tbuckley/cabot-search huggingface dataset:
Lessons learned from the metastatic castration-resistant prostate cancer phase I trial of EPI-506, a first-generation androgen receptor N-terminal domain inhibitor.
Authors: Ronan Le Moigne, Han-Jie Zhou, Jon K. Obst, C. Adriana Banuelos, Kunzhong Jian, David Williams, Peter Virsik, Raymond J Andersen, Marianne Sadar, Frank Perabo, Kim N. Chi
Journal: Journal of Clinical Oncology (2019)

257 Background: Aniten compounds bind to the N-terminal domain (NTD) of the androgen receptor (AR) and inhibit AR dependent transcription. EPI-506, the pro-drug of EPI-002, was the first AR NTD inhibitor tested in a Phase 1 study in men with metastatic castration-resistant prostate cancer (mCRPC). The drug was well-tolerated but required high doses. At doses &gt;1280 mg, EPI-506 treatment resulted in PSA declines; however, these were minor and of short duration, reflecting EPI-506’s low potency and short half-life. To understand EPI-506’s metabolic vulnerabilities, patient plasma samples were analyzed to identify metabolites. Methods: PSA serum levels were assessed after a month of dosing. Patient plasma samples were analyzed and pharmacokinetic (PK) parameters calculated. Three plasma samples from patients (one 80 and two 3,600 mg doses), were pooled across timepoints and metabolites were analyzed. EPI-506 metabolism was assessed in in vitro ADME assays and metabolite activity was measured. Results: EPI-002 patient plasma profiles exhibited dose-proportional C max and AUC following once or twice-daily EPI-506 administration. PSA declines (range of 8-29%) were observed, especially at higher doses (≥ 1,280 mg). A total of 19 metabolites were identified. Metabolite M19, a glycerol-moiety oxidant, was the major drug-related component. Other metabolic pathways included O-glucuronidation, sulfation, carboxylic acid formation, and oxidative chlorine loss. The major metabolites were tested in an AR driven reporter assay and were shown to be inactive. Interestingly, in vitro ADME assays predicted glucuronidation and sulfation but not cytochrome dependent metabolism. Conclusions: EPI-506 was tested in a phase 1 trial and showed minor PSA declines. The drug was well-tolerated but was highly metabolized. Patient plasma samples identified 19 metabolites. Newer molecules have been synthesized to address EPI-002’s metabolic liabilities and demonstrate &gt; 20-fold improved potency and higher stability. These next generation Anitens are currently being characterized for IND filing. Clinical trial information: NCT02606123.
Long-term outcomes in elderly patients (pts) from IMvigor210: Atezolizumab (atezo) in metastatic urothelial cancer (mUC).
Authors: Arjun Vasant Balar, Robert Dreicer, Yohann Loriot, Jose Luis Perez-Gracia, Jean H. Hoffman-Censits, Daniel Peter Petrylak, Michiel Simon Van Der Heijden, Xiaodong Shen, Beiying Ding, Teresa Ramirez-Montagut, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2019)

394 Background: Cisplatin-based chemotherapy is currently the standard 1L treatment for mUC, but many pts are ineligible and progression is common. Atezo (anti–PD-L1) is approved for certain types of mUC, and long-term efficacy and safety have been shown (Balar, ASCO 2018). Elderly pts in particular tend to have poor outcomes and may be chemotherapy intolerant, so this analysis sought to evaluate clinical outcomes in pts aged ≥ 65 and ≥ 75 y from the Phase II IMvigor210 study. Methods: This 2-cohort, single-arm study enrolled pts ineligible for 1L cisplatin and previously platinum-treated pts. Atezo 1200 mg IV q3w was given until PD (Cohort 1) or loss of clinical benefit (Cohort 2). RECIST v1.1 ORR (independent review; primary endpoint) and DOR and OS (secondary) were evaluated in pt subgroups based on PD-L1 status and age. Results: Evaluable pts as of July 12, 2018, are shown in the Table. In Cohort 1 pts ≥ 75 y, ORR was 29% overall, CR rate was 8%, DOR was NE and median OS was 21.4 mo. In Cohort 2 pts ≥ 75 y, ORR was 23%, CR rate was 7%, mDOR was 20.9 mo and mOS was 9.2 mo. Updated safety analyses in elderly pts will be presented. Conclusions: Efficacy outcomes in IMvigor210 elderly pts with mUC, and PD-L1 subgroup analysis appear generally consistent with those in the overall population in this long-term analysis. (Cohort 1; Balar Lancet 2017; NCT02951767). (Cohort 2; Rosenberg Lancet 2016; NCT02108652). Clinical trial information: NCT02951767 and NCT02108652. [Table: see text]
A retrospective comparison of the ability of lesion volumes and longest diameters to predict clinical outcome in metastatic colorectal cancer.
Authors: David Raunig, Ninad Mantri, Emmanuelle Magherini, Marie Hospitel, Pierre Mancini, Susanta K. Sarkar
Journal: Journal of Clinical Oncology (2015)

