tbuckley/cabot-search huggingface dataset:
Efficacy of palbociclib after everolimus in hormone receptor-positive, HER2-negative advanced breast cancer.
Authors: Anja Kovac, Cvetka Grasic Kuhar, Tanja Ovcaricek, Erika Matos, Marina Mencinger, Simona Borstnar
Journal: Journal of Clinical Oncology (2020)

e13030 Background: Palbociclib and other selective cyclin-dependent kinases 4 and 6 inhibitors in combination with endocrine therapy (ET) have become the standard of care in the treatment of patients with hormone receptor-positive (HR+), HER2-negative advanced breast cancer (ABC). Their role in the first and second line of therapy is well established, whereas their use in subsequent lines and after treatment with everolimus remains unclear. Methods: We performed retrospective observational study of all patients who initiated treatment with palbociclib at the Institute of Oncology Ljubljana between March 8, 2018 and March 8, 2019 and received at least two prior lines of treatment for ABC. We collected individual patient data from electronic medical records. Patients were divided in two groups – everolimus-pretreated (group A) and everolimus-naïve (group B). The primary study outcomes were clinical benefit rate (CBR), time to treatment failure (TTF) and overall survival (OS). Results: Overall, 65 patients´ data was evaluated. The majority of patients (n = 50, 76.9%) received palbociclib in combination with fulvestrant, others (n = 15, 23.1%) with aromatase inhibitors. There were 25 (38.5%) patients in group A and 40 (61.5%) in group B. Patients´ and previous treatment characteristics are shown in table. CBR was the same, 40%, in both groups. The median follow-up time was 14.9 months. The median TTF was 5.28 months for the whole group, 5.0 months for everolimus-pretreated and 5.5 months for everolimus-naïve group (p = 0.7). The median OS was 18.1 months for the whole group, 14 months for everolimus-pretreated and 18.1 months for everolimus- naïve group (p = 0.7). Conclusions: Patients with HR+, HER-2-negative ABC benefit from addition of palbociclib to ET after two lines of prior systemic therapy. The benefit remained unchanged if the patients were previously treated with everolimus. [Table: see text]
Discovery of a novel shared tumor antigen in human lung cancer.
Authors: Diane Tseng, Shin-Heng Chiou, Xinbo Yang, Alexandre Reuben, Julie Wilhelmy, Alana McSween, Stephanie Conley, Rahul Sinha, Barzin Nabet, Chunlin Wang, Joseph B Shrager, Mark F. Berry, Leah Monique Backhus, Natalie Lui, Heather A. Wakelee, Joel W. Neal, Jianjun Zhang, K. Christopher Garcia, Crystal Mackall, Mark Davis
Journal: Journal of Clinical Oncology (2020)

3087 Background: While there has been much attention on mutation-associated neoantigens in tumors, there is less known about non-mutated tumor antigens that are shared across individuals. Understanding tumor-infiltrating T cell recognition of shared tumor antigens is important for understanding cancer immune recognition and escape, and may reveal novel targets for therapy. Methods: We have established a novel approach for discovering shared tumor antigens in human lung cancer. This approach involves identifying candidate T cell receptor (TCR) alpha/beta pairs that are predicted to exhibit specificity for shared tumor antigens in the context of a given human leukocyte antigen (HLA). We then screen the T cell receptor for binding to yeast display libraries of peptide-HLA. The Mark Davis lab at Stanford has previously developed an algorithm that groups T cell receptors into antigen specificity groups based on shared motifs within the TCR complementarity-determining region 3 (CDR3) sequences. Leveraging a dataset of over 700K CDR3 sequences from 178 HLA-typed non-small cell lung cancer (NSCLC) patients, we have found up to 4,300 antigen specificity groups after applying stringent cutoffs. We sequenced TCR alpha/beta pairs from 15 patients with lung adenocarcinoma (n = 4,705). Results: We identified an antigen specificity group enriched in tumor compared to adjacent uninvolved lungs. Antigen screening of the T cell receptor belonging to this specificity group using an A02 yeast display libraries led to the identification of a dominant peptide after four rounds of enrichment. We functionally validated that the peptide derived from the protein TMEM161A stimulated Jurkat cells expressing the TCR alpha/beta receptor of interest. We show that full-length TMEM161A protein is processed and presented into a peptide that stimulates primary T cells expressing the TCR alpha/beta receptor. We observe that a peptide from Epstein-Barr virus (EBV) protein LMP2 also stimulated the same TCR alpha/beta receptor. We have show that TMEM161A RNA and protein are overexpressed in human lung cancer compared to adjacent uninvolved lungs. Conclusions: We have demonstrated a novel approach toward antigen discovery and identified a shared tumor antigen TMEM161A in human lung cancer.
Spectrum of disease in patients with positive antineutrophil cytoplasmic antibodies in general hospitals
Authors: Jie Yu, Shi Chen, Zhan-guo Li
Journal: BMJ (2010)

