tbuckley/cabot-search huggingface dataset:
Validation of natural language processing (NLP) for automated ascertainment of EGFR and ALK tests in SEER cases of non-small cell lung cancer (NSCLC).
Authors: Bernardo H. L. Goulart, Emily Silgard, Christina S. Baik, Aasthaa Bansal, Mikael Anne Greenwood-Hickman, Annika Hanson, Scott David Ramsey, Stephen Schwartz
Journal: Journal of Clinical Oncology (2017)

6528 Background: The Surveillance, Epidemiology, and End Results (SEER) registries lack information on the Epidermal Growth Factor Receptor (EGFR) mutation and Anaplastic Lymphoma Kinase (ALK) gene rearrangement test results. With the goal of enabling population-based outcomes research in molecularly selected NSCLC subgroups, we conducted a validation study of NLP for ascertainment of EGFR and ALK testing from electronic pathology reports (e-paths) of patients included in the Seattle-Puget Sound (SPS) and Kentucky Cancer (KCR) SEER registries. Methods: We obtained 4,278 and 1,041 e-paths pertaining to 1,634 and 565 patients with stage IV non-squamous NSCLC diagnosed from 1/1/2011 to 12/31/2013 and included in the SPS and KCR registries, respectively. Two oncologists independently reviewed all reports to generate a gold-standard dataset. We used 855 of the SPS reports to train hybrid rule-based and machine learning algorithms for detection of test status (reported vs. not reported), and test result if reported (positive vs negative) for EGFR mutational analysis and ALK testing by FISH, IHC, or gene sequencing. In the remaining 3,423 SPS reports, we conducted a 5-fold cross-validation analysis to estimate the internal NLP sensitivity, specificity, positive predictive value, and negative predictive value for test status and results, respectively. We used a hierarchical rules system to assess the NLP accuracy at the patient level. For external validation, we repeated all analyses in the KCR dataset. Results: In the SPS internal validation report sample, the validity metrics ranged from 97% to 99% for EGFR and ALK test status, and from 95% to 100% for EGFR and ALK test results, respectively. In the KCR external validation report sample, the metrics ranged from 74% to 96% for EGFR and ALK test status, and 2% to 100% for test results, respectively. At the patient level, the NLP accuracy for EGFR and ALK was 95% and 96% (SPS cohort), and 70% and 72% (KCR cohort) respectively. Conclusions: NLP is a valid method for determining EGFR and ALK test status and results for patients included in SEER registries with access to e-path, but the algorithms likely need to be registry-specific.
Mutational complexity increases in lung adenocarcinoma (LADC) with the development of brain metastasis (BM).
Authors: Matthew K Stein, Michael Gary Martin, Joanne Xiu, Sandeep Mittal, Surasak Phuphanich, Aaron Paul Provenzano, Sharon Michelhaugh, Andrew Jacob Brenner, Deepa Suresh Subramaniam, Ashley Love Sumrall, Amy B. Heimberger, Santosh Kesari, W. Michael Korn, Manjari K Pandey
Journal: Journal of Clinical Oncology (2018)

