tbuckley/cabot-search huggingface dataset:
Quantifying the clinical severity of immune-related cutaneous adverse events in clinical trial patients: A prospective study using 3D-total body photography.
Authors: Yuna Oh, Mario E. Lacouture, Mehta Paras, Nicholas Kurtansky, Jeffrey Kern, Donald Y. M. Leung, Sarah J. Noor, Veronica Rotemberg
Journal: Journal of Clinical Oncology (2021)

e13548 Background: Accurate and comprehensive assessment of dermatologic adverse events (AEs) in clinical trials is challenging, given the heterogeneity of appearance and perception of these AEs. For dermatologic AEs, Common Terminology Criteria for Adverse Events (CTCAE) grading of clinical severity primarily relies on the clinician’s reporting of body surface area involved (BSA%) estimated by visual assessment combined with clinician’s interpretation of psychosocial impact, which can vary among raters. Although patient reported outcome (PRO-CTCAE) and QoL (SKINDEX-16) measures have been incorporated to improve accuracy and reliability of symptomatic AE evaluations, the subjective nature of dermatologic CTCAE grading remains. Clinical photography is routinely used to aid in visual comparison but cannot be incorporated to standardized measures due to inconsistencies in lighting, distance from the camera, and position. This prospective study aims to validate the accuracy and utility of affected BSA% using 3D-total body photography (TBP) and quantitative imaging analytics for standardized, objective assessment of immune-related cutaneous adverse events (ircAE) in clinical trials and/or prospective studies. Methods: Polarized and non-polarized TBPs (Canfield Vectra WB360) were acquired on two dermatology clinic visits 2-6 weeks apart (n = 8, to date). CTCAE, PRO-CTCAE, SKINDEX-16 were evaluated by one investigator for both visits. Image analysis including BSA% calculation was conducted using Vectra measurement software by an investigator blinded to clinical grades. Means and ranges for change in CTCAE, BSA%, and SKINDEX-16 were calculated. Results: To date, 29 patients with ircAE have been enrolled with 8 completing both visits. A greater improvement in affected BSA% (-1.9, -13.0, -20.1) and SKINDEX-16 (-8,-11.9,-19.5) were associated with a greater degree of clinical improvement measured by CTCAE (0 to -3). Widest range in the degree of change in BSA% (-24.4, -6.8) and SKINDEX-16 (-31,19) was observed in the group with intermediate change in CTCAE (-2 to -1, n = 5). Conclusions: Estimating affected BSA% via visual assessment is subject to human error and rely on memory or comparison with unstandardized photos to detect clinical improvement of dermatologic conditions. This poses a challenge particularly for cases with mild or moderate clinical improvement, demonstrated by the wide range in the degree of change for BSA% and SKINDEX-16. With consistent lighting, position, and objective measurements, 3D-TBP quantitative image analysis shows promise in reproducible, standardized monitoring and quantification of ircAE clinical severity. Furthermore, the quantitative nature of TBP measurement suggests its potential utility for correlation with underlying immunophenotyping correlative studies and clinical trials.
A scoping review of oncology medical education interventions in low and middle income countries.
Authors: Safiya Karim, Zahra Sunderji, Matthew Jalink, Sahar Mohamed, Nazik Hammad, Scott R. Berry
Journal: Journal of Clinical Oncology (2021)

e23004 Background: A large proportion of the global cancer burden occurs in low and middle income countries (LMICs). One of the significant barriers to adequate cancer control is the lack of an adequately trained oncology workforce. Medical education and training initiatives in oncology are necessary to tackle growing cancer incidence and mortality rates. We performed a scoping review of oncology medical education interventions in LMICs to understand the strategies used to train the global oncology workforce. Methods: We searched OVID MEDLINE and EMBASE databases between January 1, 1995 and March 4, 2020 using a standardized scoping review framework. Articles were eligible if they described an oncology medical education intervention within an LMIC with clear outcomes. Articles were classified based on the target population, the level of medical education, form of collaboration with another institution and if there was an e-learning component to the intervention. Results: Of the 806 articles screened, 25 met criteria and were eligible for analysis. The Middle East/Africa was the most common geographic area of the educational initiative (N=14/25). The majority of interventions were targeted towards physicians (n=15/25) and focused on continuing medical education (n=22/25). Twelve articles described the use of e-learning as part of the intervention. Twenty four articles described some form of collaboration, most commonly with an institution from a high-income country. Language barriers, technology, and lack of physical infrastructure and resources in the LMIC were the most common challenges described. The majority of the initiatives were funded through grants or charitable donations. Conclusions: There is a paucity of published interventions of oncology medical education initiatives in LMICs. Continued medical education initiatives and those targeted towards physicians are most common. There is a lack of collaboration between LMICs in these interventions. Further interventions are needed earlier during medical training and for non-physicians. In addition, increased use of e-learning interventions may overcome certain identified challenges. Encouragement of locally funded initiatives as well as scholarly evaluation and publication of these initiatives are important to improve cancer care in LMICs.
