tbuckley/cabot-search huggingface dataset:
Thyroid dysfunction and immune checkpoint inhibitor outcomes.
Authors: Mitchell S. von Itzstein, Rong Lu, Sadia Ali, Donglu Xie, Jennifer Cai, Yang Xie, David E. Gerber
Journal: Journal of Clinical Oncology (2020)

e15103 Background: Immune checkpoint inhibitors (ICI) frequently cause thyroid dysfunction. We performed a longitudinal analysis of thyroid function tests in a large, single-center cohort of patients with multiple cancer types receiving ICI. Methods: We performed a retrospective medical records review of consecutive patients treated with ICI from 1/1/2005 to 12/31/2018. We collected demographic and clinical data, including serial thyroid function tests. We compared overall survival between patients with normal and abnormal thyroid stimulating hormone (TSH) at baseline and after ICI initiation using Kaplan-Meier curves, log-rank tests, and multivariate Cox proportional hazards model. Results: A total of 910 patients were included: 63% male, 82% white, median age 67. The most common cancer types were lung (26%), kidney (18%), and melanoma (17%). ICI types were anti-PD1/L1 (78%), anti-CTLA-4 (7%), and combination ICI (15%). Normal baseline TSH and abnormal post-treatment TSH was associated with longer overall survival (median survival 26 months) compared to all other TSH permutations (median survival &lt; 10 months) ( P&lt; 0.001). This finding persisted after multivariate Cox regression adjustment for age, gender and cancer type (P &lt; 0. 001), and also after sensitivity analysis censoring patients who died within 2 months after starting ICI. Conversely, abnormal TSH at baseline was associated with lower overall survival (median 8 months) compared to normal TSH at baseline (median 18 months) ( P&lt; 0.001), which also persisted in multivariate analysis ( P&lt; 0.001). Kidney and head and neck cancers (71% and 69%) were associated with increased development of thyroid dysfunction compared to melanoma, lung and other urological cancers (52%, 50% and 35%) ( P&lt; 0.01). Conclusions: Although abnormal thyroid function after ICI initiation was associated with improved overall survival, pre-treatment thyroid abnormalities were associated with worse overall survival. Given the prevalence of thyroid abnormalities in the general population, further research into these observations is warranted.
Pembrolizumab (pembro) for the treatment of patients with Bacillus Calmette-Guérin (BCG) unresponsive, high-risk (HR) non–muscle-invasive bladder cancer (NMIBC): Over two years follow-up of KEYNOTE-057.
Authors: Arjun Vasant Balar, Ashish M. Kamat, Girish S. Kulkarni, Edward M. Uchio, Joost L. Boormans, Dean F. Bajorin, Mathieu Roumiguié, Eric A. Singer, Laurence Eliot Miles Krieger, Petros Grivas, Ho Kyung Seo, Hiroyuki Nishiyama, Badrinath R. Konety, Kijoeng Nam, João Paulo Zambon, Ekta Kapadia, Ronald De Wit
Journal: Journal of Clinical Oncology (2020)

5041 Background: Pembro was recently approved for the treatment of HR NMIBC based on results from the phase 2 KEYNOTE-057 (NCT02625961) study. Herein we present safety, efficacy, and posttreatment outcomes with &gt; 2 y follow-up from KEYNOTE-057 cohort A. Methods: Patients with histologically confirmed HR BCG-unresponsive carcinoma in situ (CIS) with or without papillary tumors who received adequate BCG therapy and were ineligible for or opted out of radical cystectomy (RC) received pembro 200 mg Q3W for up to 2 y or until disease recurrence, progression, or unacceptable toxicity. The primary end point was complete response rate (CRR). Key secondary end points were duration of response (DOR) and safety. Results: Overall, 102 patients were initially enrolled, and 96 were included in the efficacy analysis. Median time from enrollment to data cut off was 28.4 months (range, 18.2-40.5). CRR was 40.6% (95% CI, 30.7-51.1), and median DOR was 16.2 months (range, 0+ to 30.4+). Among 39 patients with CR, 18 (46.2%) had a DOR ≥12 months. No patient’s disease progressed to muscle-invasive or metastatic bladder cancer while on study treatment. Median PFS and OS were not reached. At 12 months, PFS was 82.7% and