bluuebunny/crossref_metadata_2025_split huggingface dataset:
Management of infliximab-refractory immune checkpoint inhibitor gastrointestinal toxicity: A multicenter case series.
Authors: Harvey Catriona , Nahar Kazi Jannatun , Lo Serigne N. , Ahmed Tasnia , Farag Sheima , Yousaf Nadia , Young Kate , Tas Liselotte , Meerveld-Eggink Aafke , Blank Christian U. , Thomas Austin , McQuade Jennifer Leigh , Schilling Bastian , Johnson Douglas Buckner , Martin Huertas Roberto , Arance Ana Maria , Lee Joanna , Zimmer Lisa , Long Georgina V. , Menzies Alexander M. 
Published: June 2022

2665 Background: Immune checkpoint inhibitor (ICI) GI tox (gastritis, enteritis, colitis) is a major cause of morbidity and treatment-related death. Guidelines agree steroid-refractory cases warrant infliximab (IFx); however not all pts respond and best management of IFx-Refractory ICI GI toxicity (IRIGItox) is not clear. Methods: We conducted an international multi-centre retrospective case series. IRIGItox was defined as failure of symptom resolution ≤ Gr 1 (CTCAE v5.0) following ≥ 2 IFx doses or failure of symptom resolution ≤ Gr 2 after 1 dose. Data were extracted regarding demographics, steroid use, response and survival. Tox was graded at symptom onset and time of IFx failure. Efficacy of IFx refractory therapy was assessed by symptom resolution, time to resolution and steroid wean. Results: 78 pts were identified; med age 60 yrs (95% CI 56-65), 56% male. 70 (90%) had melanoma, 55 (71%) had advanced-stage, 60 (77%) received anti-CTLA-4 (with anti-PD1 50, single agent 10). Most had colitis (N=75, 96%) and ≥ Gr 3 tox (N=74, 95%) at symptom onset. Pre-IFx investigation varied: imaging 37%; faecal calprotectin 29%; endoscopy 59%. All pts received Med time to steroid initiation was 3 days (95% CI 2-4). 46 (59%) had primary steroid refractory disease,. Med time from symptom onset to IFx was 18 days (95% CI 12-23), a med 2 (range 1-6) doses of IFx were given, 69 (88%) pts received > 1 IFx dose. Across 78 pts, 105 post IFx treatments were given: calcineurin inhibitors (ciclosporin, tacrolimus, 32); antimetabolites (mycophenolate, azathioprine, 26); non-TNF-α MABs (vedolizumab, ustekinumab, 20); non-targeted anti-inflammatory (mesalazine, 16); non-pharmacological (colectomy 5, faecal transplant 1, photophoresis 1). 4 pts did not receive therapy for IRIGItox. Of these, 2 died of melanoma prior to resolution of tox; 1 had resolution after 4 doses IFx, 1 had recurrent melanoma and flare of tox on PD1 re-challenge. IRIGItox outcomes by post IFx treatment are shown in Table. Conclusions: This retrospective case series confirms heterogeneous management of IRIGItox. Non-pharmacological interventions and calcineurin inhibitors appear most likely to result in tox resolution. Calcineurin inhibitors have the shortest time to resolution in responders. Further details on post-IFx management and oncological outcomes will be examined. [Table: see text]
AI-enabled identification prediction of homologous recombination deficiency (HRD) from histopathology images.
