tbuckley/cabot-search huggingface dataset:
Complete regression of melanoma in a murine model by RLIP76 depletion.
Authors: Sanjay Awasthi, Kenneth Drake, Sharad Singhal, Yogesh Awasthi
Journal: Cancer Research (2006)

5282  RLIP76 is a stress-responsive membrane protein implicated in the regulation of multiple cellular signaling pathways. It represents the predominant glutathione-conjugate (GS-E) transporter in cells, and our previous studies have shown that its inhibition by antibodies or depletion by siRNA causes apoptosis in a number of cancer cell types. Present studies were performed to explore potential clinical applicability of our previous observations by comparing relative expression of RLIP76 in cancer versus normal cell lines and to determine whether depletion of RLIP76 activity can exert cancer-specific apoptosis. RLIP76 expression was found to be significantly greater in malignant as compared with non-malignant cells. Inhibition of RLIP76, using antibodies towards a cell-surface epitope, or depletion of RLIP76 using either siRNA or anti-sense phosphorothioate oligonucleotides caused apoptosis in malignant cells preferentially. More importantly, in-vivo studies demonstrated that administration of RLIP76 antibodies, siRNA or anti-sense oligonucleotides to mice bearing syngeneic B16 mouse melanoma cells caused complete tumor regression within 10 days. These findings strongly suggest that RLIP76 depletion by genetic approaches or inhibition by antibodies may be a clinically viable antineoplastic therapy, particularly for melanoma (Supported by USPHS grants CA 77495 and 104661).
VAC temporization pending final margins after suprafascial myxofibrosarcoma excision to reduce the rate of local recurrence.
Authors: Mitchell Stephen Fourman, Duncan C. Ramsey, Justin Kleiner, Anser Daud, Erik T. Newman, Joseph H. Schwab, Yen-Lin Chen, Thomas F. DeLaney, John Thomas Mullen, Kevin Raskin, Santiago Lozano-Calderon
Journal: Journal of Clinical Oncology (2021)

11573 Background: The microinvasive nature of suprafascial myxofibrosarcoma complicates the accuracy of intraoperative margin assessment, and tumor bed resections after soft tissue reconstruction are unreliable. For the past 3 years we have temporized the excised tumor bed with a wound VAC, delaying soft tissue coverage until final negative margins were achieved. Here, we compare the oncologic/surgical outcomes of suprafascial myxofibrosarcomas managed with VAC temporization (VT) with single-stage excision/reconstruction (SS). Methods: We retrospectively studied suprafascial myxofibrosarcomas managed from 1/1/2000 to 1/1/2019 who received neoadjuvant or adjuvant radiation and had at least 2-years of oncologic follow-up at a tertiary referral cancer center. Our primary outcome was local recurrence. Comparisons were performed using Fisher’s Exact Test or Students t-test. A p-value &lt; 0.05 was considered significant. Results: Fifty-three patients (18 VAC temporized, 35 single stage) were included. While VT patients were older (74.9 ± 10.2 vs. 63.9 ± 13.6, p = 0.003), treatment groups did not significantly differ with respect to comorbidity, tumor volume, stage and grade. VT patients had significantly fewer local recurrences (5.6% vs. 28.6% after SS, p = 0.048) and R1 resections that required an unplanned readmission for tumor bed re-excision (0% vs. 37.1% after SS, p = 0.002). VT required more total surgeries (2.8 ± 0.9 vs. 1.8 ± 0.9 for SS, p = 0.0002). Post-operative infectious and wound complications were equivalent (Table). Conclusions: Our VAC temporization strategy had a significantly lower LR than SS treatment. While high quality multi-institutional validation is required, VT may represent a paradigm shift in the management of myxofibrosarcoma.[Table: see text]
Transitioning ifosfamide based chemotherapy to the outpatient setting: A model of implementation of transitioning chemotherapy outpatient in a safety net hospital.
Authors: Cindy Banh, Alejandra Arrendondo, Kassie Notbohm, Kendall Valsvik, Alicia Ortega, Lauren Sanders, Alejandro Recio, Andrew Kraft, Hani M. Babiker, Brian Do, Daniel O Persky, Ivo Abraham, Ali McBride
Journal: Journal of Clinical Oncology (2021)

