tbuckley/cabot-search huggingface dataset:
P04.32 Integrative analysis of DNA methylation suggests down-regulation of oncogenic pathways and reduced de-novo mutation in survival outliers of glioblastoma
Authors: T Hwang, D Mathios, K McDonald, I Daris, S Park, P Burger, S Kim, Y Dho, C Hruban, C Bettegowda, J Shin, M Lim, C Park
Journal: Neuro-Oncology (2018)

The study of survival outliers of glioblastoma (GBM) can have important implications on gliomagenesis as well as in the identification of ways to alter clinical course on this almost uniformly lethal cancer type. However, current studied epigenetic and genetic signatures of the GBM outliers have failed to identify unifying criteria to characterize this unique group of patients. We compared global DNA methylation patterns of IDH wild-type (IDH WT) GBM patients who lived longer than 3 years (n=17, LTS-GBM) with patients who lived less than 1 year (n=12, STS-GBM), and performed comprehensive enrichment analyses with genomic and epigenomic signatures in conjunction with available open source data. The analysis result was further validated with an independent set of 10 LTS-GBM samples. We found that the genome of LTS-GBM is differentially methylated relative to STS-GBM depending on CpG density: hypermethylation near CpG islands (CGIs) and hypomethylation far from CGIs. Interestingly, these two patterns are associated with distinct signature of histone mark enrichment, and oncogenic aspects in gliomagenesis. The hypomethylation pattern at the region distant from CGI is associated with H3K9me3 enrichment and lower rates of de novo mutations, while the hypermethylation at CGIs is associated with H3K27ac and correlates with transcriptional downregulation of genes involved in cancer progression pathways. These results extend our understanding of DNA methylation of survival outliers in glioblastoma in a genome-wide level and provide insight on the potential impact of DNA hypomethylation in cancer genome.
Apatinib in treating patients with platinum-resistant or platinum-refractory recurrent or metastatic nasopharyngeal carcinoma.
Authors: Xiaozhong Chen, Changjuan Tao
Journal: Journal of Clinical Oncology (2019)

e17502 Background: To evaluate the efficacy and safety of apatinib in treating patients with platinum-resistant or platinum-refractory recurrent or metastatic nasopharyngeal carcinoma. Methods: In this phase 2, single-arm, prospective study, we recruited patients aged 18–65 years with platinum-resistant or platinum-refractory recurrent /metastatic nasopharyngeal carcinoma. Patients were treated with apatinib at an initial dose of 500 mg once daily and continued until disease progression, patient withdrawal, or unacceptable toxic effects. The primary endpoint was clinical benefit rate (CBR) and toxicity. Secondary endpoints included progression-free survival (PFS) at 3 months and overall survival (OS). We used Simon’s two-stage design, and analysed efficacy and toxicity in the intention-to-treat and per-protocol populations. This study is registered with ClinicalTrials.gov, number NCT03213587. Results: Between Aug 5,2017 and Oct 13,2018, we enrolled 16 patients. Until the final follow-up (Jan 14, 2019), the CBR (complete response + partial response+ stable disease) was 69.2% (9/13) in the per-protocol population. Median PFS and 3-month PFS rate were 3.70 (95% CI, 0-8.771) months and 67.1%, respectively. Median OS and 1-year OS rate were 12.9 (95% CI 5.56-20.23) months and 47.9%, respectively. The most common grade 3-4 adverse events were neutropenia (1[6.25%]), hand-foot syndrome (2[12.5%]), albuminuria (2[12.5%]), hypertension (1[6.25%]), hyponatremia (1[6.25%]), artery dissection (1[6.25%]) and nasopharyngeal hemorrhage (2[12.5%]) in the intention-to-treat population. Serious adverse event was reported in one patient who died of nasopharyngeal hemorrhage. Conclusions: Apatinib achieved excellent disease control in platinum-resistant or platinum-refractory recurrent or metastatic nasopharyngeal carcinoma. More attention needs to be paid to toxicity management. Clinical trial information: NCT03213587.
Lack of clinician knowledge of human papillomavirus (HPV) vaccination to prevent HPV-related cancers in men: An interview study.
Authors: Stefan Varga, Suepattra Grace May, Edith Morais, Anshu Shrestha, Caroline Huber, Anupama Tantri, Meaghan Roach, Matthew Phillips, Anupam B. Jena
Journal: Journal of Clinical Oncology (2019)

