tbuckley/cabot-search huggingface dataset:
Immunopharmacology
Authors: John W. Hadden
Journal: JAMA (1992)

IMMUNOPHARMACOLOGY involves the study of the regulation of the immune system by pharmacological agents and the development of methods to selectively modify immune function to treat human disease. The delineation of the cellular immune system and the mechanisms of allograft reaction discovered in the early 1960s brought immunosuppression for transplantation and for selected use in autoimmune disease. In the last 15 years, the demonstration of the prevalence of cellular immune defects in cancer, aging, autoimmunity, and infectious diseases has generated interest in the development of immunotherapeutic agents. This chapter provides a brief introduction to immunosuppression and immunotoxicology with emphasis on recent developments in preclinical immunopharmacology and experimental immunotherapeutics. <h3>IMMUNOSUPPRESSIVE THERAPY</h3> A variety of immunosuppressive agents and procedures have been found to be useful in the treatment of autoimmune disease<sup>1</sup>as well as organ transplantation<sup>2</sup>(Table 24-1). These agents are extensively used in cancer therapy primarily because of their
Chyme Reinfusion Restores the Regulatory Bile Salt–FGF19 Axis in Patients With Intestinal Failure
Authors: Kiran V.K. Koelfat, Denis Picot, Xinwei Chang, Mireille Desille‐Dugast, Hans M. van Eijk, Sander M.J. van Kuijk, Martin Lenicek, Sabrina Layec, Marie Carsin, Laurence Dussaulx, Eloi Seynhaeve, Florence Trivin, Laurence Lacaze, Ronan Thibault, Frank G. Schaap, Steven W.M. Olde Damink
Journal: Hepatology (2021)

Background and Aims Automated chyme reinfusion (CR) in patients with intestinal failure (IF) and a temporary double enterostomy (TDE) restores intestinal function and protects against liver injury, but the mechanisms are incompletely understood. The aim was to investigate whether the beneficial effects of CR relate to functional recovery of enterohepatic signaling through the bile salt–FGF19 axis. Approach and Results Blood samples were collected from 12 patients, 3 days before, at start, and 1, 3, 5, and 7 weeks after CR initiation. Plasma FGF19, total bile salts (TBS), 7‐α‐hydroxy‐4‐cholesten‐3‐one (C4; a marker of bile salt synthesis), citrulline (CIT), bile salt composition, liver tests, and nutritional risk indices were determined. Paired small bowel biopsies prior to CR and after 21 days were taken, and genes related to bile salt homeostasis and enterocyte function were assessed. CR induced an increase in plasma FGF19 and decreased C4 levels, indicating restored regulation of bile salt synthesis through endocrine FGF19 action. TBS remained unaltered during CR. Intestinal farnesoid X receptor was up‐regulated after 21 days of CR. Secondary and deconjugated bile salt fractions were increased after CR, reflecting restored microbial metabolism of host bile salts. Furthermore, CIT and albumin levels gradually rose after CR, while abnormal serum liver tests normalized after CR, indicating restored intestinal function, improved nutritional status, and amelioration of liver injury. CR increased gene transcripts related to enterocyte number, carbohydrate handling, and bile salt homeostasis. Finally, the reciprocal FGF19/C4 response after 7 days predicted the plasma CIT time course. Conclusions CR in patients with IF‐TDE restored bile salt–FGF19 signaling and improved gut–liver function. Beneficial effects of CR are partly mediated by recovery of the bile salt–FGF19 axis and subsequent homeostatic regulation of bile salt synthesis.
The equivalency study of novel current standard 3-drugs combination regimen (ondansetron, dexamethasone and olanzapine) to netupitant containing regimen for preventing high dose cisplatin induce nausea and vomiting treatment, double blind placebo control trial.