1540 Background: Ifosfamide displays clinical activity against germ cell tumors as well as soft-tissue and bone sarcomas. It is used in different oncology regimens and commonly administered inpatient due to patient monitoring and side effect management. Transitioning certain chemotherapy regimens to the outpatient setting provides a novel approach to treating patients while maximizing patient satisfaction and decreasing total patient care costs 1 . There is limited data and protocol development to transition ifosfamide regimens to the ambulatory setting. This study’s purpose is to characterize a pharmacy managed ambulatory oncology workflow for transitioning ifosfamide based-regimens to the outpatient setting. Methods: A retrospective cohort chart review was conducted at a single center and included patients 18 years and older receiving at least one cycle of ifosfamide therapy between September 1, 2013 and July 31, 2019. The primary outcome was to evaluate the side effect profile and cost of treatment of ifosfamide. The secondary endpoint included number of hospitalizations. The adverse event grading system was defined using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. The highest grade observed for adverse effects was documented for every cycle of each patient. The cost was evaluated by labs ordered, drug used, length of stay in the hospital for chemotherapy or adverse reactions. Results: Ifosfamide therapy of 86 patients (57 OP, 29 IP) was reviewed. The predominant OP regimens were adriamycin-ifosfamide-mesna (AIM) with 43.9% and ifosfamide-etoposide (IE) with 29.8%. Grade 4 anemia, thrombocytopenia, and neutropenia were most frequent in IP vs OP therapies (22.9% IP vs 4.3% OP, 21.6% IP vs 9.2% OP, and 22.8% IP vs 19.6% OP respectively). Neutropenic fever (NF) occurred in 20 OP patients which were predominantly treated with AIM or IE, and led to average hospital stay of 6 days. Neurotoxicity, treated with methylene blue (MB), occurred in 4 OP patients. OP therapy saved a total of 783 hospital days, leading to a cost savings of $2,103,921. Conclusions: Transitioning to outpatient therapy is feasible for academic and community infusion centers. Administration of chemotherapy in the outpatient setting has shown to be safe, well-tolerated, and associated with decreased total cost of care, thereby lowering costs under the oncology care model when compared with inpatient chemotherapy costs.
Safety and feasibility of rhenium-186 nanoliposome (<sup>186</sup>RNL) in recurrent glioma: The ReSPECT phase 1 trial.
Authors: Andrew J. Brenner, Ande Bao, William Phillips, Gregory Stein, Vibhudutta Awasthi, Toral R. Patel, Jeffrey Weinberg, John Floyd
Journal: Journal of Clinical Oncology (2021)

2061 Background: While external beam radiation therapy (EBRT) remains a central component of the management of primary brain tumors, it is limited by tolerance of the surrounding normal brain tissue. Rhenium-186 NanoLiposome ( 186 RNL) permits the delivery of beta-emitting radiation of high specific activity with excellent retention in the tumor. We report the results of the phase 1 study in recurrent glioma. Methods: A Phase 1 dose-escalation study of 186 RNL in recurrent glioma utilizing a standard 3+3 design was undertaken to determine the maximum tolerated dose of 186 RNL. 186 RNL is administered by convection enhanced delivery (CED). Infusion is followed under whole body planar imaging and SPECT/CT. Repeat SPECT/CT imaging is performed immediately following, and at 1, 3, 5, and 8 days after 186 RNL infusion to obtain dosimetry and distribution. Subjects were followed until disease progression by RANO criteria. Results: Eighteen subjects were treated across 6 cohorts. The mean tumor volume was 9.4 mL (range 1.1 – 23.4). The infused dose ranged from 1.0 mCi to 22.3 mCi and the volume of infusate ranged from 0.66 mL to 8.80 mL. From 1 – 4 CED catheters were used. The maximum catheter flow rate was 15 µl/min. The mean absorbed dose to the tumor volume was 239 Gy (CI 141 – 337; range 9 - 593), to normal brain was 0.72 Gy (CI 0.34 – 1.09; range 0.005 – 2.73), and to total body was 0.07 Gy (CI 0.04 – 0.10; range 0.001 – 0.23). The mean absorbed dose to the tumor volume when the percent tumor volume in the treatment volume was 75% or greater (n = 10) was 392 Gy (CI 306 – 478; range 143 – 593). Scalp discomfort and tenderness related to the surgical procedure did occur in 3 subjects. The therapy has been well tolerated, no dose-limiting toxicity has been observed, and no treatment-related serious adverse events have occurred despite markedly higher absorbed doses typically delivered by EBRT in patients with prior treatment. Responses have been observed supporting the clinical activity. Final results from the dose escalation will be presented. Conclusions: 186 RNL administered by CED to patients with recurrent glioma results in a much higher absorbed dose of radiation to the tumor compared to EBRT without significant toxicity. The recommended Phase 2 dose is 22.3 mCi in 8.8 mL of infusate. Clinical trial information: NCT01906385. [Table: see text]
Phase 2 study of AK104 (PD-1/CTLA-4 bispecific antibody) plus lenvatinib as first-line treatment of unresectable hepatocellular carcinoma.
Authors: Li Bai, Meili Sun, Aibing Xu, Yuxian Bai, Jian Wu, Guoliang Shao, Lijie Song, Xiaoping Jin, Weifeng Song, Baiyong Li, Yu Xia, Shunchang Jiao
Journal: Journal of Clinical Oncology (2021)

