tbuckley/cabot-search huggingface dataset:
Neoadjuvant talazoparib in patients with germline<i> BRCA1/2</i> (g<i>BRCA1/2</i>) mutation-positive, early HER2-negative breast cancer (BC): Results of a phase 2 study.
Authors: Jennifer Keating Litton, Joseph Thaddeus Beck, Jason M. Jones, Jay Andersen, Joanne Lorraine Blum, Lida A. Mina, Raymond Brig, Michael A. Danso, Yuan Yuan, Antonello Abbattista, Kay Noonan, Jayeta Chakrabarti, Akos Czibere, William Fraser Symmans, Melinda L. Telli
Journal: Journal of Clinical Oncology (2021)

505 Background: Talazoparib (TALA) is a poly(ADP-ribose) polymerase inhibitor approved as monotherapy for treating adult patients (pts) with g BRCA1/2-mutated HER2-negative locally advanced or metastatic BC. Methods: This phase 2, non-randomized, single-arm, open-label study (NCT03499353) evaluated the efficacy and safety of TALA in the neoadjuvant setting for pts with early g BRCA1/2-mutated HER2− BC. Primary endpoint was evaluation of pathologic complete response (pCR) as assessed by Independent Central Review (ICR) after completing 24 weeks of neoadjuvant TALA monotherapy 1 mg QD (0.75 mg for moderate renal impairment) followed by surgery. Secondary endpoints included pCR by investigator (INV) and residual cancer burden (RCB) by ICR (RCB: 0 [pCR], I [minimal], II [moderate], III [extensive]). The evaluable population included pts who received at least 80% of the TALA dose prescribed at treatment start and underwent breast surgery and pCR assessment, plus those who progressed before pCR could be assessed. The intent-to-treat (ITT) population included all pts who received at least 1 dose of TALA. Results: Of 61 pts treated with TALA (ITT and safety populations), 48 comprised the evaluable population. All pts had triple-negative BC. 60 pts had adenocarcinoma and 1 had squamous cell histology, with the following staging: I=20, II=27, III=14. Mean age was 44.6 years, mean duration of 4.5 wks since disease onset, mean duration of treatment of 23.3 wks, and mean overall relative dose intensity of 84.5% (ITT population). pCR (assessed by ICR and INV) and RCB (by ICR) for the evaluable and ITT populations are shown in the table below. Ten (16.4%) patients discontinued treatment due to progressive disease. One pt had a disruption of treatment as a result of COVID-19 restrictions, 2 pts for other reasons: to undergo surgery early and consent withdrawal; 9 patients received &lt;80% dose. Treatment-emergent adverse events (AEs) were reported in 98.4% of pts (27.9% grade [G] 1, 23.0% G2, 45.9% G3, 1.6% G4); the most common were fatigue (78.7%; G1 54.1%; G2 21.3%; G3 3.3%), nausea (68.9%; G1 54.1%; G2 13.1%; G3 1.6%), and alopecia (57.4%; G1 54.1%; G2 3.3%). Three (4.9%) pts discontinued treatment due to AEs (G3 anemia [n=2] and G3 vertigo [n=1]) and continued on study. Conclusions: TALA monotherapy in the neoadjuvant setting was active and showed pCR rates comparable to those observed with combination anthracycline and taxane-based chemotherapy regimens and was generally well tolerated. Clinical trial information: NCT03499353. [Table: see text]
Neoadjuvant intraarterial cytoreductive chemotherapy for lacrimal gland adenoid cystic carcinoma: A 33-year single-institution experience.
Authors: Philippos Apolinario Costa, Daniel Pelaez, David Tse, Pasquale W. Benedetto
Journal: Journal of Clinical Oncology (2021)