Authors: Shafi Gowhar , P.M. Shivamurthy , Ulle Anand , Srinivasan Krithika , Vasudevan Aravindan , Jadhav Vikas , Joshi Dr Sujit , Raut Nirmal Vivek , Khandare Jayant , Uttarwar Mohan , Bloom Kenneth Joel 
Published: June 2022

3019 Background: Homologous recombination deficient (HRD) tumors are highly responsive to platinum-based chemotherapy and poly (ADP-ribose) polymerase inhibitor (PARPi) therapy. Pathogenic BRCA-1 and BRCA-2 (BRCA1/2) alterations are key members of the HR DNA repair pathway but genomic instability status, including loss of heterozygosity, telomeric allelic imbalance and large scale state transitions across the genome are also predictive of HRD. HRD testing is currently performed by next generation sequencing which can take 2-4 weeks for results, has a high failure rate, requires significant tissue and is costly. We developed and tested the ability of an AI enabled platform to predict HRD status from the analysis of whole slide imaging of the diagnostic H&E slide. This platform, iPREDICT-HRD is rapid, precise, and cost effective. Methods: The AI engine was trained on 120 H&E slides that were used to identify tumor prior to manual microdisseection for HRD assessment by NGS. Histopathological features were extracted, followed by feature mapping to predict HRD status based on the results of NGS testing. ResNet AI algorithm was trained to segment, annotate and predict HRD status. 10 lac tiles of 256x256 size at 40x magnification were generated per pathological class. 70% of the data set was used for training and 30% for validation of the AI model. Results: Using single blinded clinical samples, iPREDICT-HRD tool detected HRD + ve samples with 99.3% accuracy with 100% sensitivity and 99% specificity in the test set. Patch-level predictions of HRD status demonstrated intra-tumor heterogeneity within the H&E slides. Visual inspection of the heatmap suggested the presence of patches with high predictive ability of HRD status and this outperformed an average HRD score for slides with heterogeneity. Conclusions: AI-enabled prediction of HRD status can be accurately performed on diagnostic H&E slides potentially yielding results quickly and afforadably, even when limited tissue is available for testing.
Safety of the cyclin dependent kinase 9 (CDK9) inhibitor FIT039 for cervical intraepithelial neoplasia (CIN) 1 or 2 in a phase I/II trial.
Authors: Hamanishi Junzo , Sumi Eriko , Miyamoto Taito , Uozumi Ryuji , Yamanoi Koji , Tada Harue , Amino Yoko , Hidaka Yu , Ukita Masayo , Yamaguchi Ken , Asada Ryuta , Ajiro Masahiko , Sawada Teruo , Hagiwara Masatoshi , Mandai Masaki 
Published: June 2022

3022 Background: Human papillomaviruses (HPVs) infect uterine cervical epithelial cells, leading to cervical intraepithelial neoplasia (CIN) and cervical cancer. However, there is no treatment for HPV infection in the uterine cervix prior to vaccination. We recently reported that cyclin dependent kinase 9 (CDK9) plays a critical role in viral RNA transcription of DNA viruses such as HPVs in host cells, and that FIT-039, a specific inhibitor of CDK9, suppresses the proliferation of several DNA viruses. Here, we evaluated the safety and antiviral effect of a FIT039-releasing vaginal tablet (FIT039CT) for CIN1 or 2 (CIN1/2). Methods: A multi-institutional, single-blind, placebo-controlled randomized phase I/II clinical trial involving 2 cohorts was designed to evaluate the safety of transvaginal FIT039CT for CIN1/2 as follows:. In the first cohort, 8 healthy women were randomized into FIT039CT (50mg/day or 100mg/day) or control group. In the second cohort, 14 women with a primary diagnosis of CIN1/2 were randomized into either FIT039CT (100mg/day) or control group. The primary endpoints were adverse events and plasma concentrations of FIT039. Results: 22 patients (8 volunteers, 11 CIN1 and 3 CIN2) were enrolled. There were no serious adverse events. Adverse events considered related to treatment were mild (vaginal discharge Grade 1: FIT039CT 16/17 women [94%] vs placebo 2/6 [33%]) and self-limiting in both cohorts. No patient discontinued this study due to adverse events. Maximum concentration (C max) and terminal elimination half-life (t 1/2) of serum FIT039 concentrations after single transvaginal treatment of FIT039CT were similar between the two doses as follows; C max (mean ± standard deviation) was 4.5 ± 0.5 ng/mL (50mg/day) and 4.4 ±1.4 ng/mL (100mg/day) at 6-7 hours; mean t1/2 was 14.8 ± 2.1 hours (50mg/day) and 12.1 ± 2.6 hours (100mg/day) hours. Conclusions: This study demonstrated the safety and validity of transvaginal FIT039CT once a day and may contribute to the development of an antiviral agent that can cure CIN1/2, and supports the design of the ongoing phase 2 clinical study. Clinical trial information: jRCT2051180201.