Authors: Chalermchai Lertanansit, Wasamol Mahaparn, Virote Sriuranpong, Piyada Sitthideatphaiboon, Nattaya Sintawichai, Suebpong Tanasanvimon, Chanida Vinayanuwattikun
Journal: Journal of Clinical Oncology (2021)

12100 Background: Prevention of chemotherapy-induced nausea and vomiting (CINV) is vital in cancer treatment. Here, we compared the efficacy of netupitant-containing regimen; composed of NEPA, dexamethasone, and olanzapine (NEPAs), which is recommended for preventing CINV from high-emetogenic chemotherapy (HEC) to standard 3-drugs; ondansetron, dexamethasone, olanzapine for preventing CINV from high-dose cisplatin (≥75 mg/m 2 ). Methods: This randomized, double-blind, placebo-control trial randomly assigned untreated patients who were received high-dose cisplatin in a 1:1 ratio to either NEPAs or standard 3-drugs combination regimen. Dose of dexamethasone in NEPAs regimen was modified after preplanned interim safety analysis to increase from 4 to 8 mg per day on days 2-4. The stratification factors were concurrent treatment with radiation and sex. The primary endpoint was the overall complete response (CR) rate defined as no vomiting and no use of rescue antiemetic drugs. The protocol allowed crossover to NEPAs for those who received standard 3-drugs and did not reach CR in the first cycle. We collected outcome in the first 2-cycle of treatment. Results: Between January 2019 and December 2020, hundred patients were randomly assigned to either NEPAs (n = 51) or in-house standard 3-drugs (n = 49). Demographic characteristics were well-balanced in both arms. Total events in both arms were 101 events for NEPAs and 78 events for standard 3-drug. Overall CR rate were 70% and 69% in NEPAs and standard 3-drugs, ( p-value 0.87) respectively. According to emesis phase, CR in acute (0- 24 hrs.) and delay phase (24-120 hrs.) were not different in both arms; 91% vs. 89% and 72% vs. 71% in NEPAs and standard 3-drugs respectively. However, mean nausea VAS score was significantly lower in NEPAs (1.63 vs. 2.02, p-value = 0.001). The ad hoc subgroup analysis shown similar efficacy between before and after protocol amendment of NEPAs regimen in term of delay emesis CR rate; 70.9% vs. 73.9% ( p-value 0.73). Conclusions: The NEPA-containing regimen did not show superiority compare to standard 3-drug in terms of complete response rate for CINV prevention among patients receiving high-dose cisplatin. Furthermore, the dexamethasone dosage of 4 vs. 8 mg per day might not affect the efficacy of delay emesis of the NEPAs regimen. Clinical trial information: TCTR20190508001. [Table: see text]
Methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) versus gemcitabine, and cisplatin (GC) as neoadjuvant chemotherapy in muscle-invasive bladder cancer, a systematic review and meta-analysis.
Authors: Raed Benkhadra, Tarek Nayfeh, Naga Sai Krishna Patibandla, Chelsea Peterson, Larry Prokop, Omar Alhalabi, M. Hassan Murad, Shifeng Mao
Journal: Journal of Clinical Oncology (2021)

e16522 Background: Cisplatin-based neoadjuvant chemotherapy is the standard of care for muscle invasive bladder cancer (MIBC) in cisplatin-eligible patients. This systematic review and meta-analysis provide an updated efficacy and safety comparison between the two most commonly used cisplatin-based regimens; dose-dense (dd) or conventional MVAC versus GC. Methods: We searched different databases for studies comparing MVAC versus GC in the neoadjuvant setting. Outcomes of interest included overall survival, downstaging to pT≤1, pathologic complete response (pCR), recurrence, and toxicity. Meta-analysis was conducted using the random-effects model. Results: We identified 24 studies from inception to March 2020; among them 17 were peer reviewed and 7 were only reported as abstracts in national or international meetings, including a phase 3, randomized-controlled clinical trial. Among peer-reviewed published studies, efficacy outcomes such as OS, downstaging and pCR were comparable between conventional MVAC and GC for MIBC. If including non-peer-reviewed studies, dd-MVAC was associated with favorable efficacy compared to GC in terms of downstaging (OR 1.45; 95% CI 1.15–1.82), and OS at longest follow-up (OR 0.63; 95% CI 0.44–0.81). However, GC was associated with a better safety profile in terms of febrile neutropenia (OR 0.32; 95% CI 0.13–0.80), anemia (OR 0.32; 95% CI 0.18–0.54), nausea and vomiting (OR 0.27; 95% CI 0.12–0.65) compared to dd-MVAC. Compared to MVAC, patients receiving GC had an increased risk of developing grade 3–4 thrombocytopenia (OR 4.70; 95% CI 1.59–13.89) and a lower risk of nausea and vomiting (OR 0.05; 95% CI 0.01-0.31). Certainty in the estimates was very low for most outcomes. Conclusions: Among peer-reviewed published studies, efficacy and safety outcomes were comparable between conventional MVAC and GC for MIBC. However, If including non-peer-reviewed studies, this analysis showed higher efficacy with dd-MVAC. A phase III randomized trial comparing the two regimens is needed to guide clinical practice
<i>BRAF</i><sup>V600E</sup> frequency and impact on outcomes in adults with langerhans cell histiocytosis.
