tbuckley/cabot-search huggingface dataset:
Real-world incidence and costs of serious infections and cardiovascular complications among patients with indolent non-Hodgkin lymphoma treated with first-line ibrutinib or bendamustine/rituximab.
Authors: Debra E. Irwin, Stephen Thompson, Rinat Ribalov, Azhar Choudhry
Journal: Journal of Clinical Oncology (2021)

e19528 Background: Patients with Indolent non-Hodgkin lymphoma (iNHL) have shown positive outcomes with ibrutinib monotherapy (IM) as well as bendamustine/rituximab combination (BR) therapy, but no studies have reported on patient outcomes using real-world data. The current analysis evaluated serious infections and cardiovascular complications in iNHL patients treated with first-line IM or BR therapy using US real-world data. Methods: Administrative claims from the MarketScan® Research Databases were used to identify adult patients enrolled in commercial or Medicare supplemental insurance plans based on a first prescription fill of IM or BR therapy (the index date) from 2/1/14 to 9/1/19. Patients included in the study were diagnosed with iNHL, were treatment naïve, and were continuously enrolled for ≥12 months both prior to and following the index date. Serious infections and cardiovascular complications requiring hospitalization (diagnosis code in any position) and associated inpatient costs were evaluated during a fixed 12-month follow-up period. Statistical differences in outcome distributions and costs (reported per patient per month [PPPM]) between the groups were tested. Results: Of 1,948 iNHL patients, 147 had IM and 1,058 had BR as index therapy with ≥12 months of follow-up data. Patients receiving IM were older, more often male, and more likely to have had a lower respiratory tract infection (LRTI) or atrial fibrillation (AF) during baseline compared to BR patients, otherwise the groups had similar baseline characteristics. Hospitalization for serious infections was similar for IM and BR patients during the follow-up period (17.0% vs. 14.4%; p = 0.397); among hospitalized patients, the IM and BR groups incurred similar PPPM inpatient costs ($2,839 vs. $3,954; p = 0.188). Specifically, 7.5% of IM patients had a bacterial infection hospitalization and incurred $2,561 PPPM vs 7.6% of BR patients who incurred $3,975 PPPM (both p &gt; 0.05); 8.8% of IM patients had a LRTI hospitalization and incurred $3,629 PPPM vs 6.1% of BR patients who incurred $4,980 PPPM (both p &gt; 0.05). Hospitalization for cardiovascular complications was similar during follow-up for IM and BR patients (15.6% vs. 12.2%; p = 0.237); among hospitalized patients, the IM and BR groups incurred similar PPPM costs ($3,777 vs. $3,862; p = 0.948). Specifically, 7.5% of IM patients had a hospitalization for AF and incurred $4,481 PPPM vs 3.6% of BR patients who incurred $4,860 PPPM (p = 0.025 and p = 0.875, respectively). Conclusions: In a real-world setting, serious infections and cardiovascular complications requiring hospitalization, including associated costs, were similar among iNHL patients treated with first-line IM or BR over 12 months, although IM patients were more likely to have an AF-related complication.
Roles of Endocannabinoids and Endocannabinoid-Like Molecules in Energy Homeostasis and Metabolic Regulation: A Nutritional Perspective
Authors: S.M. Khaledur Rahman, Toru Uyama, Zahir Hussain, Natsuo Ueda
Journal: Annual Review of Nutrition (2021)

The endocannabinoid system is involved in signal transduction in mammals. It comprises principally G protein-coupled cannabinoid receptors and their endogenous agonists, called endocannabinoids, as well as the enzymes and transporters responsible for the metabolism of endocannabinoids. Two arachidonic acid–containing lipid molecules, arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol, function as endocannabinoids. N-acylethanolamines and monoacylglycerols, in which the arachidonic acid chain is replaced with a saturated or monounsaturated fatty acid, are not directly involved in the endocannabinoid system but exhibit agonistic activities for other receptors. These endocannabinoid-like moleculesinclude palmitoylethanolamide, oleoylethanolamide (OEA), and 2-oleoylglycerol. Endocannabinoids stimulate feeding behavior and the anabolism of lipids and glucose, while OEA suppresses appetite. Both central and peripheral systems are included in these nutritional and metabolic contexts. Therefore, they have potential in the treatment and prevention of obesity. We outline the structure, metabolism, and biological activities of endocannabinoids and related molecules, and focus on their involvement in energy homeostasis and metabolic regulation.
C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation
Authors: Deepti Lall, Ileana Lorenzini, Thomas A. Mota, Shaughn Bell, Thomas E. Mahan, Jason D. Ulrich, Hayk Davtyan, Jessica E. Rexach, A.K.M. Ghulam Muhammad, Oksana Shelest, Jesse Landeros, Michael Vazquez, Junwon Kim, Layla Ghaffari, Jacqueline Gire O’Rourke, Daniel H. Geschwind, Mathew Blurton-Jones, David M. Holtzman, Rita Sattler, Robert H. Baloh
Journal: Neuron (2021)
Predicting dying from lung cancer: Urine metabolites predict the last weeks and days of life.
Authors: Seamus Coyle, Elinor Chapman, James Baker, Hannah Coleman, Brendan Norman, David Hughes, Andrew Davison, Stephen Mason, Mark Boyd, John E Ellershaw, Chris Probert
Journal: Journal of Clinical Oncology (2021)