First-in-human study of OBI-999: A globo H-targeting antibody-drug conjugate in patients with advanced solid tumors.
Authors: Tsimberidou Apostolia Maria , Hsu Pei , Pearce Tillman E. 
Published: June 2022

3029 Background: OBI-999 is a novel antibody-drug conjugate, composed of a humanized monoclonal IgG1 antibody which targets the tumor-associated carbohydrate antigen Globo H, conjugated with monomethyl auristatin E (MMAE, vedotin). Upon binding to Globo H, OBI-999 is internalized into the tumor cell, and the linker (Thiobridge) connecting MMAE (an ultrapotent antimitotic agent) to the monoclonal antibody is cleaved by cathepsin B to release MMAE, thereby causing cell cycle arrest by inhibiting tubulin polymerization. We conducted a first-in-human, phase 1, dose-escalation study of OBI-999 monotherapy in patients with advanced cancer (NTC04084366). Methods: OBI-999 was administered intravenously at doses of 0.4, 0.8, 1.2, and 1.6 mg/kg on Day 1 of a 21-day cycle. Patients received study treatment until disease progression, unacceptable toxicity, or up to 2 years of treatment. Results: Overall, 15 adult patients were treated. OBI-999 administered on Day 1 of each 21-day cycle was well tolerated up to 1.2 mg/kg, the maximum tolerated dose (MTD). Treatment-related AEs (TRAEs) were noted in 40% (6/15) of patients. TRAEs ≥Grade 3 were noted in 27% (4/15) of patients; of whom 3 had neutropenia and 2 had anemia. OBI-999 exhibited non-linear pharmacokinetics from 0.4 mg/kg to 1.6 mg/kg, with lower clearance at higher doses. A retrospective validated automated immunohistochemistry assessment indicated 50% of patients with advanced solid tumors had high Globo H staining (H-score cutoff ≥100). Of 3 patients treated at the 1.6 mg/kg dose level; 2 developed Grade 4 neutropenia during Cycle 1 and the third developed Grade 4 neutropenia on Cycle 2 Day 15. One patient (1.6 mg/kg) with Grade 4 neutropenia also developed Grade 4 renal insufficiency and died from progressive disease (direct bilirubin, 3.5 mg/dL). Five (33.3%) patients had stable disease (SD), including 1 patient with adenoid cystic carcinoma of the oropharynx (SD for 13 cycles); 1 patient with gastroesophageal junction adenocarcinoma (SD for 8 cycles), and 3 patients with other tumor types (SD for 4, 2, and 2 cycles). Conclusions: We completed the dose-escalation portion of the study. OBI-999 was well tolerated. The recommended phase 2 dose was determined to be 1.2 mg/kg once every 3 weeks. Dose-dependent, non-cumulative neutropenia was dose limiting. We are currently enrolling patients with high Globo H expressing solid tumors (H-score ≥100) in the expansion phase of the study, which includes pancreatic, colorectal, and cancers of other histologic subtypes. Clinical trial information: NTC04084366.
Safety, pharmacokinetics, and clinical activity of OBI-3424, an AKR1C3-activated prodrug, in patients with advanced or metastatic solid tumors: A phase 1 dose-escalation study.
Authors: Tsimberidou Apostolia Maria , Verschraegen Claire F. , Hsu Pei , Pearce Tillman E. 
