tbuckley/cabot-search huggingface dataset:
Relative risk of pneumonitis or interstitial lung disease (ILD) associated with the use of cyclin-dependent kinase inhibitors (CDK4/6i): A systematic review and meta-analysis of phase 3 randomized controlled trials.
Authors: Nusrat Jahan, Sariya Wongsaengsak, Shabnam Rehman, Myrian Vinan-Vega, Lukman Aderoju Tijani, Fred L. Hardwicke
Journal: Journal of Clinical Oncology (2021)

1072 Background: All three currently approved cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) such as palbociclib, abemaciclib, and ribociclib are reported to cause significant pulmonary toxicities including fatal pneumonitis or interstitial lung disease (ILD). We conducted a systematic review and meta-analysis of phase 3 randomized controlled trials (RCTs) to determine the relative risk of pneumonitis or ILD associated with CDK4/6i. Methods: We conducted a systematic search using PRISMA guidelines in PubMed, EMBASE, American Society of Clinical Oncology and San Antonio Breast Cancer Symposium meeting abstracts from inception through Jan 30, 2021. Phase 3 RCTs using CDK4/6i in the intervention arm and reporting the number of events for pneumonitis or ILD were included in the analysis. The Cochran-Mantel-Haenszel method and random effects model were used to calculate the pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested by Cochran’s Q test and I 2 value. Results: Five phase 3 RCTs — MONALEESA-3, MONALEESA-7, MONARCH plus, monarchE, and PALLAS — reported the number of events for any grade pneumonitis or ILD and were included in the final analysis. A total of 13,191 patients — 6,758 in the CDK4/6i arm and 6,433 in the control arm — were analyzed. Following regimens were used in CDK4/6i arms — MONALEESA-3: ribociclib + fulvestrant; MONALEESA-7: ribociclib + tamoxifen or a non-steroidal aromatase inhibitor + goserelin; MONARCH plus: in cohort A, abemaciclib + anastrozole or letrozole, and in cohort B, abemaciclib + fulvestrant; MonarchE: abemaciclib + standard-of-care adjuvant endocrine therapy (ET); PALLAS: Palbociclib + ET. In the control arms, all studies used placebo and respective endocrine therapies. Any grade pneumonitis or ILD was reported in 1.64% of patients in the CDK4/6i arm versus 0.68% of patients in the control arm. The pooled RR of any grade pneumonitis or ILD was 2.26, 95% CI: 1.60-3.19, P &lt; 0.00001, I 2 = 0%. Grade 3/4 pneumonitis or ILD was reported in 0.28% of patients in the CDK4/6i arm and 0.06% of patients in the control arm with pooled RR of 2.35, 95% CI: 0.37-15.08, P = 0.37, I 2 = 34%. One grade 5 pneumonitis was reported in the monarchE. Conclusions: Cyclin-dependent kinase 4/6 inhibitors are associated with increased risk of any grade pneumonitis or ILD. Early detection and prompt initiation of appropriate interventions are vital to reduce the morbidity and mortality associated with CDK4/6i induced pneumonitis or ILD.
John Craig Hay
Authors: Angus McKellar
Journal: BMJ (2021)

John Craig Hay was a much loved doctor in Uig and Bernera, Isle of Lewis, for more than 30 years until retiring in 1997. His life and career were built on his Christian faith. This was reflected in both his role as a lay preacher and the compassion and devotion with which he cared for his patients and the local community.

