tbuckley/cabot-search huggingface dataset:
Pre-existing interstitial lung abnormalities are risk factors for immune checkpoint inhibitor-induced interstitial lung disease in non-NSCLC cancers.
Authors: Kiyofumi Shimoji, Takeshi Masuda, Yu Nakanishi, Kakuhiro Yamaguchi, Shinjiro Sakamoto, Yasushi Horimasu, Taku Nakashima, Shintaro Miyamoto, Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori
Journal: Journal of Clinical Oncology (2020)

e15171 Background: Immune check point inhibitor (ICI) induced interstitial lung disease (ICI-ILD) is a clinically serious and life-threatening toxicity. Pre-existing ILD has been reported to be a risk factor for ICI-ILD in patients with non-small cell lung cancer (NSCLC). In addition, we have previously reported that interstitial lung abnormality (ILA) is also a risk factor for the ICI-ILD. Therefore, we investigated whether any patient characteristics, including ILA, were risk factors for ICI-ILD in patients with non-NSCLC cancers. Methods: Head and neck cancer, malignant melanoma, oral cavity cancer, renal cell carcinoma or gastric cancer patients who received anti PD-1 antibody (Nivolumab or Pembrolizumab) at Hiroshima University Hospital from December 2015 to May 2019 were enrolled. Information on patient characteristics before anti-PD-1 antibody administration, including chest CT findings and laboratory data, were obtained. Results: Two hundred patients were enrolled, and 20 (10%) developed ICI-ILD. Grade1 was observed in 15 patients, grade2 in 3, and grade3 and 5 in 1. There was no significant difference in the background factors between patients with and without ICI-ILD. On the other hand, the proportion of patients with ILA was significantly higher in the patients with ICI-ILD than those without (P &lt; 0.01). Furthermore, univariate logistic regression analysis revealed ILA was the risk factor for ICI-ILD (p &lt; 0.01), and multivariate logistic regression analysis showed that GGA or reticulation in ILA was an independent risk factor for ICI-ILD (p = 0.016, 0.011). Conclusions: Pre-existing ILA is a risk factor for ICI-ILD, and GGA or reticulation in ILA is an independent risk factor for ICI-ILD in patients with non-NSCLC cancers. Therefore, we should pay more attention to the development of ICI-ILD in patients with ILA, especially GGA or reticulation.
Application of early rehabilitation treatment for patients with anterior cruciate ligament injury of knee undergoing artbroscopic reconstruction
Authors: 杨东辉, 顾全霞
Journal: BMJ (2012)

A total of 74 patients undergoing arthroscopic reconstruction for anterior cruciate ligament (ACL) injury from January 2007 to September 2009 were randomly divided into the treatment and control groups.The treated patients started training at day 1 post-operation while the controls had initial external plaster fixation for 4 - 6 weeks followed by supporting devices with active and passive functional exercises of knee flexion and extension.All Lysholm scores in two groups were better at Month 12 than those at Month 3 [(93.8±2.7)vs.(81.8±4.2),(80.0±7.6) vs.(75.2±4.2); t=2.85,P＜0.0l,t=2.16,P＜0.05,respectively].The scores in the treatment group achieved better curative effects than those in the control group at Months 3,6 and 12 (P ＜0.01 ) ; Early and standard rehabilitation training for the patients with ACL injury of knee after reconstruction will facilitate the recovery of knee joint fumction.

Key words: 
Exercise therapy; Anterior cruciate ligament
Hyperprogression on immune checkpoint inhibitors: A single institution, real-world retrospective analysis.
Authors: Koosha Paydary, Krishna Rekha Moturi, Binav Baral, Muhammad Zain Farooq, Thomas E. Lad, Ankit Mangla
Journal: Journal of Clinical Oncology (2020)