Published: June 2022

3030 Background: OBI-3424 is a novel nitrogen mustard prodrug that can be selectively converted in the presence of the AKR1C3 enzyme into the bis-alkylating agent OBI-2660, which forms intra- and inter-strand DNA crosslinks resulting in cell death. This selective mode of activation distinguishes OBI-3424 from traditional alkylating agents, and potentially improves the safety profile and antitumor activity against chemo- and radio-resistant tumors. We conducted a first-in-human, phase 1, dose-escalation study of OBI-3424 monotherapy in patients with advanced solid tumors (NCT03592264). Methods: OBI-3424 was administered intravenously at doses of 1, 2, 4, 6, 8, or 12 mg/m2 (Days 1 and 8 every 21 days, Schedule A) or 8, 10, 12, or 14 mg/m2 (Day 1 every 21 days, Schedule B). A “3+3” design was used for dose escalation. Patients received study treatment until disease progression, unacceptable toxicity, or up to 2 years of treatment. Results: Overall, 39 adult patients were treated. In patients receiving Schedule A, the maximum tolerated dose (MTD) of OBI-3424 was determined to be 8 mg/m2. Dose limiting toxicities (DLTs) were reported at the 12 mg/m2 dose level, including thrombocytopenia (Grade 3-4, 5 of 6 patients) and anemia (Grade 3-4, 5 of 6 patients). Platelet count nadirs were noted on Day 15 or Day 22. These cytopenias led to dose modification and resulted in protocol amendment (Schedule B). In Schedule B, the MTD was not reached at the maximum dose tested (14 mg/m2). Grade 3 or higher anemia was noted in 3 of 6 patients treated at 14 mg/m2; the recommended phase 2 dose (RP2D) is 12 mg/m2 (Day 1 every 21 days). Treatment-related AEs (TRAEs) were noted in 82% (32/39) of patients. The most common TRAEs were anemia (64%), thrombocytopenia (51%), nausea (26%), and fatigue (21%). No patient had a fatal TRAE, 49% had ≥Grade 3 TRAEs, including 3 patients who had serious TRAEs. OBI-3424 showed linear pharmacokinetics from 1 to 14 mg/m2, with minimal accumulation after repeated dosing. A retrospective validated automated immunohistochemistry assessment indicated that 27% of patients had high AKR1C3 staining (H-score ≥135). Best confirmed response was stable disease in 21 patients (54%). Conclusions: We completed the dose-escalation portion of the study. The RP2D was determined to be 12 mg/m2 once every 3 weeks. OBI-3424 was well tolerated. Dose-dependent, non-cumulative thrombocytopenia and anemia were dose limiting. We are currently enrolling patients with pancreatic cancer and other tumor types with overexpression of AKR1C3 (H-score ≥135) in the expansion phase of the study. Clinical trial information: NCT03592264.
Detection of homologous recombination deficiency (HRD) in cell-free DNA (cfDNA) using an amplicon-based next-generation sequencing (NGS) assay.
Authors: Poh Jonathan , Kaur Harvinder , Ho Jia Min , Choudhury Yukti , Tan Min-Han 
Published: June 2022

3042 Background: Homologous recombination (HR) deficiency is characterized by tumor genomic instability, often due to alterations in BRCA1/2 and other HR-related genes. HRD predicts sensitivity to PARP inhibitors (PARPi) in prostate, ovarian and breast cancers. For the subset of cancers that have genomic instability without detectable alterations in HR genes, profiling biomarkers of HRD such as loss of heterozygosity (LOH) could identify additional HRD positive (HRD+) patients that may benefit from PARPi. Here, we present a novel cfDNA NGS assay that can detect tumor LOH non-invasively to improve assessment of HRD+ status. Methods: An amplicon-based HRD NGS assay covering > 1000 SNPs was developed to detect LOH both globally and on the gene level in cfDNA. Analytical validation was done using LOH+ BRCA-mutant cell lines in limiting dilution admixtures. Clinical performance was assessed by benchmarking findings from 46 tumor tissue DNA samples against results from an orthogonal NGS-based genomic scarring assay. Clinical utility of the HRD assay was evaluated in 75 cfDNA samples, including 