12030 Background: Recognising dying is difficult. We believe there is a predictable biological process to dying and previously demonstrated that urinary volatile organic compounds change in the last weeks and days of life of patients with lung cancer. We further analysed our urine samples using a different metabolomic platform, Liquid Chromatography QTOF Mass Spectrometry (LC-QTOF-MS). Methods: We prospectively collected urine samples from people with lung cancer many of whom were in the last 4 weeks of life. The samples were analysed using a LC-QTOF-MS. Volcano plots identified metabolites that changed 2 fold for different time periods (0-28 days, 0-14 days, 0-7days, 0-5 days and 0-3 days). All metabolites were also grouped into weeks. A One-way ANOVA between the groups identified metabolites that changed significantly. Cox regression with Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression was used to analyse the data and create a statistical model. Results: 234 urine samples from 112 patients were analysed by LC-QTOF-MS. 90 metabolites were identified that increase or decrease in the last weeks or days. Pathway Analysis using MetaboAnalyst demonstrated a number of biochemical pathways affected during different time intervals; 0-2 weeks and 0-3 days before death. Cox LASSO regression analysis was performed for the last 28 days. A model using 21 metabolites, prognosticates for each day in the last 28 days with high AUC values (88-90%). Patients can be categorized into high, medium and low risk of death. A Kaplan-Meier survival analysis demonstrated the groups were well separated. Conclusions: The results confirm urine metabolites predict when people with lung cancer are in the last weeks and days of life. Our model, using 21 metabolites, prognosticates for each of the last 28 days of life and is approximately 88% -90% accurate. This is the only model able to prognosticate for the last week or days of life.
The validity of progression-free survival (PFS) 2 as a surrogate endpoint for overall survival (OS) in randomized controlled trials (RCTs) of advanced solid tumors.
Authors: Rachel Woodford, Deborah Zhou, Peey-Sei Kok, Sally Lord, Ian Marschner, Michael Friedlander, Chee Khoon Lee
Journal: Journal of Clinical Oncology (2021)

1516 Background: OS is the gold-standard endpoint for treatment efficacy in oncology RCTs. However, prolonged follow-up is required to obtain mature data, which impedes regulatory approval of potentially beneficial therapies. Furthermore, increasing therapeutic options including cross over to investigational agents at disease progression often confound OS findings. PFS-2, defined as time from randomization to progression on second-line therapy, has been proposed as a potential surrogate endpoint for OS. Using a meta-analytic approach, we aimed to assess the association between OS and PFS-2, and its validity compared with other surrogate endpoints. Methods: We performed an electronic literature search to identify RCTs of systemic therapies that reported PFS-2 as a pre-specified endpoint with defined follow up protocols. Articles were screened for eligibility and outcome data were extracted. Correlations in the relative treatment difference between treatment arms for OS vs PFS-2, PFS-1, and objective response rate (ORR) were assessed as the comparison of hazard ratios (HR) and odds ratio (OR) respectively. Results: 38 eligible RCTs comprising of 44 analysis units, with 19,031 patients across 8 unique tumor types were identified. The majority received targeted therapies (72.2%), followed by immunotherapy (IO; 26.3%). The correlations of HR-OS/HR-PFS-2, HR-OS/HR-PFS-1 and HR-OS/OR-ORR were r = 0.67 (95% CI 0.08-0.69), r = 0.12 (95% CI 0.00-0.13) and r = 0.21 (95% CI 0.00-0.33) respectively. Correlations between OS with surrogates was assessed in different subgroups according to post-progression survival times (SPP), types of treatment agents and rate of subsequent therapy after progression (table). Conclusions: Across diverse tumors and therapies, treatment effect on PFS-2 has modest to strong correlation with OS, but poor correlations were observed between OS-PFS-1 and OS-ORR respectively. Across all subgroups, PFS-2 performs consistently better than traditional surrogates of PFS-1 and ORR, validating and providing support for use in future RCTs.[Table: see text]
A phase I, open-label, dose-escalation trial of BI 764532, a DLL3/CD3 bispecific antibody, in patients (pts) with small cell lung carcinoma (SCLC) or other neuroendocrine neoplasms expressing DLL3.
Authors: Martin Wermke, Enriqueta Felip, Valentina Gambardella, Yasutoshi Kuboki, Daniel Morgensztern, Zohra Oum'Hamed, Junxian Geng, Matus Studeny, Taofeek K. Owonikoko
Journal: Journal of Clinical Oncology (2021)