e15143 Background: Hyper progressive disease (HPD) refers to the paradoxical acceleration of tumor growth following immune-checkpoint inhibitor (ICI) therapy. We aimed to evaluate the factors associated with HPD and its impact on overall survival (OS) in patients treated with ICI in our institution. Methods: We retrospectively reviewed the charts of 104 patients with solid tumors diagnosed from 04/01/2011 to 06/30/2018 who received ICI at John H. Stroger Jr. Hospital of Cook County, Chicago, IL. The OS, incidence of HPD and their demographic, clinical and laboratory correlates were recorded. HPD was defined as tumor growth ratio &gt; = 2 on CT imaging after treatment with at least 2 cycles. The Log-rank method survival analysis was done to compare survival of patients with and without HPD. Results: Majority of patients were treated with either nivolumab (71.1%) or pembrolizumab (21.2%) in the second (50%) or third line (29.8%) setting. After excluding two patients without follow up scans, 14 out of 102 patients (13.7%) had HPD during the course of study. The patients with small cell lung cancer had higher incidence of HPD (4 out of 9). Patients who had evidence of HPD had significantly shorter OS (22.21±16.23 months versus 37.52±230.8 months, P value = 0.01). The variables associated with HPD were liver metastasis (Pearson Chi squared = 18.68, P value &lt; 0.001) and persistently high LDH ( &gt; 240 IU/L) during therapy (Pearson Chi squared = 16.85, P value &lt; 0.001). Other variables that were significantly associated with HPD on univariate analysis, but not on multivariate analysis are as below. Conclusions: Although the etiopathogenesis of HPD is incompletely understood, the correlation of LDH to HPD is intriguing and warrants further studies as possible predictive marker of HPD. [Table: see text]
Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington's disease Young Adult Study (HD-YAS): a cross-sectional analysis
Authors: Rachael I Scahill, Paul Zeun, Katherine Osborne-Crowley, Eileanoir B Johnson, Sarah Gregory, Christopher Parker, Jessica Lowe, Akshay Nair, Claire O'Callaghan, Christelle Langley, Marina Papoutsi, Peter McColgan, Carlos Estevez-Fraga, Kate Fayer, Henny Wellington, Filipe B Rodrigues, Lauren M Byrne, Amanda Heselgrave, Harpreet Hyare, Cristina Sampaio, Henrik Zetterberg, Hui Zhang, Edward J Wild, Geraint Rees, Trevor W Robbins, Barbara J Sahakian, Douglas Langbehn, Sarah J Tabrizi
Journal: The Lancet Neurology (2020)

Disease-modifying treatments are in development for Huntington's disease; crucial to their success is to identify a timepoint in a patient's life when there is a measurable biomarker of early neurodegeneration while clinical function is still intact. We aimed to identify this timepoint in a novel cohort of young adult premanifest Huntington's disease gene carriers (preHD) far from predicted clinical symptom onset.
Value of acoustic radiation force impulse in the differential diagnosis of benign and malignant hepatic neoplasms
Authors: Yan Zhang, Lei Dong, Yuan-yuan Sun, Xiao-feng Zhao
Journal: BMJ (2013)

To explore the value of acoustic radiation force impulse (ARFI) technique in the differential diagnosis of benign and malignant hepatic neoplasms. Retrospective analysis of touch tissue quantification (VTQ) and general ultrasonic examination of interesting region were performed for hepatocellular carcinoma (HCC), hepatic hemangioma, focal nodular hyperplasia (FNH) and controls. Significant differences existed between HCC and hepatic hemangioma, hepatic FNH and controls (all P 0.05). There was no significant difference between hepatic hemangioma, FNH and controls (all P>0.05). With a cut-off VTQ value of 1.95 m/s, the sensitivity and accuracy rate in the differentiation of benign and malignant hepatic neoplasms was 90% and 83% respectively. The sensitivity and accuracy rate in general ultrasound examination of hepatic neoplasms was 88% and 70% respectively. Significant differences existed in accuracy rate between two methods (P<0.01). It was confirmed that ARFI could reflect the stiffness of liver neoplasm noninvasively. Compared with general ultrasonography, ARFI is better at differentiating benign and malignant hepatic neoplasms.


Key words: 
Liver neoplasm; Ultrasonography
Does time to treatment initiation affect survival in patients with gallbladder cancer?
Authors: KM Islam, Lorriane Achieng Odhiambo, Benjamin Ansa, Mehmet Sitki Copur
Journal: Journal of Clinical Oncology (2020)