Objective To investigate clinical significance of positive antineutrophil cytoplasmic antibodies (ANCA) in diagnosis for vasculitis or other diseases. Methods From January 2005 to December 2008, 104 patients with positive ANCA detected by enzyme-linked immunosorbent assay (ELISA) in People's Hospital of Peking University were randomly selected and their clinical features and diagnoses were analyzed retrospectively. Results Among 104 ANCA-positive patients, 22 were diagnosed as vasculitis and 13 as ANCA-associated vasculitis, and 82 (78. 8% )were diagnosed as non-vasculitis including 40 of connective diseases such as systematic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and 42 of non-connective diseases with the most common of ulcerative colitis. According to the results of ANCA tests by ELISA, ANCA-positive patients could be divided into those with proteinase 3 (PR3)-positive and myeloperoxideaso (MPO)-positive. More organs were involved in MPO-positive patients (n =48 ) than that in PR3-positive ones ( n = 49), and more frequent involvement of the kidneys and less frequent involvement of the gastrointestinal tract in MPO-positive than those in PR3-positive ones (P < 0. 01 ). As compared to those with non-vasculitis, more organs (2. 28 organs vs. 3.55 organs in average) were involved in patients with vasculitis (P <0. 01 ) and more frequent involvement of the upper or lower respiratory tracts and the kidneys in vasculitis patients ( P <0. 01 or <0. 05, respectively). Elevated leukocyte count and accelerated erythrocyte sedimentation rate (ESR) were also more common in vasculitis patients than those in non-vasculitis ones (P <0. 01 and P <0. 05, respectively). Positive ANCA combined with number of organs involved, clinical manifestations and other laboratory findings, its positive predictive value (PPV) in diagnosis for vasculitis can be improved. Conclusions Spectrum of disease in patients with positive ANCA was varied. Diagnostic value of positive ANCA in diagnosis for vasculitis can be improved if combined with comprehensive analysis of their clinical features and laboratory examinations.

Key words: 
Antibodies; antineutrophil cytoplasmic;  Vasculitis;  Diagnosis
系统性红斑狼疮的消化道表现
Authors: 方卫纲
Journal: BMJ (2010)

系统性红斑狼疮(systemic lupus erythematosus,SLE)是自身免疫性疾病的典型代表,它通过致病性的自身抗体、免疫复合物及T淋巴细胞造成人体损伤,其临床表现复杂多样,几乎可以累及所有的器官和系统。
Bevacizumab associated calcifications might be a prognostic marker in patients with metastatic colorectal cancer.
Authors: Yuwen Zhou, Qiu Meng
Journal: Journal of Clinical Oncology (2020)