2067 Background: Up to 40% of LADC patients (pts) develop BM but little is known about the inciting molecular events. Methods: We compared mutational profiles of LADC BM pts with primary (P) LADC submitted to Caris Life Sciences from 2015-2017. Testing included next-generation sequencing (NGS) of 592 cancer-related genes, PD-L1 IHC and tumor mutational burden (TMB). NGS aberrations were test-defined as pathogenic (PATH), variants of undetermined significance or unclassified mutations (VUS). TMB was defined as: high (H; ≥17 mutations/megabase), intermediate (I; 7-16) and low (L; 0-6). Results: 145 BM (57% female (f)) and 1145 P (58% f) cases were identified; BM median age was 64 (range 31-86) vs. 70 (25-90) in P pts. BM had 55 PATHs (38% pts) in KRAS, 34 STK11 (23%), 17 EGFR (12%), 5 BRAF (3%); 3 were MET-amplified (2%), 3 ALK (2%) and 1 ROS1-rearranged (1%). Compared to P, more BM pts harbored STK11 PATHs (23% vs. 11%, P < 0.0001); no other difference in PATHs was observed. 143 BM and 1102 P pts had TMB data. BM cases were more-frequently TMB-H compared to P (39% (N = 56) vs. 12% (132), P < 0.0001) and less likely to be TMB-L (8% (12) vs. 33% (366), P < 0.0001). 131 (92%) BM pts were TMB-I or H. Of 142 BM and 1060 P with PD-L1 testing, incidence of ≥1% (46% BM vs. 49% P) and ≥50% (24% vs. 23%) cases were similar. 327 VUS in 28 receptor tyrosine kinases (RTK) were observed in 117 BM (median 1 (0-12)) vs. 1648 VUS in 807 P pts (median 1 (0-13); 79% vs. 70%, P = 0.007). RTK VUS more frequently observed in BM included: 51 EPHA3 VUS (17% pts vs. 8%. P = 0.0002), 25 EPHA5 (15% vs. 8%, P = 0.004), 26 NTRK3 (14% vs. 6%, P = 0.0002), 22 EPHB1 (13% vs. 6%, P = 0.0001) and 17 PDGFRA (12% vs. 5%, P = 0.0001). No significant difference was observed between BM specimen site and EGFR, KRAS, TMB and PD-L1 status. Conclusions: While classic LADC biomarkers including PD-L1, EGFR and KRAS were similar between BM and P cases, nearly 40% BM pts were TMB-H (≥25% more than P) and > 90% either TMB-I or H, indicating an increased mutational complexity in BM development, suggesting immune checkpoint inhibitor use. In addition to STK11 PATHs, RTK VUSs including NTRK3, EPHA3, EPHA5 and EPHB1 were more-frequently mutated and warrant further evaluation as biomarkers or targets in BM.
Two cases of monkeypox imported to the United Kingdom, September 2018
Authors: Aisling Vaughan, Emma Aarons, John Astbury, Sooria Balasegaram, Mike Beadsworth, Charles R Beck, Meera Chand, Catherine O’Connor, Jake Dunning, Sam Ghebrehewet, Nick Harper, Ruth Howlett-Shipley, Chikwe Ihekweazu, Michael Jacobs, Lukeki Kaindama, Parisha Katwa, Saye Khoo, Lucy Lamb, Sharon Mawdsley, Dilys Morgan, Ruth Palmer, Nick Phin, Katherine Russell, Bengü Said, Andrew Simpson, Roberto Vivancos, Michael Wade, Amanda Walsh, Jennifer Wilburn
Journal: Eurosurveillance (2018)

In early September 2018, two cases of monkeypox were reported in the United Kingdom (UK), diagnosed on 7 September in Cornwall (South West England) and 11 September in Blackpool (North West England). The cases were epidemiologically unconnected and had recently travelled to the UK from Nigeria, where monkeypox is currently circulating. We describe the epidemiology and the public health response for the first diagnosed cases outside the African continent since 2003.
Prognostic and predictive value of mRNA expression of mTOR and VEGF pathway members in metastatic renal cell carcinoma (mRCC).