e16600 Background: Gallbladder cancer (GBC) is the most aggressive malignancy of the biliary tract. Though rare, most diagnoses are made in advanced stages, which significantly impacts survival outcomes. In the U.S., only 20% of GBC cases are diagnosed early. In addition to late diagnosis, time to treatment initiation (TTI) after diagnosis may contribute to poor prognosis in GBC patients. The role TTI plays on survival is not well understood in patients with GBC. This study aimed to determine the effect of time to treatment initiation on overall survival and by stage. Methods: Data on 26,952 GBC patients from 2004 to 2012 were obtained from the National Cancer Database (NCDB). The primary outcome was overall survival in months. TTI was defined as the number of days between diagnosis and treatment initiation (surgery, chemotherapy, radiation). The Kaplan-Meier method was used to calculate survival estimates and Cox proportional hazards regression model to evaluate the effects of TTI (continuous variable) stratified by stage. Results: The overall median survival was 8.6 months (I.Q.R. = 2.6-23.9). The effect of TTI on survival (unadjusted Hazard Ration (UHR) 1.0 (p = &lt; 0.0001)) was significant, but not after adjusting for other variables, (adjusted Hazard Ratio (AHR) 1.0 (p = 0.1506)). The trend was different across cancer stages. TTI showed a negative effect on survival in stages III (AHR: 1.00, p = 0.0083) and IV (AHR: 0.99, p &lt; .0001). Other factors associated with lower survival are advanced stage, male, older age, comorbidity, community cancer facility, and whether a patient visited more than one facility for treatment. Conclusions: In general, time to treatment initiation did not affect survival but advanced stage lowered survival significantly. More attention should be given to patients who decide to seek second opinion at or those given treatment referrals to other facilities as the adjustments may contribute to delays in treatment initiation.
The contribution of B cells to transplantation tolerance
Authors: Luis Graca
Journal: Journal of Clinical Investigation (2020)

Since it was shown in the early 1950s that it is possible to induce transplantation tolerance in neonates, immune tolerance strategies have been actively pursued. It was found that T cells play a critical role in graft rejection, but can also be major players in mediating transplantation tolerance. Consequently, many experimental systems focused on T cells, often with a complete exclusion of B cells from in vivo animal models. It is now becoming clear that in addition to T cells, B cells can mediate graft rejection and transplantation tolerance. In this issue of the JCI, Khiew et al. investigated the contribution of alloreactive B cells to transplantation tolerance using a mouse cardiac transplantation model. The authors revealed a distinct tolerant B cell phenotype possessing the ability to suppress naive B cells. These data lead to a better understanding of B cell contributions to transplantation tolerance, and may inform the development of future immune tolerance protocols.
In-depth plasma proteomics reveals increase in circulating PD-1 during anti-PD-1 immunotherapy in patients with metastatic cutaneous melanoma
Authors: Haris Babačić, Janne Lehtiö, Yago Pico de Coaña, Maria Pernemalm, Hanna Eriksson
Journal: Journal for ImmunoTherapy of Cancer (2020)

Immune checkpoint inhibitors (ICIs) have significantly improved the outcome in metastatic cutaneous melanoma (CM). However, therapy response is limited to subgroups of patients and clinically useful predictive biomarkers are lacking.To discover treatment-related systemic changes in plasma and potential biomarkers associated with treatment outcome, we analyzed serial plasma samples from 24 patients with metastatic CM, collected before and during ICI treatment, with mass-spectrometry-based global proteomics (high-resolution isoelectric focusing liquid chromatography-mass spectrometry (HiRIEF LC-MS/MS)) and targeted proteomics with proximity extension assays (PEAs). In addition, we analyzed plasma proteomes of 24 patients with metastatic CM treated with mitogen-activated protein kinase inhibitors (MAPKis), to pinpoint changes in protein plasma levels specific to the ICI treatment. To detect plasma proteins associated with treatment response, we performed stratified analyses in anti-programmed cell death protein 1 (anti-PD-1) responders and non-responders. In addition, we analyzed the association between protein plasma levels and progression-free survival (PFS) by Cox proportional hazards models.Unbiased HiRIEF LC-MS/MS-based proteomics showed plasma levels' alterations related to anti-PD-1 treatment in 80 out of 1160 quantified proteins. Circulating PD-1 had the highest increase during anti-PD-1 treatment (log2-FC=2.03, p=0.0008) and in anti-PD-1 responders (log2-FC=2.09, p=0.005), but did not change in the MAPKis cohort. Targeted, antibody-based proteomics by PEA confirmed this observation. Anti-PD-1 responders had an increase in plasma proteins involved in T-cell response, neutrophil degranulation, inflammation, cell adhesion, and immune suppression. Furthermore, we discovered new associations between plasma proteins (eg, interleukin 6, interleukin 10, proline-rich acidic protein 1, desmocollin 3, C-C motif chemokine ligands 2, 3 and 4, vascular endothelial growth factor A) and PFS, which may serve as predictive biomarkers.We detected an increase in circulating PD-1 during anti-PD-1 treatment, as well as diverse immune plasma proteomic signatures in anti-PD-1 responders. This study demonstrates the potential of plasma proteomics as a liquid biopsy method and in discovery of putative predictive biomarkers for anti-PD-1 treatment in metastatic CM.
Sex and gender differences and biases in artificial intelligence for biomedicine and healthcare
Authors: Davide Cirillo, Silvina Catuara-Solarz, Czuee Morey, Emre Guney, Laia Subirats, Simona Mellino, Annalisa Gigante, Alfonso Valencia, María José Rementeria, Antonella Santuccione Chadha, Nikolaos Mavridis
Journal: npj Digital Medicine (2020)