OS was 97.9%. A total of 36 patients (37.5%) underwent RC after discontinuation from study treatment, which included 9 of 22 patients (40.9%) who had recurrence after initial CR and 27 of 57 (47.4%) nonresponders. Of the 36 who underwent RC, 33 (91.6%) had no pathological upstaging to MIBC and 3 (8.3%) had at least pT2 disease at time of RC. For subsequent treatments other than RC, 27 of 96 (28.1%) patients received additional intravesical therapy (eg, BCG, gemcitabine, or mitomycin), 21 of 96 (21.9%) underwent local procedures (eg, TURBT), and 3 of 96 (3.1%) received systemic therapy (eg, pembro). In 102 patients treated with pembro, treatment-related AEs (TRAEs) occurred in 67 (65.7%) patients; most frequently reported TRAEs were fatigue, pruritus, and diarrhea (10.8% each). Grade 3/4 TRAEs occurred in 13 patients (12.7%), and 21 patients (20.6%) experienced immune-mediated AEs. There were no grade 5 TRAEs. Conclusions: After &gt; 2 y of follow-up, durable and clinically meaningful activity of pembro was observed in patients who had HR BCG-unresponsive CIS with or without papillary tumors and who were ineligible for or opted out of RC. Pembro did not seem to limit the opportunity for subsequent therapies, including RC. The safety profile was consistent with what is reported in the literature. Clinical trial information: NCT02625961 .
A first-in-man phase I/II study of OBI-3424, an AKR1C3-selective bis-alkylating agent prodrug, in subjects with advanced cancer, including hepatocellular carcinoma (HCC) and castrate-resistant prostate cancer (CRPC).
Authors: Apostolia Maria Tsimberidou, Claire F. Verschraegen, Pei Hsu, Tillman E. Pearce
Journal: Journal of Clinical Oncology (2020)

TPS3658 Background: Aldo-keto reductase family 1 member C3 (AKR1C3) modulates cellular differentiation and proliferation through indirect regulation of ligand access to hormone and nuclear receptor signaling. AKR1C3 is expressed at high levels in various human cancers, including HCC. In prostate cancer cells exposed to anti-androgen therapies, AKR1C3 is adaptively upregulated. CRPC is a potential indication for this targeted alkylating agent. AKR1C3 tumor expression is associated with poor patient survival and resistance to cancer therapies. OBI-3424 is a nitro-benzene prodrug of a nitrogen mustard that can be selectively cleaved in the presence of AKR1C3 enzyme into a bis-alkylating agent capable of forming intra- and inter-strand crosslinks with DNA, thereby resulting in cell death. The selectivity of OBI-3424 for AKR1C3 distinguishes it from traditional alkylating agents, which are nonselective. The primary objectives of the study are to evaluate the safety and tolerability of single-agent OBI-3424. The dose-escalation phase will determine the dose-limiting toxicities (DLT), maximum tolerable dose (MTD), and recommended Phase 2 dose (RP2D) of OBI-3424 through assessment of PK of OBI-3424 and OBI-2660 in plasma and urine. After determining the maximum tolerated dose (MTD), the study will enroll subjects with advanced HCC or CRPC, two tumor types with a high likelihood of overexpression of AKR1C3, into the dose expansion portion of the study according to a Simon two-stage phase 2 design. This phase is designed to assess the objective response rate, and progression-free survival in patients with HCC and CRPC. Immunohistochemistry assays are being developed to assess tumor expression of AKR1C3 for this study. The clinical safety and relationship of efficacy to AKR1C3 tumor expression will serve to guide further clinical development of OBI-3424 in these two unmet need settings. Methods: Based on the toxicology and PK results in cynomolgus monkeys, the starting dose is one sixth of the human equivalent dose of the highest non-severely toxic dose observed. Doses of 1, 2, 4, 6, 8, 12, and 14 mg/m 2 will be used. OBI-3424 is administered intravenously (IV) over 30 minutes on days 1 and 8 of each 21-day cycle. Subjects without clinically significant disease progression may continue on treatment for up to 2 years, if they do not experience a DLT or other significant toxicity. Clinical trial information: NCT03592264 .
