, in ProVENT compared to IMPACT (P&lt;0.001 per comparison) as was TNC count (P&lt;0.001 per comparison). Conclusions: This preliminary analysis of product parameters in ProVENT suggest sip-T potency is higher in pts undergoing active surveillance. Clinical trial information: NCT03686683. [Table: see text]
Causes and patterns of mortality in patients with lethal germ cell tumor (GCT).
Authors: Anis Hamid, Samuel Aaron Funt, Sarah C. Markt, Maria Bromberg, Devon O'Donnell, Nabil Adra, Fadi Taza, Costantine Albany, Mark D. Krailo, A. Lindsay Frazier, Lawrence H. Einhorn, Darren R. Feldman, Christopher Sweeney
Journal: Journal of Clinical Oncology (2020)

421 Background: Most metastatic GCTs are cured with cisplatin-based chemotherapy. Clinical factors of adverse GCT-specific survival have been identified, however patterns of death are not well-defined and would inform clinical care and biological investigation. Methods: This multi-institutional study pooled data of male pts with death related to GCT from high-volume adult GCT academic centers (Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, Indiana University) over 20 years (1997-2017). Pts were annotated for site, stage, IGCCC risk, histology, primary therapy and relapse variables (including relapse histology, metastatic (met) burden, salvage and palliative therapies), and detailed cause of GCT death. Cox regression assessed associations with survival. Results: The pooled cohort of 620 pts comprised 90% non-seminoma, 21% mediastinal primary and at diagnosis, 59% were stage III, 64% poor risk; 48% received high-dose chemotherapy plus transplantation. Median survival (OS) from first relapse after metastasis was 12.0 mos. Leading causes of death were chemorefractory GCT (83.1%), secondary somatic malignancy (SSM) arising from teratoma (9.4%), acute toxicity (4.5%), late toxicity (2.3%) and progressive untransformed pure teratoma (0.8%). Late relapse (relapse &gt;2 years after 1st-line therapy) occurred in 11.3% at a median of 5.9 yrs. Of these pts, 1/3 were stage I at initial diagnosis and 75% were good or intermediate risk at met diagnosis, and were more likely to have SSM histology/death vs early relapse. Late relapsing disease (HR 0.48, p&lt;0.0001) and presence of SSM (HR 0.74, p=0.017) were associated with longer OS from first relapse after metastasis. Brain metastasis at any time occurred in 29.8%, associated with poorer OS. Conclusions: Comprehensive characterization of GCT-related death reveals a predominant pattern of mortality marked by de novo metastatic, poor-risk disease with subsequent early relapse and death due to chemorefractory non-teratomatous GCT. By contrast, a subset of pts with late-relapsing disease are more likely to have SSM-teratoma and a protracted clinical course. Lethal late relapses frequently occurred beyond 5 years, emphasizing the importance of long-term follow-up.
Elevated Fructose and Uric Acid Through Aldose Reductase Contribute to Experimental and Human Alcoholic Liver Disease
Authors: Min Wang, Wei‐Yang Chen, Jingwen Zhang, Leila Gobejishvili, Shirish S. Barve, Craig J. McClain, Swati Joshi‐Barve
Journal: Hepatology (2020)

Background and Aims Alcohol‐associated liver disease (ALD) is a common chronic liver disease worldwide with high morbidity and mortality, and no Food and Drug Administration–approved therapies. Fructose (dietary or endogenous), its metabolite uric acid, and aldose reductase (AR, the only endogenous enzyme that produces fructose) are strongly associated with the development of nonalcoholic fatty liver disease. However, the role of AR or its metabolites in ALD remains understudied and was examined using human specimens, cultured cells, and mouse model systems. Approach and Results We demonstrated in liver specimens from patients with alcoholic hepatitis, the AR up‐regulation and elevated AR metabolites (sorbitol, fructose, and uric acid), which correlated significantly with (1) increased lipid peroxidation byproducts and endoplasmic reticulum (ER) stress, (2) decreased protective ER chaperones, and (3) greater cell death and liver injury. Furthermore, we established a causal role for AR in ALD by showing that the genetic deficiency of AR (knockout mice) prevented alcohol‐induced increase in harmful AR metabolites, toxic aldehydes, steatosis, ER stress, apoptosis, and liver injury. Finally, we demonstrated the therapeutic potential of pharmacological AR inhibition against alcohol‐induced hepatic injury in experimental ALD. Conclusions Our data demonstrate that hepatic AR up‐regulation, and consequent elevation in fructose, sorbitol and/or uric acid, are important factors contributing to alcohol‐induced steatosis, ER stress, apoptosis, and liver injury in both experimental and human ALD. Our study provides a strong rationale to evaluate AR as a potential therapeutic target and to test AR inhibitors to ameliorate alcohol‐induced liver injury.
A phase II pilot study of the efficacy and safety of nivolumab and ipilimumab in T1aN0M0 renal cell carcinoma patients ineligible for surgical treatment.
Authors: Ilya Tsimafeyeu, Maria Volkova, Rustem Airatovich Gafanov, Dmitry Nosov, Axel Bex
Journal: Journal of Clinical Oncology (2020)