72% (54/75) from BRCA-associated cancers (36 breast, 12 prostate, 4 ovarian, 2 pancreatic) and 28% from other cancer types. All cfDNA samples were previously clinically tested by an NGS assay that included BRCA1/2 (LiquidHALLMARK). A subset of cfDNA samples identified as HRD+ were further assessed for alterations in 26 key HR genes ( ARID1A, ATM, ATR, ATRX, BAP1, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FANCC, FANCG, FANCL, MRE11, NBN, PALB2, PTEN, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, and XRCC2). Results: In analytical validation, the assay could detect HRD in admixtures with as low as 18% tumor fraction. In tissue samples, overall concordance of HRD status with the orthogonal test was 91.3% (42/46), with a positive percent agreement of 94.4% (34/36) and negative percent agreement of 80.0% (8/10). In cfDNA, 26.7% (20/75) of samples were HRD+, including 29.6% of BRCA-associated cancers (16/54; 12 breast, 2 prostate, 1 ovarian, and 1 pancreatic) and 19.1% (4/21) of other cancer types. In the three HRD+ breast cancers with pathogenic BRCA mutations, the assay also identified BRCA-specific LOH. Nine HRD+ breast cancers (two BRCA+ and seven BRCA-) were further analyzed for alterations in 26 HR genes. Of the two BRCA+ HRD+ breast cancers, one harbored an additional PTEN loss-of-function (LOF) mutation. Of the seven BRCA- HRD+ breast cancers, one harbored biallelic PALB2 and CDK12 LOF mutations, while another harbored a CDK12 LOF mutation. Conclusions: LOH detection in cfDNA provides additional diagnostic yield of HRD+ status in multiple cancer types, even in the absence of pathogenic HR gene alterations. Further clinical studies to evaluate the utility of HRD detection in cfDNA using LOH and to determine concordance with tumor tissue are ongoing.
Imaging of solid tumors using 68Ga-FAP-2286.
Authors: Hope Thomas A. , Aggarwal Rahul Raj , Dhawan Mallika Sachdev , Kelley Robin Kate , Flavell Robert R. , Lawhn Heath Courtney , Li Yan , Porten Sima P. , Rugo Hope S. , Yom Sue S. , Ippisch Robin , Koshkin Vadim S 
Published: June 2022

3059 Background: Fibroblast Activation Protein (FAP) is a transmembrane protein overexpressed on cancer associated fibroblasts (CAFs), and is abundantly present in many epithelial cancers, suggesting FAP is an attractive imaging and therapeutic target. FAP-2286 is a cyclic peptide that binds to FAP and is currently being evaluated as a radioligand therapy to treat patients (pts) with FAP-positive solid tumors. The role of 68Ga-FAP-2286 as a diagnostic agent is unknown. We present an interim analysis of the ability of 68Ga-FAP-2286 to detect metastatic disease across multiple cancer types. Methods: This is a first in human Phase I/II study of 68Ga-FAP-2286 (NCT04621435) with a planned total enrollment of 65 pts across 3 cohorts: dosimetry cohort (n = 5), cohort with RECIST measurable disease (n = 30) and a cohort at risk for metastases without measurable disease (n = 30). By the cutoff date of February 12, 2022, 27 pts were enrolled (3 in cohort 1, 15 in cohort 2 and 9 in cohort 3). For each pt, the five largest lesions were included for analysis, and for each lesion, the maximum standardized uptake value (SUVmax) of the 68Ga-FAP-2286 and the size (short axis for lymph nodes) were documented. In pts who had an available FDG PET performed within 8 weeks of 68Ga-FAP-2286 PET, uptake on the two scans was compared. Results: Of the 27 enrolled pts, 9 had bladder cancer, 5 sarcoma, 4 head and neck squamous cell cancer (HNSCCA), 3 breast cancer (BC), and 3 castration resistant prostate cancer (CRPC). Most pts (89%, 24/27) had tumors positive for uptake on 68Ga-FAP-2286 PET, including 30 lesions < 1.5 cm, and 17 less than 1.0 cm. 16 pts had a paired FDG PET. In these pts, the average SUVmax on 68Ga-FAP-2286 PET was 244% higher than on FDG PET. Only two pts had higher uptake on FDG PET than on 68Ga-FAP-2286 PET (HNSCCA and DSRCT). The highest relative uptake was seen in 2 pts with BC (both 3.4 times higher