John was born in Paisley. During the war years, he was evacuated to a farm in Ayrshire, and he later recalled that it was during this period that he was inspired by a church notice board which carried the text of Matthew chapter 11, verse 28: “Come to me, all you who are weary and burdened, and …
Pooled analyses of immune-related adverse events (irAEs) and efficacy from the phase 3 trials IMpower130, IMpower132, and IMpower150.
Authors: Mark A. Socinski, Robert M. Jotte, Federico Cappuzzo, Makoto Nishio, Tony S. K. Mok, Martin Reck, Gene Grant Finley, Wei Yu, Hina Patel, Nindhana Paranthaman, Ilze Bara, Howard West
Journal: Journal of Clinical Oncology (2021)

9002 Background: PD-L1/PD-1 inhibitors have transformed the treatment (tx) of advanced NSCLC. Evidence suggests that the occurrence of irAEs with these agents may predict improved outcomes in cancers such as NSCLC. Atezolizumab (atezo; anti–PD-L1) has shown efficacy and tolerability in NSCLC and is currently approved in the 1L and 2L+ settings. The Ph 3 IMpower130, IMpower132 and IMpower150 trials evaluated atezo + chemo ± bevacizumab (bev) as 1L tx of NSCLC. We explore the association between irAEs and efficacy in these trials. Methods: Each trial enrolled tx-naive patients (pts) with nonsquamous stage IV NSCLC. Pts were randomized to: carboplatin (carbo) + nab-paclitaxel alone or with atezo in IMpower130; carbo or cisplatin alone or with atezo in IMpower132; atezo (A) + bev (B) + carbo + paclitaxel (CP), ACP or BCP in IMpower150. Data were pooled (data cutoffs: Mar 15 2018 [IMpower130]; May 22 2018 [IMpower132]; Sep 13 2019 [IMpower150]) and analyzed by tx (atezo-containing vs control) and irAE status. A time-dependent Cox model and landmark analyses at 1, 3, 6 and 12 mo were used to control for immortal bias. Study protocols required atezo tx interruption/discontinuation for grade (Gr) ≥3 irAEs. Results: 2503 pts were included in the analysis (atezo, n = 1577; control, n = 926). In both arms, baseline characteristics were generally balanced between pts with irAEs (atezo, n = 753; control, n = 289) and without irAEs (atezo, n = 824; control, n = 637). Any-Gr irAEs occurred in 48% (atezo) and 32% (control) of pts; Gr 3-5 irAEs occurred in 11% (atezo) and 5% (control). The most common irAEs (atezo vs control) were rash (28% vs 18%), hepatitis (lab abnormalities; 15% vs 10%) and hypothyroidism (12% vs 4%). Median time to onset of first irAE was 1.7 (atezo) vs 1.4 mo (control). OS HRs (95% CI) from the time-dependent Cox model between pts with vs without irAEs were 0.69 (0.60, 0.78) in the atezo arm and 0.82 (0.68, 0.99) in the control arm; after excluding rash (perceived as the least specific irAE), OS HRs (95% CI) were 0.75 (0.65, 0.87) and 0.90 (0.71, 1.12), respectively. OS landmark data are in the Table. Conclusions: In this exploratory pooled analysis, pts with irAEs had longer OS vs pts without irAEs in the atezo-containing and control arms per the time-dependent Cox model and landmark analyses; this trend remained for the atezo arm after excluding rash. Landmark analyses suggest that in the atezo arm, pts with Gr 1/2 irAEs had the longest OS and pts with Gr ≥3 irAEs had the shortest OS, potentially due to tx interruption/discontinuation. Clinical trial information: NCT02367781; NCT02657434; NCT02366143. [Table: see text]
A single-arm phase Ib study of multiple target cytotoxic T-lymphocyte (MCTL) in combination with toripalimab as second-line therapy in advanced non-small cell lung cancer (NSCLC).
Authors: Xiubao Ren, Weihong Zhang
Journal: Journal of Clinical Oncology (2021)