TPS769 Background: Surgery remains the standard curative-intent therapy for localized renal cell carcinoma (RCC). Thus, systemic therapy for RCC should only be considered in patients who have contraindications to surgery. The phase 3 CheckMate 214 trial showed that a combination of nivolumab and ipilimumab has a significant impact on tumor burden in intermediate- and poor-risk metastatic RCC patients with a complete response rate of 11%. Median time to objective response was 2.8 months. Among all complete responders to nivolumab plus ipilimumab in the intention-to-treat population, 5% achieved a complete response at the first scan. We hypothesize that this combination could eliminate the primary tumor in T1aN0M0 patients ineligible for surgical treatment. Methods: This is a prospective, multicenter, non-randomized phase 2 pilot study. Patients with biopsy-proven clear-cell RCC of ≤4 cm (cT1a), no evidence of any metastases, and unable to have surgery or other nephron-sparing interventions (ablation) for any reason (functional single kidney with a central, high-complexity RCC, high risk of nephrectomy and dialysis, patients with complex coagulation disorders, etc.) or with preference to have no surgery or intervention for any reason will receive combination of ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, and nivolumab (240 mg intravenously) every 2 weeks during 16 weeks. The primary endpoint is complete response rate. Simon's two-stage design (Simon, 1989) is used. The null hypothesis that the true complete response rate is 11% will be tested against a one-sided alternative. This design yields a type I error rate of 0.05 and power of 0.9 when the true complete response rate is 60% (alternative hypothesis). In the first stage, 3 patients will be accrued. If there are no complete responses in these 3 patients, the study will be stopped. Otherwise, 5 additional patients will be accrued for a total of 8. The null hypothesis will be rejected if 3 or more responses are observed in 8 patients. Clinical trial information: NCT04134182.
Retrospective study to identify clinical factors related to a high benefit of axitinib in mRCC: Results from AXILONG Spanish real-world study.
Authors: Alvaro Pinto, Clara Iglesias Gomez, Miguel Ángel Climent, Enrique Gallardo Diaz, Xavier Garcia del Muro, Teresa Alonso Gordoa, Julia Inmaculada Llinares Legido, Cristina Suarez Rodriguez, Georgia Anguera, José Muñoz-Langa, Nuria Lainez, Angel Rodriguez Sanchez, Esther Martínez Ortega, Maria L. Villalobos, Oscar Reig Torras
Journal: Journal of Clinical Oncology (2020)

650 Background: AXILONG is a Pfizer observational multi-institutional retrospective study, evaluating clinical factors which could be related with a higher benefit of axitinib in pretreated mRCC patients in two pre-specified subgroups with extreme response to axitinib. Methods: Medical records from 157 patients treated in 40 Spanish hospitals with axitinib under clinical practice were retrospectively reviewed and included in the study. Of note, patients had to had an extreme response with axitinib, which means being a long responder (LR) to axitinib, defined as those patients who achieved a median Progression Free Survival (mPFS) of 9 months or longer, or refractory patients (RP) those who achieved a Progression Disease (PD) as best response. Results: In this analysis, we describe the results of a subgroup of patients who received axitinib in second-line after sunitinib, which represents the 68,2% (n=107) of the patients included in the whole study. The 55,1% (n=59) of this subgroup were LR and the 44,9% (n=48) were RP. In this sub-group of patients, the mPFS in LR was 18,7 months (95%CI; 12,9-24,4) and the overall response rate (ORR) was 43,9% (3,5% CR). Median overall survival (mOS) since the start of axitinib was 28,2 months for both sub-groups included, being 44,8 months in the LR patients and 7,3 months in the RP (95% CI, 12.79–34.65; p &lt;0,001). In this population the 1 st line mPSF was 27,2 months in LR and 10,9 months in RP (95%CI; 12,97-20,15; p ≤0,001). Conclusions: Despite the limitations of the AXILONG study there were a subgroup of patients who can be considered long responders o axitinib in whom we can obtain a high benefit in terms of efficacy, when treating with the sequence sunitinib-axitinib. Clinical trial information: NCT03538717 .[Table: see text]
Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy
Authors: Conor Gruber, Marta Martin-Fernandez, Fatima Ailal, Xueer Qiu, Justin Taft, Jennie Altman, Jérémie Rosain, Sofija Buta, Aziz Bousfiha, Jean-Laurent Casanova, Jacinta Bustamante, Dusan Bogunovic
Journal: The Journal of Experimental Medicine (2020)