Authors: Dmitry Nosov, Ekaterina Voroshilova, Natalya Apanovich, Mikhail Fedyanin, Alexander Karpukhin
Journal: Journal of Clinical Oncology (2016)

e16130 Background: Although targeted therapy has dramatically improved outcomes in mRCCs there are no predictive biomarkers for patient selection. Activation of mTOR and/or VEGF pathways members in tumor tissue may have prognostic or predictive value for mRCC. We have explored the expression level of mRNA genes of both pathways in mRCC patients who received VEGFR and mTOR inhibitors. Methods: Paraffin-embedded tumor tissue specimens of 43 mRCC patients were retrospectively examined by quantitative RT-PCR for the expression of mRNA VEGFR-1 and -2, VEGFÀ, PDGFRα and -β, PI3K, AKT, mTOR, RPS6, PTEN, STAT3, EGFR, RAF1. The 43 specimens were derived from primary tumor after nephrectomy and additionally 28 were derived after metastasectomy. All patients (n = 43) received VEGFR-inhibitors (pazopanib, sunutinib, sorafenib or tivozanib) as first line targeted therapy (VEGFR group). Of them 13 patients (mTOR group) received everolimus as the second-line treatment after VEGFR inhibitors failure. Results: In the VEGFR and mTOR groups the ORR was 48% and 7%, median PFS was 11 and 6 months respectively. Median OS was not reached. In VEGF group overexpression of VEGFR1 mRNA in metastasis but not in primary tumor was associated with higher ORR compared to normal or decreased expression level (92% vs 18% vs 0%, respectively, p = 0.05). The increased level of VEGFR2 mRNA in primary tumor and RAF1 mRNA in metastasis was associated with decreased PFS (HR 1.72, 95%CI: 0.96-3.09, p = 0.05 and HR 2.12, 95%CI: 0.94-4.8, p = 0.06, respectively). In mTOR group overexpression of mTOR mRNA in primary tumor was associated with tumor shrinkage ( > 10%) compared to hypoexpression (100% vs 0%, p = 0.008). The increased level of PI3KmRNA in primary tumor was associated with better PFS. (HR 0.4, 95%CI: 0.16-0.98, p = 0.04).The overexpression of RAF1 mRNA either in primary tumor or metastases (25% and 28%) was mutually exclusive with overexpression of mRNA PI3K, AKT, mTOR and RPS6 (p < 0.05). Conclusions: The overexpression of mRNA VEGFR1 and mTOR in tumor tissue are promising predictive biomarkers for patient selection to anti-VEGFR or mTOR therapy. Activation of PI3K/ AKT/ mTOR and RAF/MEK pathways is likely mutually exclusive events in mRCC.
Real-time single-walled nanotube (SWNT)-based imaging system to improve tumor detection and survival in ovarian cancer preclinical model.
Authors: Lorenzo Ceppi, YoungJeong Na, Neelkanth M. Bardan, Andrew Siegel, Nandini Rajan, Angela M. Belcher, Michael J. Birrer
Journal: Journal of Clinical Oncology (2016)

5530 Background: Residual tumor detection in advanced stage ovarian cancer (OC) represents a critical challenge in the treatment of the disease. Optimal abdominal cytoreduction until no evidence of macroscopic disease is the primary surgical endpoint, with demonstrated survivaladvantages, however current imaging modalities have shown low detection sensitivity below 10 mm diameter. Novel targeted molecule-based imaging systems offer higher detection rate and are likely to extend the aim of complete resection to the microscopic scale. We applied a custom designed imaging system to a preclinical OC model and observed higher microscopic tumor detection and survival advantage compared to non-image guided debulking surgery. Methods: A two component imaging system was developed. The contrast agent is an intra-peritoneal injectable nanomolecular probe, composed of a single walled carbon nanotube (SWNT) coupled with an engineered M13-bacteriophage carrying a modified peptide targeting secreted protein, acidic and rich in cysteine (SPARC), extracellular protein overexpressed in OC. The imaging device system is capable of detecting SWNT inherent fluorescence in near-infrared second window (NIR2) and of displaying real-time images to guide intraoperative tumor debulking. Results: In an orthotopic OC animal model, the imaging system detected microscopic tumors in the millimeter and sub-millimeter scale resolution with a mean tumor diameter of Mean and SD 1.36±1.01 and 3.27±2.10 mm (p: 0.0005) compared to eye detected tumors. The imaging system demonstrated sensitivity of 97.2% and specificity of 70.9%, and a Receiver Operator Area under the Curve (ROC±SE) of 0.86±0.04. In a survival surgery animal model, the imaging guided resection surgery compared to non guided surgery showed a survival advantage for the experimental arm, with median survival time of 40.5 and 28.0 days, respectively (HR 0.26, 95% CI 0.07 to 0.93, p: 0.039). Conclusions: The accuracy of the imaging system and its survival advantage in this OC preclinical model are promising to support the translation to first-in-human investigation, and suggest further exploitation in targeted delivery therapies.