e16108 Background: Cetuximab associated calcifications is a positive predictive factor in metastatic colorectal cancer (mCRC). In patients with glioblastoma, bevacizumab-induced calcifications are also related to a better prognosis. However, tumor calcifications are rarely recognized in mCRC patients treated with bevacizumab. This study was to investigate the correlation between clinical outcome and calcification in mCRC who received bevacizumab and chemotherapy as the first-line treatment. Methods: A single retrospective cohort study was conducted with all diagnosed mCRC cases who received bevacizumab and chemotherapy as the first-line therapy in our hospital from January 2016 to January 2019. Clinical variables were retrieved from medical records and tumor calcification were evaluated independently by radiologists on the basis of computed tomography scans. A univariate and multivariate COX regression analysis was performed to evaluate the association between calcification and outcome. Results: 159 patients with an average age of 59.0 years were included. Median follow-up was 29.6 months. Among all enrolled patients, 31 had tumor calcification [31/159 (19.5%)]. The median overall survival (OS) and progression-free survival (PFS) was significantly better in patients with calcification than those without calcification (28.0 vs. 24.9 months, p= 0.024; 12.0 vs. 10.0 months, p= 0.026). A higher objective response rate (61.3% vs. 50.0%) was also observed in calcification group. On multivariate analysis, tumor calcification was independently associated with OS (hazard ratio 1.799, 95% CI 1.002–3.230) and PFS (hazard ratio 1.609, 95% CI 1.013–2.557). Conclusions: Tumor calcification was independently associated with improved prognosis in colorectal cancer. It might be a potential prognostic marker.
Prognostic role of pre-treatment magnetic resonance imaging (MRI) radiomic analysis in patients with squamous cell carcinoma of the head and neck (SCCHN).
Authors: Salvatore Alfieri, Rebecca Romanò, Marco Bologna, Giuseppina Calareso, Aurora Mirabile, Andrea Ferri, Alessandra Marcantoni, Enrica Grosso, Achille Tarsitano, Sara Valerini, Stefania Vecchio, Letizia Deantonio, Fulvia Blengio, Toni Ibrahim, Moela Mancinelli, Francesco Ascoli, Paolo Bossi, Laura Deborah Locati, Luca Mainardi, Lisa F. Licitra
Journal: Journal of Clinical Oncology (2020)

6553 Background: Emerging data suggest that radiomics can be used to predict outcomes in SCCHN. At present, only few data are available for pre-treatment MRI. Methods: Study population was retrieved from an ongoing multicenter, randomized, prospective trial (NCT02262221, HETeCo) evaluating health and economic outcomes of two different follow-up (FUP) strategies (intensive vs non-intensive) in effectively cured stage III-IV (VIII TNM ed.) SCCHN. We selected only patients with both pre- and post-contrast enhancement T1 and T2-weighted baseline MRI (b-MRI) and at least 2 years (2y) of FUP. A radiomic model was developed to identify high risk (HR) and low risk (LR) of disease recurrence. Radiomic features (RF) were extracted from the primary tumor in the b-MRI. The best RF combination was selected by Least Absolute Shrinkage and Selection Operator (LASSO). Ten-fold cross-validation was used to compute sensitivity, specificity and area under the curve (AUC) of the classifier. Kaplan-Meier (KM) curves were estimated for HR and LR, for both overall survival (OS) and disease-free survival (DFS) and log rank test was performed. Three years (3y)-DFS and OS were also estimated for the two groups. The radiomic risk class was used as a new variable in a multivariate Cox model including well established prognostic factors in SCCHN (TNM stage, subsite and HPV). Results: Out of 155 enrolled HETeCO patients, 98 baseline imaging were retrieved of which 57 b-MRI. Of these, 51 met the eligibility criteria (25 in intensive and 26 in non-intensive arm). Baseline patients’ characteristics were: median age 66 yr (38-86); sex (M 42; F 9); median smoking history: 30 packs/y (1-100); 25 oral cavity (49%), 18 oropharynx (35%, 14 HPV+), 6 larynx (12%), 2 hypopharynx (4%). At a median FUP of 42 months (25-64), 45 (88%) patients are still alive. The recurrence rate was 20% (10/51, of which 2 distant). In total, 1608 RF were extracted. The sensitivity, specificity and AUC of the classifier were 90%, 76%, and 80%, respectively. The radiomic risk class was found to be an independent prognostic factor for both DFS and OS (p=0.01 and p=0.046, respectively). KM curves for DFS and OS were significantly different between HR and LR groups (p=0.002 and p=0.04, respectively). In HR vs LR, 3-y DFS and OS were: 78% [61-100%] vs 97% [90-100%], and 88% [75-100%] vs 96% [88-100%], respectively. Conclusions: Radiomics of pre-treatment MRI can predict outcomes in SCCHN. External validation of this preliminary radiomics-based model is currently ongoing.
Influence of antibiotic therapy (ATB) on oncological outcomes of metastatic non-small cell lung cancer (mNSCLC) patients treated with chemo-immunotherapy (CIT).
Authors: James Clark, Biagio Ricciuti, Anita Bolina, Deepti Venkatraman, Thomas Newsom-Davis, Diego Ottaviani, Karla Lee, Mark M. Awad, David James Pinato
Journal: Journal of Clinical Oncology (2020)

