tbuckley/cabot-search huggingface dataset:
Clinical validation of a prognostic 11-gene assay in prospectively collected FFPE tissue of patients with AJCC v8 stage II cutaneous melanoma (CM).
Authors: Claus Garbe, Tobias Sinnberg, Heike Niessner, Heiko Sülberg, Thomas K. Eigentler, Teresa Amaral
Journal: Journal of Clinical Oncology (2019)

9518 Background: AJCC comprises two markers (Breslow thickness and ulceration) to subdivide stage II CM patients into groups with relatively low, average, or high risk of death. Recent updates of clinical guidelines (NCCN, AAD) suggest that patient management be further tailored to an individual prognosis, e.g. through gene expression profiling (GEP). The aim of this single center study was to clinically validate a prognostic GEP-based risk score (MelaGenix) for stage II CMs. Methods: All obtainable, formalin-fixed paraffin-embedded (FFPE) primaries of AJCC stage II CMs from the Central Malignant Melanoma Registry of Germany archived in Tuebingen were included. Study hypothesis and protocol were prospectively formulated. Tumors were analyzed blinded to clinical outcome (data exchange overseen by independent data clearing house) to determine GEP low- vs. high-score groups with a pre-specified GEP score cut-off (≤0.00 &gt; ). Melanoma specific survival (MSS) was evaluated by Kaplan-Meier (KM) analysis and prognostic performance was assessed by multivariate Cox regression. Results: Study cohort comprised 245 stage II primaries (IIA/B/C n = 118/78/49). Median follow-up was 40 months, 5y/10y MSS was 86/75%, median thickness was 3.0 mm, 142 tumors were ulcerated. GEP low-score group had 5y&amp;10y MSS of 92%; GEP high-score group had 5y/10y MSS of 82/67%. KM log-rank was significant (p = .018); GEP score contributed independent prognostic information in multivariate Cox regression (p = .024 HR = 1.45 [1.05 – 2.00]) vs. covariates pT categories (p = .002 HR = 1.59 [1.19 - 2.13]) and age (p = .001 HR 1.05 [1.02 - 1.09]). Conclusions: MelaGenix has been validated as an independent predictor of MSS in stage II patients and refines prognosis beyond AJCC. MelaGenix could serve as an important prognostic decision tool regarding patient management, especially whether adjuvant systemic treatment is appropriate – once drugs become available. It seems reasonable to include this score in future clinical trials. [Table: see text]
Contemporary changes in localized and metastatic prostate cancer incidence by geographic area following decreased PSA screening.
Authors: Daniel X. Yang, Danil V. Makarov, Cary Philip Gross, James B. Yu
Journal: Journal of Clinical Oncology (2019)

1567 Background: In the setting of decreased PSA screening, the incidence of metastatic prostate cancer has been increasing in the United States. This was chronologically proceeded by decreasing localized prostate cancer incidence. While decreased detection of localized disease is hypothesized to increase likelihood of metastatic disease at diagnosis, it is unclear whether the two are geographically connected. Methods: Prostate cancer incidence was obtained from the of Surveillance, Epidemiology, and End Results (SEER) database for men 70 years or older. SEER Summary Stage 2000 was used to classify localized (local) and metastatic (distant) prostate cancers. Changes in incidence rates were calculated by health services areas (HSA), which each represents a relatively self-contained region of hospital care. We chose a priori to examine most recent years 2012-2015 for changes in metastatic disease, and proceeding years 2008-2011 for changes in localized disease. Population-weighted linear regression that was robust to outliers was performed. Results: A total of over 66,600 cases of localized and 6,400 cases of metastatic prostate cancer from 200 HSAs were included for analysis. From 2008 to 2011, localized incidence decreased from 613.6 to 534.2 per 100,000 men overall, and for each HSA on average decreased by 30.3 per 100,000 men for each year. From 2012 to 2015, metastatic incidence increased from 54.7 to 62.1 per 100,000 men overall, and for each HSA on average increased by 2.1 per 100,000 men for each year. Linear regression between HSA-level changes in localized and metastatic disease revealed a correlation coefficient of -0.023 (SE = 0.017, p = 0.16, 95% CI -0.056 to 0.009), representing lack of a statistically significant relationship between decreases in localized disease and later increases in metastatic disease within each health services region. Conclusions: Despite concerns of increasing metastatic prostate cancer incidence coinciding with decreases in PSA screening and localized cancer incidence, we do not observe a statistically significant geographic and temporal relationship between metastatic and localized disease at the HSA level. Our study is limited by short lead time and thus this trend warrants continued surveillance.
SP0017 USING AVAILABLE DATASETS TO ANSWER NEW RESEARCH QUESTIONS
Authors: Daniel Prieto-Alhambra
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Clinical data are continuously recorded in clinical encounters in the form of electronic medical records, registries, audits ans similar databases. Such large datasets are available to researchers, and provide unique opportunities. However, challenges arise from the use of routinelly collected data, that need special attention and specific skills to minimise a waste in research. <h3>Objectives:</h3> To discuss available data sources (data discovery), their advantages and limitations, their uses, and to cover examples of research conducted using routinely collected datasets. <h3>Methods:</h3> We will discuss a list of data sources at high level (types of data), their main pros and cons, and then cover challenges and solutions through a number of previously published examples. <h3>Disclosure of Interests:</h3> Daniel Prieto-Alhambra Grant/research support from: Grants from Amgen, UCB Biopharma and Servier outside the submitted work, Consultant for: UCB Biopharma, Speakers bureau: Amgen
Hysterectomy utilization among newly diagnosed endometrial cancer patients by body mass index category: A real-world analysis using a claims and electronic health record database.
Authors: Debra E. Irwin, Ellen Thiel
Journal: Journal of Clinical Oncology (2019)