The feasibility and efficiency of wait and see policy for patients with complete clinical response following neoadjuvant therapy in rectal cancer: A prospective cohort study from China.
Authors: Jin Gu, Changzheng Du, Ming Li, Yifan Peng, Yunfeng Yao, Jun Zhao, Tiancheng Zhan, Yong Cai, Yongheng Li, Jing Jin
Journal: Journal of Clinical Oncology (2017)

3610 Background: It has been reported that non-operative treatment (wait and see) is feasible for the selected rectal cancer cases with a complete clinical response (cCR) following neoadjuvant therapy (NT). The aim of this study is to determine whether "wait and see" policy is efficient for the cCR patients in China. Methods: We designed a prospective cohort study in China (ChiCTR-TRC-12002488). From Jul 2012 to August 2016, totally 45 patients with locally advanced rectal cancer who were cCR following NT were enrolled in the study; within whom, 32 patients were assigned to wait and see group, and the remaining 13 patients were assigned to surgery group (intent-to-treat grouping). Results: The median follow-up time was 24 months (range: 3-51). Of the patients who were followed up more than 12 months (n=37), 8 patients developed tumor progression (7 in wait and see group and 1 in surgery group, respectively). In the wait and see group, the local regrowth took an account of 23.1% (6/26), while the distant metastasis rate was 3.8% (1/26). In the surgery group, there were 23.1% (3/13) of patients who has residual cancer confirmed by postoperative pathological assessment. All the patients with tumor regrowth underwent radical surgery and no body died of cancer. Conclusions: Wait and see policy has an acceptable safety and efficiency, it may become an alternative treatment for the patients who were cCR following NT. Clinical trial information: ChiCTR-TRC-12002488. [Table: see text]
Circulating tumor DNA (ctDNA) for genomic profiling of non-small cell lung cancer (NSCLC): Experience in a large community-based cancer center.
Authors: Giselle Alexandra Suero-Abreu, Miguel Gonzalez Velez, Tracy Ann Proverbs-Singh, Martin Gutierrez
Journal: Journal of Clinical Oncology (2018)

e24026 Background: Comprehensive genomic profiling to identify driver mutations for which effective therapies or clinical trials are available is part of the standard diagnostic evaluation for NSCLC. The objective of this report is to provide real world evidence on how ctDNA is being implemented in a large community-based cancer center for profiling of NSCLC patients. Methods: ctDNA genomic profiling was performed in a total of 115 NSCLC cancer patients using Guardant360. We analyzed the context of testing, turnaround times, and clinical use of ctDNA NGS in the clinic. Results: Circulating tumor DNA genomic profiling was performed in a total of 115 NSCLC cancer patients between September 2015 and January 2018. 70% of patients had Stage IV disease and Adenocarcinoma was the most predominant pathologic subtype (66%). The median age of the patient population at time of diagnosis was 68 years and 57% were female. 65% were Caucasian, 14% African-American, 16% Hispanic, and 5% other. 33% of patients had no history of tobacco use, while 56% and 11% reported former and active tobacco use, respectively. 56% of the patients underwent ctDNA genomic profiling prior to first line therapy, 36% after disease progression and 8% for monitoring stable disease; and there was a 3.5 fold increase in the rate of ctDNA profiling throughout the study period. The median response time for biomarker testing results was 12 days. ctDNA profiling was possible for all patients and the median number of plasma somatic alterations detected was 3.9. The resistance mechanism due to EGFR T790M mutation was the most frequently identified in ctDNA at time of relapse. Based on actionable clinically relevant genomic alterations detected by plasma ctDNA, 41% of pts had alterations theoretically matched to at least one FDA approved treatment or clinical trial. Serial ctDNA was obtained in fourteen patients and illustrative cases with dynamic changes in response to treatment will be presented. Conclusions: Plasma ctDNA is a novel feasible teachnique to identify clinically relevant mutations and with short turnaround time and represents an opportunity to increase adherence to molecular profiling guidelines in NSCLC.