e18051 Background: Lacrimal gland adenoid cystic carcinoma (LGACC) has historically been associated with a poor prognosis even in localized disease, with the survival of 56% at 5 years and 49% at 10 years. In 1988, our group treated the first patient with neoadjuvant intra-arterial chemotherapy (IACC) followed by adjuvant chemoradiation. Since then, we use this protocol as the standard approach for localized LGACC. Herein, we aim to analyze the clinical characteristics and outcomes of LGACC patients at a single academic institution treated with the protocol to provide information on this approach's efficacy. Methods: We prospectively assessed all patients with pathologically confirmed LGACC treated at Bascom Palmer, Sylvester Comprehensive Cancer Center, or Jackson Memorial Hospital between 1988 and 2021. We calculated overall survival (OS) using the Kaplan-Meier and Cox proportional-hazards modeling methods with Log-Rank Test to estimate the 95% confidence interval. Results: 42 LGACC patients were identified, and 37 (88%) underwent IACC, with 2 (5%) being metastatic at the time of the protocol. In our cohort, the median follow-up was 10 years, 21 (56%) were men, and the median age at diagnosis was 42 (range 20-72). The average tumor size was 3cm (range 0.8-7.6). The dominant histological pattern was cribriform (n = 23, 54%), followed by basaloid (n = 6, 14%) and solid (n = 6, 14%). 16 patients underwent whole genome sequencing, and the most common mutations found were NOTCH1 (n = 7, 41%), ATM (n = 4, 25%), BPTF (n = 4, 25%), FGFR 2 (n = 3, 18%), Frem3 (n = 3, 18%), and NOTCH2 (n = 3, 18%), with additional biomarker data forthcoming. The 5, and 10-year survival rates were 85% (95% CI 73–97) and 71% (95% CI 53-89), respectively, giving and overall mean survival of 23 years (95% CI 19–28). The risk of death was higher with a tumor size larger than 3 cm and with bone invasion (HR: 6.5 and 7.5 respectively; P &lt; 0.05). Conclusions: Despite the historically described poor prognosis, patients with LGACC treated with IACC have an excellent prognosis. Future research on tumor molecular characteristics might identify susceptibility to targeted therapies such as NOTCH or FGFR inhibitors that could be incorporated into the IACC protocol, further extending its benefits.
Calprotectin: from biomarker to biological function
Authors: Almina Jukic, Latifa Bakiri, Erwin F. Wagner, Herbert Tilg, Timon E. Adolph
Journal: Gut (2021)

The incidence of inflammatory bowel diseases (IBD) emerged with Westernisation of dietary habits worldwide. Crohn's disease and ulcerative colitis are chronic debilitating conditions that afflict individuals with substantial morbidity and challenge healthcare systems across the globe. Since identification and characterisation of calprotectin (CP) in the 1980s, faecal CP emerged as significantly validated, non-invasive biomarker that allows evaluation of gut inflammation. Faecal CP discriminates between inflammatory and non-inflammatory diseases of the gut and portraits the disease course of human IBD. Recent studies revealed insights into biological functions of the CP subunits S100A8 and S100A9 during orchestration of an inflammatory response at mucosal surfaces across organ systems. In this review, we summarise longitudinal evidence for the evolution of CP from biomarker to rheostat of mucosal inflammation and suggest an algorithm for the interpretation of faecal CP in daily clinical practice. We propose that mechanistic insights into the biological function of CP in the gut and beyond may facilitate interpretation of current assays and guide patient-tailored medical therapy in IBD, a concept warranting controlled clinical trials.
Large-Scale Coding Sequence Change Underlies the Evolution of Postdevelopmental Novelty in Honey Bees
Authors: W. Cameron Jasper, Timothy A. Linksvayer, Joel Atallah, Daniel Friedman, Joanna C. Chiu, Brian R. Johnson
Journal: Molecular Biology and Evolution (2016)

During a subsequent analysis of the RNA-Seq data sets in Jasper et al. (2015), we discovered an error in the script we used to generate gene counts.The recommended HTSeq -i option initially did not work with the Apis melliera gff3 file.After examination of the gff3 file, we decided to use "-i Dbxref," as Dbxref seemed to show the same pattern as the recommend identifiers.We checked expression levels for many genes and found that this option worked well.However, in a recent reanalyses of this data, we discovered that this option does not work for all genes and some genes with high expression showed zero expression in our original analyses.To correct this problem, we created a GTF file with the gffread script from Cufflinks for the most recent Apis mellifera gff3 file and reanalyzed our data using STAR with the built-in HTSeq option (--quantMode GeneCounts).None of the conclusions drawn in Jasper et al. ( 2015) change with the new analysis, but expression levels change for many genes.Because researchers may use expression values in later work, we have published corrected gene counts (supplementary table S1, see Supplementary Data online in doi:10.1093/molbev/msu292).We also updated supplementary table S3 as the follow up analysis found many more differentially expressed genes in addition to those we identified in the initial analysis (supplementary table S2, see Supplementary Data
Improving antitumor immunity using antiangiogenic agents: Mechanistic insights, current progress, and clinical challenges
Authors: Shu‐Jin Li, Jia‐Xian Chen, Zhi‐Jun Sun
Journal: Cancer Communications (2021)