e14566 Background: Tumor volume defines patient cancer severity but to date volume studies have been limited. Images from 933/1226 patients with metastatic colorectal cancer (mCRC) from the VELOUR study (NCT00561470), which demonstrated a significant improvement of OS when treated with aflibercept FOLFIRI compared to placebo FOLFIRI, were used to measure lesion volumes. Baseline and an early follow-up image data were evaluated and target lesions were selected by the independent central reviewers. Lesions in liver (N = 1960), lung (N = 560) and lymph nodes (N = 377) were chosen in that order for a maximum of 5 lesions per patient. Volumes and longest diameters (LD) were compared for variability, linear relationship and ability to predict clinical outcome. Methods: Volumes and longest diameters (LD) were derived from CT images and lesion segmentation was conducted using MIRA. A statistical model estimated variances and Cox proportional hazard models were used to derive time-dependent ROC curves and C-indices. Results: The volumes followed a linear relationship to the cube of the LD for both individual lesions and the sum of longest diameters (SLD) and sum of volumes (SOV) (Radj2 = 0.81 – 0.94). The intraclass correlation coefficient (ICC) was slightly better for the SLD (0.89) than for SOV (0.79). Visit-to-visit repeatability correlations were equivalent (0.91). Percent change from baseline and baseline-alone had poor to fair ability to predict clinical outcome for both SLD and SOV. C-indices for Change from baseline were 0.62 vs. 0.55, (p<0.05), and for Baseline were 0.52 vs. 0.53 (ns). Conclusions: Both LDs and volumes are at most fair predictors of overall survival in mCRC. This study is limited by the absence of non-target lesion contribution to progression or overall survival and treatment-related differences may confound the evaluation. Finally, a valid percent change for progression free survival will be larger for SOV than SLD per RECIST 1.1 criteria of 20%. Clinical trial information: NCT00561470.C-Index values for SLD and SOV. Type Endpoint C-Index SE p-value (Bonferroni) Change SLD (%) 0.6192 0.009996 < 0.05 SOV (%) 0.5469 0.004863 Baseline SLD 0.5187 0.019592 Not significant SOV 0.5265 0.004896
Feasibility and activity of everolimus in patients (pts) with advanced urothelial carcinoma (UC) pretreated with 2 lines of chemotherapy (CT) including a platinum containing regimen (PCR): The French AFINIVEST study.
Authors: Christine Theodore, Gwenaelle Gravis Mescam, Jérome Meunier, Aline Guillot, Tifenn Lharidon, Eric Voog, Delphine Aubert
Journal: Journal of Clinical Oncology (2015)