Authors: Aldo A. Acosta-Medina, Jithma P. Abeykoon, N. Nora Bennani, Caroline Davidge-Pitts, Matthew J. Koster, Aishwarya Ravindran, Karen Rech, Jay H. Ryu, Susan M. Schram, Mithun Vinod Shah, W. Oliver Tobin, Robert Vassallo, Jason R. Young, Ronald S. Go, Gaurav Goyal
Journal: Journal of Clinical Oncology (2021)

7050 Background: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm manifesting as unifocal, multifocal, multisystem (MS) or pulmonary LCH (smoking-related). In pediatric LCH, somatic BRAF V600E prevalence is reported at 55-70%, and associated with increased risk of multisystem disease and early treatment failure. Our aim was to describe the prevalence of BRAF V600E mutation and evaluate its association with clinical manifestations and outcomes in adults with LCH. Methods: A retrospective review of adult patients diagnosed with LCH consecutively seen at Mayo Clinic from 2011 to 2020 was performed.Evaluation of association of BRAF V600E mutational status and clinical factors was conducted by the Chi-square test for independence. Progression-free survival (PFS) and overall survival (OS) were analyzed via the Kaplan Meier method and compared with the log-rank test to assess the effect of BRAF V600E . Results: Of the total LCH cohort ( n= 128), 88 patients with available BRAF V600E results were included in the study. Median age at diagnosis was 41y (range 19 - 88); 52.3% were male. 40 (45.5%) patients had a BRAF V600E mutation. Increasing age was associated with BRAF V600E (10-year increase OR 1.42, 95%CI 1.07-1.89; p= 0.017). No correlation was observed between BRAF V600E status and site of disease, risk organ (RO: liver, spleen, marrow) involvement, or MS disease. Patients with BRAF V600E were 4 times more likely to receive targeted therapy ( BRAF inhibitor) than non- BRAF V600E patients ( p= 0.018). After a median follow up of 46 mo (95% CI 30.8-61.2), PFS was similar between BRAF V600E and non- BRAF V600E patients ( p= 0.167). However, patients with BRAF V600E had a worse 3-year OS compared with non- BRAF V600E patients (84% vs. 97.1%, p= 0.027). Patients who died had a significantly higher age at LCH diagnosis (median 62 vs. 38 years; p= 0.0002). Conclusions: In our cohort of adults with LCH, BRAF V600E was less frequent than reported in pediatric literature and was associated with worse OS. The frequency of BRAF V600E was positively correlated with increasing age. Contrary to reports in pediatric LCH, there were no significant associations between BRAF V600E and high-risk or multisystem disease.[Table: see text]
ATRT-04. CORRELATION OF CLINICOPATHOLOGIC FEATURES AND CUMULATIVE INCIDENCE OF RELAPSE FOR PATIENTS WITH ATYPICAL TERATOID RHABDOID TUMOR ON ACNS0333: A REPORT FROM THE CHILDREN’S ONCOLOGY GROUP
Authors: Alyssa Reddy, Jaclyn Biegel, Annie Huang, Douglas Strother, Alexander Judkins, Ian Pollack, Allen Buxton, Anita Mahajan, Ben Ho, Claire Mazewski, Victor Lewis, Maryam Fouladi, Mark Krailo
Journal: Neuro-Oncology (2021)

Abstract Purpose Intensive multi-modal regimens have improved survival for patients with atypical teratoid rhabdoid tumor, however relapse rates remain high. A better understanding of clinical and pathologic features associated with tumor relapse is critical to risk-stratifying patients. Patients and Methods ACNS0333 treatment consisted of multi-agent chemotherapy, high-dose chemotherapy, and radiation therapy, lasting approximately 6 months. Variables including patient age, sex, tumor location, M-stage, degree of resection, order of therapy, germline status, and molecular subgroup were analyzed. Cumulative incidence (CI) of event free survival due to relapse was evaluated for each variable. Results Thirty-three of 65 evaluable patients had tumor relapse. For the entire cohort, the CI of relapse was 21.8% at 6 months, 40.6% at one year and 50.3% at 4 years. For patients with infratentorial tumors, CI of relapse was 26.3%, 34.2% and 37.2%, at 6 months, 1 and 4 years respectfully compared to 15.3%, 49.9%, and 69.7% for those with supratentorial tumors (p 