e18273 Background: Human papillomavirus (HPV) has a well-established link to cervical cancer and anogenital and oropharyngeal malignancies. Recognition of the HPV-caused cancer burden in males has led to expansions of female-only HPV vaccination programs to all genders. This study explored drivers of and barriers to gender-neutral HPV vaccination (GNV) program adoption, implementation, and potential impacts on the HPV-caused cancer burden. Methods: We conducted in-depth interviews with academic oncologists as well as advocacy, public health, infectious disease, and policy experts in six countries (Argentina, Australia, Austria, Brazil, Canada and Italy) from April-August 2018. Using a semi-structured discussion guide, we sought to elicit expert perceptions on factors affecting uptake of HPV vaccination in males and subsequent effects on the incidence of HPV-associated cancer. Data were analyzed for key themes. Results: Eighteen experts participated in the study, including three academic oncologists and two doctoral level oncology researchers. A key theme from the analysis was the critical need to promote education and awareness about GNV across all healthcare providers to facilitate vaccine uptake and high GNV coverage rates. Participants reported a lack of awareness among segments of practitioners about the effectiveness of the HPV vaccine in preventing HPV infection and associated cancers in all genders. They also described strategies to overcome knowledge gaps, such as partnerships with oncologists, cancer advocacy organizations, and professional medical societies, emphasizing the key role that all health care providers can play in raising awareness of the importance of HPV vaccination for all genders. Conclusions: Findings from this study suggest the need to enhance healthcare provider education about GNV, and the importance of a multi-specialty approach to promoting HPV vaccination to prevent infection and HPV associated morbidity and mortality in all genders.
Employment outcomes and quality of life in patients with early breast cancer and their support persons: A dyadic study.
Authors: Christine M Veenstra, Daniela Wittmann, Chandler McLeod, Thomas Braun, Sarah T. Hawley
Journal: Journal of Clinical Oncology (2019)

e18241 Background: Many women with breast cancer face job loss related to their diagnosis, but little is known about employment outcomes among their partners and other supporters. Moreover, virtually nothing is known about associations between patients’ quality of life and supporters’ employment status. Methods: Breast cancer patients reported to Georgia and LA SEER registries in 2014-15 (N = 2,502, 68% RR) and their key decision support person (DSP) were surveyed separately. 1234 DSPs responded (71% RR). Patients and DSPs were asked about employment impacts of the patient’s breast cancer. Patients’ quality of life (QOL) was measured with the PROMIS scale for global health. Descriptive analyses of employment outcomes (job loss, missed days due to cancer) were generated for patients and DSPs. Associations between patients’ QOL and employment status of patients and their DSPs were assessed using linear mixed model regression analyses stratified by dyad type (partner vs. non-partner DSP). Results: Among DSPs, 43% were partners. 57% were non-partners (daughters, other family, friends). 67% were employed at time of patient’s diagnosis. Among these, 11% were no longer employed at survey completion. 39% missed &gt; 30 days work. Non-partner DSPs were as likely as partners to lose their job or miss work because of the patient’s cancer. 65% patients were employed at diagnosis. Compared to patients whose DSP was a partner, patients with non-partner DSP were more likely to lose their job (39% vs. 24%; p &lt; 0.01) or miss &gt; 30 days work (55% vs. 45%; p &lt; 0.01). For patients with a partner DSP, both patient and DSP employment at diagnosis were associated with improved patient QOL (each associated with a QOL score 24% of 1 standard deviation higher; each p &lt; 0.05). For patients with non-partner DSPs, only patient employment at diagnosis was associated with improved patient QOL (QOL score 51% of 1 standard deviation higher; p &lt; 0.01). Conclusions: Both non-partner and partner DSPs faced negative employment impacts related to patients’ breast cancer. Job loss and &gt; 30 days of missed work were more likely among patients with non-partner DSPs. Only the employment of partner DSPs at diagnosis positively contributed to patients’ QOL.
A crossroads between the heart and lungs: air pollution and pulmonary hypertension
Authors: Meredith C. McCormack, Stephen C. Mathai
Journal: European Respiratory Journal (2019)