e15635 Background: The mammalian target of rapamycin pathway has been shown to be upregulated in UC ad represents a potentiel target for therapeutic intervention. Methods: The present study is a single arm open label phase II trial in which all pts received everolimus 10 mg orally once daily continously. A sample size of 53 evaluable pts was calculated using Simon’s optimal two stage design with a 5% progression free survival (PFS) at 12 weeks as its primary endpoint. Secondary endpoints were safety, objective response rate (ORR), PFS and overall survival (OS). Pts with metastatic UC and measurable disease according to RECIST 1.1 criteria , progressing after 2 lines of CT, one of which contained platinum, were eligible. Results: Fifty four evaluable pts from 6 different sites were enrolled from 2011 to 2013.Fifty percent of pts (27) had previously received intensified M-VAC and a combination of paclitaxel and gemcitabine. Median treatment duration was 10.8 weeks [0-54]. Six pts (11.1%) had at least one dose reduction and 12 pts (34.3%) had at least one cycle delay ≥ 7 days because of toxicity. Reason for discontinuation of treatment was toxicity for 6 pts (11.1%) and disease progression for the other pts. The most common grade 3/4 toxicities were anaemia (14.8%), fatigue (9.3%), and interstitial pneumonitis (3.7%). PFS rate at 12 weeks was 52.2 % (95%CI [37.0 - 65.4] ) Median PFS was 12.36 weeks(95% CI [ 7.14-17.57]).There was no confirmed OR according to RECIST criteria. Median OS was 7.9 months (95% CI [4.0-15.3]). Conclusions: Everolimus met its primary endpoint in this biologically unselected population of heavily pretreated pts with UC. Safety profile was similar to that previously reported with everolimus in renal cell carcinoma. Median OS was better than expected in this pt population. Further studies of everolimus in UC pts including a biological characterization of tumors is warranted. Clinical trial information: NCT01801137.
Reply:
Authors: Lovkesh Anand, Ashok Choudhury, S.K. Sarin
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. We thank Dr. Habib for his interest in our study1 and emphasizing the difficulties in diagnosing autoimmune hepatitis (AIH) in patients presenting with first acute decompensation with no known history of cirrhosis. Our study provides a much‐needed criterion for diagnosing such patients. We agree the acute on chronic liver failure (ACLF) term often includes a heterogeneous population and includes patients without cirrhosis, compensated patients with cirrhosis, previously decompensated patients with cirrhosis, with or without liver failure, and sepsis.2 On the other hand, patients in our study cohort were homogenous and were defined as per APASL ACLF Research consortium (AARC).3 According to the AARC definition, patients with evident sepsis and decompensated cirrhosis are excluded, because sepsis is considered to be a result of liver failure. ACLF patients in our study had flare of AIH as the cause, resulting in liver failure3 with underlying chronic liver disease attributed to AIH. These patients are different from acute AIH patients in the study by Stravitz et al.,4 where acute liver failure (ALF) patients of indeterminate etiologies were biopsied and included (n = 72). Analogous to their study, we included ACLF patients with International AIH Group score ≥10 or simplified AIH score ≥6. In the absence of previous histopathological data for diagnosis of AIH‐ACLF, we included features of both classical and autoimmune acute liver failure (AI‐ALF) and categorized for simplified AIH score allocation. We evaluated biopsies of 74 patients and compared features with those described for AI‐ALF. We found fibrosis of varying degrees and less‐common portal lymphoid aggregates and perivenulitis in AIH‐ACLF patients. Our study showed no difference in 90‐day survival probability between patients not receiving corticosteroids and having sepsis at baseline (start of therapy) and those without. Patients receiving steroids had better 90‐day survival compared to patients not receiving corticosteroids, with or without sepsis. We agree that exclusion of common factors is mandatory before establishing diagnosis of AIH. This was indeed carefully done in our study. However, we would like to reiterate that it is necessary to recognize AIH‐ACLF as an entity separate from AI‐ALF. It would be worthwhile to plan future therapeutic interventions on this very sick group of patients, utilizing clinicohistological characteristics described in our study.
Prediction of early-onset gastric carcinoma by the multiplicative model: a case-control study of hereditary polygenic gastric cancer in Han Chinese.
Authors: Jiajia Yuan, Jing Gao, Lin Shen
Journal: Journal of Clinical Oncology (2015)

