tbuckley/cabot-search huggingface dataset:
PROTEUS: A randomized, double-blind, placebo (PBO)-controlled, phase III trial of apalutamide (APA) plus androgen deprivation therapy (ADT) versus PBO plus ADT prior to radical prostatectomy (RP) in patients with localized high-risk or locally advanced prostate cancer (PC).
Authors: Mary-Ellen Taplin, Martin Gleave, Christopher P. Evans, Eleni Efstathiou, Philip W. Kantoff, Ashley Ross, Neal D. Shore, Alberto Briganti, Boris A. Hadaschik, Axel Heidenreich, Oliver Brendan Rooney, Shaozhou Ken Tian, Lisa Wetherhold, Weichun Xu, Shinta Cheng, Sabine Doris Brookman-May, Angela Lopez-Gitlitz, Adam S. Kibel
Journal: Journal of Clinical Oncology (2020)

TPS383 Background: Patients (pts) with localized high-risk PC have disease progression rates of ~50% after RP (Kane et al. J Urol. 2007). Neoadjuvant studies show that androgen blockade can improve local disease control at the time of RP (McKay et al. Prostate Cancer Prostatic Dis. 2017; Taplin et al. JCO. 2014; Efstathiou et al. Eur Urol. 2019). This study will determine if treatment with APA + ADT before RP in pts with localized high-risk or locally advanced PC improves pathologic complete response (pCR) rate and if neoadjuvant and adjuvant peri-operative treatment with APA + ADT improves metastasis-free survival (MFS) compared with PBO + ADT. Methods: This international multicenter trial is enrolling candidates for RP with localized high-risk or locally advanced PC. Eligibility criteria: any combination of Gleason score (GS) 4 + 3 (= Grade Group [GG] 3) and GS 8 (4 + 4 or 5 + 3) from ≥ 6 systematic biopsy cores (SB) or targeted biopsy cores (TB) (with ≥ 1 core GS 8 [4 + 4 or 5 + 3] included); any combination of GS 4 + 3 (= GG 3) and GS 8 (4 + 4 or 5 + 3) from ≥ 3 SB or TB (with ≥ 1 core GS 8 [4 + 4 or 5 + 3]) included and prostate-specific antigen (PSA) ≥ 20 ng/mL; GS ≥ 9 (GG 5) in ≥ 1 SB or TB; or ≥ 2 SB or TB with continuous GS ≥ 8 (GG 4), each with ≥ 80% involvement. Stratification: GS (7 or ≥ 8), cN0 or N1, and region. Randomization: 1:1 to APA (240 mg) + ADT or PBO + ADT. Pts will receive 6 months neoadjuvant treatment and RP + 6 months adjuvant treatment. Dual primary end points: pCR rate (assessed by blinded independent central pathology review) and MFS (assessed by blinded independent central radiology review). Secondary end points: PSA-free survival and progression-free survival. Imaging with CT or MRI and bone scan at screening, after RP, and then every 6 months following biochemical failure until documented distant metastasis, or death. ~1500 pts will be enrolled globally over 3 years at 240 sites in 19 countries. An independent data monitoring committee is commissioned to review trial data. Clinical trial information: NCT03767244.
When Discontinuing SSRI Antidepressants Is a Challenge: A Response to Letters to the Editor
Authors: Manish K. Jha, Madhukar H. Trivedi
Journal: American Journal of Psychiatry (2019)

medical therapies and appropriate consultations.Finally, a basic disagreement with the recommendations of Jha et al.(1) is whether we view withdrawal syndromes as isolated, self-limiting manifestations or as related to other clinical phenomena.According to the oppositional model of tolerance (4), continued drug treatment may trigger processes that oppose the initial acute effects of a drug.When drug treatment ends, oppositional processes may operate for some time, resulting in appearance of withdrawal symptoms, resistance if treatment is reinstituted, and a more malignant and treatmentunresponsive course (4), as was found to be the case in the clinical case presented (1).We should be aware that by reintroducing the antidepressant that was initially used or by switching to another antidepressant to suppress clinical manifestations of withdrawal (1), we are simply postponing, and most likely aggravating, the problem (4).Discontinuing SSRIs is far more difficult than prescribing them.We absolutely need sound research on withdrawal phenomena related to antidepressant drugs and to redefine the use and indications of these medications, including their differential likelihood of inducing behavioral toxicity (4).
Survival analysis of anticoagulant treatment of non-small cell lung cancer.
Authors: Junyan Wang, Fan Zhang, Lei Hong, Da Jiang, Minting Ma, Suju Wei
Journal: Journal of Clinical Oncology (2019)