0.051). Patients with SHH subtype had no relapses in the first 6 months and CI of relapse of 37.5% at 4 years, while those with TYR and MYC subgroups had CI of relapse of 33.3% and 26.7% at 6 months and 46.3% and 73.3% at 4 years respectfully (p 0.088). Patients with germline mutations had a cumulative incidence of relapse of 20% at 6 months and 60% at 12 months compared to 22.6% and 37.7% respectfully for those without. No obvious trends were noted based on other analyzed variables. Conclusions ACNS0333 was not powered to determine prognostic indicators of relapse, however, this data suggest interesting trends based on tumor location, subtype and germline status. Infratentorial location and SHH subtype maybe associated with lower risk of relapse. Larger data sets must be compiled to further investigate these variables, perform multivariate analyses and inform risk-stratification on future trials.
The association between real-world CA19-9 level monitoring patterns and with clinical outcomes among patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) in the second- and third-line of therapy.
Authors: Ben George, Aleksander Chudnovsky, Paul Cockrum, Neil Lamarre, Matthew Kent, Andy Surinach
Journal: Journal of Clinical Oncology (2021)

e16251 Background: Pancreatic cancer has an aggressive disease course, mandating close clinical monitoring while on treatment. Evaluation of treatment response in patients with mPDAC necessitates scheduled clinical and radiographic assessments along with monitoring serum CA 19-9 levels. We investigated the impact of serum CA 19-9 monitoring and its association with clinical outcomes in patients with mPDAC who received second- (2L) and third line (3L) in a population-based setting. Methods: Data were extracted from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database for patients diagnosed with mPDAC and subsequently treated in the 2L or 3L setting between January 1, 2014 and June 30, 2020. Serum CA 19-9 levels at baseline were extracted – defined as the values obtained ≤ 60 days of treatment initiation and during treatment. CA 19-9 levels &gt; 40 IU/mL were considered elevated. Survival analysis was performed using Kaplan-Meier methods. Categorical measures were compared with a chi-square test and survival outcomes with a log-rank test. Results: There were 2,402 patients who received 2L and 790 patients who received 3L treatment included in the study. Among the 2L cohort, median age at treatment initiation was 67 years (IQR: 60 – 73), 54% were male, 57% had an ECOG score of 0-1, and 82% had a baseline serum CA 19-9 level available. Among the 3L cohort, median age at treatment initiation was 67 years (IQR: 60 – 73), 53% were male, 58% had an ECOG score of 0-1, and 84% had a baseline CA 19-9 level available. Most patients in the 2L and 3L cohorts had an elevated CA 19-9 at baseline, 85.2% and 82.0%, respectively. Among the 2L and 3L cohorts, 38.5% and 31.9% had CA 19-9 levels decrease/remain stable during treatment and 27.6% and 31.4% had levels increase during treatment, respectively. Patients with normal baseline CA 19-9 experienced longer survival than patients with elevated levels [2L: 7.2 months (95% CI: 6.1 – 9.2) vs 5.2 months (4.9 – 5.6), p &lt; 0.001; 3L: 6.1 months (5.4 – 9.1) vs 3.9 months (3.4 – 4.3), p &lt; 0.001]. Similarly, patients with decreasing/stable CA 19-9 during treatment had longer survival than patients who had their CA 19-9 levels increase [2L: 8.2 months (7.7 – 8.5) vs 4.3 months (4.1 – 4.7), p &lt; 0.001; 3L: 7.5 months (6.6 – 9.2) vs 3.7 months (3.4 – 4.3), p &lt; 0.001]. Conclusions: In this large, contemporary, real-world study of patients with mPDAC, CA 19-9 levels at treatment initiation had a prognostic value across later lines of therapy. Routine serial monitoring of CA 19-9 levels during treatment, in addition to clinical and radiographic assessment, may help with timely additional diagnostic testing and treatment intervention. Further validation studies are needed to understand the generalizability of these results.
