tbuckley/cabot-search huggingface dataset:
Comprehensive genomic profiling of metastatic cutaneous adnexal carcinomas to reveal multiple routes to targeted and immunotherapies.
Authors: Nicolas Girard, Laurie M. Gay, Julia Andrea Elvin, Jo-Anne Vergilio, James Suh, Shakti Ramkissoon, Sugganth Daniel, Eric Allan Severson, Keith Killian, Siraj Mahamed Ali, Alexa Betzig Schrock, Jon Chung, John Arthur Carlson, David Jones, Vincent A. Miller, Martin C Mihm, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2018)

9587 Background: Carcinomas that arise from the skin adnexae (Cutaneous Adnexal Carcinomas, CAC) may progress to refractory, metastatic disease. We queried whether comprehensive genomic profiling (CGP) of CAC could reveal genomic alterations (GA) that could guide the use of targeted and immune checkpoint inhibitor (ICPI) therapies. Methods: A total of 103 relapsed/refractory and metastatic CAC underwent CGP using 50 ng of DNA and a hybrid-capture, adaptor ligation-based next-generation sequencing assay to a median coverage depth of > 600X. Results were analyzed for all classes of GA and tumor mutational burden (TMB) was determined on up to 1.2 Mb of sequenced DNA; microsatellite instability (MSI) determined by principal components analysis of optimal homopolymer loci. Results: The 103 CAC included 56 (54%) sweat duct (SWCAC), 21 (20%) sebaceous (SBCAC), 5 (4%) hair shaft/follicle (HRCAC) and 20 (19%) not otherwise specified (NOS) samples (Table). The CAC subtypes had similar median age and male preponderance, except for HRCAC (Table). The CAC had a mean GA/tumor of 5.47 (range 4.33 to 6.90). In CAC overall, potentially targetable GA were in PTEN, ERBB2, BRCA2, PTCH1, NF1 and BRAF. More than 20% of CAC had TMB of > 20 mut/Mb, indicating high potential for immunotherapies. Potential ICPI resistance-associated GA included STK11 inactivating GA (4%) and MDM2 amplification (2%). MSI-High status was found in 2% of CAC overall, and limited to the SBCAC cohort. Conclusions: CAC are a rare and heterogeneous group of epithelial malignancies for which CGP can uncover multiple routes to targeted therapies. The prevalence of high TMB predicts that ICPI could play a role in relapsed and refractory disease. All CAC (n = 103) Sweat Duct (n = 56) Sebaceous Gland (n = 21) Hair Shaft (n = 6) NOS (n = 20) Median Age 67 71 64 31 64 Gender 35% F 65% M 36% F 64% M 29% F 71% M 82% F 18% M 25% F 75% M Mean GA/tumor 5.47 4.95 6.90 4.33 5.60 GA in Targetable Genes PTEN 10% ERBB2 9% BRCA2 8% PTCH1 8% NF1 7% BRAF 4% ERBB2 8% BRAF 6% BRCA2 6% PTCH1 6% PTCH1 14% ERBB2 5% ROS1 5% MET 5% KIT 5% ERBB2 10% EGFR 10% NF1 10% ICPI Relevant Genes STK11 4% PRMB1 1% MDM2 2% STK11 2% STK11 10% Median TMB 3.6 3.5 6.1 5.2 5.2 TMB ≥ 20 mut/MB 21% 20% 29% 18% 15% MSI-High 2% 0% 11% 0% 0%
Incidence and risk factors for early chronic anthracycline induced cardiotoxicity in patients with osteogenic sarcoma: A case control study.
Authors: Alok Gupta, Jyoti Bajpai, Jaya Ghosh, Sudeep Gupta
Journal: Journal of Clinical Oncology (2016)