3080 Background: ATB exposure is proven to worsen response and survival in immunotherapy recipients. However, its influence on outcomes from CIT is currently undefined. Methods: We conducted a retrospective, multi-centre observational study including 77 mNSCLC patients who received pembrolizumab, pemetrexed and carboplatin CIT as first-line therapy for mNSCLC, between December 1, 2018 and January 1, 2020 in 3 academic referral centres in Europe and in the United States. We documented ATB exposure in the 30 days prior to CIT commencement (pATB) or concurrently (cATB) until CIT cessation. Outcome measures included overall (OS) and progression-free survival (PFS) calculated from commencement of CIT, and overall response rates (ORR) defined by Response Evaluation Criteria in Solid Tumors (v1.1). Results: We enrolled 77 patients, 41 of whom were female (n = 53%) with adenocarcinoma (n = 73, 95%), performance status (PS) 0-1 (n = 69, 90%) PD-L1 Tumour Proportion Score &lt; 50 (n = 57, 74%). Median OS was 16.4 months (95%CI 8.4-24.4), median PFS was 6.7 months (95%CI 5.7-7.6). ORR was 48% including 1 complete (1%) and 36 partial responses (47%). Eleven patients (14%) received pATB, with penicillin/cephalosporins (p/c, n = 7, 63%) for &lt;7 days (n = 10, 90%). Thirty-five patients (45%) received cATB with p/c (n = 11, 40%) for &lt;7 days (n = 28, 80%). Most common indication for ATB was peri-procedure prophylaxis in pATB (n = 7, 63%) and suspected febrile neutropenia in cATB (n = 14, 40%). pATB (p = 0.004) but not cATB (p = 0.85) predicted for worse OS (19.6 vs 6.5 months, Hazard Ratio [HR] 2.9 95%CI 1.3-6.3). Neither pATB nor cATB predicted for PFS or ORR (p &gt; 0.05). Multivariable analyses confirmed pATB (HR 2.3 95%CI 1.1-5.5, p = 0.05) to predict for OS independent of PD-L1 status, PS and cATB. pATB+/- groups were balanced with regards to age, gender, PS nor PD-L1 status (p &gt; 0.05). Conclusions: Whilst cATB does not compromise outcome from CIT, this study reproduces the detrimental effects observed for pATB exposure in immunotherapy recipients. Mechanistic verification of the immune-biologic foundations underlying this association is urgently warranted.
Effect of enasidenib (ENA) plus azacitidine (AZA) on complete remission and overall response versus AZA monotherapy in mutant<i>-IDH2</i> (<i>mIDH2</i>) newly diagnosed acute myeloid leukemia (ND-AML).
Authors: Courtney Denton Dinardo, Andre C. Schuh, Eytan M. Stein, Pau Montesinos, Andrew Wei, Stephane De Botton, Amer Methqal Zeidan, Amir Tahmasb Fathi, Lynn Quek, Hagop M. Kantarjian, Mark G. Frattini, Frederik Lersch, Jing Gong, Aleksandra Franovic, Paresh Vyas, Hartmut Dohner
Journal: Journal of Clinical Oncology (2020)