e17112 Background: For endometrial cancer (EC), laparoscopic hysterectomy (LH) is an effective, minimally invasive surgical treatment; however, this approach may not be recommended for obese patients due to increased risk for complications. Methods: This retrospective study utilized insurance claims linked to electronic health record (EHR) data contained in the IBM MarketScan Explorys Claims-EHR Data Set. Newly diagnosed EC patients (1/1/2007 - 6/30/2017) with continuous enrollment during a 12-month baseline and 6-month follow-up period were selected. Patients were stratified into four BMI subgroups based on baseline BMI on the EHR: normal or underweight (BMI &lt; 25), overweight (BMI 25- &lt; 30), obese (BMI 30- &lt; 40), morbidly obese (BMI &gt; 40), and were required to have had a hysterectomy within the follow-up period. Emergency room visits and rehospitalization within 30 days of hysterectomy were measured. Results: A total of 1,090 newly-diagnosed EC patients met the selection criteria, of whom, 16% were normal/underweight, 19% were overweight, 39% were obese, and 26% were morbidly obese. The proportion of patients receiving LH increased as BMI category increased (Table 1). Among those with LH between 6% and 15% had an ER visit or rehospitalization in 30 days, and rates were higher among other hysterectomy modalities. Conclusions: This real-world analysis shows that LH is utilized in a high proportion of morbidly obese EC patients, despite that it is frequently deemed infeasible in this patient population. Although the rate of ER visits and rehospitalization is lower among LH patients than those undergoing traditional hysterectomy across all BMI strata, further research is needed to determine the optimal patient population to receive LH.[Table: see text]
Preliminary results of a phase I clinical trial using an autologous dendritic cell cancer vaccine targeting HER2 in patients with metastatic cancer or operated high-risk bladder cancer (NCT01730118).
Authors: Hoyoung M. Maeng, Lauren Virginia Wood, Brittni Moore, Mohammadhadi H. Bagheri, Santhana Webb, Lee England, Giselle Martinez, Seth M. Steinberg, Svetlana Pack, David Stroncek, John Charles Morris, Masaki Terabe, Jay A. Berzofsky
Journal: Journal of Clinical Oncology (2019)