10075 Background: Anthracyclines are an important component of multiple drug chemotherapy regimens used in the treatment of osteosarcoma (OGS). Limited data exists regarding early chronic anthracycline induced cardiotoxicity (AIC) in this young and healthy patient population. The aim was to determine the incidence and risk factors associated with early chronic AIC in OGS patients. Methods: This is a retrospective case-control study of patients with OGS treated with anthracycline based chemotherapy with curative intent from Jan 2010 to March 2013. Patients were monitored for any decline in cardiac function using 2D- echocardiography at serial time points. Early chronic AIC was defined as a decrease in left ventricular ejection fraction (LVEF) by more than 20 percentage points to a value > 50%, a decrease in LVEF by more than 10 percentage points to a value < 50%, or clinical manifestations with signs and symptoms of heart failure. Those who developed early chronic AIC were included as cases and those who did not were included as controls. Data was analyzed to determine the incidence and potential factors associated with increased risk of symptomatic and asymptomatic early chronic AIC. Results: Three hundred two OGS patients treated with anthracycline based chemotherapy were included in this analysis. The median age was 17 years (range 7-65 years). Of 302 patients included, 202 were male and 100 female. The incidence of early chronic AIC was 13% while the incidence of symptomatic cardiac dysfunction was 1.7%. The median fall in LVEF among cases was 10 percentage points (range 10- 45). Evaluation of potential risk factors revealed that hemoglobin < 10 gm/dl, albumin < 4 gm/dl, GFR < 90 ml/min, LDH > 200 U/L, alkaline phosphatase > 360 U/L, iron > 60 ug/dL, ferritin > 250 ng/ml, vitamin B12 < 180 pg/ml, folate < 1.7 ng/ml, BSA > 1.7 m2 and BMI > 25 kg/m2is not associated with increased risk of early chronic AIC. Conclusions: We conclude from this large case-control study that incidence of early chronic AIC in OGS patients is high in our setting. Risk factors for AIC in this relatively young patient population who lack conventional risk factors for cardiotoxicity, still remain to be identified.
Pediatric oncology phase 1 trial efficiency in the era of targeted and biological therapies.
Authors: Tabitha Cooney, Duy C Tran, Arzu Onar-Thomas, Robin Elizabeth Norris
Journal: Journal of Clinical Oncology (2017)

e14100 Background: Prior reviews have assessed the conduct and efficiency of pediatric phase 1 trials evaluating conventional chemotherapy. Additional analyses are now needed to evaluate the conduct and design of pediatric phase 1 trials of targeted and biologic agents. Methods: A systematic review of pediatric oncology phase 1 trials published between 2000-2015 was performed. Patient characteristics, study design, and trial endpoints were evaluated. When available, the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) was compared to the adult MTD/RP2D. Results: 166 pediatric phase 1 trials meeting pre-defined selection criteria were identified. Sixty-six trials evaluated conventional chemotherapeutic agents and 100 evaluated biologic agents. Of the 4,763 enrolled patients, 1933 were female and 2487 were male (ratio 1:1.3). Race or ethnicity data was included in only 31.3% of published articles. Seventy-five percent of trials used a 3+3 dose escalation strategy. Eight percent of studies used an adaptive/Bayesian strategy and 7% used the rolling six design. Eighty-eight percent of trials cited the MTD as their primary endpoint and 10.8% of studies did not define an MTD/RP2D. The median (range) ratio of pediatric to adult RP2D for small molecule phase studies (n = 41) was 1.13 (0.45-11.9). The median (range) ratio for phase 1 studies of biologic agents (n = 6) was 1.15 (0.6-1.6). Conclusions: Consistent with prior reports, more males than females were enrolled on pediatric phase 1 studies and racial and ethnic characteristics continued to be underreported. The majority of trials used the MTD as the primary endpoint. While there was some variability based on evaluated agent, the pediatric RP2D of the small molecule and biologic agent was similar to that determined in the adult population. These results are consistent with similar evaluations of pediatric phase 1 studies of conventional chemotherapy.
Effect of perioperative oral care on prevention of postoperative pneumonia associated with esophageal cancer surgery: A multicenter case-control study with propensity score matching analysis.
Authors: Sakiko Soutome, Souichi Yanamoto, Madoka Funahara, Takumi Hasegawa, Takahide Komori, Shin-ichi Yamada, Hiroshi Kurita, Chika Yamauchi, Yasuyuki Shibuya, Yuka Kojima, Hirokazu Hirokazu, Takahiko Oho, Masahiro Umeda
Journal: Journal of Clinical Oncology (2018)

