tbuckley/cabot-search huggingface dataset:
Deep learning-based predictive biomarker for immune checkpoint inhibitor response in metastatic non-small cell lung cancer.
Authors: Sehhoon Park, Chang Ho Ahn, Geunyoung Jung, Sarah Lee, Kyunghyun Paeng, Jiwon Shin, Inwan Yoo, Hyun Ae Jung, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park, Yoon La Choi, Sang-Yong Song, Se-Hoon Lee
Journal: Journal of Clinical Oncology (2019)

9094 Background: In the era of immunotherapy, immune checkpoint inhibitor (ICI) has changed the treatment paradigm in metastatic non-small cell lung cancer (NSCLC). Along with clinical trials, there is an ongoing investigation to discover the predictive biomarker of ICI which so far has unsatisfactory reliability. As an effort to enhance the predictive value of ICI treatment, we applied deep learning and developed artificial intelligent (AI) score (range from 0 to 1) to analyze the specific context of immune-tumor microenvironment (TME) extracted by scanned images from H&amp;E slides. Methods: As a ground work, deep learning-based H&amp;E image analyzer, Lunit SCOPE, has been trained with H&amp;E images (n = 1824) from ICI naive NSCLC samples. For the calculation of AI score, training was conducted using responder/non-responder labeled ICI treated samples from the exploratory cohort. The ICI responder was defined as the patient with a best overall response of partial or complete response and stable disease for more than 6 months. The positivity of PD-L1 immunohistochemistry (IHC) was assessed manually by pathologists. Results: The exploratory cohort is composed of NSCLC patients treated with ICI (n = 189) in Samsung Medical Center, and response to ICI was observed in 72 (38.1%) patients. Median follow-up duration was 6.8 months (6.6~8.2). Samples with PD-L1 IHC positive, defined by ≥ 1%, was observed in 138 (73.0%) patients. AI score was significant higher in the responder group (median: 0.391 vs 0.205, P = 6.14e-5), and the patients with AI score above the cut-off (0.337) showed a better response to ICI (odds ratio [OR] 3.47 P = 7.34e-5) which is higher than patients with PD-L1 ≥ 1% (OR 1.92, P = 0.069). High AI score group (n = 83) showed significantly favorable PFS compared to low AI score group (n = 106, median PFS: 5.1m vs 1.9m, hazard ratio [HR] 0.51, P = 9.6e-5) and this outcome was independent with PD-L1 status (P = 6.0e-5). In subgroup analysis, PFS of PD-L1 high / AI score high group (n = 63) had longer median PFS (6.7m) compared to both PD-L1 high / AI score low group (n = 70, 4.0m, P = 0.001) and PD-L1 low/AI score low group (n = 35, 1.9m, P = 4.0e-6). Tumor infiltrating lymphocyte (TIL) density of cancer epithelium was significantly correlated with AI score (Pearson’s r = 0.310, P = 1.43e-5), which suggests that AI score may partly reflect TME represented by TIL. Conclusions: The AI score by machine-learned information, extracted from H&amp;E images without additional IHC stain, could predict responsiveness and PFS of ICI treatment independent of PD-L1 IHC positivity.
Phenotype characterisation of <i>TBX4</i> mutation and deletion carriers with neonatal and paediatric pulmonary hypertension
Authors: Csaba Galambos, Mary P. Mullen, Joseph T. Shieh, Nicolaus Schwerk, Matthew J. Kielt, Nicola Ullmann, Renata Boldrini, Irena Stucin-Gantar, Cristina Haass, Manish Bansal, Pankaj B. Agrawal, Joyce Johnson, Donatella Peca, Cecilia Surace, Renato Cutrera, Michael W. Pauciulo, William C. Nichols, Matthias Griese, Dunbar Ivy, Steven H. Abman, Eric D. Austin, Olivier Danhaive
Journal: European Respiratory Journal (2019)