A Neoadjuvant Chemotherapy Trial for Early Breast Cancer is Impacted by COVID-19: Addressing Vaccination and Cancer Trials Through Education, Equity, and Outcomes
Authors: David A. Potter, Alexandra Thomas, Hope S. Rugo
Journal: Clinical Cancer Research (2021)

Abstract While COVID-19 vaccine distribution has addressed vulnerabilities related to age and comorbidities, there is a need to ensure vaccination of patients with cancer receiving experimental and routine treatment, where interruption of treatment by infection is likely to result in inferior outcomes. Among patients with cancer, those undergoing neoadjuvant chemotherapy (NAC) or adjuvant chemotherapy (Adj chemo) for early breast cancer (EBC) are at particularly high risk for inferior outcomes, in part, because optimal timing of chemotherapy is essential for promoting distant disease-free survival. COVID-19 data from the ongoing multicenter I-SPY 2 trial of NAC for EBC provides a window into the magnitude of the problem of treatment interruption, not only for the trial itself but also for routine Adj chemo. In the I-SPY 2 trial, 4.5% of patients had disruption of therapy by COVID-19, prior to wide vaccine availability, suggesting that nationally up to 5,700 patients with EBC were at risk for adverse outcomes from COVID-19 infection in 2020. To address this problem, vaccine education and public engagement are essential to overcome hesitancy, while equity of distribution is needed to address access. To accomplish these goals, healthcare organizations (HCO) need to not only call out disinformation but also engage the public with vaccine education and find common ground for vaccine acceptance, while partnering with state/local governments to improve efficiency of vaccine distribution. These approaches are important to improve trial access and to reduce susceptibility to COVID-19, as the pandemic could continue to impact access to clinical trials and routine cancer treatment.
Two-year follow-up of single PD-1 blockade in neoadjuvant resectable NSCLC.
Authors: Shugeng Gao, Ning Li, Shunyu Gao, Qi Xue, Shuhang Wang, Fang Lv, Liang Zhao, Fan Zhang, Ziran Zhao, Kai Su, Fengwei Tan, Yun Ling, Zhijie Wang, Wei Tang, Jianming Ying, Ning Wu, Jie Wang, Jie He
Journal: Journal of Clinical Oncology (2021)

8522 Background: Early stage non-small-cell lung cancer (NSCLC) could benefit from anti-programmed cell death-1 (PD-1) monotherapy; however, the survival profiles remain to be disclosed. Here, we presented the two-year follow-up outcomes from a phase 1b study of sintilimab, an anti-PD-1 inhibitor in the neoadjuvant setting of NSCLC. Methods: Treatment-naive pts with resectable NSCLC (stage IA–IIIB) received two cycles of sintilimab followed by surgical resection. Postoperative treatment of sintilimab was at the discretion of investigator. The primary endpoint was AE, and key secondary endpoints included major pathological response (MPR), disease free survival (DFS) rate of 1 year and 2 years, and overall survival (OS) rate of 2 years. Results: Among 40 enrolled pts, 36 (90%) underwent R0 resection and were included in the R0 resection population. By data cutoff (January 20, 2021), the median follow-up for DFS and OS for all the enrolled pts was 23.9 (IQR 20.5–24.4) months and 26.4 (IQR 24.2–29.0) months. A total of 12 (33.3%) pts experienced relapse, and 6 pts died. The 1-yr and 2-yr DFS rate was 91.7%/73.3%. The 2-yr OS rate for overall population and R0 population was 87.5%/91.7%, respectively. In the R0 resection population, the median