Melanoma in African Americans: An Example of Healthcare Disparities or a Different Gene Expression Profile?
Authors: Whitney M Guerrero, Elizabeth F Lee, Martin D. Fleming
Journal: Journal of Clinical Oncology (2016)

e21044 Background: Melanoma is the 6thmost common cancer in the United States. In 2015 the incidence of melanoma in Caucasians was 25/100,000 with 93% 5 yr overall survival. In African Americans the incidence is 1/100,000 with 70% 5 yr overall survival. This gap may be due to care disparities or differences in melanoma gene expression. Methods: After IRB approval, a retrospective review was performed for patients treated for melanoma from 2004-2013. Patients underwent treatment by multiple surgeons in a community setting. There were 45 African Americans patients with melanoma treated at our institution during the study time frame. Of these, 25 had a complete data set for the purpose of this review. These were compared to an age- and histology-matched cohort of 24 Caucasian patients with melanoma. Results: Both groups were equally likely to be employed and insured with no difference in highest level of education, and on average both groups lived a similar distance from the treatment hospital. The cohorts were evenly matched by age at diagnosis and by gender (58 yr, 48% male, 52% female for African Americans; 59 yr, 46% male, 54% female for Caucasians). Melanoma subtype and histology were evenly matched. African American patients on average presented later (7.5 mo v 4.6 mo). All patients underwent similar surgical management; there was no statistical difference in average depth of invasion (3.62 mm for African Americans and 3.26 mm for Caucasians, p = 0.4). Both groups were as likely to undergo sentinel node biopsy (76% v 63%) but African Americans were more likely to have nodal disease (53% v 10%). Conclusions: There were no differences in age, gender, income, education, insurance status or distance to care. Though African Americans presented 3 months later than Caucasian patients, the histologic distribution and depth of tumor invasion were the same. We did not observe a survival difference. African American patients were more likely to have nodal spread; similar tumors appeared more virulent when they affected African Americans. In the absence of proven healthcare disparities, subset differences may be explained by variations in gene expression. Gene expression profiling may be helpful in identifying these differences.
A prospective study to assess the effect of a discharge intervention on readmission rates in patients with a low Rothman Index score admitted to the inpatient oncology unit.
Authors: Tara Beth Sanft, Olatokunbo Famakinwa, Salimah Velji, Tessa Chu, Xiaopan Yao, Bethany Larkin, Maureen Raucci, Peter Longley, Jennifer Kapo, Kerin B. Adelson, Rogerio Lilenbaum
Journal: Journal of Clinical Oncology (2016)

e18198 Background: Hospitalizations in patients with cancer are common near the end-of-life, associated with poor prognosis and often against patients’ expressed wishes. The Rothman Index (RI) is a validated prognostic score that reflects severity of illness. In a prior study, we found RI < 60 was associated with a 64% readmission rate at 30 days (30d RA) for patients discharged to home. We implemented a discharge intervention (DI) delivered by the palliative care team to address goals of care with the hypothesis that the intervention would reduce 30d RA. Methods: Patients with stage IV solid tumors admitted to the Oncology Unit who had a length of stay > 24 hours and a RI < 60 on the day prior to discharge were identified for DI. 30d RA was recorded. One-sample proportion test was used to compare the observed readmission rate with the historical control. The significance level is 0.025 for one-sided tests. For patients who did not qualify for DI, discharge destination, last RI and 30d RA was recorded for comparison. Results: From 11/3/14-12/31/15, 75 patients were identified for DI. 4 were excluded from analysis because of death prior to discharge. Observed 30d RA was 34/71 (0.48, 95% CI 0.36-0.60, p = 0.0034). The most common cancer sites were: GI (37%), lung (15%) and head and neck (15%).The DI delayed discharge in 5 cases and resulted in a change in discharge destination to hospice in 7 cases (10%). None of the patients discharged to hospice were readmitted. Of the 616 patients who did not qualify for DI, 17% (103) had a RI < 60, 25/103 were readmitted,13/52 (52%) were from rehabilitation, none were readmitted from hospice. Conclusions: A discharge intervention was associated with a significantly lower 30-day readmission rate in patients with low RI being discharged to home compared to historical controls.Discharge destination changed to hospice in 10% of cases. Discussing goals of care in patients with low RI may influence readmission rates. Those who did not qualify for DI, but had an RI < 60 still had high risk for 30d RA, highlighting opportunities for DI across discharge dispositions, including rehab.