e20623 Background: More and more evidence shows that coagulation cascade reaction and some vascular factors can promote the deterioration of tumor. Preventive interventions for high-risk patients with venous thromboembolism can reduce cancer mortality and improve quality of life. Anticoagulants have anti-tumor activity and can participate in the process of adhesion, metastasis, invasion, thrombogenesis and immune escape of cancer cells. So we want to explore the effects of anticoagulants on the survival of patients with non-small cell lung cancer. Methods: This study retrospectively analyzed the clinical data of876 cases with non-small cell lung cancer. According to whether or not to apply anticoagulant drugs, it was divided into 2 groups including application group (270 cases) and non-application group (606 cases), and the survival status of the two groups were followed up. Results: The median survival ofthe non-application group was 14.2 months, the 1, 2, 3, and 5 years survival rates of patients were 56.6%, 31.8%, 21.0% and 6% respectively. The application group median survival of the application group was 17.7 months, the 1, 2, 3, and 5 years survival rates of patients were 66.6%, 36.6%, 28.8% and 16.8% respectively. The median OS and survival rate were extended in anticoagulation group compared with another. The overall comparison of the survival curves of the two groups by Log Rank was P = 0.016. Conclusions: Anticoagulant therapy can significantly improve the overall survival of patients with non-small cell lung cancer.
Clinical benefit of EGFR-TKIs plus radiotherapy for treating EGFR-mutated metastatic non-small cell lung cancer.
Authors: Ran Lin Wang, Tao Li, Jiahua Lv, Chang Sun, Qiuling Shi
Journal: Journal of Clinical Oncology (2019)

e20694 Background: Despite the high response rate and prolonged OS of patients with EGFR mutations treated with gefitinib or erlotinib, there are still major clinical obstacles. The local control rate is still low, only 19.4%–58%, with first-line treatment using EGFR-targeted therapy. The aim of this study is to provide scientific evidence to support the clinical benefits of EGFR-TKI combined with radiotherapy compared to EGFR-TKI alone. Methods: From February 2015 to May 2017, a total of 103 patients with stage IV EGFR-mutated NSCLC treated at Sichuan Cancer Hospital &amp; Institute were analysed retrospectively. 50 patients were treated with EGFR-TKIs (gefitinib or erlotinib) plus radiotherapy (Group TKI-RT) and 53 patients received EGFR-TKIs alone (Group TKI). Tumour response, survival and toxicities were compared between the two groups. Results: Median follow up time was 11.7 months (range: 2.8–36.3 months). The overall response rate (ORR) and disease control rate (DCR) in Group TKI-RT vs. Group TKI were 62% vs. 37.7% (P = 0.014) and 88% vs. 75.5% (P = 0.101), respectively. The median progression-free survival (PFS) and median overall survival (OS) in Group TKI-RT were superior to those of Group TKI (18.87 months vs. 12.80 months, P = 0.035 and 23.10 months vs. 18.30 months, P = 0.011). OS rates in Group TKI-RT and Group TKI were 56.0% vs. 35.8% at 1-year (P = 0.04) and 16.0% vs. 3.8% at 2-year (P = 0.036). Multivariate Cox model found that TKI-RT related to significantly better OS (hazard ratio = 0.209; 95% CI, 0.066 to 0.661; P = 0.008) than TKI alone. Adverse events did not differ significantly between the two groups. Conclusions: Compared with EGFR-TKIs alone, EGFR-TKIs combined with radiotherapy was well tolerated and showed benefit in tumour response and survival for EGFR mutation-positive metastatic NSCLC patients.
Helen Salisbury: Great expectations
Authors: Helen Salisbury
Journal: BMJ (2019)

Modern medicine is marvellous. Before the 20th century our main tools were surgery and sympathy. Even in my lifetime our ability to treat and cure has increased dramatically: think of HIV and hepatitis C in the past few years alone. Most of our patients are aware of this and have high expectations of the medical profession.