TPS8588 Background: First-line standard of care for pts with metastatic SCLC and neuroendocrine carcinoma (NEC) is platinum-based chemotherapy ± immunotherapy. While the addition of anti-PD1 antibodies has improved outcomes, nearly all pts relapse and prognosis is poor. There is a major unmet need for additional treatment (tx) options. BI 764532 is a delta-like ligand 3 (DLL3)/CD3 T cell engaging bispecific antibody. DLL3 is expressed on the cell surface of many SCLC and NEC tumors, but not on normal cells. In preclinical studies, BI 764532 induced cytotoxicity of DLL3-positive cells and showed anti-tumor activity in animal models. Methods: NCT04429087 is a first-in-human, open-label, dose-escalation trial of BI 764532 in adults with locally advanced/metastatic SCLC, large cell neuroendocrine lung carcinoma, NEC or small cell carcinoma of any other origin. Pts must have failed on or be ineligible for available standard therapies (including ≥1 line of platinum-based chemotherapy). Tumors must be positive for DLL3 expression (archived tissue/in-study fresh biopsy) according to central review. Pts must have ≥1 evaluable lesion (modified RECIST 1.1) outside of CNS and adequate liver, bone marrow and renal organ function. Main exclusion criteria: previous tx with T cell engagers or DLL3-targeted therapies; persistent toxicity from previous tx that has not resolved to ≤ CTCAE grade 1; immunodeficiency or receiving immunosuppressive therapy ≤7 days, prior anti-cancer therapy ≤3 wks/5 half-life periods or extensive field radiotherapy ≤2 wks of first dose of BI 764532. The main objective of phase Ia is to determine the maximum tolerated dose (MTD) or recommended dose for expansion of BI 764532, based on dose-limiting toxicities during the MTD evaluation period. Further objectives are to evaluate safety, tolerability, PK/PD and preliminary efficacy. The phase Ib objectives, endpoints and design will be specified after availability of phase Ia results. The trial will assess ≤3 dosing regimens: Regimen A (fixed iv dose once every 3 wks); Regimen B1 (fixed iv dose once every wk); Regimen B2 (step-in dose[s] followed by fixed-dose weekly doses; optional). Tx will continue until confirmed progressive disease, unacceptable toxicity, other withdrawal criteria or a maximum tx duration of 36 mos, whichever occurs first. For Phase Ia, ̃160 pts will be screened and 110 pts accrued. As of Feb 2021, pts are being recruited and treated in early dose escalation cohorts. Clinical trial information: NCT04429087.
Tucatinib favourably modulates the immune microenvironment and synergises with anti-PD1 therapy in a trastuzumab resistant HER2 murine model
Authors: Ran Li, Sneha Sant, Emmaline Brown, Franco Caramia, Ann Byrne, Kylie Clarke, Michael Neeson, Paul J Neeson, Phillip K Darcy, Scott Peterson, Sherene Loi
Journal: Cancer Research (2021)
ICES (International Carboplatin Emesis Survey) for the evaluation of the emetogenicity of continuous cycles of carboplatin-based chemotherapy with focus on nausea: A MASCC emesis study group, prospective, observational, real-world multi-centric study.
Authors: Bernardo Leon Rapoport, Alexandre Chan, Martin Robert Chasen, Teresa Smit, Liezl Heyman, Chia Jie Tan, Ravi Bhargava, Snezana Bosnjak, Ana Zilic, Adnan Abdul Jabbar, Yaxiong Zhang, Margreet De Necker, Tina V Mhazo
Journal: Journal of Clinical Oncology (2021)