Type I interferonopathies are monogenic disorders characterized by enhanced type I interferon (IFN-I) cytokine activity. Inherited USP18 and ISG15 deficiencies underlie type I interferonopathies by preventing the regulation of late responses to IFN-I. Specifically, USP18, being stabilized by ISG15, sterically hinders JAK1 from binding to the IFNAR2 subunit of the IFN-I receptor. We report an infant who died of autoinflammation due to a homozygous missense mutation (R148Q) in STAT2. The variant is a gain of function (GOF) for induction of the late, but not early, response to IFN-I. Surprisingly, the mutation does not enhance the intrinsic activity of the STAT2-containing transcriptional complex responsible for IFN-I–stimulated gene induction. Rather, the STAT2 R148Q variant is a GOF because it fails to appropriately traffic USP18 to IFNAR2, thereby preventing USP18 from negatively regulating responses to IFN-I. Homozygosity for STAT2 R148Q represents a novel molecular and clinical phenocopy of inherited USP18 deficiency, which, together with inherited ISG15 deficiency, defines a group of type I interferonopathies characterized by an impaired regulation of late cellular responses to IFN-I.
Marmot 10 years on: austerity has damaged nation’s health, say experts
Authors: Gareth Iacobucci
Journal: BMJ (2020)

The UK prime minister must lead a national strategy for reducing health inequalities that have widened after a decade of austerity, a 10 year update to the landmark Marmot review has concluded.

The update to Michael Marmot’s 2010 review1 found that the UK has been moving in “the wrong direction” on almost all of the report’s original recommendations for creating a fairer society and reducing health inequalities.2

In the past 10 years health inequalities have widened, health as a whole has deteriorated, and life expectancy has stalled for the first time since 1900. Among the poorest 10% of women life expectancy has declined, in the latest review findings by Marmot and colleagues …
Targeted pharmacological therapy restores β-cell function for diabetes remission
Authors: Stephan Sachs, Aimée Bastidas-Ponce, Sophie Tritschler, Mostafa Bakhti, Anika Böttcher, Miguel A. Sánchez-Garrido, Marta Tarquis-Medina, Maximilian Kleinert, Katrin Fischer, Sigrid Jall, Alexandra Harger, Erik Bader, Sara Roscioni, Siegfried Ussar, Annette Feuchtinger, Burcak Yesildag, Aparna Neelakandhan, Christine B. Jensen, Marion Cornu, Bin Yang, Brian Finan, Richard D. DiMarchi, Matthias H. Tschöp, Fabian J. Theis, Susanna M. Hofmann, Timo D. Müller, Heiko Lickert
Journal: Nature Metabolism (2020)
QOL and Survival Survey of Cancer Cachexia in Advanced NSCLC Patients - JNUQ-LC Study, TORG0912
Authors: S. Atagi, F. Imamura, A. Yokoyama, K. Minato, T. Harada, N. Katakami, T. Yokoyama, Y. Ohashi, K. Watanabe, K. Eguchi
Journal: Annals of Oncology (2012)
Erratum: Corrigendum: Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility
Authors: Kelly D Smith, Erica Andersen-Nissen, Fumitaka Hayashi, Katie Strobe, Molly A Bergman, Sara L Rassoulian Barrett, Brad T Cookson, Alan Aderem
Journal: Nature Immunology (2004)
Associations between macrolide antibiotics prescribing during pregnancy and adverse child outcomes in the UK: population based cohort study
Authors: Heng Fan, Ruth Gilbert, Finbar O’Callaghan, Leah Li
Journal: BMJ (2020)