Distinct somatic alterations in right- versus left-sided colorectal cancers.
Authors: Robin Imperial, Zaheer Ahmed, Omer M Toor, Ateeq Khaliq, Niklas Melton, Paul Case, James Case, Lee Saville Cummings, Kevin F Kennedy, Seemeen Hassan, Shui Qing Ye, Ramzi M Mohammad, Arif Hussain, Timothy J. Pluard, Janakiraman Subramanian, Ashiq Masood
Journal: Journal of Clinical Oncology (2018)

3592 Background: Right-sided (RCC) and left-sided colon cancers (LCC) have different clinical/biological characteristics. Comprehensive genomic analysis (Whole exome/genome, Copy number, RNA, MicroRNA) using The Cancer Genome Atlas (TCGA) was performed to identify underlying genomic differences between RCRC, LCRC and rectal cancers (RC). Methods: 443 microsatellite stable RCC, LCC and RC samples were analyzed. Transverse and rectosigmoid tumors were excluded. MutsigCV and ConsensusDriver were used for significantly mutated gene analysis, GISTIC for copy number alterations (CNA), deSeq2 for RNA and microRNA analysis. Supervised clustering was applied to somatic mutations using Fuzzy ARTMAP. Results: AMER1 (gene in Wnt pathway) was mutated in 24% of RCC, 3% of LCC and 3% of RC. Mutations in AMER1 and other key Wnt family members (CTNNB1, GSK3, AXIN1, AXIN2, LRP5, LRP6) were mutually exclusive of each other. A novel driver B Melanoma Antigen Family, Member 2 (BAGE2) not previously described in CRC was discovered in a subset of samples using Fuzzy ARTMAP. KRAS, PIK3CA, SOX9 (all p < 0.05) mutations were enriched in RCC. New driver mutations in BCOR, MUC4, RELN, ROBO2, RP1L1, and MGAM were also enriched in RCC (all p < 0.05). Hotspot mutation analysis revealed distinct oncogenic mutations in RCC, including in APC (R1450*, p = 0.0246). We identified unique amplifications and deletions in RCC (1 amplification/10 deletions) and LCC (13 amplifications/10 deletions). Somatic mutation, CNA and hotspot analysis revealed similar changes in LCC and RC. RNA analysis revealed 53 genes differentially expressed between RCC and LCC and 73 genes between RCC and RC. The top upregulated and downregulated genes were common between the two groups (n = 32). INSL5 and PRAC1 are among the most downregulated genes while SLC10A2, DRD5, and APOA4 are among the most upregulated genes. MicroRNA analysis showed 12 miRNA differentially expressed between RCC and LCC. Conclusions: RCC and LCC have distinct molecular profiles, whereas LCC and RC appear to be similar at the genomic level. Several specific/novel gene mutations are associated particularly with RCC (APC and AMER1 genes among others). A novel driver gene, BAGE2, was discovered in a subset of colorectal cancers.