e24086 Background: Chemotherapy induced nausea and vomiting (CINV) following carboplatin containing chemotherapy regimen remains a considerable problem for cancer patients (pts) despite standard antiemetic prophylaxis. This study was undertaken to prospectively evaluate the incidence of CINV in pts undergoing carboplatin-based chemotherapy receiving guidelines consistent CINV prophylaxis (GCCP). All sites did not prescribe NK1-RA as it is not included in all institutional guidelines. Methods: The study enrolled 207 pts undergoing carboplatin-based chemotherapy, the final analysis evaluated cycle 1 - 6 with a total of 183 evaluable pts from 6 countries. Pt diaries were used to collect data from day 1-10 beginning with cycle 1. Nausea was reported by the pts using a visual analog scale (VAS) with the end-point being no nausea. Vomiting episodes were recorded in the pts’ diaries. Demographic, occurrence and severity of emesis, numbers of emetic episodes and time to the onset of emesis, were summarized using descriptive statistics. Results: There were 129 females and 54 males. The overall incidence of acute and delayed nausea for was 17% and 25% respectively. The incidence of nausea of entire population was significantly higher than vomiting (58% vs. 14%; Chi 2 22.271 p&lt;0.000). The use of NK1-RA was associated with a significant decrease in time to first vomiting for cycle 1 (p&lt;0.041) and subsequent cycle 2-6 (p&lt;0.0075). Additional results are reported in the Table. In a logistic regression model factors associated with acute nausea in cycle 1 included history of motion sickness (p&lt; 0.0090), comorbidities (p&lt; 0.0084), history of morning sickness (p&lt; 0.0090), previous chemotherapy (p&lt; 0.0096), anemia (p&lt; 0.0209). A separate logistic regression analysis for delayed nausea in cycle 1 showed that prior radiotherapy (p&lt;0.0093) and a history of morning sickness (p&lt;0.0195) were also significant. During subsequent cycles (1 – 6), the incidence of nausea remained higher than vomiting and was documented in the acute and delayed phases ranging from 6% to 25%. The use of NK1-RA was associated with a lower incidence of vomiting during cycle 1-6 with 91% patient receiving NK1-RA experiencing no vomiting vs 78% of patients not receiving NK1-RA with no vomiting (log rank = 0.0287). Conclusions: Despite GCCP and the usage of NK1-RA, carboplatin induced nausea remains a major unmet medical need in cancer pts. Further research should focus on management of nausea, risk factors and the impact of nausea on quality of life and in pts undergoing carboplatin-based treatment.[Table: see text]
Patterns and predictors of treatment in muscle-invasive bladder cancer (MIBC): A real-world study.
Authors: Zengqi Lu, Jessica M. Clement, Qi Pan, Helen Swede, Rajni Mehta, Xiaoyan Wang
Journal: Journal of Clinical Oncology (2021)

e16531 Background: Among the approaches to curative-intent therapy for MIBC, neoadjuvant cisplatin-based chemotherapy (NAC) is recognized as the gold standard. The combined modality approach of concurrent chemo-radiation is also considered a standard of care. Despite guidelines recommending multidisciplinary care, studies have shown a low adoption rate of multidisciplinary approaches for MIBC. This study aimed to describe the treatment patterns for MIBC pts using real world data. Methods: Following the appropriate IRB approvals, investigators followed a common protocol under the auspices of the Rapid Case Ascertainment at the Yale Cancer Center. Manual chart review was performed on MIBC pts diagnosed in Connecticut from 2004 –2015 and treated at investigator-affiliated hospitals. Information on medical history, comorbidity, and treatment types were recorded. This data set was linked to the Surveillance, Epidemiology, and End Results (SEER) database for demographic information. The descriptive and logistic regression were used to analyze treatment patterns and predicators in each treatment lines: surgery alone, chemotherapy alone, radiation alone and standard care (NAC followed by surgery; surgery followed by adjuvant chemotherapy and concurrent chemo-radiation). Results: The number of adult MIBC pts in the cohort was 1,198. Among them, 290 (24.2%) received surgery as the only treatment; 117 (9.8%) received chemotherapy only; 100 (8.3%) received concurrent chemo-radiation; 96 (8.0%) received NAC followed by surgery. Besides age ( OR: 0.546, 95% CI: 0.289-0.986), when comparing female to male patients on the likelihood of receiving NAC to the alternative treatment types (radiation or surgery), female pts were less likely to receive NAC than males (OR: 0.421, 95% CI: 0.184-0.930). Conclusions: Regardless of demographics, the overall adoption rate of standard care was low, consisting of 236 pts (19.7%) of the population. From the logistic regression results, age was consistently shown as a predictor for receiving NAC over the alternative treatment types, and sex was identified as another strong predictor. Older and female patients were less likely to receive NAC than younger males.[Table: see text]
The COVID-19 pandemic led to a reduction in cancer services in Australia.
Authors: Christine Biondi, Vivienne Milch, Van Nguyen, Regina Ryan, David Roder, Alan Woods, Kristie Cooper, Rhona Wang, Cleola Anderiesz, Dorothy Mary Kate Keefe
Journal: Journal of Clinical Oncology (2021)