Acquired progressive cutaneous lymphangioma: a report of two cases
Authors: Yingjun Wang
Journal: BMJ (2018)

报道2例皮肤获得性进行性淋巴管瘤。例1发生于电凝治疗尖锐湿疣4个月后；例2发病前有宫颈癌手术淋巴结清扫和左下肢复发性丹毒及橡皮肿史，均经病理检查确诊为皮肤淋巴管瘤。例1手术切除后痊愈；例2拒绝手术。
Long-term analysis of the WHO-defined molecular subgroups of high-risk grade II gliomas treated with radiation and temozolomide on NRG Oncology/RTOG 0424.
Authors: Erica Hlavin Bell, Stephanie L. Pugh, Barbara Jean Fisher, Glenn Jay Lesser, David R. Macdonald, Jessica L. Fleming, Joseph P. McElroy, Aline P. Becker, C Leland Rogers, Thomas J. Doyle, Maria Werner-Wasik, Jean-Paul Bahary, Michael Yu, David D'Souza, Nadia N. Laack, Patricia Penny Sneed, Young Kwok, Steven P. Howard, Minesh P. Mehta, Arnab Chakravarti
Journal: Journal of Clinical Oncology (2020)

2518 Background: This study sought to evaluate the prognostic significance of the three WHO-defined molecular glioma subgroups ( IDHwt, IDHmt/non-codel, and IDHmt/codel) in NRG Oncology/RTOG 0424, a phase II trial of high-risk low-grade gliomas treated with radiation (RT) and concurrent and adjuvant temozolomide (TMZ) after biopsy/surgical resection. Notably, this is the first clinical study to evaluate the prognostic value of the WHO subgroups in RT + TMZ-treated high-risk grade II (G2) gliomas using prospectively-collected long-term survival data. Methods: IDH1/2 mutation status was determined by next-generation sequencing. 1p/19q co-deletion status was determined by Oncoscan and/or 450K methylation data. Overall survival (OS) and progression-free survival (PFS) by marker status were determined by the Cox proportional hazard model and tested using the log-rank test in a post-hoc analysis. Patient pre-treatment characteristics were included as covariates in multivariate analyses. Results: Of all the eligible patients (N=129), 80 (62%) had sufficient quality DNA for both IDH and 1p/19q analyses. Of these 80, 54 (67.5%) were IDHmt, and 26 (32.5%) were IDHwt. Of the 54 IDHmt patients, 26 (32.5% of total, 48% of IDHmt) were IDHmt/codel, and 28 (35% of total, 52% of IDHmt) were IDHmt/non-codel. Both IDHmt subgroups were significantly correlated with longer PFS ( IDHmt/co-del = 8.1yrs (5.2-not reached (NR)); IDHmt/non-codel = 7.5yrs (3.9-11.8); IDHwt = 1.0yr (0.6-1.7), p&lt;0.001) and OS ( IDHmt/co-del = 9.4yrs (8.2-NR); IDHmt/non-codel = 8.8yrs (5.9-NR); IDHwt = 2.3yrs (1.4-3.4), p&lt;0.001) relative to the IDHwt subgroup. Upon univariate and multivariate analyses, both molecular IDHmt subgroup comparisons relative to IDHwt remained significant (p&lt;0.001) even after incorporation of known clinical variables. Conclusions: These analyses suggest that G2 glioma patients harboring IDH1/2 mutations, regardless of co-deletion status, demonstrated longer survival with RT + TMZ relative to IDHwt tumors, although sample size is limited and analyses were post-hoc. These results also support the notion that outcomes for IDHwt high-risk G2 gliomas remain dismal (median = 2.3yrs, similar to G3 anaplastic astrocytoma); these patients should be separated from IDHmt patients in future G2 glioma trials, and warrant novel treatment strategies. Funding: U10CA180868, U10CA180822, U24CA196067, CURE, PA Dept. of Health, and Merck. Also, R01CA108633, R01CA169368, RC2CA148190, U10CA180850, BTFC, OSUCCC (all to AC). Clinical trial information: NCT00114140 .