2639 Background: We developed a HER2 targeting autologous dendritic cell (DC) vaccine transduced with an adenovirus expressing the extracellular and transmembrane domains of HER2 (AdHER2). In mice, the homologous vaccine cured virtually all mice with established or metastatic tumors. Protection was dependent on antibodies against HER2 that inhibited phosphorylation, but was ADCC independent. We translated these findings into a clinical trial. Methods: This is an open-label, phase I study in patients with 1) metastatic cancer that progressed after ≥ 1 standard therapies, or 2) history of high risk bladder cancer with definitive treatment, whose tumor is HER2 immunohistochemistry (IHC) score ≥ 1+ or FISH HER2/CEP17 ratio ≥ 1.8. Part 1 of the study enrolled patients naïve to HER2-directed therapies and Part 2 enrolled patients who progressed with ≥ 1 anti-HER2 therapy. Results: In Part 1, the lowest dose level (5E+6 viable DCs, N=7, 2 inevaluable) showed no benefit. At the second and third dose level (10E+6 and 20E+6; N=7 and N=4; 0 and 1 inevaluable in each), 1 CR (ovarian), 1 PR (stomach), and 3 SD (1 ovarian carcinosarcoma and 2 colon) were observed. Two bladder cancer patients who received vaccine as an adjuvant did not recur for +24 and +36 month each. In Part 2 (N=6, 2 inevaluable), 1 male breast cancer patient showed SD. Response assessed by Modified Immune Related Response Criteria is summarized in the Table. Injection-site reactions occurred in all patients and were self-limited. Echo, EKG and troponin follow up to 2 years showed no cardiac toxicity. Dose-expansion cohort (40E+6) is enrolling. Conclusions: We have translated a cancer vaccine from mice to a clinical trial. Preliminary results of a phase I trial of an autologous AdHER2 DC vaccine show potential clinical benefit in select patients with HER2 expressing tumors with no cardiac toxicity. Clinical trial information: NCT01730118. [Table: see text]
Phase 1 trial of TLR9 agonist lefitolimod in combination with CTLA-4 checkpoint inhibitor ipilimumab in advanced tumors.
Authors: Matthew Reilley, Apostolia Maria Tsimberidou, Sarina Anne Piha-Paul, Timothy A Yap, Siqing Fu, Aung Naing, Jordi Rodon, Ly Minh Nguyen, Casey Ager, Martin Meng, Priyamvada Jayaprakash, Manuel Schmidt, Matthias Baumann, Funda Meric-Bernstam, Michael A. Curran, David S. Hong
Journal: Journal of Clinical Oncology (2019)

TPS2669 Background: Drugs targeting pathogen associated molecular patterns are an attractive strategy to stimulate the immune system. Toll-like receptors (TLR) have generated significant interest as an effective means of stimulating the immune system that result in the killing of tumor cells. TLR-9 agonists can function to promote an early immune response and are an appealing partner for combination with checkpoint blockade to improve immune activation. Lefitolimod (MGN1703) is a covalently closed dumbbell-shaped DNA molecule that functions as a TLR-9 agonist. We developed a clinical trial combining lefitolimod with ipilimumab (anti-CTLA4) in patients with advanced malignancies. In the dose-escalation phase 19 patients were enrolled and no DLTs were encountered. Safety data and maximum planned dose level of lefitolimod at 120mg weekly and ipilimumab 3mg/kg every 3 weeks was previously presented. Adverse events related to the combination included fatigue, appetite loss, rash, and anemia. Methods: This trial (NCT02668770) was designed to evaluate the safety profile and maximum tolerated dose of lefitolimod with ipilimumab. A 3+3 trial design was used to establish safety of the combination at each dose level and guide the decision to escalate dose. Lefitolimod is administered via subcutaneous (SC) injection weekly while ipilimumab is given at 3mg/kg intravenous on day 8 of each 3 week cycle. Lefitolimod starting dose was 15mg SC weekly with 3 dose level escalations up to 120mg SC weekly. Patients receive treatment for 4 cycles (total 12 weeks) with the combination, and those with stable disease or response were eligible to remain on lefitolimod therapy for up to 1 year. Eligible patients have a metastatic or unresectable solid tumor refractory to standard therapies, ECOG ≤ 2, and normal organ and bone marrow function. Patients are allowed to have received prior checkpoint blockade agents. Enrollment in expansion cohorts in ongoing. To better understand relevant immunologic changes associated with treatment, paired pre- and post-treatment biopsies of target lesions and peripheral blood collection during treatment is required for target expansion cohort patient populations. In addition to evaluating target patient populations at the combination dose established during escalation, an expansion cohort for patients with cutaneous metastases involves combination treatment with intratumoral delivery of lefitolimod. Clinical trial information: NCT02668770.
Clonal expansion of tumor infiltrating lymphocytes (TILs) in the peripheral blood of metastatic melanoma patients is significantly associated with response to CTLA4 blockade-based immunotherapy.
Authors: Arjun Khunger, Julie Rytlewski, Erik C. Yusko, Ahmad A. Tarhini
Journal: Journal of Clinical Oncology (2019)