4101 Background: Anti–PD-(L)1 plus anti-CTLA-4 therapies (e.g. nivolumab/ipilimumab, tremelimumab/durvalumab) produce durable immune responses in patients (pts) with advanced hepatocellular carcinoma (HCC). More recent data suggests that the combination of immune checkpoint inhibitors (ICIs) with a multi-kinase inhibitor is efficacious against unresectable HCC (uHCC). AK104 is a humanized IgG1 bispecific antibody that simultaneously binds to PD-1 and CTLA-4. Early data suggests that AK104 possesses encouraging anti-tumor activity in selected tumour types and an improved safety profile compared to the co-administration of anti-PD-1 plus anti-CTLA-4 antibodies. Lenvatinib is a multi-kinase inhibitor and approved for first-line treatment of uHCC. Here, we report results from a phase 2 study of AK104 plus lenvatinib in pts with uHCC. Methods: In this single-arm, multicenter phase II study (NCT04444167), pts with uHCC, BCLC stage B or C, Child-Pugh class A, who had not previously received systemic treatment received AK104 (6 mg/kg IV q2w or 15 mg/kg IV q3w) and lenvatinib (8 mg [bodyweight &lt; 60 kg] or 12 mg [weight ≥ 60 kg] PO QD). Primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints include disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: As of February 1 2021, 30 pts (86.7% male, median age 52.5yrs [31-71], 30% was ECOG 1, 93.3% was HBV+) had received the combination therapy of (AK104 6 mg/kg q2w plus lenvatinib). Of 18 pts evaluable for antitumor activity (defined as pts with the opportunity to be followed for at least 2 scans [≥13 weeks]), ORR per RECIST v1.1 was 44.4% (8/18), DCR was 77.8% (8 PRs and 6 SDs including 2 pts who had 28.4% and 29.2% reduction in tumor size from baseline). Median PFS has not been reached. Treatment-related adverse events (TRAEs) occurred in 83.3% of pts (G3 TRAEs occurred in 26.7% [8/30], and no G4 TRAEs or TRAEs leading to death). Most common TRAEs (≥15%) were increased AST (36.7%) and ALT (36.7%), decreased platelet count (33.3%), decreased neutrophil count (30.0%), and increased blood bilirubin (26.7%), with the vast majority being grades 1 or 2. Conclusions: AK104 plus lenvatinib as first-line therapy for uHCC has showed promising antitumor activity and an acceptable safety profile. Toxicities were manageable, with no unexpected safety signals. Enrollment for AK104 15 mg/kg q3w plus lenvatinib is currently ongoing, and longer follow-up is needed to further evaluate the durability of response. Clinical trial information: NCT04444167.
Familial aggregation and heritability: a nationwide family-based study of idiopathic inflammatory myopathies
Authors: Weng Ian Che, Helga Westerlind, Ingrid E Lundberg, Karin Hellgren, Ralf Kuja-Halkola, Marie Holmqvist
Journal: Annals of the Rheumatic Diseases (2021)