7501 Background: ENA and AZA each induce overall response rates (ORR) of ~30% and complete remission (CR) rates of ~20% in ND-AML. In vitro, combining ENA + AZA enhances cell differentiation. We report results of the phase II portion of an open-label, randomized phase I/II study of ENA + AZA (“E+A”) vs. AZA monotherapy (“A”) in patients (pts) with m IDH2 ND-AML (NCT02677922). Methods: Pts age ≥ 18 years ineligible for intensive chemotherapy, with ECOG PS ≤ 2 and intermediate- or poor-risk cytogenetics, were randomized 2:1 to E+A or A in 28-day (d) cycles. All pts received SC AZA 75 mg/m 2 /d x 7 d/cycle; pts randomized to E+A also received ENA 100 mg QD. The primary endpoint was ORR (CR, CR with incomplete recovery, partial remission, morphologic leukemia-free state). Other endpoints include duration of response (DOR), overall and event-free survival (OS, EFS), safety, and m IDH2 VAF. Results: 101 pts received E+A (n = 68) or A (n = 33). Median age was 75 years (57–85); most pts (83%) had intermediate-risk cytogenetics. 21 pts in the E+A arm and 1 in the A arm were ongoing at data cutoff (Aug 2019). Most common reason for discontinuation was disease progression (E+A 31%, A 52%). Median number Tx cycles was 10 (1–26) in the E+A arm and 6 (1–28) in the A arm. 7 pts (21%) in the A arm received subsequent Tx with ENA. ORR, CR rate and DOR were significantly improved with E+A vs. A (Table). Median OS was 22 mo in both arms (HR 0.99 [95%CI 0.52, 1.87]; P = 0.97). Median EFS was 17.2 and 10.8 mo in the E+A and A arms, respectively (HR 0.59 [95%CI 0.30, 1.17]; P = 0.13). Maximal m IDH2 VAF change from BL was –83.4% with E+A vs. –17.7% with A ( P &lt; 0.01). No baseline co-mutation predicted primary resistance. Common Tx-related grade 3–4 AEs in the E+A arm were thrombocytopenia (37%), neutropenia (35%), anemia (19%), and febrile neutropenia (15%); these occurred in 19%, 22%, 22%, and 16% in the A arm. Grade 3–4 infections occurred in 18% of E+A pts and 31% of A pts. IDH differentiation syndrome occurred in 12 pts (18%) in the E+A arm. 5 E+A pts (7%) and 1 A pt (3%) died in the first 60 d. Conclusions: Combining ENA + AZA resulted in significantly improved response rates and durations, and was generally well-tolerated in older patients with m IDH2 ND-AML. The impact of subsequent Tx on OS/EFS and new translational data will be presented at the meeting. Clinical trial information: NCT02677922 . [Table: see text]
Integration of TMB and tumor heterogeneity identify an immunologic subtype of melanoma with favorable survival.
Authors: Chunhe Yang, Guodong Zhao, Jianfei Wang, Lingyu Wang, Ge Jin, Rongbo Lin, Yadong Yang
Journal: Journal of Clinical Oncology (2020)

e15183 Background: Tumor mutational burden (TMB) has been reported a predictive marker of response to immune checkpoint inhibition (ICI) therapy in previous clinical trials. However, TMB alone is not sufficient to accurately predict immunotherapy benefit. Additional biomarkers are needed for better stratification of immunotherapy sensitive patients. Methods: Here we combined TMB with tumor heterogeneity for evaluating response to ICI treatment. Mutation and clinical data were collected from several melanoma immunotherapy studies, including cohort treated with Ipilimumab and anti-PD-(L)1/anti-CTLA-4 (VanAllen_2015, n = 110; Miao_2018, n = 151) and a cohort treated with Nivolumab (Riaz_2017, n = 60). Tumor heterogeneity was estimated with mutant-allele tumor heterogeneity (MATH) or clone number. Benefit score was defined as ratio between TMB and tumor heterogeneity and the most significant critical values were selected to group patients. Besides, we calculated clonal TMB and investigated its correlation with TMB and tumor heterogeneity. Statistical analyses were performed using R software. Results: Benefit score was tested in several cohorts as a marker of ICI therapy response. In VanAllen_2015 and Miao_2018 cohort, TMB/MATH score significantly improved the performance of stratifying the overall survival (OS) of patients with ICI treatment compared with TMB alone as predictor (p = 0.0068 vs. p = 0.1 and p = 0.028 vs. p = 0.042). In Riaz_2017 cohort, we used clone number to calculate the benefit score due to the unavailability of the raw data. In this cohort, benefit score is also positively associated with higher overall survival (p = 0.056), which outperforms TMB alone with a significance of p = 0.57. Moreover, clonal TMB showed positive correlation with TMB (R &gt; 0.3) and negative correlation with tumor heterogeneity (R &lt; -0.3) in one melanoma cohort (Miao_2018). Conclusions: Tumor heterogeneity, combined with TMB showed superior efficacy in predicting response of ICI therapy. This may further help delineating the mechanisms of immunotherapy in melanoma patients.
Part 2: Evidence Evaluation and Management of Conflicts of Interest
Authors: Laurie J. Morrison, Lana M. Gent, Eddy Lang, Mark E. Nunnally, Melissa J. Parker, Clifton W. Callaway, Vinay M. Nadkarni, Antonio R. Fernandez, John E. Billi, Jonathan R. Egan, Russell E. Griffin, Michael Shuster, Mary Fran Hazinski
Journal: Circulation (2015)
Phase II trial of guadecitabine priming and pembrolizumab in platinum resistant recurrent ovarian cancer.
Authors: Daniela Matei, Alok Pant, John William Moroney, Gini F. Fleming, Edward Tanner, Wendy M Swetzig, Jiahui Xu, Horacio Cardenas, Manoj Kandpal, Andreea Gavrilescu, Siqi Chen, Masha Kocherginsky, Ramana V Davuluri, Bin Zhang
Journal: Journal of Clinical Oncology (2020)