e16017 Background: Postoperative pneumonia is a severe adverse event associated with esophageal cancer surgery. It is thought to be caused by aspiration of oropharyngeal fluid containing pathogens. However, the relationship between oral health status and postoperative pneumonia has not been well investigated. Methods: This study included 539 patients with esophageal cancer undergoing surgery at one of seven university hospitals. While 306 patients received perioperative oral care, 233 did not. Various clinical factors as well as occurrence of postoperative pneumonia were retrospectively evaluated. Propensity-score matching was performed to minimize selection biases associated with comparison of retrospective data between the oral care and control groups. Factors related to postoperative pneumonia were analyzed by logistic regression analysis. Results: Of the original 539 patients, 103 (19.1%) experienced postoperative pneumonia. The results of multivariate analysis of the 420 propensity score-matched patients revealed longer operation time, postoperative dysphagia, and lack of oral care intervention to be significantly correlated with postoperative pneumonia. Conclusions: The present findings demonstrate that perioperative oral care can reduce the risk of postoperative pneumonia in patients undergoing esophageal cancer surgery. Clinical trial information: UMIN000018918.
Eosinopenia and Adverse Outcomes After <i>Clostridium difficile</i> Infections
Authors: Shuyan Wei, Lillian S. Kao
Journal: JAMA Surgery (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Efficacy of photoactivated generation of a meditope-enabled anti-EGFR antibody drug conjugate in RAS/RAF mutant colorectal carcinoma.
Authors: Elisabeth Gardiner, Karin Forster, Calin Dumitru
Journal: Journal of Clinical Oncology (2016)

e14059 Background: EGFR is a clinically validated target for advanced colorectal carcinoma, but EGFR targeted therapies are useless against EGFR expressing tumors with K/NRAS mutations. We hypothesized that an anti-EGFR antibody drug conjugate (ADC) that used EGFR to target the tumor and deliver a cytotoxic payload rather than blocking EGFR pathways may be useful for K/NRAS mutant EGFR expressing cancers. To this end, an anti-EGFR ADC was designed using a “meditope-directed” site-specific conjugation strategy. This strategy uses proprietary peptides that bind an antibody Fab fragment noncovalently in a unique site outside the paratope. This novel binding is exploited for site-specific covalent conjugation of cytotoxic payloads to any meditope-enabled antibody. The meditope peptide can be designed with a photoactivatable side chain, allowing the peptide-antibody interaction to be covalent. Herein, we report the development of an anti-EGFR ADC, utilizing a technology which we call SnAP (site-specific novel antibody platform) which may be effective against KRAS/NRAS mutant forms of colorectal carcinoma. Methods: An ADC was designed and tested for cytotoxicity in wild type and KRAS mutant cancer cell lines. Highly efficient site-directed covalent attachment of a toxin to the antibody was facilitated by a novel photoactivatable meditope peptide. Non-GLP safety studies were performed, and conjugation stability was assessed. Efficacy studies were performed in KRAS wildtype as well as KRAS mutant EGFR expressing xenografts. Results: A stable ADC with precisely controlled drug-antibody ratio (DAR) and unaltered affinity for EGFR was created using a novel photoactivation strategy. The meditope-directed ADC showed selective cytotoxic activity in EGFR+ cell lines, irrespective of KRAS mutation status. The potency of the ADC against EGFR dependent tumors was demonstrated in an EGFR expressing colon carcinoma xenograft study. Conclusions: Meditope-directed photoactivation is a novel way to generate site-directed ADCs. Anti-EGFR ADCs created in this fashion may permit patients with KRAS mutated EGFR expressing tumors to receive EGFR targeted therapies.
<i>PD-L1</i> genomic alterations (GA) in solid tumors and hematologic malignancies: A comprehensive genomic profiling (CGP) study.
Authors: Laurie M. Gay, David Fabrizio, Garrett Michael Frampton, Lee A. Albacker, Ethan Sokol, Julia Andrea Elvin, Jo-Anne Vergilio, James Suh, Shakti H. Ramkissoon, Eric Allan Severson, Sugganth Daniel, Siraj Mahamed Ali, Jon Chung, Alexa Betzig Schrock, Vincent A. Miller, Jeffrey J. Pu, Robert John Corona, Gennady Bratslavsky, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2018)