Abstract Precision Medicine implies a deep understanding of inter-individual differences in health and disease that are due to genetic and environmental factors. To acquire such understanding there is a need for the implementation of different types of technologies based on artificial intelligence (AI) that enable the identification of biomedically relevant patterns, facilitating progress towards individually tailored preventative and therapeutic interventions. Despite the significant scientific advances achieved so far, most of the currently used biomedical AI technologies do not account for bias detection. Furthermore, the design of the majority of algorithms ignore the sex and gender dimension and its contribution to health and disease differences among individuals. Failure in accounting for these differences will generate sub-optimal results and produce mistakes as well as discriminatory outcomes. In this review we examine the current sex and gender gaps in a subset of biomedical technologies used in relation to Precision Medicine. In addition, we provide recommendations to optimize their utilization to improve the global health and disease landscape and decrease inequalities.
Survival analysis of CLL/SLL patients with Richter’s transformation to DLBCL: An analysis of the SEER database.
Authors: Radowan Elnair, Moataz Ellithi, Avyakta Kallam, Jonathan Bleeker, Gregory Bociek
Journal: Journal of Clinical Oncology (2020)

e20024 Background: Richter's transformation (RT) from Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) to a Diffuse Large B-Cell Lymphoma (DLBCL) is a rare complication with an estimated incidence of less than 5% and a poor prognosis based on small retrospective studies. Large studies investigating the natural history and patient outcomes with this entity of DLBCL are lacking, and prospective data on the best treatment option are scarce and limited by rarity of this condition. Methods: We queried the US Surveillance, Epidemiology, and End Results (SEER) 18 database for patients sequentially diagnosed with CLL/SLL followed by DLBCL from January 2000 to December 2016 with a cutoff latency of 2 months. Data obtained included patient demographics, history of treatment for CLL/SLL, overall survival (OS) after DLBCL diagnosis and latency period between CLL/SLL and DLBCL diagnoses. For comparison, SEER data was obtained for patients with de novo DLBCL and for CLL/SLL patients without RT in the same date range. Survival was estimated by Kaplan Meier method and log rank test was used to compare outcomes. Results: 471 patients who developed RT to DLBCL and 98425 patients with de novo DLBCL were identified. The median time for developing RT to DLBCL was 54 months. Median OS was worse for DLBCL arising from RT compared to de novo DLBCL (64 months versus 10 months, p &lt; 0.0001). In patients with RT to DLBCL, no statistically significant difference in median OS was seen in patients who received treatment for CLL/SLL versus those assigned as No/Unknown treatment status (p = 0.51). In patients with CLL/SLL in the specified time period; median OS was significantly lower for those who developed RT to DLBCL compared to those who did not (91 months versus 100 months, p = 0.0012). Conclusions: DLBCL arising from RT in CLL/SLL patients is not necessarily a late complication. Prognosis is dismal with a trend towards a poor OS in the subset of patients with pretreated CLL/SLL. This large population study correlates with prior reports and highlights the need for prospective data to inform prognosis and treatment decisions.
A phase II trial of PD-1 inhibition with INCMGA00012 in patients with previously treated unresectable or metastatic adenosquamous pancreatic cancer.
Authors: Christopher Jakubowski, Elizabeth D Thompson, Hao Wang, Rosalind Walker, Elizabeth M. Jaffee, Nilofer Saba Azad
Journal: Journal of Clinical Oncology (2020)