对老人认知功能动态变化的随访调查
Authors: 王英, 杨宗儒, 杨金锁, 马宝山, 谭庆荣
Journal: BMJ (2004)

对2 563名老年人做5年前瞻性随访,以5年后诊断分为痴呆组与正常组.两组简易智力状态检查5年前后分值,以简易智力状态检查下降分数判断,在性别、年龄及教育程度上均差异有显著性.MMSE分数与5年后痴呆发生率相关。
Efficacy and safety of DCVAC/LuCa Treatment plus standard chemotherapy and TCM in patients with advanced non-small cell lung cancer: A single-arm phase II study.
Authors: Yanni Lou, Liqun Jia, Qing Liu, Liya Li, Huijuan Cui, Chao Deng, Meng Liu, Fei Su, Zhiqiang Cheng, Donggui Wan
Journal: Journal of Clinical Oncology (2020)

e21590 Background: Lung cancer remains the leading cause of cancer-related death in China. DCVAC/LuCa is an active autologous cellular immunotherapy consisting of autologous DCs loaded with NSCLC antigens from NSCLC cell lines. SQFZ is a kind of TCM injection commonly uesed for NSCLC, made from Ginseng and Astragalus membranaceus. Intent of this study is to evaluate the efficacy and safety of DCVAC/LuCa plus chemotherapy and TCM in patients with advanced NSCLC and wild type driving gene(EGFR/ALK). Methods: This study consist of screening/leukapheresis/treatment/follow-up period. On the treatment period, chemotherapy started after leukapheresis. Four cycles are recommended with limitation to maximum 6 cycles. Up to 12 subcutaneous doses of DCVAC/LuCa treatment were administrated on the 15th day of chemotherapy cycle every 3 weeks for 4 doses, and continued alone after chemotherapy finishes/stops every 6 weeks for the remaining 8 doses. TCM therapies were administered on the -3 to 3 days of DCVAC/LuCa. After completion of the total 12 doses DCVAC/LuCa or discontinuation of study treatment, patients will be followed up until experienced OS event or till 1 year of survival time. The primary efficacy endpoint included ORR, PFS and survival. Results: 23 pts were included, 19 males and 4 females, median age 63(48-80). Pathological type:16 adenocarcinoma, 5 squamous cell carcinoma and 1 other. 7 Ⅲb and 16 Ⅳ stage. ORR was 17.39%(4/23), DCR was 60.87%(14/23). Median PFS was 10.9 months, median follow-up in surviving patients was 22.3 months, 1-year survival is currently 92.86%, 18-months survival is currently 79.59%. 1 case was diagnosed as acute myelogenous leukemia myelodysplastic syndrome after 9 doses of DCVAC/LuCa. There were no other adverse events related to DCVAC/LuCa treatment TCM therapies in this study. Conclusions: DCVAC/LuCa, combined with standard chemotherapy and TCM had exhibited the potential to improve the survival in patients with advanced NSCLC, and decrease the occurrence of adverse events. But the sample size of this study is small, a further clinical investigation is needed.
Validation of the fully automated idylla system for microsatellite instability detection in Chinese colorectal cancer patients.