Descriptive study of the therapeutic aggressiveness in oncology patients in the hospital area of Huelva.
Authors: María Amor Urbano, Laura Sánchez Escudero, Rocío Palomo Rodríguez, Angel Inoriza, Tomás Camacho Pizarro, Juan L. Bayo
Journal: Journal of Clinical Oncology (2021)

e18645 Background: The therapeutic aggressiveness (TA) criteria or Earle criteria (EC) (Table) explore indicators that reflect the quality of end-of-life cancer patients (pts). They are considered the gold standard to evaluate TA. The aim of our study is to analyze TA by applying EC in deceased cancer patients (pts) in the hospital area of Huelva. Methods: Observational and descriptive study of deceased cancer pts in the area of Juan Ramón Jiménez (HJRJ) and Vázquez Díaz (HVD) hospitals (2017– 2019). We used the IBM SPSS Statistics 22 program to analyze the overuse of oncology therapies (OT) and invasive therapies near death, as well as underutilization of hospice services (HS). Results: 922 pts were classified according to the type of tumor. The most prevalent was lung-pleural cancer (LC) 27%, followed by colorectal cancer (CRC) 17.7%. 25.3% died in an acute care unit of the HJRJ, 48.7% in the hospice care unit (HCU) of the HVD and 26% at home with follow-up by HCU. 70.3% received OT in the last month of life. 11% started a new treatment and 17% received it in the last 14 days of life. 75.8% of the pts were included in the HCU before death. Of these, 4.3% were included in the 72 hours before death. 18.5% of pts went to the Emergency Service more than once in the last month of life. We also analyzed the previous data according to the type of tumor (Table). Conclusions: Our study reflects an overuse of oncology therapies near death. This produces a greater use of resources, such as assistance to the Emergency Service or aggressive actions to alleviate the adverse effects secondary to the treatments. There is a greater TA in pts with head and neck cancer (HNC). These pts usually initially show malnutrition, comorbidities (heart disease, liver disease) and a borderline performance status before starting the treatment. Our data show that the rise of new therapeutic options in LC and breast cancer generated an overuse of treatment near the end-of-life.[Table: see text]
Targeted and intracellular delivery of protein therapeutics by a boronated polymer for the treatment of bone tumors
Authors: Yang Yan, Lei Zhou, Zhengwang Sun, Dianwen Song, Yiyun Cheng
Journal: Bioactive Materials (2021)

The treatment of malignant bone tumors by chemotherapeutics often receives poor therapeutic response due to the specific physiological bone environment, and thus calls for the development of new therapeutic options. Here, we reported a bone-targeted protein nanomedicine for this purpose. Saporin, a toxin protein, was co-assembled with a boronated polymer for intracellular protein delivery, and the formed nanoparticles were further coated with an anionic polymer poly (aspartic acid) to shield the positive charges on nanoparticles and provide the bone targeting function. The prepared ternary complex nanoparticles showed high bone accumulation both in vitro and in vivo, and could reverse the surface charge property from negative to positive after locating at tumor site triggered by tumor extracellular acidity. The boronated polymer in the de-shielded nanoparticles further promote intracellular delivery of saporin into tumor cells, exerting the anticancer activity of saporin by inactivation of ribosomes. As a result, the bone-targeted and saporin-loaded nanomedicine could kill cancer cells at a low saporin dose, and efficiently prevented the progression of osteosarcoma xenograft tumors and bone metastatic breast cancer in vivo. This study provides a facile and promising strategy to develop protein-based nanomedicines for the treatment of malignant bone tumors.