The importance of exploring these expectations is routinely taught in medical schools, as part of that triad of “ideas, concerns, and expectations.” But the skills needed to do this well are sometimes underdeveloped. Students know that they should ask …
Genomic landscape of metastatic hormone sensitive prostate cancer (mHSPC) vs. metastatic castration-refractory prostate cancer (mCRPC) by circulating tumor DNA (ctDNA).
Authors: Andrew W Hahn, Edwin Lin, John Esther, Neysi Anderson, Nityam Rathi, Mark Yandell, Benjamin Louis Maughan, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2019)

5043 Background: mCRPC carries a poor prognosis, and targeted therapies have had minimal success in mCRPC. Novel genomic targets could improve drug development. To date, large ctDNA studies in metastatic prostate cancer have been descriptive with limited or no clinical annotation. Herein, we hypothesize that profiles of genomic alterations (GAs) in ctDNA not only differ significantly between, but can also be used to predict mCRPC vs. mHSPC. These findings could help identify new drug targets for mCRPC treatment. Methods: Men with mHSPC or mCRPC who underwent NGS of ctDNA using G360 (Guardant Health Inc.) at the Huntsman Cancer Institute were included. Men were classified as mCRPC or mHSPC (patients with current or no prior ADT). G360 detects somatic mutations in selected exons of 73 genes, amplifications in 18 genes, and selected fusions in 6 genes. Two-sided students t-test was used to compare the %cfDNA and total GAs. The Chi squared test was used to compare the frequency of each GA. Machine learning (ML) algorithms were trained on GAs and benchmarked by cross-validated performance. GAs contributing to mCRPC vs. mHSPC classification were measured by ML feature importance (e.g. odds ratios, regression coefficients). Results: Of the 259 men included, 119 men had mHSPC and 140 had mCRPC. Men with mCRPC had more GAs (4.5 vs. 1.86, p&lt;0.0001) and higher %cfDNA (9.56% vs. 5.02%, p=0.02). In mHSPC, there was no significant difference in the number of GAs or %cfDNA between men on ADT and those who hadn’t yet started ADT. ML algorithms used GAs to predict mCRPC with 78.1% sensitivity, 64.0% specificity, 76.7% PPV, 65.1% NPV, and 70.3% overall accuracy. mCRPC was enriched with GAs in AR, ARID1A, BRAF, BRCA2, CCNE1, CTNNB1, EGFR, FGFR1, KIT, MET, MYC, PDGFRB, PIK3CA, and TP53. Of note, many of these genes are involved in MAP/ERK signaling. Conclusions: Men with mCRPC have more GAs, higher %cfDNA, and enrichment of GAs in the MAP/ERK pathway compared to men with mHSPC. The distinct GAs seen in mCRPC represent novel therapeutic targets, especially in the MAP/ERK pathway. We also show that machine learning can differentiate mHSPC and mCRPC based on GAs detected in ctDNA.
A phase I study (E011-MEL) of a TriMix-based mRNA immunotherapy (ECI-006) in resected melanoma patients: Analysis of safety and immunogenicity.
Authors: ANA Maria Arance Fernandez, Jean-Francois Baurain, Christof Vulsteke, Annemie Rutten, Ainara Soria, Javier Carrasco, Bart Neyns, Brenda De Keersmaecker, Tim Van Assche, Bertil Lindmark
Journal: Journal of Clinical Oncology (2019)

2641 Background: ECI-006 is a combination of TriMix (mRNAs encoding for dendritic cell [DC] activating molecules [CD40L, CD70 and caTLR4]), and mRNAs encoding for melanoma-specific tumor-associated antigens (TAAs): tyrosinase, gp100, MAGE-A3, MAGE-C2, and PRAME. DCs transfected ex vivo with TriMix and TAAs mRNAs showed significant clinical activity in combination with ipilimumab in metastatic melanoma without increasing toxicity. This study aims to assess the safety and immunogenicity of ECI-006 vaccine administered intranodally (i.n.) in an adjuvant setting for patients with resected melanoma. Methods: Twenty patients who underwent resection of stage IIc/III/IV cutaneous melanoma received 5 administrations of ECI-006 (either 600 µg or 1800 µg [n = 10, each]) injected i.n. on Day 1 and after 2, 4, 6 and 14 weeks. Treatment-emergent adverse events (TEAEs) were graded using CTCAE version 4.0.3. Blood samples for immune monitoring (ELISPOT and intracellular cytokine staining [ICS]) were collected pre-dose and at weeks 4, 7, 14 and 15. Results: Nineteen patients completed the treatment. One patient in the low dose group discontinued the study after 4 doses due to disease relapse. Administration of ECI-006 was well tolerated. No serious adverse events or TEAEs Grade 3 or higher were reported. Of all TEAEs, myalgia and fatigue were the most reported in 3 (15%) and 5 (25%) patients, respectively. ELISPOT and ICS were performed on T cells pre-stimulated in vitro for 10-12 days, using a previously in-house validated protocol. Vaccine-induced immune responses according to predefined criteria were detected in 4/10 and 3/9 patients treated with the low and high dose, respectively. Samples from these patients are currently being subjected to T-cell receptor repertoire analysis. Conclusions: Among patients undergoing resection of stage IIc/III/IV melanoma, i.n. administration of ECI-006 at 600 or 1800 µg was generally well tolerated. ECI-006 demonstrated to be immunogenic in a proportion of patients. These results warrant further development of ECI-006 in combination with anti-PD-1 therapy in melanoma patients. Clinical trial information: NCT03394937.
Treatment Outcomes of Topical Calcineurin Inhibitor Therapy for Patients With Vitiligo
Authors: Ji Hae Lee, Hyuck Sun Kwon, Han Mi Jung, Hyunyong Lee, Gyong Moon Kim, Hyeon Woo Yim, Jung Min Bae
Journal: JAMA Dermatology (2019)