2541 Background: Patients with metastatic melanoma were treated on a clinical trial with tremelimumab and High Dose Interferon-Alfa (HDI) (Tarhini. J Clin Oncol. 2012). We previously reported that patients who achieved disease control and clinical response had significantly greater T-cell clonality (p = 0.0008) and T-cell fraction (p = 0.044) respectively in their pretreatment tumor biopsy samples (Tarhini. J Clin Oncol. 2017). In this study, we further characterize T-cell repertoire clonality and clonal expansion in the peripheral blood at different time points to evaluate the association between repertoire features and clinical response. Methods: Patients received tremelimumab 15 mg/kg I.V. every 12 weeks and HDI was given concurrently. Responses were assessed by RECIST as complete (CR) or partial (PR), stable disease (SD) or progression (PD). Peripheral blood mononuclear cells (PBMCs) from treated patients (N = 33) were obtained at baseline, day 29, and day 85 (following tremelimumab-HDI treatment); tumor samples at baseline were also obtained (N = 18). The T-cell receptor beta chain (TCRB) repertoire of PBMCs and tumor samples was immunosequenced using the immunoSEQ assay (Adaptive Biotechnologies), and repertoire clonality was assessed at baseline, day 29, and day 85. Differential abundance analysis was used to detect and quantify peripheral clonal expansion pre- versus post-treatment and identify the subset of peripheral clones also detected in the tumor repertoire. The Morisita Index of repertoire similarity was also calculated to compare global repertoire changes between pre- and post-treatment PBMC samples. Results: T-cell repertoire turnover, as measured by the Morisita Index, showed a trend towards responders (CR/PR) having greater turnover (lower Morisita Index) post-treatment than non-responders (SD/PD). Similarly, the total number of clones expanding in the peripheral repertoire varied over time within an individual (p = 0.034) but was not significantly affected by response to therapy (p = 0.275) or by on-treatment time point (p = 0.768). When the analysis was restricted to peripherally expanded clones that were also found in the tumor repertoire, responders had significantly more TILs expanded in the periphery at day 29 than non-responders (p = 0.036). Conclusions: Our analysis of the peripheral T-cell repertoire following treatment showed that detection of TILs in early peripheral clonal expansion correlates with response to therapy.
A comparison of risk factors for cigarette and e-cigarette use in the United States adult population.
Authors: Leo Chen, Nai Wen Wang, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2019)

1546 Background: The US CDC and public health agencies have reported alarming increases in e-cigarette (ecig) use among youth, even as cigarette (cig) use among youth decline. In this study, other risk factors for cig and ecig use are compared. Methods: This study used data from the Health Information National Trends Survey 5 Cycle 1 survey, conducted in 2017. Univariate survey-weighted logistic regression analyzed responses as a nationally representative US population. Results: Inverted trends included being 35 or older (cig: OR=1.22, p&lt;0.01; ecig: OR=0.79, p&lt;0.01), being a student (cig: OR=0.77, p&lt;0.01; ecig: OR=1.24, p&lt;0.01) or retired (cig: OR=1.09, p&lt;0.01; ecig: OR=0.89, p&lt;0.01) compared to being employed, and being single (cig: OR=0.92, p&lt;0.03; ecig: OR=1.18, p&lt;0.01). Having considered quitting smoking was not significantly associated with ecig use. Conclusions: Segments of the US adult population educated with anti-tobacco campaigns may remain at increased risk for ecig use.[Table: see text]
The impact of Epstein-Barr virus status on primary CNS lymphoma survival.
Authors: Isabel P Prado, Frank Barbiero, Joachim M. Baehring, Kevin Becker, Zachary Corbin
Journal: Journal of Clinical Oncology (2019)

e13528 Background: Primary CNS lymphoma (PCNSL) incidence is increasing among the elderly and immunocompromised. Especially for these vulnerable populations, a deeper understanding of the prognostic value of tumor biomarkers is necessary to recommend more targeted therapies. Our primary objective is to evaluate the predictive strength of immunohistochemical markers on PCNSL overall survival. Secondary objectives include estimating the impact of these biomarkers on event-free survival. Methods: We retrospectively analyzed PCNSL patients treated at Yale between 2000 and 2018. The primary endpoint is overall survival. Event-free survival, measured by time to relapse or death, is the secondary endpoint. Kaplan-Meier survival curves with log-log confidence intervals were used to estimate survival outcomes. Cox proportional hazards regression models were used to evaluate the statistical significance (at alpha = 0.05) of immunohistochemical markers. Results: One hundred ten subjects were analyzed. Not all biomarkers were available for every subject. The median age of the cohort is 64 years. Sixty-three patients died, and seventy-six experienced an event (progression or death). Surviving patients had a median follow-up of 4.36 years. The median overall survival is 2.63 years (95% confidence interval (CI): 1.13 to 5.98 years). Epstein-Barr virus (EBV) status by immunohistochemistry significantly impacted overall survival. Adjusting for age and immunocompromised status, EBV-positive patients had a higher risk of death than EBV-negative patients (n = 13, hazard ratio (HR) = 33.75, 95% CI: 1.61-708.68). Other significant biomarkers include the GFAP and S100 proteins. The median event-free survival is 1.13 years (95% CI: 0.66 to 2.12 years), and EBV-positive patients had an increased risk of event (HR = 38.23, 95% CI: 2.32-630.88). CD10, BCL2, BCL6, and MUM1 were not significant to predict either survival outcome. Conclusions: We describe a large cohort of PCNSL patients treated at a single institution with comparable survival outcomes to similar research yet conflicting evidence of biomarker significance. Multi-institutional studies may further clarify the prognostic role of immunohistochemistry for improved PCNSL patient survival.
Ocular ultrasound evaluation of optic nerve sheath diameter in military environments
Authors: Maddalena De Bernardo, Livio Vitiello, Palmiro Cornetta, Nicola Rosa
Journal: Military Medical Research (2019)