The magnitude of the genetic contribution to idiopathic inflammatory myopathies (IIMs) is unknown. In this project, we aimed to investigate the familial aggregation and heritability of IIM.This is a family-based study using nationwide healthcare register data in Sweden. We matched each patient with IIM to individuals without IIM, identified their first-degree relatives and determined the IIM status among all first-degree relatives. We estimated the adjusted ORs (aORs) of familial aggregation of IIM using conditional logistic regression. In addition, we used tetrachoric correlation to estimate the heritability of IIM.We included 7615 first-degree relatives of 1620 patients with IIM diagnosed between 1997 and 2016 and 37 309 first-degree relatives of 7797 individuals without IIM. Compared with individuals without IIM, patients with IIM were more likely to have ≥1 first-degree relative affected by IIM (aOR=4.32, 95% CI 2.00 to 9.34). Furthermore, the aOR of familial aggregation of IIM in full siblings was 2.53 (95% CI 1.62 to 3.96). The heritability of IIM was 22% (95% CI 12% to 31%) among any first-degree relatives and 24% (95% CI 12% to 37%) among full siblings.IIM has a familial component with a risk of aggregation among first-degree relatives and a heritability of about 20%. This information is of importance for future aetiological studies and in clinical counselling.
Homologous recombination deficiency associated with response to poly (ADP-ribose) polymerase inhibitors in ovarian cancer patients: The first real-word data from China.
Authors: Xiaoxiang Chen, Jing Ni, Xia Xu, Wenwen Guo, Xianzhong Cheng, Qian Zhao, Rui Zhou, Hongyuan Gu, Chen Chen
Journal: Journal of Clinical Oncology (2021)

e17543 Background: Homologous recombination deficiency (HRD) is the first phenotypically defined predictive biomarker for Poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer. However, the proportion of HRD positive in real world and the relationship of HRD status with PARPi in Chinese ovarian cancer patients remains unknown. Methods: A total of sixty-four ovarian cancer patients underwent PARPi, both Olaparib and Niraparib, were enrolled from August 2018 to January 2021 in Jiangsu Institute of Cancer Hospital. HRD score which was the sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI) and large-scale state transitions (LST) events were calculated using tumor DNA-based next generation sequencing (NGS) assays. HRD-positive was defined by either BRCA1/2 pathogenic or likely pathogenic mutation or HRD score ≥42. Progression-free survival (PFS) was analyzed with a log-rank test using HRD status and summarized using Kaplan-Meier methodology. Univariate and multiple cox-regression analysis were conducted to investigate all possible clinical factors. Results: 71.9% (46/64) patients were HRD positive and the rest 28.1% (18/64) were HRD negative, which was higher than the HRD positive proportion reported in Western countries. The PFS among HRD positive patients was significantly longer than those HRD negative patients (medium PFS 8.9 m vs 3.6 m, hazard ratio [HR]: 0.22, p &lt; 0.001). Among them, 23 patients who were BRCA wild type but HRD positive had longer PFS than those with BRCA wild type and HRD negative (medium PFS 9.2 m vs 3.6 m, HR: 0.20, p &lt; 0.001). Univariate cox-regression analysis found that HRD status, previous treatment lines, secondary cytoreductive surgery (SCS) were significantly associated with PFS after PARPi treatment. After multiple regression correction, HRD status (HR: 0.39, 95% CI: [0.20-0.76], p = 0.006), ECOG score (HR: 2.53, 95% CI: [1.24-5.17], p = 0.011) and SCS (HR: 2.21, 95% CI: [1.09-4.48], p = 0.028) were the independent factors. Subgroup analysis in ECOG = 0 subgroup (N = 36), HRD positive patients had significant longer PFS than HRD negative patients (medium PFS 10.3 m vs 5.8 m, HR: 0.14, p &lt; 0.001). Also in the subgroup of patients without SCS, PFS in patients with HRD was longer than patients without HRD (medium PFS 10.2 m vs 5.7 m, HR: 0.29, p = 0.003). Conclusions: This is the first real-world data of HRD status in ovarian cancer patients from China and demonstrate that HRD is a valid biomarker for PARP inhibitors in Chinese ovarian cancer patients.
Salvage immune checkpoint inhibitor (ICI) plus tyrosine kinase inhibitor (TKI) combination therapy for metastatic renal cell carcinoma (mRCC).
Authors: Anish B. Parikh, Sarah P. Psutka, Yuanquan Yang, Katharine Collier, Abdul Miah, Mingjia Li, Sherry Mori-Vogt, Megan Hinkley, Delaney Orcutt, Elliott Trott, Evan Gross, Duncan Hussey, Joel Kramer, Kaylee Oliva, Amir Mortazavi, Paul Monk, Edmund Folefac, Steven K. Clinton, Ming Yin
Journal: Journal of Clinical Oncology (2021)