Abstract Cancer immunotherapy, especially immune checkpoint blockade (ICB), has revolutionized oncology. However, only a limited number of patients benefit from immunotherapy, and some cancers that initially respond to immunotherapy can ultimately relapse and progress. Thus, some studies have investigated combining immunotherapy with other therapies to overcome resistance to monotherapy. Recently, multiple preclinical and clinical studies have shown that tumor vasculature is a determinant of whether immunotherapy will elicit an antitumor response; thus, vascular targeting may be a promising strategy to improve cancer immunotherapy outcomes. A successful antitumor immune response requires an intact “Cancer‐Immunity Cycle,” including T cell priming and activation, immune cell recruitment, and recognition and killing of cancer cells. Angiogenic inducers, especially vascular endothelial growth factor (VEGF), can interfere with activation, infiltration, and function of T cells, thus breaking the “Cancer‐Immunity Cycle.” Together with immunostimulation‐regulated tumor vessel remodeling, VEGF‐mediated immunosuppression provides a solid therapeutic rationale for combining immunotherapy with antiangiogenic agents to treat solid tumors. Following the successes of recent landmark phase III clinical trials, therapies combining immune checkpoint inhibitors (ICIs) with antiangiogenic agents have become first‐line treatments for multiple solid tumors, whereas the efficacy of such combinations in other solid tumors remains to be validated in ongoing studies. In this review, we discussed synergies between antiangiogenic agents and cancer immunotherapy based on results from preclinical and translational studies. Then, we discussed recent progress in randomized clinical trials. ICI‐containing combinations were the focus of this review because of their recent successes, but combinations containing other immunotherapies were also discussed. Finally, we attempted to define critical challenges in combining ICIs with antiangiogenic agents to promote coordination and stimulate collaboration within the research community.
IMMU-15. QUANTIFYING INTRATHECAL DRUG DELIVERY UTILIZING PROGRAMMABLE VENTRICULOPERITONEAL SHUNTS
Authors: Sheila McThenia, Neeta Pandit-Taskar, Milan Grkovski, Maria Donzelli, Safiatu Diagana, Jeffrey Greenfield, Mark Souweidane, Kim Kramer
Journal: Neuro-Oncology (2021)

Abstract Background Programmable ventriculoperitoneal (pVP) shunts are increasingly utilized for intraventricular chemotherapy, radioimmunotherapy, and/or cellular therapy. Shunt adjustments allow optimization of thecal space drug concentrations with minimization in the peritoneum. Drug delivery quantification using several types of pVP shunts has not been reported. Methods We performed a retrospective analysis on patients with CNS tumors and pVP shunts at Memorial Sloan Kettering Cancer Center from 2003–2020, noting shunt model. CSF flow through the pVP shunt was evaluated using In-111-DTPA scintigraphy at approximately 4 hours and 24 hours after injection. pVP shunts were calibrated pre-injection to minimize peritoneal flow and re-calibrated to baseline setting 4–5 hours following injection. Scintigraphy studies quantified ventricular-thecal and peritoneal drug activity at these 2 time points. Results Twenty-one CSF flow studies were administered to 15 patients, ages 1–27 years. Diagnoses included medulloblastoma (N=10), metastatic neuroblastoma (N=3), pineoblastoma (N=1), and choroid plexus carcinoma (N=1). pVP shunt models included Aesculap Miethke proGAV (N=3), Aesculap Miethke proGAV2.0 (N=3), Codman HAKIM (N=2), Codman Certas Plus (N=1), Medtronic STRATA (N= 5), and Sophysa Polaris (N= 1). All 21 studies (100%) demonstrated ventriculo-thecal drug activity. 29% (6 of 21) of the studies had no peritoneal uptake visible by imaging. 73% (16 of 21) of the studies had minimal peritoneal uptake (&amp;lt;12%), and 24% (5 of 21) demonstrated moderate peritoneal uptake (12–37%). pVP shunt models measuring minimal to no peritoneal uptake included: Aesculap Miethke proGAV (N=2), Aesculap Miethke proGAV2.0 (N=3), Codman HAKIM (N=2), Codman Certas Plus (N=1), Medtronic STRATA (N= 3), and Sophysa Polaris (N= 1). Conclusions Successful drug delivery to the ventriculo-thecal space can be accomplished using pVP shunts: 80% of studies have minimal (&amp;lt;12%) peritoneal drug activity. Though efficacy varies by shunt model, low numbers preclude conclusions regarding model superiority. CSF flow scintigraphy studies reliably assess drug distribution.
Association of kappa light chain restriction with peripheral neuropathy among patients with non-IgM monoclonal gammopathy of undetermined significance.
Authors: Constantin A. Dasanu, Jaspreet Kaur, Shahaf Tuler, Stephanie Farrell, Steven C. Plaxe
Journal: Journal of Clinical Oncology (2021)