<h3>Importance</h3> Topical calcineurin inhibitors (TCIs), including tacrolimus and pimecrolimus, have been widely used for the treatment of vitiligo; however, the efficacy of TCI monotherapy is often underestimated. <h3>Objectives</h3> To estimate the treatment responses to both TCI monotherapy and TCI accompanied by phototherapy for vitiligo, based on relevant prospective studies, and to systematically review the mechanism of action of TCIs for vitiligo treatment. <h3>Data Sources</h3> A comprehensive search of the MEDLINE, Embase, Web of Science and Cochrane Library databases from the date of database inception to August 6, 2018, was conducted. The main key words used were<i>vitiligo</i>,<i>topical calcineurin inhibitor</i>,<i>tacrolimus</i>,<i>pimecrolimus</i>, and<i>FK506</i>. <h3>Study Selection</h3> Of 250 studies initially identified, the full texts of 102 articles were assessed for eligibility. A total of 56 studies were identified: 11 studies on the TCI mechanism, 36 studies on TCI monotherapy, 12 studies on TCI plus phototherapy, and 1 study on TCI maintenance therapy. <h3>Data Extraction and Synthesis</h3> Two reviewers independently extracted data on study design, patients, intervention characteristics, and outcomes. Random-effects meta-analyses using the generic inverse variance weighting were performed for the TCI monotherapy and TCI plus phototherapy groups. <h3>Main Outcomes and Measures</h3> The primary outcomes were the rates of at least mild (≥25%), at least moderate (≥50%), and marked (≥75%) repigmentation responses to treatment. These rates were calculated by dividing the number of participants in an individual study who showed the corresponding repigmentation by the total number of participants who completed that study. <h3>Results</h3> In the 56 studies included in the analysis, 46 (1499 patients) were selected to evaluate treatment response. For TCI monotherapy, an at least mild response was achieved in 55.0% (95% CI, 42.2%-67.8%) of 560 patients in 21 studies, an at least moderate response in 38.5% (95% CI, 28.2%-48.8%) of 619 patients in 23 studies, and a marked response in 18.1% (95% CI, 13.2%-23.1%) of 520 patients in 19 studies after median treatment duration of 3 months (range, 2-7 months). In the subgroup analyses, face and neck lesions showed an at least mild response in 73.1% (95% CI, 32.6-83.5%) of patients, and a marked response in 35.4% (95% CI, 24.9-46.0%) of patients. For TCI plus phototherapy, an at least mild response to TCI plus phototherapy was achieved in 89.5% (95% CI, 81.1-97.9%) of patients, and a marked response was achieved in 47.5% (95% CI, 30.6-64.4%) of patients. <h3>Conclusions and Relevance</h3> The use of TCIs, both as a monotherapy and in combination with phototherapy, should be encouraged in patients with vitiligo.
Blocking Sodium‐Taurocholate Cotransporting Polypeptide Stimulates Biliary Cholesterol and Phospholipid Secretion in Mice
Authors: Reinout L.P. Roscam Abbing, Davor Slijepcevic, Joanne M. Donkers, Rick Havinga, Suzanne Duijst, Coen C. Paulusma, Johan Kuiper, Folkert Kuipers, Albert K. Groen, Ronald P.J. Oude Elferink, Stan F.J. van de Graaf
Journal: Hepatology (2019)