e16567 Background: ICI/TKI combinations are a new standard of care for the initial treatment (tx) of mRCC. Efficacy and toxicity of such combination regimens beyond the first-line (1L) setting remain unknown. Methods: We retrospectively reviewed charts for adult patients (pts) receiving an ICI/TKI combination in any line of tx for mRCC of any histology at one of two academic centers as of May 1, 2020. ICIs included pembrolizumab (Pm), nivolumab (Ni), ipilimumab (Ip), or avelumab (Av); TKIs included sunitinib (Su), axitinib (Ax), pazopanib (Pz), lenvatinib (Ln), or cabozantinib (Ca). Clinical data including pt demographics, histology, International mRCC Database Consortium (IMDC) risk group, tx history, and ICI/TKI tx and toxicity details were recorded. Outcomes included objective response rate (ORR), median progression-free survival (mPFS), and safety, analyzed via descriptive statistics and the Kaplan-Meier method. Results: Of 85 pts, 69 (81%) were male and 67 (79%) had clear cell histology. IMDC risk was favorable (24%), intermediate (54%), poor (20%), and unknown (2%). 39% had ICI/TKI tx in the 1L setting. ICI/TKI regimens included Pm/Ax (33%), Ni/Ca (25%), Ni/Ax (20%), Av/Ax (11%), Ni/Ip/Ca (8%), Ni/Su (2%), and Ni/Ln (1%). ORR and mPFS stratified by line of tx and prior tx are shown in the table. Of 52 pts who received ICI/TKI tx as salvage (after 1L), 52% had a grade 3 or higher (≥G3) adverse event (AE), of which the most common were anorexia (13.5%), diarrhea and hypertension (11.5% each), and fatigue (9.6%). 65% of pts on salvage ICI/TKI tx stopped tx for progression/death, while 16% stopped tx for ≥G3 AE. ≥G3 AE rates by line of tx were 62.5% (2L), 50% (3L), and 45% (≥4L). Conclusions: ICI/TKI combination therapy is effective and safe beyond the 1L setting. Prior tx history appears to impact efficacy but has less of an effect on safety/tolerability. These observations will need to be confirmed in prospective studies.[Table: see text]
NTRK genomic alterations in Latin-American cancer patients.
Authors: Daniel Carvajal, Claudio Salas, Katherine Marcelain, Francisco Perez, Solange Rivas, Evelin Feliu, Kurt Schalper, Ricardo Armisén
Journal: Journal of Clinical Oncology (2021)

e15088 Background: The neurotrophic receptor tyrosine kinase genes NTRK1-3 encode the tropomyosin receptor kinase proteins TRKA, TRKB, and TRKC, respectively. TRK fusions lead to overexpression of the chimeric protein, resulting in constitutively active, ligand-independent downstream signaling. NTRKs act as oncogenes, they can be targeted, and it is estimated that they are present in up to 0.3% of tumors. The incidence of actionable alterations in these genes is currently unknown in Latin-American patients. We investigated the presence of NTRK1-3 mutations/rearrangements in 3 independent patient series from several tertiary hospitals from Chile, Brazil and Peru. Methods: 1795 FFPE tumor samples from multiple institutions divided in 3 series were analyzed using 2 NGS panels: Oncomine Focus Assay (OFA; 52 genes) and Oncomine Comprehensive Assay (OCA; 161 genes. Data on NTRK1-3 SNVs, indels, CNVs and fusions was obtained. Bioinformatic workflows were used to study the biologic significance of these alterations. Results: Using OCA (series 1-2), 31 somatic variants were found in gastric, CRC, gallbladder, lung and pancreatic cases out of 300 patients. From these, 13 were located in the tyrosine kinase domain. Using OFA, no NTRK alteration were detected (series 3, 1495 NSCLC cases). Conclusions: NTRK alterations are rare events in Latin-American cancer patients. In 3 series including 1,795 patients, 31 somatic variants were detected. No NTRK fusions or CNVs were identified. The presence of NTRK mutations in the tyrosine kinase domain warrants further research into their potential to benefit from FDA/EMA-approved targeted therapies. [Table: see text]
Guts UK 50 years old: onwards and upwards
Authors: Julie Harrington, John McLaughlin, Jonathan M Rhodes
Journal: Gut (2021)

Guts UK is 50 years old. Despite many advances since its foundation, there is plenty left to be done. Funding for research into gut, liver and pancreas diseases has always been modest compared with their clinical impact.1 The UK Medical Research Council was established in 19192 when gastroenterology barely existed as a specialty—the British Society of Gastroenterology (BSG) was not formed until 1937.3 Medical Research Council funding reflected priorities of the day such as infectious disease and neurological disorders.

In 1971, the Council of the BSG, noting the paucity of research funding, set up the Digestive Disorders Trust Fund with Dr Thomas Hunt, a founder member of the BSG, as its first President. Sir Francis Avery …