12092 Background: Amplification (AMP) of PD-L1 (CD274/B7H1) has recently been linked to enhanced benefit from immune checkpoint inhibitor (ICPI) treatment. We used CGP to evaluate the PD-L1 GA landscape in cancer. Methods: Specimens from 140,411 cancers representing > 450 individual disease ontologies were sequenced using a hybrid capture-based, next-generation sequencing assay. PD-L1 protein expression was measured by immunohistochemistry (IHC) in a subset of cases using the Dako 22C3 anti-PD-L1 antibody. Results: 1383 (0.9%) tumors had PD-L1 GA (1414 GA): 879 (62%) AMP, 471 (33%) short variants (SV) and 60 (0.4%) truncating rearrangements (RE). PD-L2 (PDCD1LG2) and JAK2 were co-amplified in 94% and 82% of PD-L1 AMP samples; other genes commonly altered with PD-L1 AMP included TP53 (77%), CDKN2A/B (28%/20%), MYC (21%), and TERT (13%). For samples with RE or SV, PIK3CA (19%; 21%) GA were common and TERT GA were in 7% or 14% of samples. Most SV GA were missense (88%), compared with truncating (10%) or splice site (2%) GA. Recurrent somatic variants of unknown significance (VUS) were observed, including frameshift and missense GA that may regulate PD-L1 stability. Of 10 common tumors, breast (213) and lung (210) carcinomas (CA) represented the most PD-L1 AMP cases. Select cancers with notable PD-L1 AMP frequencies were anaplastic thyroid CA (4%), head and neck squamous CA (HNSCC) (2.5%), cervical SCC (2.6%), and breast (1.4%), lung (0.7%) and bladder (0.6%) CA. Of common tumor types, such as colorectal, pancreatic, ovarian, or prostatic CA, melanoma and glioblastoma, ≤0.3% had PD-L1 AMP. There was strong correlation between PD-L1 AMP and PD-L1 expression by IHC in NSCLC, with 89% AMP positive samples showing > 50% IHC staining and 11% with positive but < 50% staining. Major clinical responses to ICPI therapies for tumors with PD-L1 AMP will be presented. Conclusions: PD-L1 AMP or other GA occur rarely across many cancer types. Many somatic PD-L1 GA are uncharacterized VUS. PD-L1 AMP correlates with high membrane expression of PD-L1 measured by IHC and is linked to durable response to ICPI therapies. Further evaluation of PD-L1 AMP as a potential biomarker for immunotherapy selection appears warranted.
Periodontal complications with obesity
Authors: Jean E. Suvan, Nicholas Finer, Francesco D'Aiuto
Journal: Periodontology 2000 (2018)

Abstract The purpose of this paper was to identify and summarize current evidence describing periodontal complications associated with obesity. Electronic searches supplemented with manual searches were carried out to identify relevant systematic reviews. Identification, screening, eligibility, and inclusion of studies were performed independently by two reviewers. A MeaSurement Tool to Assess systematic Reviews (AMSTAR) was used to assess the quality and risk of bias of the included reviews. From 430 titles and abstracts screened, 14 systematic reviews were considered as eligible for inclusion in this meta‐review. Eight reviews reported on cross‐sectional studies investigating the association of obesity and periodontal diseases, 4 included longitudinal studies, 5 addressed response to periodontal therapy, 5 reported on studies investigating biomarkers, and only 2 were related to pediatric population samples. Systematic review summaries in the various study design domains (cross‐sectional, longitudinal and experimental) report that obese individuals are more likely to have periodontal diseases, with more severe periodontal conditions, than nonobese individuals, with cross‐sectional evidence congruent with longitudinal studies showing that obesity or weight gain increases the risk of periodontitis onset and progression. Published research on the effect of obesity on responses to periodontal therapy, or systemic or local biomarkers of inflammation, is variable and therefore inconclusive based on the evidence currently available, which suggests that overweight/obesity contributes to periodontal complications independently of other risk factors, such as age, gender, smoking, or ethnicity. This evidence supports the need for risk assessments for individual patients to facilitate personalized approaches in order to prevent and treat periodontal diseases.
A phase II evaluation of ixabepilone in the treatment of recurrent/persistent carcinosarcoma of the uterus: An NRG/Gynecologic Oncology Group study.
Authors: Carolyn K. McCourt, Matthew Powell, Meaghan Elizabeth Tenney, David M. Kushner, Jacob Rotmensch, James Erasmus Kendrick, David Philip Warshal, Wei Deng, Joel N. Saltzman, Don S. Dizon
Journal: Journal of Clinical Oncology (2016)