6025 Background: Platinum resistant ovarian cancer (PROC) remains a disease of high need. Immune checkpoint inhibitors (ICI) have modest activity. We hypothesized that priming with a hypomethylating agent (HMA) guadecitabine (G) will improve the anti-tumor activity of ICI in PROC by enhancing tumor cell recognition by CD8+ T cells. Methods: This open-label phase II study used a Simon’s two-stage design. Eligible patients (pts) had recurrent PROC; ECOG PS of 0-1; normal end organ function; and measurable disease. Up to 5 prior cytotoxic regimens were allowed. Treatment consisted of G 30mg/m2 sq D1-4 and pembrolizumab (P) 200mg iv D5. Each cycle was 21 days. The primary endpoint was response rate (RR). Secondary endpoints were progression-free survival (PFS), clinical benefit rate (CBR), and toxicity assessment. Translational endpoints were LINE1 methylation in PBMCs, global tumor methylation, and immune endpoints. Tumor biopsies were obtained at baseline and after 2 cycles. If 2 patients experienced clinical benefit in stage I [n = 16], enrollment proceeded to stage II. The null hypothesis was rejected for ≥ 6 responses in 35 evaluable patients. Results: 48 pts were enrolled, 43 were treated, and 33 were evaluable for response. Histology was serous (35), endometrioid (2), clear cell (3) and other (3). Median age was 63 (range 40-88) and median number of prior regimens was 4 [range 1-8]. Two PRs were recorded in the first stage, allowing second stage of enrollment. Overall, there were 2 PRs (RR = 6.6%) and 16 pts had stable disease (SD) [48%]. The clinical benefit rate (PR + SD &gt; 3 months) was 27%. One patient continued treatment for &gt; 2 yrs. Grade 3-4 related toxicities were neutropenia [20], lymphopenia, (9), anemia (2), neutropenic fever (1), rash (1), and others (8). There were 13 grade 3-4 SAEs and 4 grade 5 SAEs, assessed as being unrelated to treatment. LINE1 was hypomethylated in PBMCs D5 vs. D1 (n = 21, p = 0.001). Epic arrays measured global tumor methylation, with 39579 CpG sites (0.05%) being differentially methylated (C2D5 vs. C1D1, n = 11, paired t-test; p &lt; 0.01). Main pathways affected included endosomal transport, K+ transport, cathecolamine secretion, etc. PDL1 staining in archival tissue showed tumor staining &gt; 0 in 16 of 35 and tumor/stroma interface staining &gt; 0 in 20 of 35 specimens. Antigen-specific cytotoxic T cell activity was increased in CD8+ cells from ascites (C2D5 vs. C1D1). Conclusions: G+P has modest anti-tumor activity in patients with PROC, but some patients experienced prolonged disease stabilization. Biomarkers of response are being investigated. Clinical trial information: NCT02901899.