e20040 Background: Monoclonal gammopathy of undetermined significance (MGUS) can be associated with significant neurologic morbidity. Of non-IgM MGUS, types IgG and IgA are most commonly associated with peripheral neuropathy (PN). Methods: With IRB approval, we conducted a retrospective cohort study of consecutive patients with non-IgM type MGUS treated at our institution from 2014-2021. Other conditions potentially causing PN were excluded. Statistical analysis: Descriptive statistics were calculated to characterize the study population, and Relative Risk (RR) of PN was evaluated for selected patient, and disease, related factors. P &lt; 0.05 was defined as statistically significant. Results: During the study period, 94 patients with non-IgM type MGUS were seen and comprised the study population. Twenty-two (23.4%) had evidence of PN. Median age was 74; 82% (18/22 ) were Caucasian; 73% (16/22) were women. 82% (18/22) patients had MGUS type IgG kappa or IgA kappa. We identified only 2 patients with each MGUS kappa light chain (LC) and MGUS IgG lambda. Median M-protein size was 0.11 g/dL, and median free LC value was 6.84 mg/L. Incidence/severity of kidney disease was similar in non-IgM MGUS patients with and without PN (p &gt; 0.05). RR of PN was not found to be significantly different based on race or gender, although there appeared to be a tendency for women to be at higher risk compared to men (RR = 1.98, 95% CI = 0.85 to 4.60, p = 0.114.) Kappa LC restriction was strongly associated with PN (RR = 4.31, 95% CI = 1.58 to 11.78; p = 0.004). Electromyographic (EMG) studies identified 14 patients (64%) with distal symmetric axonal neuropathy (DSAN) and 8 patients (36%) with chronic inflammatory demyelinating polyneuropathy (CIDP). Clinically severe PN was identified in 11 (50%) patients; all were subsequently treated with IVIg therapy. Only 5/11 (45%) patients responded to IVIg, and the responses were only partial and transient. Conclusions: This is the first report, to our knowledge, of a significant association of kappa (as opposed to lambda) LC restriction with PN among patients with non-IgM type MGUS. Further investigation is warranted to explain this finding, elucidate pathophysiology and aid in developing more effective therapeutic options. Pending mechanistic characterization of this association, trials of contemporary agents used to treat other plasma cell disorders may be in order. Final statistical analysis, comparison to published series and significance will be presented.
ATRT-06. RESULTS OF MULTICENTER TRIAL CONCERNING THE TREATMENT OF CHILDREN WITH ATYPICAL TERATOID RHABDOID TUMORS OF THE CENTRAL NERVOUS SYSTEM UNDER 3 YEARS OLD
Authors: Zheludkova Olga, Olkhova Liudmila, Zubarovskaya Ludmilla, Dinikina Julia, Smirnova Anna, Kushel’ Yuri, Melikyan Armenak, Kadyrov Shavkat, Ryzhova Marina, Shishkina Liudmila, Kislyakov Alexey, Shultz Evgeniy, Gorbatykh Svetlana, Polushkina Olga, Inyushkina Eugenia, Yudina Natalia, Gevorgian Asmik, Privalova Liudmila, Minkina Liudmila, Zaichikov Artem, Fisyun Ivan, Sakun Daniil, Mitrofanov Vyacheslav, Kovalenko Sergey, Grishina Ekaterina, Pishchaeva Nadezhda, Vorob’ev Nikolay, Plakhotina Nadezhda, Popova Natalia, Pogorelov Dmitriy, Shapochnik Alexander, Korchunov Andrey
Journal: Neuro-Oncology (2021)