Rare variants in the T-box transcription factor 4 gene ( TBX4 ) have recently been recognised as an emerging cause of paediatric pulmonary hypertension (PH). Their pathophysiology and contribution to persistent pulmonary hypertension in neonates (PPHN) are unknown. We sought to define the spectrum of clinical manifestations and histopathology associated with TBX4 variants in neonates and children with PH. We assessed clinical data and lung tissue in 19 children with PH, including PPHN, carrying TBX4 rare variants identified by next-generation sequencing and copy number variation arrays. Variants included six 17q23 deletions encompassing the entire TBX4 locus and neighbouring genes, and 12 likely damaging mutations. 10 infants presented with neonatal hypoxic respiratory failure and PPHN, and were subsequently discharged home. PH was diagnosed later in infancy or childhood. Three children died and two required lung transplantation. Associated anomalies included patent ductus arteriosus, septal defects, foot anomalies and developmental disability, the latter with a higher prevalence in deletion carriers. Histology in seven infants showed abnormal distal lung development and pulmonary hypertensive remodelling. TBX4 mutations and 17q23 deletions underlie a new form of developmental lung disease manifesting with severe, often biphasic PH at birth and/or later in infancy and childhood, often associated with skeletal anomalies, cardiac defects, neurodevelopmental disability and other anomalies.
Patient-reported outcomes (PROs) in adult survivors of childhood hematopoietic cell transplant (HCT): A report from the St. Jude lifetime cohort study.
Authors: Neel S. Bhatt, Hsiu-Ju Yen, Hesham M. Eissa, Sujuan Huang, Matthew J. Ehrhardt, Nickhill Bhakta, Kirsten K. Ness, Kevin R. Krull, Deo Kumar Srivastava, Leslie L. Robison, Melissa M. Hudson, I-Chan Huang
Journal: Journal of Clinical Oncology (2019)

10049 Background: We examined PROs including symptom prevalence and quality of life (QOL) in adult survivors of childhood HCT compared to those treated with conventional therapy and non-cancer controls, and risk factors of impaired PROs. Methods: Physical and psychological symptoms and QOL were reported by 112 survivors of hematologic malignancies treated with HCT, 1106 treated with conventional therapy, and 242 non-cancer controls. PROs were self-reported using a survey, which included demographics, Brief Symptom Inventory and 36-Item Short Form Survey. Each participant completed a clinical physical health assessment and chronic health conditions (CHCs) were graded using a modified Common Terminology Criteria for Adverse Events. Multivariable logistic regression was conducted to estimate odds ratios (OR) and 95% confidence intervals (CI) for PROs using demographics and CHCs as predictors. Results: HCT and conventional therapy survivors’ mean age at survey and time since diagnosis were 28 and 29 years, and 19 and 20 years, respectively. The mean age at survey for non-cancer controls was 35 years. HCT survivors reported high prevalence of pain (64%), sensory (39%) and memory problems (29%), anxiety (29%), and depression (24%), which was not significantly different from survivors treated with conventional therapy. Compared to non-cancer controls, HCT survivors had more sensory (OR 3.2; 95% CI 1.5-6.8), motor (OR 4.3; 95% CI 1.2-15.4), and memory (OR 3.7; 95% CI 1.5-8.9) problems, and worse physical QOL (OR 5.4; 95% CI 1.6-18.6). Presence of PROs were associated with organ-specific CHCs (grade 3-4 vs. grade 0-2) not receipt of HCT: cardiac symptoms with cardiovascular CHCs (OR 3; 95% CI 1.8-4.9), pulmonary symptoms with pulmonary CHCs (OR 2.5; 95% CI 1.4-4.3), nausea with gastrointestinal CHCs (OR 2; 95% CI 1.2-3.1), and sensory (OR 1.9; 95% CI 1.2-3.1) and motor (OR 3.3; 95% CI 2-5.5) problems with neurological CHCs. Conclusions: Prevalence of symptoms and impaired QOL in HCT survivors is comparable to survivors treated with conventional therapy, but higher than non-cancer controls. PROs may have a role in facilitating identification of adverse events in survivors.
Delirium incidence, risk factors, and treatment in older adults receiving chemotherapy: A scoping review.
Authors: Shabbir M.H. Alibhai, Patrick Jung, Zuhair Alam, Lily Yeung, Uzair Malik, Ali Taqi Syed, Carla Rosario, Daniel Yokom, Leigha Rowbottom, Ana Patricia Ayala, Roger Reka, Martine Puts
Journal: Journal of Clinical Oncology (2019)