e12555 Background: Recent genome-wide association studies (GWASs) have identified several germline variations associated with gastric cancer. The aim of this study was to investigate the individual and combination effects of those single nucleotide polymorphisms (SNPs), which related to the risk of early-onset gastric cancer in a Chinese Han population. Methods: This case-control study included 167 gastric cancer patients and 173 healthy unrelated controls. Polymerase chain reaction (PCR) methods were used to perform the genotyping of the SNPs PSCA rs2294008, ZBTB20 rs4072037, and MUC1 rs9841504. Assuming each locus is independent without interactions and the risk is allele-dose-dependent with a simple multiplicative (log-additive) effect, we calculated the combined effect on the relative-risk scale. Results: We confirmed that the SNPs PSCA rs2294008, ZBTB20 rs4072037, and MUC1 rs9841504 were associated with increased risk for gastric cancer in Han Chinese. However, each of those low-penetrance susceptibility polymorphisms alone was not convincing enough to predict the absolute risk of early-onset gastric cancer. Thus, the multiplicative model for polygenes was applied for our population, and groups with different risk percentiles were stratified. The risk stratification was suggested to be useful for risk prediction of early-onset gastric cancer, and cost-effective for the general population prevention. Conclusions: These findings provide evidence that, instead of single low-penetrance susceptibility variations, application of the multiplicative model for polymorphisms may contribute to the gastric cancer screening by distinguishing population who are at high risk from those who are at low risk.
Thick perirenal fat predicts the growth pattern of renal cell carcinoma.
Authors: Eiji Kashiwagi, Kenjiro Imada, Masaki Shiota, Ario Takeuchi, Junichi Inokuchi, Katsunori Tatsugami, Masatoshi Eto
Journal: Journal of Clinical Oncology (2019)

554 Background: Partial nephrectomy is the standard surgical treatment for T1a renal cell carcinoma (RCC) and select T1b. Among these tumor classes, the tumor location can be divided into inner or outer. However, little attention has been paid to the mechanism of the pattern of RCC growth. In our body, there are two types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT is important for energy storage and BAT is important for thermogenesis. BAT expresses uncoupling protein 1 (UCP-1), and mainly located in mediastinal, supraclavicular and perirenal tissues. But no studies have been done to investigate the relationship between RCC and BAT.In this study, we examined the association between adipose tissue, especially around kidney, and the growth pattern of RCC. Methods: We retrospectively reviewed computed tomography scans of 153 patients with stage 1 RCC who underwent radical or partial nephrectomy in our hospital between January 2013 and July 2016. We calculated the visceral/subcutaneous/perirenal fat volumes using SYNAPSE VINCENT. Of the 60 patients, the perirenal fat was immunohistochemically stained for leptin, adiponectin, COX-2 and UCP-1, and the association with outward tumor protrusion was evaluated. Results: Of the 153 cases, 88 had confirmed outward expansion (57.5%), 110 were classed as pT1a (52 and 58 with outer and inner expansion, respectively), 43 were classed as pT1b (36 and 7 with outer and inner expansion, respectively; P &lt; 0.0001). Multivariate Cox model showed a trend toward significance in pT1b (vs. pT1a, OR 6.033, 95% CI = 2.409-15.108, P = 0.0001), perirenal fat percentage &gt; 1.0 (vs. ≤ 1.0, OR 2.596, 95% CI = 1.205-5.591, P = 0.014). as independent predictors for outer protrusion. Immunohistochemical staining was positive for UCP-1 expression in 31 out of 41 outgrowth types (75.6%), and all 19 endogenous types (100%; P = 0.003). Conclusions: Renal cell carcinoma with thick perirenal fat correlates with an increased likelihood of developing outward tumor protrusion; therefore, fat distribution and UCP1 expression may affect the development of renal cell carcinoma.
In vitro and in vivo killing of AML using tetravalent bispecific CD33/CD3 TandAbs.
Authors: Linda G. Eissenberg, Julie K. RItchey, Judith A. Fox, Uwe Reusch, Stefan Knackmuss, Jeanmarie Guenot, John F. DiPersio
Journal: Journal of Clinical Oncology (2015)