<b>Proximity to traffic and particulate pollution may be associated with disease severity and increased mortality in individuals with pulmonary arterial hypertension. Future studies are needed to confirm these findings.</b>http://bit.ly/2P5QE52
Digital Lung Auscultation: Will Early Diagnosis of Fibrotic Interstitial Lung Disease Become a Reality?
Authors: Luca Richeldi, Vincent Cottin, Gebhard Würtemberger, Michael Kreuter, Mariarosaria Calvello, Giacomo Sgalla
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Research projects are under way to build more evidence in this field.In an ongoing, multicenter clinical trial (clinicaltrials.govidentifier: NCT03503188), digital lung sounds and basic patient characteristics are being prospectively collected from patients with IPF and symptom-matched control subjects.A well-established teaching device for lung sounds (14) will be used as a reference.
Molecular and clinical features of hospital admissions and immunotherapy related adverse events of immune checkpoint inhibitors in thoracic malignancies.
Authors: Dan Zhao, Isa Mambetsariev, Chen Chen, Haiqing Li, Jeremy Fricke, Blake Hewelt, Patricia Fann, Prakash Kulkarni, Yan Xing, Marianna Koczywas, Erminia Massarelli, Karen L. Reckamp, Ravi Salgia
Journal: Journal of Clinical Oncology (2019)

e18192 Background: Immunotherapy related adverse events (irAEs) and hospital admissions with Immune Checkpoint Inhibitors (ICIs) in thoracic malignancies remain poorly characterized. Methods: Admissions after ICIs in all thoracic malignancies patients received ICIs at City of Hope (total 384) were identified as of 11/8/2018. IrAEs, outcomes, pathology and next-generation sequencing (NGS) data were collected, including Tumor mutation burden (TMB) and PD-L1 (22C3). Length of stay (LOS) and overall survival (OS) was calculated. Unpaired T-tests if data passed normality test, Chi-square and Fisher’s exact test, Gehan-Breslow-Wilcoxon test were used for comparison between 2 groups (irAEs VS no irAEs) for LOS, demographics and genetics, and survival respectively. Results: 100 patients had hospital admissions after ICIs therapy and 90 patients (41 women, 49 men) had stage IV disease (63 lung adenocarcinomas, 14 squamous cell lung cancer, 5 small cell lung cancer, 8 others). 28 out of 90 patients had irAEs (10 pneumonitis/pneumonia, 4 adrenal insufficiencies, 4 colitis, 3 liver toxicities, 2 nephritis, 1 heart failure, 1 pancreatitis, 1 diabetic ketone acidosis, and others including multiple irAEs). There was no difference between the patients who had irAEs VS no irAEs in LOS (median 7 days VS 6 days, P = 0.57). Patients with irAEs had more invasive diagnostic procedures than no irAEs (53.6% VS 25.8%, P = 0.02). There was a trend of longer OS in irAEs patients (median 16.4 months VS 6.8 months, P = 0.13) than no irAEs. Male gender (71.4% (20/28) VS 46.8% (29/62), OR = 2.85, P = 0.04) and smoking exposure (89.3% (25/28) VS 58.1% (36/62), OR = 6.0, P &lt; 0.01) were associated with irAEs patients. Genetic alterations of LRP1B gene (83.3% (5/6) VS 26.9% (7/26), OR = 13.6, P = 0.02) and MLL3 gene (66.7% (4/6) VS 19.2% (5/26), OR = 8.4, P = 0.04) were associated with patients who had irAES. No difference was found in age, lines of therapy, TP53, KRAS, EGFR, STK11, PIK3CA, TMB, PD-L1 between the irAEs and no irAEs patients. Conclusions: Hospitalized patients who had irAEs had similar LOS compared with patients without irAEs but potentially longer OS. Gender, smoking status and genes associated with irAEs and ICIs outcomes were explored. Larger dataset for molecular and clinical features was planned.
The prognostic factors associated with long-term survival in the patients with synchronous oligometastatic esophageal adenocarcinoma.
Authors: Masaaki Iwatsuki, Kazuto Harada, Xuemei Wang, Manoop S. Bhutani, Brian Weston, Jeffrey H Lee, Quynh Nguyen, Wayne Lewis Hofstetter, Irene Thomas, Jane E. Rogers, Hideo Baba, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2019)