e23025 Background: Older adults with cancer are at increased risk of delirium given their advanced age, multiple comorbidities and medications, prevalence of cognitive impairment, and possibly cancer treatment. Awareness of such risks and interventions to prevent or treat delirium is important to clinicians and to provide high quality care. However, there is scant published information on the risks of delirium with chemotherapy or evidence-based approaches to prevent or treat it. We performed a scoping review to summarize the available evidence. Methods: We conducted a scoping review using the framework of Arksey and O’Malley. We systematically searched peer-reviewed journal articles in English, French, and German from Medline, Embase, PsychINFO, CINAHL Plus, and Cochrane Central from inception until January 2017 to identify studies that examined delirium in patients receiving chemotherapy. We also attempted to identify any studies that reported on multivariable delirium risk prediction models and any clinical trials that examined prevention or treatment of delirium. Article titles and abstracts as well as full text articles were reviewed using Covidence software by two or more reviewers independently. Similarly, data extraction was performed by two independent reviewers. Results: A total of 21,678 titles and abstracts were screened, and 1,166 full-text articles were reviewed. Nineteen articles with varying study designs (retrospective administrative databases to clinical trials) reported on delirium using an acceptable diagnostic standard. Sample sizes varied from 15 to over 21,000. No one tumour site or treatment protocol constituted the majority of studies. The incidence of delirium ranged from 0 to 51% (mean 13.5%). The time course of delirium relative to the cycle of chemotherapy was inconsistently reported. No studies reported on risk prediction models for delirium, and no intervention studies to prevent or treat delirium were identified. An additional 109 studies reported on outcomes that could be part of the delirium syndrome but did not meet even our broad inclusion criteria (e.g. cognitive disturbance). Conclusions: Delirium may occur in over 1 in 8 older adults receiving chemotherapy, although there were substantial limitations in reported studies. This scoping review highlights the dearth of knowledge in the area, particularly for risk factors, prevention, and treatment, and emphasizes the need for high-quality studies examining these important outcomes in the oncology setting.
Changes of estrogen receptor, progesterone receptor and HER2 expression in breast cancer with/without neoadjuvant chemotherapy or endocrine therapy.
Authors: Shigeto Maeda
Journal: Journal of Clinical Oncology (2019)

e14699 Background: Concordance in hormone receptor and Human Epidermal Growth Factor Type 2 (HER2) status in breast cancer was observed between initial biopsy and surgical specimens. This study aimed to analyze the correlation in Estrogen receptor (ER), Progesterone receptor (PR) and HER2 status of the initial biopsy and surgical specimen in non-neoadjuvant therapy (CON), neoadjuvant chemotherapy (NAC) and neoadjuvant endocrine therapy (NAE). Secondary aim is to know the changed expression of ER, PR and HER2 as predictive marker for overall survival. Methods: We retrospectively analyzed 1265 surgical specimens from April 2007 to January 2018 in National Nagasaki Medical Center. Out of 1265 patients, 752 CON, 144 NAC and 28 NAE pairs of samples from initial core biopsy and surgical specimen were compared to the expression of the ER, PR and HER2 by immunohistochemically. Spearman’s rank correlation coefficient is calculated. Results: See table. Conclusions: ER and PR expression percentage is highly correlated between core needle biopsy and surgical specimen. After neoadjuvant chemotherapy, PR lost 8.2% after NAC and 40.8% after NAE. PR loss may become predictive marker after systemic therapy.[Table: see text][Table: see text]
Does the initial biopsy type affect clinically important outcomes in malignant melanoma? A meta-analysis.
Authors: Fatima Fayyaz, Richard A Shellenberger
Journal: Journal of Clinical Oncology (2019)