Pan-cancer analysis of <i>CD274</i> (PD-L1) mutations in 314,631 patient samples and subset correlation with PD-L1 protein expression
Authors: Richard S.P. Huang, Brennan Decker, Karthikeyan Murugesan, Matthew Hiemenz, Douglas A. Mata, Gerald Li, James Creeden, Shakti H. Ramkissoon, Jeffrey S. Ross
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background The effects of non-amplification short variant (SV) mutations in CD274 (programmed death-ligand 1 (PD-L1)) on PD-L1 protein expression and immune checkpoint inhibitors (ICPIs) therapy are unknown. Here, we present a retrospective analysis of CD274 mutations detected by comprehensive genomic profiling (CGP) and correlate these results with tumor-cell PD-L1 immunohistochemistry (IHC)-based expression assessment to better understand the relationship between mutations and protein expression of PD-L1. Methods CGP was performed on hybridization-captured, adaptor ligation-based libraries using DNA and/or RNA extracted from 314,631 tumor samples that were sequenced for up to 406 cancer-related genes and select gene rearrangements. PD-L1 IHC was performed on a subset of cases (n=58,341) using the DAKO 22C3 PD-L1 IHC assay and scored with the tumor proportion score (TPS). Results Overall, the prevalence of CD274 SV mutations was low (0.3%, 1081/314,631) with 577 unique variants. The most common CD274 SV mutations were R260H (n=51), R260C (n=18), R125Q (n=12), C272fs*13 (n=11), R86W (n=10), and R113H (n=10). The prevalence of CD274 mutations varied depending on tumor type with diffuse large B-cell lymphoma (1.9%, 19/997), cutaneous squamous cell carcinoma (1.6%, 14/868), endometrial adenocarcinoma (1.0%, 36/3740), unknown primary melanoma (0.9%, 33/3679), and cutaneous melanoma (0.8%, 32/3874) having the highest frequency of mutations. Of the R260H cases concurrently tested with PD-L1 IHC, most (81.8%, 9/11) had no PD-L1 expression, which contrasts to the five E237K cases where most (80%, 4/5) had PD-L1 expression. In addition, we saw a significantly lower level of PD-L1 expression in samples with a clonal truncating variant (nonsense or frameshift indel) when compared with samples with a subclonal truncating variants (mean: TPS=1 vs TPS=38; p&lt;0.001), and also in clonal versus subclonal missense mutations (mean: TPS=11 vs TPS=22, respectively; p=0.049) Conclusions We defined the landscape of CD274 mutations in a large cohort of tumor types that can be used as a reference for examining CD274 mutations as potential resistance biomarkers for ICPI. Furthermore, we presented novel data on the correlation of CD274 mutations and PD-L1 protein expression, providing important new information on the potential functionality of these mutations and can serve as a basis for future research.
Phase 1b study of AMG 757, a half-life extended bispecific T-cell engager (HLE BiTEimmune-oncology therapy) targeting DLL3, in de novo or treatment emergent neuroendocrine prostate cancer (NEPC).
Authors: Rahul Raj Aggarwal, Ana Aparicio, Axel Heidenreich, Shahneen Kaur Sandhu, Yiran Zhang, Mark Salvati, Aditya Shetty, Nooshin Hashemi Sadraei
Journal: Journal of Clinical Oncology (2021)

TPS5100 Background: NEPC is an aggressive cancer with poor prognosis. No standard treatment approach for NEPC exists and it remains an unmet need. NEPC is usually treatment-emergent, characterized by histological transformation from adenocarcinoma to a high-grade neuroendocrine tumor (NET), and may develop in 15%–20% of patients (pts) treated with standard prostate adenocarcinoma therapies, including novel hormonal therapies. The inhibitory Notch ligand, Delta-like ligand 3 (DLL3), is highly expressed on the surface of cancer cells, including NEPC cells, making it an attractive and a promising therapeutic target. AMG 757 is an HLE BiTE immuno-oncology therapy designed to redirect cytotoxic T cells to tumor cells by binding DLL3 on cancer cells and CD3 on T cells, resulting in T cell activation and expansion and T cell-dependent killing of tumor cells. AMG 757 showed in vitro activity in DLL3-expressing NETs, including NEPC. Preliminary results of an on-going first-in-human study suggest AMG 757 is safe and effective in pts with small cell lung cancer (NCT03319940), which prompted its study in NEPC. Methods: NCT04702737 is an open-label, phase 1b study evaluating AMG 757 infusion in pts with metastatic de novo or treatment-emergent NEPC, consisting of dose exploration and then dose expansion. Key eligibility criteria include adults (≥18 y) with NEPC whose disease progressed/recurred after ≥1 treatment course including a platinum-based regimen for de novo NEPC or an androgen signaling inhibitor, measurable disease per modified RECIST 1.1 per Prostate Cancer Working Group 3 modifications, ECOG performance status ≤2, life expectancy &gt; 3 mo, adequate organ function, and no untreated/symptomatic brain metastases. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose or recommended phase 2 dose of AMG 757. Secondary objectives are to evaluate antitumor activity (ie, objective response, duration of response, progression-free survival, overall response) and characterize pharmacokinetics. The starting dose for dose exploration will be based on the dose deemed safe and tolerable in the ongoing trial of AMG 757 in SCLC. The study is open to enrollment. Clinical trial information: NCT04702737.