e15523 Background: Patients with gastrointestinal cancer are increasingly being diagnosed with oligometastatic disease due to the development of sensitive imaging. Oligometastases (OLM) represent a clinical and anatomical manifestation of resistant localized cancer and/or metastases. However, oligometastatic disease is complicated by the lack of uniformity due to the heterogeneity of cancer, therefore, differing prognoses. The aim of this study is to identify the factors associated with long-term survival in the patients with synchronous oligometastatic esophageal adenocarcinoma (EAC). Methods: Between 2002 and 2016, of 1400 patients with EAC (esophagus and Siewert types I and II) treated at our institute, 233 patients initially diagnosed with stage IVB were enrolled. OLM was defined as only metastasized to one organ and less than 5 metastases. We retrospectively analyzed the association between clinicopathological factors and prognosis, especially focused on the pattern of metastases. Results: Eighty-five patients (36.5%) had OLM, and 148 (63.5%) had non-oligometastais (Non-OLM). The patients in OLM had significantly better overall survival (OS) than the patients in Non-OLM (p = 0.0001). Univariate analysis showed pattern of metastases (lymphatic OLM) and treatment method (consolidative local radiotherapy: CLT) were significantly associated with prognosis (p = 0.04 and 0.01, respectively). Multivariate analysis revealed that lymph node metastases (cN0-N1), number of metastasis (solitary) and treatment (CLT) were independent predictors for OS of patients with OLM. (p = 0.03, 0.01 and 0.001, respectively). In OLM patients, the patients with lymphatic OLM who received CLT had more favorable prognosis (5-years survival rate 25%). Conclusions: This study suggests that CLT is one of the promising modalities for oligometastatic patients with EAC, especially the patients with lymphatic OLM.
The ratio of negative lymph node count inside the thoracic cavity to the positive lymph count is a prognostic factor in esophageal squamous cell carcinoma.
Authors: Jinling Zhang, Xueyuan Heng, Fengyuan Che
Journal: Journal of Clinical Oncology (2019)

e15545 Background: It was reported that the number of positive lymph nodes (PLN) and negative lymph nodes (NLN) resected in lymphadenectomy were both independent prognostic factors in esophageal squamous cell carcinoma (ESCC). However, it is unclear which kind of combination of them would have a stronger impact on the prognosis of the ESCC patients. Methods: A total of 229 patients with ESCC were retrospectively investigated. The Cox Proportional Hazards Model was used to investigate the relationship between the PLN or NLN and the overall survival of patients. Survival analysis was performed using the Kaplan-Meier method, and the survival difference between sub-groups were explored with log-rank tests. The cut-off number of the ratio of NLN count to PLN count resulted in an improved outcome for patients was investigated by a series of log-rank tests. Results: The numbers of PLN and NLN were both independent prognostic factors, supported by the results of Cox regression model analysis (hazard ratio [HR], 1.12, P &lt; 0.001 and HR, 0.97, P = 0.024, respectively).The survival differences among sub-groups from N0 to N3 stage were statistically significant (P &lt; 0.001). Analysis using a Cox regression model revealed that the number of NLN inside the thoracic cavity had a stronger impact on the prognosis compared to the number of NLN outside the thoracic cavity (HR,0.959, P = 0.042 vs.HR, 0.973, P = 0.179). As a combination analysis consisting of the number of PLN and NLN, the log-rank test result demonstrated that patients with the ratio of NLN count inside thoracic cavity to the PLN count less than 8 could achieve a better survival. Conclusions: The ratio of NLN count inside thoracic cavity to the PLN count was a independent prognostic factor.
An artificial intelligence approach to variant calling of ALK resistance mutations.
Authors: Jochen K Lennerz, Emily Chin, Marguerite Rooney, Michael Zomnir, Enrique Dominguez Meneses, Lev Lipkin, A. John Iafrate, Long P. Le, Alice Tsang Shaw
Journal: Journal of Clinical Oncology (2019)