Abstract Objective To assess the association between macrolide antibiotics prescribing during pregnancy and major malformations, cerebral palsy, epilepsy, attention deficit hyperactivity disorder, and autism spectrum disorder in children. Design Population based cohort study. Setting The UK Clinical Practice Research Datalink. Participants The study cohort included 104 605 children born from 1990 to 2016 whose mothers were prescribed one macrolide monotherapy (erythromycin, clarithromycin, or azithromycin) or one penicillin monotherapy from the fourth gestational week to delivery. Two negative control cohorts consisted of 82 314 children whose mothers were prescribed macrolides or penicillins before conception, and 53 735 children who were siblings of the children in the study cohort. Main outcome measures Risks of any major malformations and system specific major malformations (nervous, cardiovascular, gastrointestinal, genital, and urinary) after macrolide or penicillin prescribing during the first trimester (four to 13 gestational weeks), second to third trimester (14 gestational weeks to birth), or any trimester of pregnancy. Additionally, risks of cerebral palsy, epilepsy, attention deficit hyperactivity disorder, and autism spectrum disorder. Results Major malformations were recorded in 186 of 8632 children (21.55 per 1000) whose mothers were prescribed macrolides and 1666 of 95 973 children (17.36 per 1000) whose mothers were prescribed penicillins during pregnancy. Macrolide prescribing during the first trimester was associated with an increased risk of any major malformation compared with penicillin (27.65 v 17.65 per 1000, adjusted risk ratio 1.55, 95% confidence interval 1.19 to 2.03) and specifically cardiovascular malformations (10.60 v 6.61 per 1000, 1.62, 1.05 to 2.51). Macrolide prescribing in any trimester was associated with an increased risk of genital malformations (4.75 v 3.07 per 1000, 1.58, 1.14 to 2.19, mainly hypospadias). Erythromycin in the first trimester was associated with an increased risk of any major malformation (27.39 v 17.65 per 1000, 1.50, 1.13 to 1.99). No statistically significant associations were found for other system specific malformations or for neurodevelopmental disorders. Findings were robust to sensitivity analyses. Conclusions Prescribing macrolide antibiotics during the first trimester of pregnancy was associated with an increased risk of any major malformation and specifically cardiovascular malformations compared with penicillin antibiotics. Macrolide prescribing in any trimester was associated with an increased risk of genital malformations. These findings show that macrolides should be used with caution during pregnancy and if feasible alternative antibiotics should be prescribed until further research is available. Trial registration ClinicalTrials.gov NCT03948620
PROfound: Efficacy of olaparib (ola) by prior taxane use in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations.
Authors: Johann S. De Bono, Karim Fizazi, Fred Saad, Neal D. Shore, Guilhem Roubaud, Mustafa Ozguroglu, Nicolas Penel, Nobuaki Matsubara, Niven Mehra, Giuseppe Procopio, Michael Paul Kolinsky, Kazuo Nishimura, Susan Feyerabend, Jae Young Joung, Nicholas J. Vogelzang, Michael Anthony Carducci, Jinyu Kang, Christian Heinrich Poehlein, Wenting Wu, Maha H. A. Hussain
Journal: Journal of Clinical Oncology (2020)

134 Background: Optimal sequencing of therapies for mCRPC is not established. In the Phase III PROfound study (NCT02987543), ola significantly prolonged radiographic progression-free survival (rPFS) vs physician’s choice of new hormonal agent (pcNHA) in pts with mCRPC and an alteration in genes with a direct or indirect role in HRR. We report exploratory subgroup analyses by prior taxane (yes vs no). Methods: Men with mCRPC that had progressed on prior NHA were randomized to ola (tablets; 300 mg bid) or pcNHA (enzalutamide or abiraterone). Pts had alterations in BRCA1, BRCA2 or ATM (Cohort A) or ≥1 of 12 other prespecified genes with a direct or indirect role in HRR (Cohort B). Stratification factors were prior taxane use and measurable disease. rPFS was assessed by blinded independent central review with RECIST v1.1 + PCWG3. Results: Subgroup analyses of rPFS and overall survival (OS) favored ola vs pcNHA irrespective of prior taxane in Cohort A, Cohorts A+B and pts with a BRCA1 and/or BRCA2 or CDK12 alteration (Table). In the ATM subgroup hazard ratio (HR) point estimates for rPFS and OS were lower in pts who had received prior taxane vs pts who had not, but 95% CIs overlapped and pt numbers were small so data should be interpreted with caution. Conclusions: The benefit of ola over pcNHA in pts with mCRPC and HRR gene alterations was generally independent of prior taxane status in the overall study population. Clinical trial information: NCT02987543. [Table: see text]