5585 Background: The primary objectives were to determine the objective response rate (ORR) by RECIST 1.1 and side effect profile of ixabepilone in women with recurrent or persistent uterine carcinosarcoma (UCS). Secondary objectives included defining the duration of progression-free survival (PFS) and overall survival (OS). Exploratory translational objectives included characterization of class III beta tubulin expression and its association with RR, PFS, and OS. Methods: Patients had recurrent or persistent UCS with measurable disease. Up to 2 prior chemotherapeutic regimens were allowed, but must have included a taxane; one prior non-cytotoxic regimen was also allowed. Women received ixabepilone 40mg/m2 as a 3 hour IV infusion on day 1 of a 21 day cycle. Treatment was continued until disease progression or unacceptable toxicity occurred. A 2-stage design was used. Results: 42 women were enrolled, and 34 were eligible and evaluable. Ineligible patients included wrong cell type (N = 6), second primary cancer (N = 1), and inadequate pathology (N = 1). Median age was 68 years. Performance status was 0 in 56% of women, 38% had received radiation, and 15% received 2 lines of chemotherapy. Overall ORR was 11.8% (4/34, 90% CI 4.2-25.1%); all were partial responses. With a median follow up of 37 mo, median PFS and OS were 1.7 mo and 7.7 mo, respectively. Six month PFS was 20.6%. Major grade 3 or 4 toxicities were neutropenia (47%), white blood cell decreased (44%), anemia (15%), fatigue (15%), dehydration (15%), hypertension (15%), and hyponatremia (15%); grade 2 or 3 peripheral neuropathy was reported in 21%. There were 6 deaths during active therapy, with 1 possibly related to treatment. In this small sample size, class III beta tubulin expression in the primary tumor was not associated with response to ixabepilone, PFS, or OS. Conclusions: In this cohort of women with recurrent/persistent UCS previously treated with a taxane, single agent ixabepilone did not meet the study objectives or demonstrate clinical utility. Clinical trial information: NCT01168232.
Barriers to early integration of palliative care: A qualitative analysis of medical oncologist attitudes and practice patterns.
Authors: Tim J Kruser, Jacqueline M Kruser, Jeffrey Gross, Margaret Moran, Karen Kaiser, Eytan Szmuilowicz, Sheetal Mehta Kircher
Journal: Journal of Clinical Oncology (2018)

e22191 Background: Early integration of palliative care for patients with advanced cancer has demonstrable benefits but is underutilized. We sought to characterize medical oncologists’ perspectives on palliative care and identify barriers to its early integration. Methods: A national sample of medical oncologists (N = 31) was recruited to participate in four focus groups. The focus groups were audio recorded, transcribed verbatim, and the transcripts were independently reviewed and coded by four investigators from diverse healthcare backgrounds (radiation oncology, critical care medicine, medical oncology, and public health). Sections of text were assigned a consensus code, and higher-level analysis was conducted to reveal concepts and themes. Results: Medical oncologists universally endorsed early clarification about the intent of chemotherapy (palliative versus curative). However, practice patterns related to palliative care integration and referral were variable. In this context, medical oncologists described themselves as “driving the bus” regarding the timing and utility of palliative care referral and end-of-life care planning. While medical oncologists acknowledged the evidence supporting early palliative care integration, numerous barriers to this practice were described. Medical oncologists reported patient-centered barriers such as patients’ perceptions of palliative care, the burden of extra physician visits, and copay costs. Additionally, many physician-centered barriers were voiced to justify underutilization of palliative care. Medical oncologists expressed ownership over patients’ care trajectory, and were concerned that palliative care physicians could interfere with the plan of care, provide inaccurate or misleading prognostic information, or offer options to patients that were not endorsed by the medical oncologist. Conclusions: Physician-centered concerns are potential barriers to the early integration of palliative care for patients with advanced cancer. These practice patterns may reduce patient autonomy and the benefits of early palliative care involvement.