TPS4662 Background: Adenosquamous pancreatic cancer (ASQ) constitutes 1-5% of all pancreatic cancers and compared to pancreatic adenocarcinoma (PDAC) has a worse survival. ASQ has glandular and squamous histologic components and given its rarity and aggressiveness, in practice there is no current standard regimens for ASQ. Unfortunately, checkpoint blockade has had an overall disappointing impact on survival in PDAC. In an effort to identify a patient subgroup most likely to respond to immunotherapy, the immune tumor microenviroment (TME) in ASQ was evaluated. Tissue microarrays from archived ASQ samples were first created. Then immunocytochemistry (IHC) staining for immune cells and immune checkpoint proteins was performed. PD-L1 expression and the combined presence of PD-L1+, IDO+, LAG3+, and VISTA+ was seen. All ASQ cases had some degree of tumor infiltrating lymphocytes (TIL, including CD8+ T-cells). Furthermore, PD-L1 and other checkpoint positivity correlated with increased TIL. These findings suggest the presence of adaptive immune resistance. This is in contrast to standard PDAC, in which the expression of immune checkpoints is rarely accompanied by increased effector T-cells. Methods: We are conducting a multiple-center, single arm, phase II clinical trial to evaluate PD-1 inhibition with INCMGA00012 in locally advanced unresectable and metastatic ASQ patients. INCMGA00012 is a humanized monoclonal antibody antagonistic to PD-1. The primary objective is to determine the disease control rate at 4 months using RECIST 1.1. The study is planned with 21 evaluable subjects and allows early termination for lack of efficacy. Patients have a pre-treatment biopsy followed by INCMGA00012 500 mg on Day 1 of each cycle (every 4 weeks). A second biopsy will occur eight weeks later. Eligibility criteria includes histologically- or cytologically-proven adenosquamous carcinoma of the pancreas by central pathologic review and patients must have received (or been intolerant to or ineligible for) at least 1 prior line of cytotoxic chemotherapy and received no more than 2 prior systemic treatments. Patients with known MSI-H/dMMR status are excluded. Exploratory objectives include examining changes in the TME checkpoint expression and immune cell infiltrate in the biopsies via IHC and RNA expression studies. The clinical study was activated in February 2020. Clinical trial information: NCT04116073 .
Efficacy of daratumumab + SOC versus SOC in myeloma induction regimens, by risk-stratification: Meta-analysis of phase III randomized control trials.
Authors: Nisha Joseph, Craig C. Hofmeister, Madhav V. Dhodapkar, Lawrence Boise, Sagar Lonial, Madhusmita Behera, Jonathan L. Kaufman, Ajay K. Nooka
Journal: Journal of Clinical Oncology (2020)

e20512 Background: Addition of daratumumab, a CD38 monoclonal antibody, to standard of care (SOC) myeloma induction regimens resulted in deeper responses. Phase 3 trials comparing daratumumab + SOC vs SOC consistently favored the daratumumab combinations. The objective of this analysis is to test the hypothesis that high-risk patients benefit from the addition of daratumumab to SOC induction regimens. Methods: We identified four phase 3 clinical trials (RCT) that randomized newly diagnosed myeloma patients to receive daratumumab +SOC vs. SOC. The GRIFFIN trial did not have PFS events and was excluded. A meta-analysis of 3 RCTs with updated data from ASH 2019 (ALCYONE, MAIA, CASSIOPEIA) was performed using the fixed (Mantel-Haenszel) model to calculate the impact of daratumumab + SOC versus SOC. The consistency of results (effect sizes) among studies was investigated by means of two heterogeneity tests, the χ 2-based Cochran's Q test, and the I 2 Statistic. We considered that heterogeneity was present when the P value of the Cochran's Q test was &lt; 0.1 and I 2 statistic was &gt; 50%. Results: The pooled hazard ratios (HR) for standard risk patients for PFS was HR 0.589 (95% CI 0.502-0.691; P &lt; 0.001) in favor of daratumumab. Q-statistic for PFS ( P= 3.462; df= 2; I 2 = 42.23) suggests homogeneity across studies. The pooled hazard ratios (HR) for high risk patients for PFS was HR 0.799 (95% CI 0.609-1.047; P= 0.104) in favor of daratumumab. Q-statistic for PFS ( P= 1.306; df= 2; I 2 = 0.00) suggests homogeneity across studies. Conclusions: Our meta-analysis demonstrates that addition of daratumumab to SOC myeloma induction regimens prevented progression in both standard and high-risk patients, though the impact was more pronounced in the standard-risk patients. This benefit seems to improve with longer follow up, as seen both in ALCYONE (Mateos et al ASH 2019) and MAIA trial (Bahlis et al ASH 2019). Focused accrual of high-risk patients in larger daratumumab induction trials and longer follow up of the existing trials are further needed.