3057 Background: Antibody-based targeting agents specific for CD33 and CD3 are evolving as promising strategies for treating AML. T550, T564, and T589 are TandAbs that are bispecific as well as tetravalent with high affinity for CD33 (McAleese and Eser, 2012, Future Oncol. 8: 687-695). Methods: TandAbs were incubated with purified human T cells and a VPD-450-labeled human CD33+ leukemia cell line, KG-1, or the CD33- human ALL cell line, G2 (E:T = 5:1). Flow cytometry was used to evaluate target cell lysis by TandAbs (10-15 to 10-8M for 24h at 37°C). A primary CD33+ AML patient sample (5 x 106 PBMC; 98% blasts, 2% T cells) engrafts robustly when injected iv into NSG mice. TandAb T550 and T564 were administered iv at 5 or 50 ug/mouse qd starting 4 h after injection of primary AML cells and daily thereafter for 5 days (n = 8). On day 38 human leukemic blasts and human T cells in the blood, spleen, and bone marrow (BM) were enumerated by flow cytometry (human CD33, CD34, CD45, CD45, CD14, CD3, CD4, CD8, and 7AAD). Results: Incubation of TandAbs T550, T564, and T589 with human T cells efficiently lysed KG-1 cells (IC50 ~0.01, 0.5, and 5 pM respectively). Up to 40% of T cells were activated (CD25+), rising with cytotoxic activity. A control TandAb with an irrelevant target, T151 ( > 10-7 M), did not cause significant killing of KG-1 in vitro. T564 induced lysis of KG-1 cells (IC50 = 5 x 10-12M) but had no effect on CD33- G2 cells (1 x 10-8M). In mice injected with AML cells alone > 40% of spleen cells and > 45% of BM cells were confirmed by FACS to be AML blasts by day +38. No human AML was detected in the peripheral blood. In contrast, after treatment with ≥ 5 ug of either T550 or T564, < 0.1% of cells in the spleen and < 1% in the BM were leukemic blasts, representing an ~3 log reduction in leukemic blasts by day +38. Treated and untreated mice had equivalent T cell numbers on day 38. Conclusions: T cells become activated and potently lyse tumor cells only when targeted to CD33+ leukemic cells (KG-1) and primary CD33+ AML blasts by CD33/CD3 TandAbs. In spite of the protective environments of the BM and spleen and the extremely low number of T cells infused, nearly all primary AML blasts could be eliminated in vivo.
Education level and characterization of informed consent for PSA testing among males ages 55 to 69.
Authors: Elizabeth Horn Prsic, Kalyan Mantripragada, Srinivasa Nithin Gopalsamy, Matthew Santos
Journal: Journal of Clinical Oncology (2015)

e16063 Background: Prostate cancer is the most commonly diagnosed invasive cancer in the United States, and use of the PSA test has become widespread. With varied screening guidelines across organizations, informed decision-making becomes critical. This study examines informed decision-making among males ages 55 to 69 who have received PSA screening and its association with their education level. Methods: We analyzed data from the 2012 Behavioral Risk Factor Surveillance System. The analytic sample included 31,696 males ages 55 to 69 who had PSA testing within the past 2 years. The quality of informed consent was categorized as having discussed either advantages or disadvantages of PSA testing with a health care provider, neither, or both. Education level was categorized as high school equivalent or less, or some college or more. We examined the association between education level and informed consent with the chi-square test. Results: Of the sample, 41% of patients discussed both advantages and disadvantages of testing (27% had high school or less; 73% had some college or more; p = 0.000). 7.3% of patients discussed neither (37% had high school or less; 63% had some college or more; p = 0.000). While 51% of patients discussed only advantages of the test (28% had high school or less; 72% had some college or more; p = 0.000), 0.5% discussed only disadvantages (37% had high school or less; 63% had some college or more; p = 0.000). Those who had completed some college or more were significantly more likely to have discussed only advantages of the PSA test prior to testing compared to a lower education level (p = 0.000). Conclusions: Higher education level was associated with a significant increase in receipt of informed consent among subjects. However, only 41% of all subjects reported discussing both advantages and disadvantages of testing with a health care provider. Discussion of only advantages (51%) was more likely than discussion of only disadvantages (0.5%). Given the importance of informed decision-making, health care providers should focus on improving quality of informed consent, particularly among patients with lower education levels.
A Short Regimen for Rifampin-Resistant Tuberculosis
Authors: Gavin J Churchyard
Journal: New England Journal of Medicine (2019)

Multidrug-resistant and rifampin-resistant tuberculosis remain a global health threat, with an estimated 558,000 cases and 230,000 deaths worldwide in 2017.1 Treatment is more difficult and more costly for these conditions than for drug-susceptible tuberculosis and relies on drugs that do not have a reasonable side-effect profile or that have serious side effects. In 2011, the World Health Organization (WHO) issued guidelines, based on low-quality observational data, for treating multidrug-resistant and rifampin-resistant tuberculosis with an 18-to-24-month course of multiple second-line agents, including injectable drugs. This regimen, when administered by routine tuberculosis treatment programs, has resulted in successful treatment in approximately 55% . . .