OMIC-08. COMPOUND HETEROZYGOSITY OF POLE AND PMS2 LEADS TO CMMRD-LIKE PHENOTYPE- “POLYNCH” SYNDROME
Authors: Orli Michaeli, Hagay Ladany, Yosef E Maruvka, Ayelet Erez, Shay Ben Shachar, Shai Izraeli, Yael Goldberg, Helen Toledano
Journal: Neuro-Oncology (2021)

Abstract Mono-allelic germline pathogenic variants (PV) in one of the mismatch repair (MMR) system genes cause Lynch syndrome, associated mainly with colon and endometrial cancer in adults. Germline PVs in DNA polymerase epsilon (POLE) are associated with a dominantly inherited syndrome which confers risk for polyposis and colon cancer. Brain tumors have been described as part of Lynch syndrome and POLE associated syndrome, mostly in adults. Constitutional mismatch repair deficiency (CMMRd) is caused by bi-allelic mutations in the MMR genes, associated with multiple café au lait macules (CAMs) and high incidence of pediatric cancer, including brain tumors. Both MMRD and POLE associated tumors have high tumor mutation burden (TMB), however, microsatellite status is usually unstable in MMR tumors, and stable in POLE. Germline POLE and CMMRd tumors have different mutational signatures, as is signature of MMR tumors with secondary somatic POLE. We describe a 4.5 y/o male who presented with a grossly metastatic SHH-activated, TP53-wildtype desmoplastic medulloblastoma. Physical examination was noted for CAMs. Family history was positive for a heterozygous POLE variant with variable clinical manifestations. Immunohistochemistry of the tumor showed loss of nuclear expression of the MMR gene PMS2, specifically in tumor cells. Analysis showed exceptionally high TMB (up to 276 Mut/Mb) and both the MMR and the POLE signatures. Germline analysis detected the familial POLE variant as well as a de novo heterozygous PMS2 PV. The phenotype of the patient together with the tumor’s features, led us to classify this case as a CMMRd-like. The patient had a partial response to intensive chemotherapy and is currently on immunotherapy without radiation. Collectively, our data suggest that heterozygous simultaneous germline mutations in MMR and polymerase genes can lead to novel “POLYNCH syndrome” that manifests with an ultra-hypermutant aggressive tumor and requires appropriate treatment and surveillance.
Management of Women With Breast Cancer and Pathogenic Variants in Genes Other Than <i>BRCA1</i> or <i>BRCA2</i>
Authors: Mark Robson
Journal: Journal of Clinical Oncology (2021)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in the Journal of Clinical Oncology, to patients seen in their own clinical practice.
Impact of pre-treatment derived neutrophil-lymphocyte-ratio on outcomes in patients with triple-negative breast cancer.