e21041 Background: Malignant melanoma continues to have an increasing incidence worldwide without a decline in mortality, despite advances in treatment and early detection which have led to improved mortality outcomes for most malignancies. Early detection is particularly favorable for melanoma localized to the site of disease, which confers a five year survival rate of 98.4 %. Guidelines from the American Academy of Dermatology (AAD) give three acceptable options for the initial management of pigmented lesions suspicious for melanoma: elliptical excision, wide punch excision and a deep shave or saucerization. Methods: We performed a systematic review and meta-analysis to better define the evidence for differences between punch incisional and excisional biopsy with regard to clinically important outcomes in the evaluation of skin lesions suspicious for melanoma. These were melanoma specific mortality, all-cause mortality, Breslow tumor thickness, and melanoma recurrence. The comparison groups were punch incisional and excisional biopsy; there was insufficient data to include shave biopsies. Results: The result of pooling the studies that track melanoma specific mortality finds that there is a higher, but non-significant rate of death among those in the punch incisional group. The pooled risk ratio is 1.21, p = 0.153. The results of pooling the all-cause mortality studies also finds a higher, but non-significant, rate of death among the punch incisional group, RR = 1.03, p = 0.390. Pooling the two studies that examine Breslow thickness found that values in the punch incisional group are significantly lower, with a standardized mean difference of -0.17, p = 0.006. Finally, the pooled risk ratio for recurrence was not significant, RR = 1.161, p = 0.198. Conclusions: Until further data is available, there is no evidence to suggest a preferred diagnostic procedure in the initial evaluation of pigmented lesions suspected of cutaneous melanoma related to clinically important outcomes. To our knowledge, this is the first meta-analysis done on this important question regarding melanoma epidemiology and public health.
Neutrophil to lymphocyte ratio ≥4 correlates with 6-month postoperative mortality in cancer patients age &gt;75.
Authors: Imran Yousuf Ali, Saman Sarraf, Robert J. Downey, Soo Jung Kim, Koshy Alexander, Beatriz Korc-Grodzicki, Armin Shahrokni
Journal: Journal of Clinical Oncology (2019)

e23014 Background: We assessed the correlation between elevated neutrophil to lymphocyte ratio (NLR), a pro-inflammatory biomarker, with patient frailty and post-operative 6-month mortality. Methods: Patients aged ≥75 evaluated preoperatively by the Memorial Hospital Geriatrics Service completed a geriatric assessment (GA). NLR was determined from preoperative blood work. Patients were included if they underwent elective surgery between 2015-2018 with hospital length of stay (LOS) ≥ 1 day and had ≥ 6 month follow up. Univariate analysis was used to determine correlation between GA domains and NLR. Multivariable regression (MVR) analysis was used to assess the relationship of frailty and NLR with postoperative 6-month mortality. Results: 1028 patients (median age 80) were included. 323 patients (31.4%) had NLR ≥ 4. By univariate analysis, patients with NLR ≥4 were often male ( 57% vs. 45%), had Karnofsky Performance Status (KPS) &lt; 90 (44% vs. 37%), were dependent for instrumental activities of daily living (iADL) (53% vs. 44%), had social activity limitation (57% vs. 49%) (all p &lt; 0.05) and Timed Up and Go test (TUG) &gt; 10 seconds (40% vs. 33%, p = 0.06). Other conditions, particularly cognitive function, weight loss, polypharmacy did not differ between groups, nor did operative time and blood loss. Patients with NLR ≥4 experienced more major adverse surgical events (8% vs. 5% , p = 0.03) and had longer LOS (9 vs. 6.3, p &lt; 0.001). After six months, 12% and 5% of the NLR≥4 and NLR &lt; 4 groups respectively had died. By MVR analysis, patients with NLR≥4 were at higher risk for 6-month mortality (OR = 1.91, p = 0.01) after adjustment for gender, KPS, iADL, TUG, social activity, major adverse surgical events, LOS, and metastatic disease status. Conclusions: NLR ≥4 was associated with components of the GA but correlated with risk for major adverse surgical events and 6-month postoperative mortality. Ongoing work directed at clarifying the relationship between NLR and risk of specific complications to help plan interventions is needed.
Outcomes of men with recurrent M0 prostate cancer who defer androgen deprivation therapy until metastasis.
Authors: Catherine Handy Marshall, Wei Fu, Hao Wang, Bruce J. Trock, Mario A. Eisenberger
Journal: Journal of Clinical Oncology (2019)