Authors: Qian Wang, Jing Zhang, Chengli Yu, Longlong Bao, Xu Cai, Wenhua Jiang, Dan Huang, Xiaoli Zhu, Qianming Bai, Xiaoyan Zhou
Journal: Journal of Clinical Oncology (2020)

e13644 Background: Mismatch repair (MMR)/microsatellite instability (MSI) testing is recommended by NCCN Guidelines to screen for Lynch Syndrome as well as to predict response to immune checkpoint inhibitors in solid tumors. Conventional methods for MSI detection, immunohistochemistry (IHC) and polymerase chain reaction (PCR), often require non-tumor controls as well as a long turnaround time. The Idylla system, in contrast, is a fully automated quantitative PCR unit with a turnaround time of 2.5 hours. Neither does it require normal tissue or special training to operate. The Idylla MSI Test has been CE-marked for its reliability among Caucasian colorectal cancer (CRC) patients, but has never been validated in Chinese CRC population. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue samples were collected from 87 CRC patients and were subjected to MMR/MSI detection using IHC, PCR and the Idylla test separately. The Idylla MSI Test incorporates 7 novel MSI loci, ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A, and SULF2. The sensitivity and specificity of the Idylla system were evaluated in comparison with PCR and IHC. Results: Of the 87 patients enrolled, both IHC and PCR identified 55 to be MMR-deficient (dMMR)/MSI-high (MSI-H), of which 4 were MSS using Idylla, and 32 to be MMR-proficient (pMMR)/microsatellite stable (MSS) where Idylla classified one as MSI-H, yielding a sensitivity of 92.7%, a specificity of 96.9% and an overall concordance of 94.3%. Re-examination of the 5 discordant cases (4 false negatives and 1 false positive) using DNA extractions instead of tissue slices on the Idylla platform displayed 100% consistency with IHC/PCR. Confirmation on the Idylla system using recut sections corrected 3 false negatives and 1 false positive, with all tumor contents of ≥20%, 1 Idylla-defined MSS sample with 5% tumor content remained discordant even after sample enrichment. Conclusions: The Idylla system provides a fast, reliable, and user-friendly solution to MSI detection in Chinese CRC patients with high sensitivity and specificity. Upfront assessment of tissue sample quality ( i.e. tumor area and tumor cell fraction) is critical for the accuracy of this test. The reproducibility of the assay warrants further investigation.
Ramipril in High-Risk Patients With COVID-19
Authors: Ignacio J. Amat-Santos, Sandra Santos-Martinez, Diego López-Otero, Luis Nombela-Franco, Enrique Gutiérrez-Ibanes, Raquel Del Valle, Erika Muñoz-García, Víctor A. Jiménez-Diaz, Ander Regueiro, Rocío González-Ferreiro, Tomás Benito, Xoan Carlos Sanmartin-Pena, Pablo Catalá, Tania Rodríguez-Gabella, Jose Raúl Delgado-Arana, Manuel Carrasco-Moraleja, Borja Ibañez, J. Alberto San Román
Journal: Journal of the American College of Cardiology (2020)
A phase Ib trial of the cyclin-dependent kinase inhibitor dinaciclib (dina) in combination with pembrolizumab (P) in patients with advanced triple-negative breast cancer (TNBC) and response correlation with MYC-overexpression.
Authors: Amy Jo Chien, Amelia S Gliwa, Siti Rahmaputri, Heidi F Dittrich, Melanie Catherine Majure, Hope S. Rugo, Michelle E. Melisko, Pamela N. Munster, John W. Park, Mark M. Moasser, Mehrdad Matloubian, Tasha Lea, Julia Rohrberg, Gregor Krings, Andrei Goga
Journal: Journal of Clinical Oncology (2020)

1076 Background: Increased expression of the MYC transcriptional oncogene is found in about 70% of TNBC and is associated with poor prognosis. In MYC-overexpressing TN xenografts, CDK1 inhibition with dina results in synthetic lethality, and attenuates distant metastasis. In syngeneic models, the combination of dina with anti-PD1 therapy is synergistic and increases immune cell tumor infiltration and activation. Methods: Patients (pts) with advanced TNBC received dina IV day 1 and 8 in combination with fixed dose P 200 mg once every 21 days. Dina was dose escalated using a toxicity probability interval design targeting a dose limiting toxicity (DLT) rate of 25%. Evaluable disease and pre-treatment metastatic biopsies were required. After 17 pts were enrolled, eligibility was amended to require ≤2 lines of prior chemotherapy, and LDH ≤1.5x normal. MYC IHC was performed on baseline tumor biopsies and correlated with clinical response using Welch’s unequal variances t-test. Results: 32 pts were enrolled (median age 53, median 2 prior lines of therapy, 13 pts (41%) had disease which was previously ER+). 18 pts were enrolled in the dose escalation phase with no observed DLTs; 33 mg/m2 was determined to be the recommended phase 2 dose (RP2D). 14 additional patients were enrolled in dose expansion at 33 mg/m2, completing trial accrual. Grade ≥3 adverse events (AEs) in all pts included neutropenia (ntp) (37.5%), febrile ntp (12.5%), fatigue (12.5%), transaminitis (3.2%), and neuromuscular weakness (3.2%). Most common all grade AEs included fatigue (63%), diarrhea (63%), nausea (63%), and ntp (53%). Possible immune-related AEs included sinusitis (4 pts), hemolytic anemia (1 pt), pneumonitis (1 pt), rash (2 pts), neuromuscular weakness (1 pt), and transaminitis (1 pt). Of the 29 patients evaluable for response, 1 pt (3.4%) had a CR, 4 pts (13.8%) had a PR, and 6 pts (20.6%) had SD. MYC IHC staining on baseline metastatic tumor biopsies in 19 pts correlated significantly with clinical response. Additional biomarker testing will be reported. Conclusions: The RP2D of dina given in combination with standard dose P is 33 mg/m2 on D1, 8 of a 21-day cycle. Toxicities were generally manageable and non-overlapping. In exploratory analysis, greater MYC IHC staining correlated significantly with response to study therapy. Clinical trial information: NCT01676753 .