2535 Background: Anti-PD-1/ PD-L1 (programmed cell-death 1) mAb treatment has been approved in the US and in Europe as second-line treatment for advanced NSCLC because of the good tolerance and efficacy in comparison with docetaxel. Unfortunately, The objective response rate is only around 20%. Multiple Target Cytotoxic T-lymphocyte (MCTL) cells can restore the antitumor immunity to improve patient outcome. Combining MCTL cells with anti-PD-1 mAb may strengthen the results as second-line treatment in patients with advanced NSCLC. (NCT04193098). Methods: This is a single-center, open-label, phase 1b trial of combination MCTL cells with toripalimab (anti-PD-1 mAb)as second-line treatment for advanced NSCLC. Systemic therapy patients received toripalimab every 3 weeks for 12 cycles and received MCTL cells every 3 weeks for 9 cycles, then toripalimab and MCTL cells for maintenance therapy until disease progression or unacceptable toxicity. Results: From June 2019 to October 2020, 14 pts aged 43-70 years (median age 59 years) were enrolled. The squamous/non-squamous ratio was 50%/50%. 8 (57.1%) were men, 13(92.8%) were ECOG PS=0-1, 5 (35.7%) had pleural effusion, and 3 (21.4%) had bone metastases. Among 13 evaluable pts, the ORR and DCR were 38.4% and 71.4%, At the time of data cutoff, the median DOR was not reached (range 8.25m-NA), the median PFS was 399 days (range 192d-NA), and the median OS were not mature. Adverse events (AEs) occurred in 5 (38.4%), No grade≥3 AEs events occurred. Immune-related AEs were thyroid hypofunction (3, 23%) and weak (2, 15.4%). Biomarkers which correlated with efficacy and AEs are being analyzed. Conclusions: Multiple Target Cytotoxic T-lymphocyte (MCTL) in combination with toripalimab as second-line treatment for advanced NSCLC because of the well tolerated and encouraging efficacy. Further studies are warranted to confirm these results. Research Sponsor: Tianjin Medical University Cancer Institute and Hospital. Clinical trial information: NCT04193098.
A randomized double-blind pilot study comparing cetirizine with diphenhydramine in the prevention of paclitaxel-associated infusion-related reactions.
Authors: Philippe Bouchard, Johannie Beaucage-Charron, Laurence Gaudet, Sarah Lamothe, Cloé Pelletier, Anne-Sophie Pépin, Valérie Roy, Frédéric Charpentier, Marie Lordkipanidzé, Denis Projean, Matthieu Picard
Journal: Journal of Clinical Oncology (2021)

e24080 Background: Cetirizine is a less sedative alternative to diphenhydramine for the prevention of infusion-related reactions (IRR) to paclitaxel. However, there is no prospective data to support its use in this context. In this study, we conducted a feasibility study for a future definitive non-inferiority trial comparing cetirizine with diphenhydramine as premedication to prevent paclitaxel-related IRR. Methods: This was a single center randomized double-blind parallel-group prospective pilot study. Participants were paclitaxel-naive cancer patients scheduled to start paclitaxel chemotherapy, alone or in combination. They were assigned to receive either intravenous diphenhydramine 50 mg + oral placebo (diphenhydramine group) or intravenous placebo + oral cetirizine 10 mg (cetirizine group) for their first two paclitaxel treatments. To assess the feasibility of a larger study, the percentage of eligible patients completing a first paclitaxel treatment and the recruitment rate were calculated. IRR events were documented. Change in drowsiness compared with baseline was assessed using the Stanford Sleepiness Scale (SSS). Results: Among 37 eligible patients, 27 were recruited and randomized (control 13; intervention 14) and 25 completed the study. The recruitment rate was 4.8 participants/month, meeting the primary feasibility target of 4 participants per month. One participant had an IRR (cetirizine group, CTCAE grade 2) and no unexpected serious adverse events occurred. Drowsiness was the main adverse effect associated with the premedication. The increase in drowsiness compared to baseline (ΔSSS) was greater in the diphenhydramine group compared to the cetirizine group (median ΔSSS 2 (IQR 3.25) vs median ΔSSS 0 (IQR 1), p &lt; 0.01) when measured one hour after the administration of the premedication. Patient self-assessed moderate or intense discomfort caused by drowsiness was exclusively reported in the diphenhydramine group, by 4 out of 13 participants. Conclusions: The trial methods were feasible in terms of recruitment rate, retention and patient safety. IRR were infrequent and a larger trial is warranted to confirm non-inferiority for IRR prevention. Cetirizine was significantly less sedating than diphenhydramine when administered as premedication to prevent paclitaxel-associated IRR. Clinical trial information: NCT04237090. [Table: see text]
A novel sub-staging system for prognosis prediction of Barcelona clinic liver cancer C stage hepatocellular carcinoma: 10 years observational study.
Authors: Zhiqiang Mo, Qicong Mai, Jian He, Xiaoming Chen
Journal: Journal of Clinical Oncology (2021)