DFS and OS were both not reached. Superior 2-year DFS rates were observed in pts who achieved MPR (MPR vs. Non-MPR: 86.7% vs. 63.8%). DFS of pts with non-squamous cell carcinoma tended to be shorter than that of pts with squamous cell carcinoma (HR 2.71 [95%CI 0.67–11.0], p=0.1479). Pts with tumor mutation burden (TMB) ≥10 mutations/Mb and PD-L1 tumor proportion score (TPS)≥50% tended to have a better 2-yr DFS rate compared to those with TMB&lt;10 and TPS&lt;50. [table] For the post-hoc event free survival (EFS) analysis, the same trend was observed with DFS among different subgroups, and patients with TMB ≥10 mutations/Mb had a significant improved EFS (HR 0.125[95% CI 0.02,1.03], P=0.0222). Conclusions: Anti-PD-1 monotherapy emerged to be a promising neoadjuvant therapeutic strategy for resectable NSCLC with improved clinical outcomes. MPR could serve as a surrogate efficacy biomarker in this setting. Clinical trial information: ChiCTR-OIC-17013726. [Table: see text]
Clinical and morphological characteristics or immunohostochemical factors determine the results of treatment for diffuse large B-cell lymphoma?
Authors: Luiza B. Kushtova, Elena M. Frantsiyants, Valeria A. Bandovkina, Nadezhda V. Nikolaeva, Elena A. Kapuza, Yuliya Yu. Kozel, Olga V. Kozyuk, Viktoria V. Dmitrieva
Journal: Journal of Clinical Oncology (2021)

e19539 Background: Diffuse large B-cell lymphoma (DLBCL) is and aggressive heterogeneous tumor. The treatment is ineffective in more than 30% cases: primary resistance is observed in 20%, and relapses in 10%. Clinical prognostic indices do not allow assessing the DLBCL course and treatment outcomes. The purpose of the study was to evaluate the results of treatment of DLBCL patients depending on clinical and immunohistochemical factors of the disease prognosis. Methods: Patients with DLBCL (n = 48): men – 25 (52.1%, mean age 52±3.8 years), women – 23 (47.9%, mean age 60±4.3 years) received standard treatment R-CHOP, R-CHOEP, R-EPOCH. Results: After the treatment, 27 (56.2%) patients were in remission for 3 years, 10 (20.8%) patients developed relapses, and 11 (23%) patients were refractory to the therapy. All groups demonstrated Ki-67 &gt; 80%, overexpression of Bcl2, Bcl6, CD10, MUM-1 on tumor cells, C-MYC gene rearrangements. Patients with stage I and II nodal spread were more likely to be in remission; refractory patients and those with early relapses had stages III and IV. Relapses were detected at different periods after treatment: early relapses (n = 5) within 6 months and late relapses (n = 5) after 12 months or later. Among patients with early relapses, 2 (40%) had extranodal disease and 3 (60%) nodal disease; high/medium IPI was noted in 3 patients, low/medium and low IPI – 1 patient each. Among patients with late relapses, 3 patients had nodal disease and 2 – primary extranodal disease; high/medium IPI was noted in 2 patients, low/medium – in 3 patients. Among recurrent patients, 9 had non-germ cell DLBCL and 1 - germ cell DLBCL. Among refractory patients, 8 (73%) had nodal disease and 3 (27%) - extranodal disease; low/medium IPI was registered in 4 patients, high/medium IPI in 2, low IPI in 5 patients; germ cell tumors in 2 patients, non-germ cell tumors in 9 patients. Conclusions: 33% of DLBCL patients did not benefit from the treatment. Molecular markers such as Ki-67, Bcl2, Bcl6 and CD10 were not prognostically significant. The tumor type had a prognostic value only in the group of patients with relapses - non-germ cell tumors were found in 90% of cases.