tbuckley/cabot-search huggingface dataset:
The clinical efficacy of olaparib monotherapy or combination with ceralasertib (AZD6738) in relapsed small cell lung cancer.
Authors: Sehhoon Park, Peter G. Mortimer, Simon Smith, Heejung (Rosa) Kim, Hyun Ae Jung, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Woong-Yang Park, Se-Hoon Lee, Keunchil Park
Journal: Journal of Clinical Oncology (2021)

8562 Background: The molecular profiling of small cell lung cancer (SCLC) has demonstrated a high incidence of genomic alterations in cell cycle-related genes and DNA damage and response (DDR) pathways, which correlates with devastating clinical outcomes of SCLC. Using two small molecules targeting the DNA repair pathway, olaparib (PARP inhibitor) and ceralasertib (ATR inhibitor), we evaluated their clinical efficacy in monotherapy or in combination, in relapsed SCLC. Methods: As part of the phase II biomarker-driven umbrella study in SCLC (SUKSES), patients who failed prior platinum-based regimen were enrolled and allocated based on their genomic alterations. Patients with mutations harboring HR pathway gene mutation not limited to BRCA 1 or 2, ATM deficiency or MRE11A mutations were allocated to the olaparib monotherapy (SUKSES-B, NCT03009682). As an biomarker non-matched arm, biomarker unselected patients were also allowed to receive olaparib and ceralasertib arm (SUKSES-N2, NCT0328607). The primary endpoint was objective response rate (ORR), and two-stage Simon’s design was used. Results: Based on pre-defined protocol criteria, both arms terminated at stage 1. In the olaparib monotherapy arm (SUKSES-B, n = 15), ORR was 6.7%, and disease control rate (DCR) was 26.7%, 1 partial response (PR), and 3 stable diseases (SD). Median progression-free survival (PFS) was 1.25 months (95% confidential interval [CI] 1.18–NA), and median overall survival (OS) was 8.56 months (95% CI, 6.62–NA). Adverse events that led to treatment discontinuation (n = 2 total, 13.3%) were drug related grade 3 renal impairment, thrombocytopenia, and grade 2 anemia. A patient with confirmed PR showed a tumor volume decrease of 37% compared to the baseline, and a splicing site mutation in BRCA2 was identified from deep target sequencing. In the olaparib and ceralasertib treatment arm (SUKSES-N2, n = 26), ORR was 3.8% (n = 1) and DCR was 42.3% (n = 11). Median PFS was 2.75 months (95% CI 1.77–5.44), and OS was 7.18 months (95% CI 5.97-10.79). Three patients discontinued treatment due to drug related grade 5 pneumonia, grade 3 drug-induced pneumonitis and grade 2 anemia. The most common adverse events for the combination were anemia (n = 11, 42.3%), followed by thrombocytopenia (n = 6, 23.1%). A patient with confirmed PR with a 43% decreases in tumor volume compared with baseline had a mutation in TP53. Conclusions: Targeting the DDR pathways with olaparib as single agent or in combination with ceralasertib demonstrated early signal of efficacy in relapsed SCLC patients with a tolerable safety profile. Clinical trial information: NCT03009682, NCT0328607.
Fatty Acid Synthesis in Prostate Cancer: Vulnerability or Epiphenomenon?
Authors: Laura A. Sena, Samuel R. Denmeade
Journal: Cancer Research (2021)

Tumor metabolism supports the energetic and biosynthetic needs of rapidly proliferating cancer cells and modifies intra- and intercellular signaling to enhance cancer cell invasion, metastasis, and immune evasion. Prostate cancer exhibits unique metabolism with high rates of
Antibiotic use reduces efficacy of tyrosine kinase inhibitors in patients with advanced melanoma and non-small cell lung cancer.
Authors: Nadina Tinsley, Natalie Cook, Cong Zhou, Sharon Hyo-Eun Nahm, Samuel Rack, Grace Chin Lay Tan, Paul Lorigan, Fiona Helen Blackhall
Journal: Journal of Clinical Oncology (2021)