e16139 Background: This study sought to propose a novel sub-staging system which could predict prognosis of patients with Barcelona clinic liver cancer (BCLC) C stage Hepatocellular carcinoma (HCC). Methods: Between January 2008 and September 2018, 806 patients with BCLC-C stage HCC were assessed retrospectively. The significance of clinical variables in predicting prognosis were statistical analysis. A prognostic sub-staging system of BCLC-C stage HCC was developed according to prognosis-related factors. The predictive performance was subsequently validated. Results: In training set, tumor burden (TB) &gt;50%, type III/IV portal vein tumor thrombus (PVTT), extrahepatic metastasis (M) and Child-Pugh (CP) B class were independently associated with overall survival (OS). According to those prognosis-related factors, a novel sub-staging system of BCLC-C stage was “linear predictor= TB+PVTT+M+CP”, which had good performance in predicting OS in both training and validation set. The thirtieth percentile and the third quartile of the linear predictor, namely 6 and 12, were selected as cut-off values, stratifying patients into different OS after interventional therapy (IT) or sorafenib therapy (ST), specifically, ≤6: 43.7 months for IT, 32.0 month for ST;＞6 but＜12: 43.7 months for IT, 32.0 month for ST; ≥12: 43.7 months for IT, 32.0 month for ST. Conclusions: The novel sub-staging system of BCLC-C stage HCC may stratify patients for suitable therapy and predict individual survival with favorable performance and discrimination.
Systematic review of family studies of heritable breast cancer in Africa.
Authors: Amina Dhahri, Sally Nneoma Adebamowo, Clement Adebayo Adebamowo
Journal: Journal of Clinical Oncology (2021)

e22508 Background: The incidence of breast cancer (BC) in Africa (40.4 per 100,000) is 49% that of Europe and North America (81.9 per 100,000) but the mortality rate is 42% higher (19.4 versus 13.7 per 100,000). The high mortality is due to lack of screening. However, more targeted screening based on genomic risks are also missed because of stigmatization, poor family history, and limited information on BC susceptibility gene mutations. Internationally based family members are influencing cultural attitudes to BC in Africa leading to reduced stigmatization, increased better family history and uptake of genomic screening. Family-based studies of BC in Africa would provide useful information on prevalence of mutations that can inform genomic screening panels. We conducted systemic review of all family-based studies of BC in Africa to document state of the art, identify barriers and facilitators of this research method and methods of advancing the science. Methods: Using a comprehensive research strategy, we reviewed articles indexed in PubMed and African Journals Online (AJOL) to identify studies of familial BC in Africa. Specifically, we searched for family-based, study design papers on BC in each country in Africa using the following keywords: breast cancer, family-studies, hereditary, genetic, gene, mutations, and Africa. We excluded case-control, and registry studies, and clinical trials. We extracted relevant information from each study using standardized criteria: number of first- and second-degree relatives affected by BC, mutations, genetic variations, and polymorphisms. Results: A total of 12 out of 727 studies met our inclusion criteria. 80% of these studies were published after the year 2010. There were 9 publications from North Africa evaluating 191 families in total. One study reported novel breast cancer candidate genes: MMS19, DNAH3, POLK and KATB6 and nine publications investigated the mutation spectrum of BRCA genes. One publication from West Africa and one publication from Southern Africa included 1 and 219 families, respectively. All the studies done in these two regions reported targeted genomic screening for only BRCA genes. No study was done in Central and East Africa. Conclusions: There is paucity of family-based studies of breast cancer in Africa. Given the high level of heterogeneity in African genomes, these types of studies may be needed to identify high penetrance, germline mutations to better understand hereditary BC risk and ultimately develop a multigene panel testing to for diagnosis of heritable BC in this population.
Nelfinavir Blocks Export of Newly Synthesized Protein from the ER and Interacts with ER-Resident and Mitochondrial Proteins in an Activity-Dependent Fashion
Authors: Andrej Besse, Lenka Besse, Sara C. Stolze, Marianne Kraus, Juergen Bader, Herman S Overkleeft, Christoph Driessen
Journal: Blood (2017)
Abstract 16387: IP3 Receptors are Master Regulators of Cardiac Healing in Post-Ischemic Heart Failure
Authors: Gaetano Santulli, Marco B Morelli, Alessandro Matarese, Xujun Wang
Journal: Circulation (2019)