5016 Background: Optimal timing and criteria for implementation of androgen deprivation therapy (ADT) in men with relapsed M0 prostate cancer (PCa) remains undefined. Early ADT induces the non-metastatic castration resistant PCa (nmCRPC) clinical state. FDA approved apalutamide (SPARTAN) and enzalutamide (PROSPER) for nmCRPC based on prolongation of metastasis free survival (MFS) which is now considered a valid endpoint for drug approval. Because overall survival (OS) in PCa is usually long and long-term ADT is associated with irreversible adverse events and high costs, we sought to evaluate OS and other outcomes of men with relapsed PCa and ADT deferred until metastasis. Methods: Retrospective review of 2,636 men who had radical prostatectomy (RP) between 1981-2017 and developed biochemically recurrent PCa from a single-institution. Patients who received ADT prior to metastasis were excluded. Kaplan-Meier survival estimates of MFS and OS were defined from RP to event or censor. Multivariable Cox proportional hazards regression was used to identify prognostic factors. Results: 1,686 men treated with deferred ADT until metastasis or censored metastasis-free were eligible. Medians: follow up 10 years (IQR5-16), age 60 years, PSADT 33 months, Gleason &lt; 7 (24%), Gleason 7 (55%), Gleason &gt; 7 (21%). 688 (41%) received salvage radiotherapy. Median MFS and OS were 21 and 22 years, respectively (Table). In multivariable models, age (HR 1.06, 95% CI 1.04-1.1), Gleason &lt; 8 vs ≥8 (HR 0.4; 0.3-0.5) , RP stage (organ confined vs not 0.6; 0.5-0.8), PSADT (0.995, 0.993-0.997) and salvage RT (0.88; 0.81, 0.96) were associated with OS. Conclusions: Deferred ADT in relapsing M0 patients is associated with long OS measured from time of local treatment, comparable to OS with salvage ADT in contemporary experience. Drug approval trials in nmCRPC should focus on patients at high risk for metastasis and death prior to ADT, and determine standardized criteria for initiation of ADT. Prolongation of MFS in nmCRPC requires further validation and may not necessarily reflect a net OS benefit. [Table: see text]
Evaluation of Dworak grading system as a prognostic indicator after neoadjuvant chemoradiotherapy in rectal cancer patients.
Authors: Rebecca Buecker, Hansen Torsten, Frank Hartmann, Ulrich Schafer
Journal: Journal of Clinical Oncology (2019)