3079 Background: ALK tyrosine kinase inhibitors (TKIs) are effective in treating advanced anaplastic lymphoma kinase (ALK) fusion-positive non-small-cell lung cancers (NSCLC), and specific ALK variants are associated with the development of resistance to specific TKIs. Humans struggle to harness the full potential of the highly complex next-generation sequencing bioinformatics pipeline output. As a consequence, the decision to report a variant remains difficult, and we considered the discrete nature of the data and the binary decision (report vs. not-report) as an ideal setting to apply an artificial intelligence (AI) approach for variant reporting. Methods: We assessed diagnostic performance of an AI model in calling ALK-resistance mutations in n = 50 consecutive ALK fusion positive patients who relapsed on TKI-therapy and underwent repeat biopsy at MGH. The random forest model was derived from independent datasets (training and validation) capturing the reporting decision on &gt; 36,000 variants with ~500 features per variant resulting in a matrix of &gt; 18 million data points. The model output is a contiguous prediction score from 0 (not report) to 1 (report) and a visual drill-down functionality allows exploration of the underlying features that contributed to the decision. Results: Examination of n = 76 tests from n = 50 patients with a total of n = 130 reported variants (and = 115 not reported variants) included a total of n = 31 ALK point mutations: p.1156(n = 2), p.1171(n = 8), p.1174(n = 2), p.1180(n = 2), p.1196(n = 1), p.1198(n = 1), p.1202(n = 8), p.1203(n = 1), p.1204(n = 1), p.1206(n = 1), p.1269(n = 4). Setting a screening threshold of the model at &gt; 10% for reporting showed only one false-negative (p.Ile1171Asn) variant and 96.7% sensitivity. The average model score for ALK variants was 0.664 (range: 0.08–0.98; median 0.8) and did not show significant differences from other reported variants (0.636; 0–1; 0.7; t-test 0.66). The model would have called n = 18 of the non-reported control variants (average 0.07; range &lt; 0.001–0.64; P &lt; 0.0001) and was 84% specific. Review of the drill-down function identified prior call frequency, allelic ratio, and predicted transcript consequences as common model features. Importantly, the model is currently agnostic to the medical literature and does not take clinical parameters (e.g. TKI type) into account, which may further improve performance. Conclusions: Applying artificial intelligence to large discrete datasets is one approach to help identify clinically relevant variants in the setting of ALK resistance in ALK-fusion positive NSCLC.
Effect of exonic microsatellite instability of B2M on the predictability of MSI/dMMR for immunotherapy.
Authors: Jia Wei, Fangfang Zhong, Weifeng Wang, Nandie Wu, Yao Fu, Shuo Mu, Yue Wang, Xiaoping Qian, Xiangshan Fan, Kai Wang, Baorui Liu
Journal: Journal of Clinical Oncology (2019)

2576 Background: Microsatellite instability/mismatch repair deficiency (MSI/dMMR) has been approved as a biomarker for immune checkpoint inhibitor therapy (ICI) . However, the deficiency of mismatch repair system also caused wide-spreading insertion/deletion (indel) mutations in the exonic microsatellite sites of critical immunotherapy related genes such as β-2-macroglobulin (B2M) whose product is critical to antigen presentation. Cases of aquired resistance to ICI treatment caused by the inactivation of B2M have been reported. Therefore, we investigated the mutational profile of B2M across the MSI/dMMR high prevalent cancers such as colorectal cancer (CRC), gastric cancer (GC) and endometrial cancer (EC). Methods: FFPE tumor samples from 37 CRC, 46 GC and 25 EC patients with matched normal tissues were collected for next-generation sequencing (NGS)-based 450 genes panel assay. Genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, and gene rearrangement and tumor mutational burden were assessed. Immunohistochemistry (IHC) with antibody against B2M were performed on available samples to estimate the expression and localization of these proteins. Results: Exonic microsatellite sites of B2M gene have been found instable in 51% (19/37) of CRC, 22% (10/46) of GC and 8% (2/25) of EC. MSI caused small indels at B2M coding region leads to reading frame shift and the production of nonfunctional truncated proteins. Biallelic frameshift mutations, causing non-functional proteins, were found in 47% (9/19) of CRC and 30% (3/10) of GC patients carrying Indels in B2M gene. IHC assays showed the impaired expression of B2M proteins due to frameshift mutations. In addition, NGS test confirmed concurrent mutation in B2M for a MSI-H CRC patient with primary resistance to forth-line anti-PD1 treatment. Conclusions: The extensive mutations in the coding region of genes caused by the dMMR render the cancer cell sensitive to ICI. However, the concomitant variants in exonic microsatellite sites of B2M gene may compromise the predictability of MSI/dMMR as an ICI biomarker. Biallelic mutation of B2M may cause primary resistance to ICI while the mono-allelic mutation of B2M may gain acquired resistance. Therefore, B2M status could be considered when using MSI/dMMR as a biomarker for ICI.