Introduction: Recent genome-wide association studies have evidenced a significant association between gain-of-function mutations in genes encoding for Inositol 1,4,5-trisphosphate receptors (IP3Rs)...
Systemic and local inflammation characteristics in patients with cancer after lung transplantation.
Authors: Ariane Steindl, Maja Nackenhorst, Hannah Christina Puhr, Maximilian Marhold, Katharina Sinn, Konrad Hoetzenecker, Mir Alireza Hoda, Matthias Preusser, Anna Sophie Berghoff
Journal: Journal of Clinical Oncology (2021)

e14527 Background: Immune suppressive treatment is associated with an increased cancer risk due to its negative impact on immunosurveillance. We analyzed the association of immune suppressive treatment with the inflammatory tumor microenvironment and systemic inflammation parameters in patients with solid cancers after lung transplantation. Methods: Systemic inflammation was measured by neutrophil-to-lymphocyte ratio (NLR), leucocyte-to-lymphocyte ratio (LLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and CRP/albumin ratio (CRP/Alb) and analyzed at time of lung transplantation and time of tumor diagnosis. In tumor samples, the expression of tumor infiltrating lymphocytes (TIL) including CD3, CD8, CD45RO and PD-L1 using the Ventana Benchmark Ultra system for immunohistochemistry were investigated. Automated tissue analyses were performed for CD3, CD8 and CD45RO TIL (Definiens software). PD-L1 expression was determined by using the combined positive score (CPS). Results: 28 patients with cancer (10 lung cancer, 4 colorectal cancer, 2 renal cell carcinoma, 2 gastric cancer, 2 pancreatic cancer, 2 head&amp;neck tumor, and others) were included in the study. Median time from transplantation to cancer diagnosis was 45 months (range 29-61). 57% (16/28) experienced a period of transplant rejection between transplantation and tumor diagnosis. Therefore, 25% (7/28) of the patients received intensified immunosuppression up to 8 weeks before tumor diagnosis. Median density of CD3+TIL was 5742 cells/ mm 2 (range 3,203-8,429), median density of CD8+TIL was 6,363 cells/ mm 2 (range 3,643-8,190), median density of CD45RO TIL was 72 cells/ mm 2 (range 4-635) and median expression of PD-L1 was 60 (range 5-100) in tumor samples. No statistically significant changes in systemic inflammation were observed from time of transplantation to time of tumor diagnosis (p&gt;0.05; Wilcoxon Signed-Rank Test). Furthermore, a history of transplant rejection before tumor diagnosis was not statistically significant associated with changes in TIL densities or systemic inflammation parameters (p&gt;0.05; Mann Whitney U test). Conclusions: An activated local inflammatory tumor microenvironment as well as stable systemic inflammation characteristics were observed in our cohort. These results support the further development of immunotherapy as treatment approach also in cancer patients under immunosuppression after lung transplantation.[Table: see text]
2021 MAGNIMS–CMSC–NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis
Authors: Mike P Wattjes, Olga Ciccarelli, Daniel S Reich, Brenda Banwell, Nicola de Stefano, Christian Enzinger, Franz Fazekas, Massimo Filippi, Jette Frederiksen, Claudio Gasperini, Yael Hacohen, Ludwig Kappos, David K B Li, Kshitij Mankad, Xavier Montalban, Scott D Newsome, Jiwon Oh, Jacqueline Palace, Maria A Rocca, Jaume Sastre-Garriga, Mar Tintoré, Anthony Traboulsee, Hugo Vrenken, Tarek Yousry, Frederik Barkhof, Àlex Rovira, Mike P Wattjes, Olga Ciccarelli, Nicola de Stefano, Christian Enzinger, Franz Fazekas, Massimo Filippi, Jette Frederiksen, Claudio Gasperini, Yael Hacohen, Ludwig Kappos, Kshitij Mankad, Xavier Montalban, Jacqueline Palace, María A Rocca, Jaume Sastre-Garriga, Mar Tintore, Hugo Vrenken, Tarek Yousry, Frederik Barkhof, Alex Rovira, David K B Li, Anthony Traboulsee, Scott D Newsome, Brenda Banwell, Jiwon Oh, Daniel S Reich, Daniel S Reich, Jiwon Oh
Journal: The Lancet Neurology (2021)
Does denosumab offer survival benefits? Our experience with denosumab in metastatic non-small cell lung cancer patients treated with immune-checkpoint inhibitors.
Authors: Yenong Cao, Muhammad Zubair Afzal, Keisuke Shirai
Journal: Journal of Clinical Oncology (2021)