on 68Ga-FAP-2286 PET); the average SUVmax in BC was 16.6. The lowest uptake on 68Ga-FAP-2286 PET was CRPC with an average SUVmax of 7.0. Sarcoma had variable uptake with one pt having an SUVmax of 4.5 (Ewing’s), while two pts had an SUVmax over 30 (both undifferentiated pleomorphic). Although sarcoma had high uptake on 68Ga-FAP-2286 PET, it was similar to FDG PET uptake across the 5 pts (ratio to FDG PET = 1.0). Conclusions: 68Ga-FAP-2286 is a promising imaging agent across cancers, although its benefit is not seen equally. BC had the highest absolute uptake and highest relative uptake compared to FDG PET; prostate cancer had the lowest uptake. Further work should be undertaken to define the settings where 68Ga-FAP-2286 PET may inform clinical decision making, and which pts may benefit from FAP-targeted radioligand therapy. Clinical trial information: NCT04621435.
Repeat large panel genomic sequencing identifies actionable alterations and characterizes the genomic landscape in patients with metastatic solid tumors.
Authors: Coleman Niamh , DiPeri Timothy P. , Nguyen Daniel , Naing Aung , Piha-Paul Sarina Anne , Tsimberidou Apostolia Maria , Zheng Xiaofeng , Johnson Amber , Wang Wanlin , Shaw Kenna R. , Dumbrava Ecaterina Elena , Fu Siqing , Rodon Ahnert Jordi , Hong David S. , Subbiah Vivek , Yap Timothy A. , Luthra Rajyalakshmi , Patel Keyur P. , Meric-Bernstam Funda 
Published: June 2022

3076 Background: The implementation of genomic profiling with next generation sequencing has revolutionized the field of precision oncology. Comprehensive genomic testing of tumors to identify actionable genomic alterations is now commonly performed in the care of patients with advanced/metastatic disease. Although the genomic profile of tumors has been shown to evolve with progression and intervening treatments, the role of repeat genomic testing is not well established. We sought to determine the evolution of actionable genomic alterations in patients undergoing repeat genomic testing on the same comprehensive genomic panel. Methods: We retrospectively examined the molecular profiles and medical records of 262 patients with metastatic solid tumors treated in MD Anderson who underwent genomic testing on the same panel (Oncomine, Thermo Fisher) for the detection of somatic mutations in the coding sequence of 143 cancer-related genes, on at least 2 separate occasions. Genomic alterations were reviewed by a central Precision Oncology Decision Support (PODS) team in order to provide annotations at the alteration level on the functional significance. Results: 262 patients underwent repeat genomic testing using the same genomic panel on samples collected at different time points from July 2010 to Dec 2021 across tumor types. Changes in alterations (gain or loss) were identified on repeat testing in most patients (66%) We then specifically assessed changes in alterations that were categorized as actionable if annotated by the PODS team at the time of reporting. A gain or loss of an actionable alteration was detected in 38% (100/262) patients. New actionable alterations were frequently identified (73%; 73/100), while 41% had loss of an actionable alteration (41/100). 14% had both loss and gain of actionable alteration on repeat testing; 58% had new actionable alteration identified alone; 27% had loss of actionable alteration only. Actionable alterations identified on repeat testing included alterations in PI3K/AKT (27%), EGFR (15%), and MAPK (16%). On repeat testing, changes in ³2 actionable alterations were frequently identified in the same test (43%). Conclusions: Repeat large panel genomic testing identifies both gain and loss of actionable alterations in patients with advanced metastatic cancers. Actionable aberrations frequently co-exist with alterations in a variety of other genes, which highlights the complexities of treating patients with metastatic cancer on progression of disease and suggests that tailored combination strategies may be necessary in these patients.