In this letter to the Editor, we would like to comment on the article by Betcher et al., concerning the possibility of teaching military trainees to obtain accurate optic nerve sheath diameter measurements, using a brief didactic and a hands-on training session. In particular, this letter notes the importance of the measurement of optic nerve sheath diameter in detecting the eventual elevated intracranial pressure following traumatic brain injury, highlights several limitations in the use of B-scan for such a purpose and suggests a more accurate evaluation with the standardized A-scan.
Evaluation of pathologic and genomic characteristics in female breast cancer patients.
Authors: Damien Mikael Hansra, Amber Moran, Becky Slawik, Shirelle Clark, Vicki Doctor, Ankur Rasik Parikh, Pamela A. Crilley, Cynthia Lynch, Daniel W. Nixon, Maurie Markman, Eugene R. Ahn
Journal: Journal of Clinical Oncology (2021)

e13001 Background: The genomic landscape of female breast cancer is rapidly evolving partially owing to advancements in next generation sequencing (NGS). Here we report the genomic characteristics of female breast cancer patients with locally recurrent inoperable and metastatic disease. Methods: IRB approval was obtained for a retrospective analysis of archived pathology on patients treated at Cancer Treatment Centers of America. Comprehensive genomic profiling of tumors was derived from Foundation One (F1) and Guardant 360 NGS. Clinical information was derived from retrospective chart review. Inclusions: adult females with breast cancer with stage IV metastatic disease or locally recurrent inoperable disease. Exclusions: Males, missing genomic and pathologic information. Results of clinical, pathologic, and genomic data were summarized. Results: 1788 patients met study criteria. Median age: 48 yrs., range 20-79 yrs. Race: Caucasian 1029/1788 (58%), African American 582/1788 (32%), Hispanic 77/1788 (4%), Asian 26/1788 (1%), other 73/1788 (4%). Receptor status: Hormone receptor ER(+) &amp;/or PR(+) 950/1788 (53.1%); Triple negative 390/1788 (21.8%); HER2(+) 205/1788 (11.5%); missing/incomplete: 243/1788 (13.6%). Ki-67 status: High 548/705 (77.7%)/Low 57/705 (8.1%)/Intermediate (INT) 100/705 (14.2%). PD-L1 status: PD-L1(-) 346/544 (63.6%)/ PD-L1(+) 179/544 (32.9%)/PD-L1 (indeterminate or QNS) 19/544 (3.5%). NGS test total (1984 tests): F1 1023/1984 (52%), F1 CDx 703/1984 (35%), F1 Act 91/1984 (6%), F1 Liquid 82/1984 (6%), Guardant 360 85/1984 (4%). Biomarkers (1096 results): Microsatellite Instability (MSI) High 4/1096 (0.3%), MSI- Intermediate (INT) 2/1096 (0.1%), MS-stable 1017/1096 (93%), Cannot be determined (CBD) 73/1096 (7%). Tumor Mutation Burden (TMB) (842 results): TMB high 22/842 (3%), TMB INT 233/842 (28%), TMB low 513/842 (61%), CBD 74/842 (9%). Genomic abnormalities (% alterations per patient): TP53 999/1783 (56.03%), PIK3CA 610/1783 (34.21%), MYC 425/1783 (23.84%), CCND1 318/1783 (17.84%), FGF19 298/1783 (16.71%), FGF3 296/1783 (16.60%), FGF4 293/1783 (16.43%), ESR1 266/1783 (14.92%), FGFR1 276/1783 (15.48%), PTEN 239/1783 (13.40%), ZNF703 251/1783 (14.08%), ERBB2 218/1783 (12.23%), GATA3 178/1783 (9.98%), CDH1 165/1783 (9.25%), RAD21 157/1783 (8.81%). Pathway defects (expressed as total % of alterations): Alterations in FGF genes 10.64%, mTOR pathway 8.36%, HHR pathway 3.17%. Conclusions: Female breast cancer patients display a heterogeneous variety of complex genomic alterations. Mutations in FGF genes were most common. The single most common alteration was in TP53. Other common alterations include PIK3CA, MYC, CCND1, and ESR1.