e18812 Background: Australian oncologists reported dramatic decreases in cancer referrals during the pandemic. As real time data were difficult to acquire, Cancer Australia used surrogate measures to infer where reductions in medical services occurred. We analysed data available through the Medicare Benefits Schedule (MBS), a list of the medical services and professional attendances subsidised by the Australian Government, for the five highest incidence cancers: breast, colorectal, lung, prostate, and skin cancers. Methods: We identified over 500 MBS item codes for diagnostic and treatment procedures for malignancies and pre-cancerous conditions. Item codes were categorised into analysis groups based on cancer type and/or similarities in type of service. Data were examined at national and jurisdictional levels for 2020 to determine reductions during the initial COVID-19 period and to monitor subsequent recovery. Data were compared to 2019 to account for normal seasonal variation. Results: Australia’s first wave of the pandemic ran from March to May, and a second wave in the state of Victoria alone ran from July to September 2020. We observed notable reductions across all diagnostic and surgical procedure groups examined, with initial reductions observed between March and April for diagnostic procedures, and a one-month delay for surgical procedures, between April and May. Some services showed an initial recovery in May, with many showing partial or full recovery by June. For some groups, analyses showed sustained reductions over the 12-month period. While COVID-19 case numbers were greater during the second wave, the impact on services was less pronounced, likely owing to more refined policy approaches to managing health system and workforce capacity. There was further recovery by September for some but not all services. Similar patterns of change were observed across all Australian states and territories, with some variation by jurisdiction. Conclusions: The pandemic has impacted the delivery of cancer care. Any potential delays in diagnoses and treatment due to these reductions in services may lead to more advanced cancer stage at diagnosis and poorer patient outcomes including recurrence and survival. Impact of COVID-19 on selected cancer services in Australia in 2020.[Table: see text]
COVID-19 vaccine success enables a bolder vision for mRNA cancer vaccines, says BioNTech CEO
Authors: Asher Mullard
Journal: Nature Reviews Drug Discovery (2021)

Uğur Şahin, an oncologist and mRNA pioneer, discusses his firm’s development plans for cancer vaccines, mRNA-encoded proteins and more. Uğur Şahin, an oncologist and mRNA pioneer, discusses his firm’s development plans for cancer vaccines, mRNA-encoded proteins and more.
TMOD-04. IMAGE-BASED DRUG RESPONSE PROFILING FROM PEDIATRIC TUMOR CELL SPHEROIDS USING PATIENT-BY-PATIENT DEEP TRANSFER LEARNING
Authors: Yannick Berker, Dina ElHarouni, Heike Peterziel, Ina Oehme, Matthias Schlesner, Olaf Witt, Sina Oppermann
Journal: Neuro-Oncology (2021)

Abstract Introduction Image-based phenotypic drug profiling is receiving increasing attention in drug discovery and precision medicine. Compared to classical end-point measurements quantifying drug response, image-based profiling enables both the quantification of drug response and characterization of disease entities and drug mechanisms of actions. In pediatric precision oncology, we aim to study drug response in patient-derived 3D spheroid tumor cell cultures and tackle the challenges of a lack of image-segmentation methods and limited patient-derived material. Methods We investigate deep transfer learning with patient-by-patient fine-tuning for cell-viability quantification. We fine-tune a convolutional neural network (pre-trained on ImageNet) with many cell-line-specific and few patient-specific assay controls. The method is validated using 3D cell cultures in 384-well microplates derived from cell lines with known drug sensitivities and tested with primary patient-derived samples. Network outputs at different drug concentrations are used for drug-sensitivity scoring; dense-layer activations are used in t-distributed stochastic neighbor embedding and clustering of drugs. Results Cell-line experiments confirm expected hits, such as effective treatment with BRAF inhibitors in a BRAF V600E mutated brain tumor model and NTRK inhibitors in a cell line harboring an NTRK-fusion, indicating the predictive power of deep learning to identify drug-hit candidates for individual patients. In patient-derived samples, clustering of drugs further confirms phenotypic similarity according to their mechanisms of actions. Combining drug scoring with phenotypic clustering may provide opportunities for complementary combination treatments. Conclusion Deep transfer learning with patient-by-patient fine-tuning is a promising, segmentation-free image-analysis approach for precision medicine and drug discovery based on 3D spheroid cell cultures.