3100 Background: Antibiotic (ABX) use and disruption of the gut microbiome has been demonstrated to reduce the efficacy of immune checkpoint inhibitors and chemotherapeutics in cancer patients. Little is known about the impact of ABX use in patients treated with targeted therapies, such as tyrosine kinase inhibitors (TKI). Methods: Retrospective data analysis was performed on advanced melanoma and non-small cell lung cancer (NSCLC) patients treated with TKIs between January 2015 and April 2017 at The Christie NHS Foundation Trust, UK. Demographics, prior systemic treatment, extent of disease, lactate dehydrogenase level (LDH), presence of brain metastases, performance status, comorbidities, TKI agent and the use of ABX (class, route, duration) were collected. Progression free survival (PFS) and overall survival (OS) were compared between the ABX+ group (defined as patients treated with ABX within 2 weeks of TKI initiation or 6 weeks after) and the ABX – group (patients with no ABX during specified period). Statistical analyses were performed with univariate and multivariable models. Results: In total, 168 patients were included; 89 patients (53%) with advanced NSCLC and 79 patients (47%) with melanoma. Over a third of patients, (57/168, 34%) received ABX in the specified period (ABX+). On univariable analysis, ABX use was associated with shorter PFS (208 days vs 357 days, p = 0.008) and OS (294 days vs 438 days, p = 0.024). Increased age, poorer performance status, and higher LDH were also associated with shorter PFS and OS. On multivariable analysis, ABX use was independently associated with shorter PFS (HR 1.57, 95% CI 1.05-2.34, p = 0.028) and OS (HR 2.19, 95% CI 1.44-3.32, p = 0.0002). The negative impact of ABX on OS was particularly pronounced for patients with worse performance status (HR 3.82, 95% CI 1.18-12.36, p = 0.025). Conclusions: To our knowledge, this is the largest multivariable analysis showing ABX use independently reduces PFS and OS in patients treated with TKIs. It is the first analysis to demonstrate this phenomenon across two distinct tumour sites. The data suggests that ABX use could be an independent predictor of shorter PFS and OS in cancer patients treated with TKIs, and warrants further validation in a larger cohort.
Optimizing SARS-CoV-2 Surveillance in the United States: Insights From the National Football League Occupational Health Program
Authors: Christina DeFilippo Mack, Michael Osterholm, Erin B. Wasserman, Natalia Petruski-Ivleva, Deverick J. Anderson, Emily Myers, Navdeep Singh, Patti Walton, Gary Solomon, Christopher Hostler, Jimmie Mancell, Allen Sills
Journal: Annals of Internal Medicine (2021)

Evidence to understand effective strategies for surveillance and early detection of SARS-CoV-2 is limited.
A prospective, randomized, controlled, multicenter study of apatinib combined with S-1 plus docetaxel as adjuvant therapy for locally advanced gastric cancer.
Authors: Zhili Shan, Feng Guo, Hong Chen, Dapeng Li, Zhongqi Mao, Jun Zhou, Yongyou Wu, Xudong Sheng, Lijun Hu, Jiang Su, Xu Cheng, Zhiyuan Kong, Huizhu Qiu, Li Shan, Jianzhong Wu, Zhenghai Qiang, Yulan GU, Xiaojun Zhou
Journal: Journal of Clinical Oncology (2021)

e16019 Background: Postoperative adjuvant chemotherapy is commonly given after the curative resection of gastric cancer (GC) in both Eastern and Western countries. Several studies have investigated the feasibility and safety of S-1 plus docetaxel or S-1 plus cisplatin. However, the best choice of adjuvant treatment for patients with gastric cancer is still debated. Apatinib, an oral small molecular of VEGFR-2 TKI, has been confirmed to improve OS and PFS with acceptable safety profile in patients with advanced gastric cancer refractory to two or more lines of prior chemotherapy. In this study, we aimed to evaluate the efficacy and safety of apatinib combined with S-1/docetaxel for locally advanced gastric cancer (T 3-4a N + M 0 ). Methods: This is a prospective, randomized, controlled, multicenter clinical study. Patients with locally advanced gastric cancer, pathological stage T 3-4a N + M 0 who underwent D2 lymphadenectomy without prior anti-cancer therapy were included. All these patients were assigned to group A or B. Patients in group A received 6 cycles (21 days a cycle) of adjuvant therapy using S-1 (80-120mg/d, d1-14), and docetaxel (40mg/m2, d1). Group B received the same regimen with the addition of apatinib (250mg, qd.). The primary endpoint was disease-free survival (DFS). The final analysis cutoff date was 30 November, 2020. Results: A total of 45 patients were enrolled from January 2019 to November, 2010 and assigned to group A (21) or group B (24). The DFS was not reached in both of the groups. The 1-year disease-free survival rate was 60% in group A and 90% in the group B, while the difference was not significant. The main AEs in group A were anemia (55%), nausea (50%) and neutropenia (40%); The most common AEs in group B were anemia (45%) neutropenia (40%) and diarrhea (25%). There were no treatment-related deaths. The longest administered time of apatinib with no progression was 457 days. And the median time to receive apatinib was 329 days. Conclusions: Combination of apatinib with S-1/docexal chemotherapy shows clinical benefits in locally advanced gastric cancer (T 3-4a N + M 0 ), with tolerable toxicity. The study is still ongoing to reach our final endpoint, DFS. Clinical trial information: ChiCTR2000038900.
Secret sauce in collaborative tumor boards: Team-based characteristics that optimize tumor board functionality.
Authors: Barbara Oureilidis-DeVivo
Journal: Journal of Clinical Oncology (2021)