Active secretion of bile salts into the canalicular lumen drives bile formation and promotes biliary cholesterol and phospholipid output. Disrupting hepatic bile salt uptake, by inhibition of sodium‐taurocholate cotransporting polypetide (NTCP; Slc10a1) with Myrcludex B, is expected to limit bile salt flux through the liver and thereby to decrease biliary lipid excretion. Here, we show that Myrcludex B–mediated NTCP inhibition actually causes an increase in biliary cholesterol and phospholipid excretion whereas biliary bile salt output and bile salt composition remains unchanged. Increased lysosomal discharge into bile was excluded as a potential contributor to increased biliary lipid secretion. Induction of cholesterol secretion was not a consequence of increased ATP‐binding cassette subfamily G member 5/8 activity given that NTCP inhibition still promoted cholesterol excretion in Abcg8 −/− mice. Stimulatory effects of NTCP inhibition were maintained in Sr‐b1 −/− mice, eliminating the possibility that the increase in biliary lipids was derived from enhanced uptake of high‐density lipoprotein–derived lipids. NTCP inhibition shifts bile salt uptake, which is generally more periportally restricted, toward pericentral hepatocytes, as was visualized using a fluorescently labeled conjugated bile salt. As a consequence, exposure of the canalicular membrane to bile salts was increased, allowing for more cholesterol and phospholipid molecules to be excreted per bile salt. Conclusion: NTCP inhibition increases biliary lipid secretion, which is independent of alterations in bile salt output, biliary bile salt hydrophobicity, or increased activity of dedicated cholesterol and phospholipid transporters. Instead, NTCP inhibition shifts hepatic bile salt uptake from mainly periportal hepatocytes toward pericentral hepatocytes, thereby increasing exposure of the canalicular membrane to bile salts linking to increased biliary cholesterol secretion. This process provides an additional level of control to biliary cholesterol and phospholipid secretion.
Bevacizumab beyond progression: Impact of subsequent bevacizumab retreatment in patients with ovarian, fallopian tube, and peritoneal cancer after progression.
Authors: Rebecca Ann Previs, Daniel Spinosa, Bryan M. Fellman, Amelia Lorenzo, Isabelle Mulder, May Mahmoud, Ahmed Enbaya, Jean M. Hansen, Lauren Patterson Cobb, Pamela T. Soliman, Robert L. Coleman, Angeles Alvarez Secord, Shannon Neville Westin
Journal: Journal of Clinical Oncology (2019)

5557 Background: The Food and Drug Administration approved the use of bevacizumab for treatment of recurrent epithelial ovarian, fallopian tube, and primary peritoneal carcinoma (OC) in combination with chemotherapy. This study evaluates whether patients immediately retreated with bevacizumab derive benefit after progressing on a bevacizumab-containing regimen. Methods: This multi-institutional, retrospective study compared patients with high grade non-mucinous epithelial OC who received bevacizumab followed directly by another bevacizumab-containing treatment regimen to patients who received bevacizumab followed by a regimen that did not contain bevacizumab (or received no further treatment). All patient retreated with bevacizumab had stable or progressive disease on prior bevacizumab containing regimen. Progression free survival (PFS) and overall survival (OS) were estimated using Kaplan and Meier product-limit estimator and modeled via Cox proportional hazards regression. PFS was measured from the date of first bevacizumab treatment to the date of first progression, date of death or date of last clinic visit. OS was measured from the date of first bevacizumab treatment after progression to the date of death or date of last contact/clinic visit. Statistical significance was defined at the 0.05 level. Results: 275 patients received bevacizumab, of which 226 were evaluable; 102 received sequential treatment with bevacizumab and 124 received a bevacizumab containing regimen followed by a non-bevacizumab containing regimen at the time of progression. There was no significant difference between tumor grade, stage, or BRCA mutation. Median follow-up for all subjects was 17 months (range: 1.2-138.2 months). Median PFS was 10.21 months (95%CI: 8.05 - 11.79) and median OS was 22.14 months (95%CI: 17.1 – 27.4). Median PFS for patients who received bevacizumab without retreatment was 5.1 months (95%CI: 4.3 – 6.3) and 17.6 months (95%CI: 14.3 – 21.3) for patients who received sequential bevacizumab retreatment (p &lt; 0.001). Median OS for patients who received bevacizumab without retreatment was 12.9 months (95%CI: 9.3 – 16.7) and 30.1 months (95%CI: 26.1 – 35.4) for patients who received sequential bevacizumab retreatment (p &lt; 0.001). Conclusions: Our study shows OC patients treated with bevacizumab-containing regimens sequentially at the time of progression have significantly prolonged survival outcomes compared to those patients who received no re-treatment with bevacizumab.