Phase II trial of the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886 Hydrogen Sulfate) in adults with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN).
Authors: Geraldine Helen O'Sullivan Coyne, Andrea M. Gross, Eva Dombi, Cecilia Tibery, Amanda Carbonell, Naoko Takebe, Joanne Derdak, Dominique Pichard, Apurva K. Srivastava, William Herrick, Ralph E. Parchment, Staci Martin, Pamela Wolters, Patricia Whitcomb, Lawrence Rubinstein, James H. Doroshow, Alice P. Chen, Brigitte C. Widemann
Journal: Journal of Clinical Oncology (2020)

3612 Background: NF1-related PN are locally invasive tumors characterized by increased activation of the RAS pathway causing significant morbidity including disfigurement, pain and functional limitations. Selumetinib has received breakthrough designation for NF1 PN based on phase I / II trials in children. We present results for the ongoing phase II study of selumetinib in adults with NF1 PN, which includes pharmacodynamic (PD) evaluation of serial tumor biopsies as well as functional/patient-reported outcomes (PROs). Methods: Open-label Simon 2-stage design. Eligibility: NF1 patients (pts) ≥18 years old with inoperable/symptomatic/progressive PN. First 2 pts received selumetinib 75 mg BID; subsequent pts received selumetinib 50 mg BID. Primary objective: response rate by volumetric MRI analysis (partial response [PR]; ≥20% volume decrease). Secondary objectives: PD studies on pre/on-treatment biopsies of PN and cutaneous neurofibromas, assessment of clinical benefit using PROs (Numeric Rating Scale-11, Pain Interference Index), and PN-specific functional assessments. Validated, fit-for-purpose, isozyme-specific measurements of pERK/ERK/pMEK/MEK performed using SOPs designed for labile phosphoproteins (PMID 27001313). Results: As of February 2020, 27 pts have enrolled. Outcomes are reported for 23 pts (74% male; median age 33 years, range 18-60). Most common PN-related morbidity: pain (19 pts). Sixteen pts achieved PR (69%), with 13/16 confirmed; no disease progression. Time to response: 11 months (range 5-25); median change in PN volume at best response: -22% (range -41% to +5.5%); median duration of treatment: 28 months (range 2-50). Selumetinib suppressed tumor pERK1,2/ERK1,2 but not pMEK1,2/MEK1,2 ratios from 1-10 hours following oral dosing (one t ½ ). Pt-reported target tumor pain intensity and pain interference scores significantly improved (both p &lt; 0.03). Pts 1 and 2 were dose-reduced due to grade 3 intolerable rash (n = 2) and pain (n = 1). Grade ≥3 drug-related toxicities on 50 mg (21 pts) include transaminitis (5 pts), rash (1 pt) and pancreatic enzyme elevation (1 pt). Two pts were dose reduced (rash = 1 pt, transaminitis = 1 pt). Two pts discontinued by choice, 2 pts withdrawn by PI (best interest of patient), and 1 pt each removed for transaminitis, surgical resection, serious concurrent medical illness, and non-compliance. Conclusions: Selumetinib shrinks the majority of adult PN and results in molecular target suppression and clinical benefit. Clinical trial information: NCT02407405 .