Abstract Objective To evaluate the prognostic factors in children with AT/RT aged under 3 years. Patients and methods: The prognostic factors were analyzed in 106patients under 3 years who got treatment and follow-up from 2008 to 2020.There were 41children younger than 12 months and 65patients older than 12 months. The location of the tumor was infratentorial in 58 patients, supratentorial in 46, and spinal cord in 2. There were 54 boys and 52 girls. Among the patients,57 had stage M0,36 had stage М+ or a multifocal tumor, and 13 had stage Mx. All the patients had undergone surgical treatment: total tumor removal in 27, subtotal-33, partial-42, biopsy - 4;67patients had got chemoradiotherapy according to the ATRT-2006(IRS III) protocol; 15, MUV-ATRT protocol; 3, CWS protocol; 9, EU-RHAB protocol; 6, HIT-SKK protocol; and 6 according to individual treatment schemes.12 patients received HDC with AuHCR. Results 47 are alive,1 was lost to follow-up, and 58 died:52 of progressive disease,6 of chemotherapy complications. The five-year PFS was 0.27; the five-year OS was 0.40. The PFS was significantly better in patients older than 12months old compared to patients under 12months: 0.33 and 0.17, respectively; p=0.0047. The PFS after total resection was higher than after subtotal resection, partial resection, and tumor biopsy: 0.51, 0.29, 0.09, and 0%, respectively (p=0.025).The PFS after radiotherapy was markedly higher compared to patients without radiotherapy: 0.63 and 0.0, respectively (р&amp;lt;0.001). The tumor location, stage, and gender did not affect the PFS. The survival rate was statistically significantly higher among the patients who had got treatment according to the ATRT-2006 protocol compared to MUV-ATRT,EU-RHAB, individual therapeutic regimens, CWS, and HIT-SKK: 0.33, 0.26, 0.11, 0.30, and 0.0, respectively; p=0.0020. The PFS was higher among the patients who had got intraventricular/intrathecal chemotherapy; p=0.0002. HDC with AuHCR did not statistically affect the PFS; p=0.0546.In multivariate analysis, the PFS was influenced by the age, tumor location, extent of surgery, radiotherapy, regional chemotherapy, HDC with AuHCR. Conclusions The survival of patients with CNS AT/RT aged under 3years significantly depended on the patients’ age, extent of surgery, chemotherapy protocol, radiotherapy, and regional administration of chemotherapeutic drugs.
HGG-14. ACT001 – A PROMISING THERAPEUTIC FOR DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Dannielle Upton, Sandra George, Jie Liu, Dongpo Cai, Steven Yung-Chang Su, Neevika Manoharan, Steve Foresto, Tim Hassall, Maria Tsoli, David Ziegler
Journal: Neuro-Oncology (2021)

Abstract Diffuse Intrinsic Pontine Gliomas (DIPGs) are a subset of Diffuse Midline Gliomas (DMG) and are the most devastating of all brain tumors. There are no effective treatments and all children die of their tumor within 12-months. We performed a high-throughput drug screen with 3,570 biologically active, clinically approved compounds against a panel of DIPG cultures. Parthenolide, a compound derived from the herb T.parthenium, was found to be one of the most effective drugs tested, demonstrating significant anti-tumor activity. However, parthenolide also affected healthy cell viability and showed no in-vivo efficacy. ACT001 is a novel agent in clinical development that is a fumarate salt form of dimethylamino-micheliolide, which is semi-synthesized from parthenolide. ACT001 is blood-brain-barrier permeable and exerts an anti-tumor effect via inhibition of NF-κB and STAT3 pathways. ACT001 demonstrated potent anti-tumor activity against a panel of DIPG-neurospheres, with minimal effect on normal cells and inhibited colony formation in-vitro. To determine whether this activity could be replicated in-vivo, we tested ACT001 in a DIPG-orthotopic model. ACT001 was well tolerated and significantly improved survival of tumor-bearing animals, extending survival by 33% in ACT001 treated mice. We have initiated a Phase 1 paediatric trial of ACT001 for children with relapsed/refractory solid or CNS tumors, with an expansion cohort planned for patients with DIPG/DMG. Eleven patients have been enrolled, and the dose escalated from dose level-1 at 188mg/m2 bd to dose level-4 at 700mg/m2 bd. To date, no dose limiting or Grade 3/4 toxicities have been observed. At the highest dose level, clinical activity has been demonstrated in two patients, one with DIPG with a reduction in tumor burden, and another with DMG with H3K27M mutation with an objective radiographic and clinical response. These combined preclinical and clinical results suggest that ACT001 is an active novel therapy for patients with DIPG/DMG.