e15053 Background: The objective of this study was to assess the prognostic role of Tumor Regression Grading (TRG) according to the Dworak system on progression free survival (PFS) after chemoradiotherapy (CRT) in locally advanced rectal cancer. Methods: In total, 159 patients with locally advanced rectal cancer who underwent neoadjuvant CRT from January 2007 and December 2016 were enrolled. PFS (any relapse after surgery) was tested against TRG (Dworak grade 1+2 versus Dworak grade 3+4) and other potential risk factors (age, gender, pre- and postoperative T-stage, pre- and postoperative N-stage, grading, lymph invasion, vessel invasion, chemotherapy regime, resection margin, treatment delay). Risk factors with a highly significant influence (p &lt; 0.01) in the univariate Kaplan-Meier (KM) estimation were tested for independence using the multivariate cox regression model. Results: With a mean follow-up of 42.5 months, 5 years and 10 years estimated PFS for all patients was 60.1% and 49.1% respectively. Estimation of 5 years and 10 years PFS was 49.7% and 45.5% for TRG Dworak grade 1+2 (n = 109) and 83.8% and 67% respectively for TRG Dworak grade 3+4 (n = 50). This difference was highly significant (p &lt; 0.001). Other highly significant risk factors were postoperative N-stage (negative versus positive), lymph invasion (L0 versus L1), and resection margin (R0 versus R1/2). In the multivariate analysis, only TRG and post-op N-stage were identified as independent risk factors for PFS. Conclusions: In this analysis, Dworak Tumor Regression Grading appears to be a prognostic marker for oncologic outcomes in locally advanced rectal carcinoma patients treated with neoadjuvant CRT.
Safety and preliminary immunogenicity of JNJ-64041809, a live attenuated, double-deleted <i>Listeria monocytogenes</i>-based immunotherapy, in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Charles G. Drake, Russell Kent Pachynski, Sumit Kumar Subudhi, Douglas G. McNeel, Emmanuel S. Antonarakis, Todd Michael Bauer, Daniel Patricia, Mark Wade, Enrique Zudaire, Gary Mason, Roland Elmar Knoblauch, Nicole L. Stone, Jeffrey R. Infante, Marco Gottardis, Lawrence Fong
Journal: Journal of Clinical Oncology (2019)

e16509 Background: The safety and immunogenicity of JNJ-64041809 (JNJ-809), a live attenuated, double-deleted Listeria monocytogenes (LADD- Lm)-based immunotherapy targeting relevant prostate cancer antigens, was evaluated in a phase 1, multicenter, open-label study in patients (pts) with mCRPC. Methods: Men aged ≥18 years with progressive mCRPC who had received ≥2 prior approved therapies were included. The recommended phase 2 dose (RP2D) and the safety and immunogenicity of JNJ-809 were evaluated. Dose-limiting toxicities (DLTs), adverse events (AEs), T cell response, tumor response, and JNJ-809 bacterial shedding profile were assessed at 2 dose levels, 1 x 10 8 and 1 x 10 9 colony forming units (CFU). Results: 26 pts (median age 66.5 years, White 96%) were enrolled (1 x 10 8 CFU, n = 6; 1 x 10 9 CFU, n = 20). Median duration of treatment was 2.5 months (range 0-9.7). No DLTs occurred and 1 x 10 9 CFU was selected as the RP2D. Most common AEs were chills (n = 24, 92%), pyrexia (n = 21, 81%), and fatigue (n = 16, 62%). Grade ≥3 AEs were reported in 18 (69%) pts and serious AEs in 7 (27%) pts including 1 pt with investigator-assessed treatment-related grade 3 intestinal obstruction. At 1 x 10 8 CFU, all pts had negative blood cultures. At 1 x 10 9 CFU, 6 pts had LADD- Lm-positive blood cultures on day 1; blood cultures on all subsequent days were negative. JNJ-809 transiently induced peripheral cytokines including interferon-γ, interleukin-10, and tumor necrosis factor-α. Of 7 evaluable pts (1 x 10 9 CFU), post-treatment T cell responses were demonstrated in 6 pts to the Listeria antigen LLO and in 5 pts to ≥1 of the 4 encoded tumor antigens. Best overall response was stable disease (SD) in 13/25 evaluable pts with SD ≥16 weeks in 4 pts. The study was terminated early as the data collected from 26 pts were considered sufficient to evaluate safety and immune responses. Conclusions: JNJ-809 has a manageable safety profile consistent with that of other LADD- Lm-based therapies. Observed activation of immune responses with monotherapy did not translate into clinical activity, and further development of JNJ-809 will likely require a combination approach. Clinical trial information: NCT02625857.
Doctors for Extinction Rebellion: new group fights for planetary and public health
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Over 200 doctors from a variety of specialties have joined forces to fight climate change and promote planetary and public health, as part of a new group called Doctors for Extinction Rebellion.1

The group initially met through social media and has now officially formed an organisation that has started to hold meetings around the UK.

Its creation comes in response to the Extinction Rebellion movement, which held protests last month calling …