Authors: Rakesh Kumar Sharma, Ajay Gogia, Ritu Gupta, SVS Deo, Dayanand Sharma, Sandeep Mathur, Hari Krishna Raju Sagiraju
Journal: Journal of Clinical Oncology (2021)

e12556 Background: There is an ambiguity of data regarding the predictive and prognostic significance of pre-treatment-derived neutrophil-lymphocyte-ratio (DNLR) to attain pathologic complete response (pCR) after neo-adjuvant chemotherapy (NACT) and survival in patients with triple-negative breast cancer (TNBC). Methods: In this ambispective study, conducted at Dr. B.R.A., I.R.C.H., AIIMS, New Delhi, 328 patients of TNBC registered from a period of May 2013 to June 2020, who received treatment with curative intent were included. Patients with oligometastatic TNBC who received NACT with curative intent were also included in the analysis. Survival analysis to evaluate the correlation of pre-treatment DNLR with relapse-free survival (RFS) and overall survival (OS) was done. Logistic regression analysis was done to evaluate the association of DNLR with pCR among the subset of the sample who completed NACT and underwent surgery. Results: The median age of our cohort was 45 (18-74) years. Study cohort comprised of 165 (50.3%) pre-menopausal, 150 (45.7%) post-menopausal and 12 (3.7%) peri-menopausal patients respectively. Stage distribution as per AJCC 7th edition was stage-I 8 (2.4%), stage-II 127 (38.7%), stage-III 171(52.1%), and stage-IV 22 (6.7%) patients respectively. The median duration of symptoms was 3 (0.25-36) months. One seventy-three (52.7%) patients received NACT and underwent surgery, out of which 52 (30.1%) patients achieved pCR. Median DNLR in the overall population was 1.7 (0.4-10.1) and the median derived lymphocyte count of 2290 (370-11700) with &lt; 5%(n = 14) having baseline lymphopenia( &lt; 1000). Based on the maximum sensitivity and specificity, a DNLR cut-off point of 1.77 in the overall population and 1.88 among those patients who underwent surgery following NACT were used to categorize low and high DNLR. Median RFS was 73.5 months in our sample, whereas median OS was not reached. The 3-year RFS and OS rates were 65.8% (59.0-71.8) and 85.1% (79.5-89.2%) respectively. High DNLR( &gt; 1.77) was not associated with RFS [HR (95%CI): 1.36 (0.90-2.06)] and OS [HR (95% CI): 0.97 (0.52-1.81)]. In a subset analysis of patients (173) undergoing surgery following NACT, high DNLR ( &gt; 1.88) was not found to be associated with pCR [OR (95% CI): 0.81 (0.42-1.57)]. Conclusions: Pre-treatment DNLR is an easily available inflammatory marker. Indian patients of TNBC usually have raised baseline lymphocyte count, hence, pre-treatment DNLR may not be a reliable predictor of pCR and survival outcomes in these patients. Association of DNLR at various treatment and post-treatment time points with survival outcomes needs further exploration.
Inhibition of myocardial cathepsin-L release during reperfusion following myocardial infarction improves cardiac function and reduces infarct size
Authors: Weihong He, Charlotte S McCarroll, Katrin Nather, Kristopher Ford, Kenneth Mangion, Alexandra Riddell, Dylan O’Toole, Ali Zaeri, David Corcoran, David Carrick, Mathew M Y Lee, Margaret McEntegart, Andrew Davie, Richard Good, Mitchell M Lindsay, Hany Eteiba, Paul Rocchiccioli, Stuart Watkins, Stuart Hood, Aadil Shaukat, Lisa McArthur, Elspeth B Elliott, John McClure, Catherine Hawksby, Tamara Martin, Mark C Petrie, Keith G Oldroyd, Godfrey L Smith, Keith M Channon, Colin Berry, Stuart A Nicklin, Christopher M Loughrey
Journal: Cardiovascular Research (2021)

Abstract Aims Identifying novel mediators of lethal myocardial reperfusion injury that can be targeted during primary percutaneous coronary intervention (PPCI) is key to limiting the progression of patients with ST-elevation myocardial infarction (STEMI) to heart failure. Here, we show through parallel clinical and integrative preclinical studies the significance of the protease cathepsin-L on cardiac function during reperfusion injury. Methods and results We found that direct cardiac release of cathepsin-L in STEMI patients (n = 76) immediately post-PPCI leads to elevated serum cathepsin-L levels and that serum levels of cathepsin-L in the first 24 h post-reperfusion are associated with reduced cardiac contractile function and increased infarct size. Preclinical studies demonstrate that inhibition of cathepsin-L release following reperfusion injury with CAA0225 reduces infarct size and improves cardiac contractile function by limiting abnormal cardiomyocyte calcium handling and apoptosis. Conclusion Our findings suggest that cathepsin-L is a novel therapeutic target that could be exploited clinically to counteract the deleterious effects of acute reperfusion injury after an acute STEMI.