e23015 Background: Interdisciplinary teams are an indispensable characteristic of modern organizations, particularly in healthcare settings that require specialists to work together to solve multifaceted patient care problems. Multidisciplinary tumor boards (TBs) aim to coordinate multidisciplinary perspectives to help the oncology team devise the best treatment program for the patient. Yet, while this is their purpose, studies have found that TBs do not always achieve that goal effectively. Why are some tumor board (TB) teams more effective than others? This study shed light on key characteristics found among highly effective TBs. It provides a theoretical explanation of their organizational behaviors and structures and their effect on cancer treatment decision-making. The research is grounded in organizational behavior theories that have historical prominence in group decision-making, social hierarchy, and interdisciplinary collaboration, and are used to explain the phenomenon under investigation best. Methods: Qualitative research was used in the study. Data from 44 different TB observations and 18 interviews were gathered over four years at seven research hospitals in the United States and United Kingdom. The data were then coded, analyzed and synthesized with organizational behavior theory to explain the social phenomena under investigation. Results: The study revealed that certain TBs practice strong collaboration displaying high levels of partnership, cooperation, equality, and interdependency, which was incorporated explicitly into their meeting systems to achieve their common goal. Team-based characteristics such as members’ consistent shared preferences and identity, coordinated interactions, a collective learning process, and shared power and partnership are key markers found within these teams that positively influenced treatment decision-making processes and outcomes, earmarking best practices in TB groups. Conclusions: Organizational theory that suggests that for a collaborative process to be effective, team-based mechanisms need to be adopted in which each member respects, trusts, and acknowledges the skills and expertise of other disciplines in the organization, shares team values, decision-making processes, responsibilities, and planning, relies mutually upon other team members, and works outside normal professional boundaries openly and willingly. In an egalitarian structure like that of the TBs reviewed in this study, where preferences and identities are consistent and groups are collaborative, treatment decisions are less biased and incorporate multidisciplinary perspectives. Thus, this study suggests that by possessing both team- and task-based characteristics and practices, TBs engage in best practices, and thereby optimize their functionality.
Estimating costs of adverse events (AEs) and healthcare resource use (HRU) in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) receiving tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel): A summary of real-world evidence.
Authors: Hongbo Yang, Cynthia Zhengyun Qi, Anand Dalal, Vamsi Bollu, Jie Zhang, Su Zhang, Stephen Lim
Journal: Journal of Clinical Oncology (2021)