e21039 Background: Lung cancer is the leading cause of cancer-related death in the United States. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small-cell lung cancer (NSCLC). Denosumab is a humanized monoclonal antibody to RANK ligand used to prevent skeletal-related events of bone metastases in solid tumors. In preclinical and some clinical studies, denosumab have shown to have some anti-tumor properties. We are reporting the clinical outcomes in our NSCLC patients who received RANKL inhibitor in combination with ICIs. Methods: This observational study used retrospective data from a tertiary cancer center from 2015-2020. Stage IV non-small cell lung cancer patients who received denosumab within 30 days of ICIs (pembrolizumab, nivolumab, atezolizumab, ipilimumab) were included. Median overall survival (OS), progression free survival (PFS), best radiographic responses were obtained. Univariate, multivariate analyses and logistic regression analyses were done, and Kaplan-Meier curves were obtained for survival analysis. Results: We identified 69 patients and all had skeletal metastasis, and 37.7% had brain metastases. Median duration of concomitant use of denosumab and ICI was 1.5 months. Median OS was 6.3 months and median PFS was 2.8 months. Overall response rate was 18.8% and disease control rate was 40.6%. Median OS in patients with concomitant denosumab and ICIs more than 3 months was 11.5 months, comparing to 3.6 months in patients with &lt; 3 months of concomitant therapy (P=0.0005). OS and PFS did not differ with respect to brain metastases or number of skeletal metastases. However, the duration of ICIs and denosumab overlap was associated with improved OS and PFS. Among the 18.8% of patients who achieved complete response (CR) and partial response (PR), six-month survival rate was 100% and one-year survival rate was 69.2%. Conclusions: Patients receiving combination therapy did not perform poorly despite of poor prognostic features such as brain metastases and numerous skeletal metastases. Although we did notice potential benefit of the longer duration of concomitant use of ICI and denosumab, future prospective clinical trials are needed to evaluate the synergistic effect of RANKL inhibitors/ICI and if duration of RANKL inhibitors matters.