e19551 Background: The AE rates and HRU reported in multiple real-world evidence (RWE) studies of chimeric antigen receptor T-cell (CAR-T) therapies tisa-cel and axi-cel in r/r DLBCL have differed from those in their clinical trials. However, the cost implications from these findings are not well understood in existing literature. This study summarizes information from these RWE studies of tisa-cel and axi-cel and quantifies the associated costs. Methods: A literature review was conducted to identify RWE studies reporting AE rates and HRU of tisa-cel and axi-cel in the United States (US). AE rates and HRU were summarized and the associated costs were estimated using a micro-costing approach. Costs of AE management included hospitalization and pharmacy costs, such as intensive care unit (ICU) stays, inpatient admissions, and medications for the treatment of cytokine release syndrome (CRS) and neurotoxicity events (NE). HRU costs included hospitalization, ICU stays, and outpatient visit costs. Unit costs were from public health databases that are representative of US healthcare system and from literature. Costs were inflated to 2020 US dollars. A range was reported to present evidence if inputs are available from multiple studies. Results were summarized for tisa-cel and axi-cel separately. Results: Four publications were identified: Jaglowski 2019, Pasquini 2019, Riedell 2019, and Jacobson 2020. Across studies, grade 3+ CRS and NE occurred in 1%-4% and 0%-5% of tisa-cel-treated patients and 7%-16% and 20%-35% of axi-cel-treated patients, respectively. Tocilizumab usage was reported in 14%-20% of tisa-cel- and 62%-71% of axi-cel-treated patients. CAR-T infusion was inpatient for 36% of tisa-cel- and 92%-100% of axi-cel-treated patients. The median hospitalization days was 2 for tisa-cel and 15-16 for axi-cel. ICU transfer was observed for 7% and 28%-38% of tisa-cel- and axi-cel-treated patients, respectively, with median stays of 4 and 5 days, respectively. The median number of outpatient visits within 28 days after infusion was 6 for tisa-cel and 4 for axi-cel. The total estimated costs for managing AEs per patient were $843-$1,962 for tisa-cel and $5,979-$10,878 for axi-cel. The total estimated HRU costs per patient were $3,321 for tisa-cel and $32,394-33,166 for axi-cel. Conclusions: RWE studies suggest that patients with r/r DLBCL receiving tisa-cel had numerically lower AE rates, HRU, and cost burden than those receiving axi-cel in the US. The additional cost burden for axi-cel was primarily driven by the incremental ICU and hospitalization care due to a higher proportion of inpatient infusion among patients receiving axi-cel. Further research is warranted to compare the costs associated with the two CAR-Ts in r/r DLBCL.
Live endoscopy events (LEEs): European Society of Gastrointestinal Endoscopy Position Statement – Update 2021
Authors: George J. Webster, Tareq El Menabawey, Marianna Arvanitakis, Cesare Hassan, Jeanin E. van Hooft, Helmut Messmann, Mário Dinis-Ribeiro
Journal: Endoscopy (2021)

Abstract The European Society of Gastrointestinal Endoscopy (ESGE) is dedicated to improving the quality of gastrointestinal endoscopy, including through educational activities such as live endoscopy events (LEEs). The primary goal of LEEs should be to facilitate the improvement of endoscopic patient care through the acquisition of best endoscopic practice. Patients should not expect additional benefit from being treated during a LEE compared to a routine setting. There is limited available evidence on LEE safety but to date there is no indication that patients are at increased risk from participation. Pre-recorded cases with live facilitation can also be used to fulfill learning outcomes. Establishing an endoscopic curriculum with clear learning outcomes is important to structure attendees’ learning, assess course outcomes, and allow appropriate targeting of courses to learner experience. Increasingly, LEEs are streamed online and therefore the necessary measures should be taken to ensure that patients have given appropriate consent and that their anonymity has been safeguarded. ESGE recommends that an endoscopist who is not participating in the live demonstrations is named as patient advocate, and that patient safety should must be prioritized throughout. In all ESGE-organized LEEs the intended learning outcomes, procedural indications and descriptions, attendee feedback, and adverse events should be recorded and submitted in a post-event report to ESGE.
First-in-human study of PM14 in patients with advanced solid tumors.
Authors: Maria Vieito, Santiago Ponce Aix, Luis G. Paz-Ares, Rastilav Bahleda, Christophe Massard, Leyre Agreda, Eva Banus, Cristian Marcelo Fernandez, Elena Y Cristoveanu, Gema Corral, Lourdes Llanero, Rubin Lubomirov, Carmen Maria Kahatt, Salvador Fudio, Antonio Nieto, Martin Cullell-Young, Ali Hassan Zeaiter, Honey Kumar Oberoi, Elena Garralda
Journal: Journal of Clinical Oncology (2021)

3078 Background: PM14 is a new chemical entity that forms DNA adducts which specifically inhibit RNA synthesis and block active transcription of protein-coding genes. Antitumor activity has been demonstrated in vitro in several cell lines (e.g. lung, kidney, prostate), and in vivo in mice bearing xenografted human-derived tumors (soft tissue sarcoma, small cell lung cancer, ovarian, gastric, breast and renal cancer). Methods: Open-label, dose-escalating, phase I trial of PM14 administered as a 3-hour infusion i.v. every 3 weeks (q3wk) in patients (pts) with advanced solid tumors, adequate organ function and ECOG PS score of 0-1. Two schedules were explored: Schedule A (Day 1 [D1], Day 8 [D8]) and Schedule B (D1). Results: 37 pts were treated (Schedule A/B: 28/9 pts). Baseline characteristics of pts (A/B): median age 56/47 years; male 57%/56%; ECOG PS 0: 57%/56%; median of prior lines (range): 3 (1-8)/4 (1-10). Most common tumor types (A + B): STS (n=7 pts), ovarian (n=6), pancreatic (n=4), prostate cancer (n=3). The maximum tolerated dose was 4.5 mg/m 2 for A (dose-limiting toxicities [DLTs]: D8 omission due to lack of recovery of lab parameters for re-treatment [n=2 pts]) and 5.6 mg/m 2 (DLTs: G4 febrile neutropenia [n=1], G4 transaminase increase [n=1]) for B. The recommended dose (RD) was 3.0 mg/m 2 on D1,D8 (A), and 4.5 mg/m 2 on D1 (B). No DLTs were present at the RDs. Most common toxicities were hematological abnormalities and transaminase increase. Main toxicities at the RDs are shown below. Antitumor activity comprised stable disease ≥4 months in 7 heavily pretreated pts (6 in A; 1 in B) at all dose levels. Linear pharmacokinetics were observed for PM14 at tested doses (0.25-5.6 mg/m²), with geometric mean (CV%) total plasma clearance 5.9 L/h (88%), volume of distribution 128 L (81%) and median (range) terminal half-life 15.9 h (7.5-34.3 h). Less than 1.6% of administered dose was recovered in urine. Conclusions: RDs were determined for two PM14 schedules in pts with advanced solid tumors. At the RDs, PM14 is well tolerated and has a manageable safety profile. An expansion phase in specific tumor types, with an optional Bayesian continual reassessment method for RD fine-tuning, is ongoing with both schedules.[Table: see text]
DNA mismatch repair and microsatellite instability in colorectal tumors: An observational study in the Veterans Affairs Health Care System.
Authors: Zachary William Abraham Klaassen, Justin Waller, Lin Gu, Amanda M. De Hoedt, Tongtong Wang, Mayur Amonkar, Deepti Aurora-Garg, Kai-Li Liaw, Amy Wehn, Daniel Albo, Stephen J. Freedland
Journal: Journal of Clinical Oncology (2021)

e15562 Background: Microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR) cancers exhibit high mutational load and are observed in colorectal carcinomas (CRC). The objectives of this study were to determine the proportion of MSI-H/dMMR in CRC and to describe clinical and demographic characteristics among MSI-H/dMMR and non-MSI-H/dMMR CRC patients receiving standard of care in an equal access health care system. Methods: Using the Veteran Affairs (VA) Healthcare system data, we conducted a retrospective study of patients, aged ≥18 years old, diagnosed with CRC who underwent MSI/MMR testing from January 1, 2010 to December 31, 2018. MSI/MMR testing was defined as having received an MSI status determined by polymerase chain reaction and/or next-generation sequencing test or an MMR status determined by immunohistochemistry test. Median and interquartile range (IQR) were calculated for continuous variables while frequencies and percentages were calculated for categorical variables. Results: A total of 291 patients diagnosed with CRC who underwent MSI/MMR testing between 2010-2018 were identified from VA centers. The majority of patients were white (69.8%) and male (95.5%), with median (IQR) age of 65 (56-70) years at diagnosis. Sixty-four (22.0%) patients had stage I CRC at diagnosis, 84 (28.9%) stage II, 87 (29.9%) stage III, and 45 (15.5%) stage IV; 11 (3.7%) had no stage information. Fifty-four (18.6%) patients were reported to have MSI-H and/or dMMR CRC, with rates similar for MSI-H [17.4% (21/121)] vs. dMMR [19.7% (44/223)] alone. The proportion of MSI-H/dMMR varied by CRC stage, and was more common in stage II (26%) and stage III (23%) than in stage IV (6%). Patients were similar between MSI-H/dMMR and non-MSI-H/dMMR with regards to age at diagnosis, gender, race, and ethnicity. Of 54 patients with MSI-H/dMMR CRC, three had metastatic CRC (mCRC) at diagnosis and seven progressed to mCRC. Among 51 MSI-H/dMMR patients without metastatic disease at diagnosis, 18 (35%) underwent chemotherapy and 44 (86%) underwent curative surgery. A similar pattern was also observed among non-MSI-H/dMMR CRC patients. Conclusions: In this real-world observational study in a VA population, we found MSI-H/dMMR was present in 18.6% of CRC patients who received MSI testing, highest in stage II (26%) and stage III (23%) and lowest in stage IV (6%) disease. Results are consistent with published estimates seen across other populations and geographies. Additional research is needed in larger cohorts of patients to further assess utilization patterns and real-world clinical outcomes of newer treatments (immunotherapies) approved for MSI-H/dMMR CRC.