bluuebunny/crossref_metadata_2025_split huggingface dataset:
Breast cancer incidence according to age, race, and hormone receptor subtype: A SEER database analysis.
Authors: Schwartz Theresa Lynn , Wirth Lorinette , Diggs Laurence , Hinyard Leslie J. 
Published: September 2018

e13059 Background: While incidence rates of breast cancer have been shown to vary based on age and race, hormone receptor (HR) subtype is an important prognostic indicator and it is unclear to what extent HR subtype varies across age and race. Identifying breast cancer at an early stage, especially in the more aggressive subtypes, correlates with improved overall outcomes. In this study we sought to examine the distribution age, race, within HR subtype in women diagnosed with incident breast cancer. Methods: Data from the SEER registry, years 2010-2013, was queried to produce race stratified age distributions of incident cases of invasive female breast cancer according to HR subtype: Her2+/HR+ (n = 21288), Her2+/HR- (n = 9325), Her2-/HR+ (n = 153130), Her2-/HR- (n = 24455). Race was categorized as White, Black, and Other. Mantel-Haenszel Chi-Square (χ2MH) test was used to determine whether racial variations across the age categories (20-44 years, 45-64 years, and 65+ years) were the same across hormone receptor subtypes. Results: Across all HR subtypes and race categories, incident breast cancer burden was highest among women aged 45-64 years (p < 0.001). Age distribution differed significantly across HR subtypes (p < 0.001). Variations across age distributions and race differed by HR subtypes (p < 0.001). When the incident burden for younger Black women (aged ≤ 44 years) to Black women aged 45-64 years was compared to the same age categories for White women, it was found that variations across the racial and age groups were different across HR subtypes (p < 0.001). These results would suggest a significant three-way interaction between age, race, and HR subtype. Conclusions: There are significant differences in breast cancer incidence according to age, race, and HR subtype. Further investigation into a mortality effect is necessary to determine breast cancer screening strategies when these variables are taken into consideration.
Relationship between survival to breast cancer and level of HER2 expression by immunohistochemistry.
Authors: Provencher Louise , Diorio Caroline , Desbiens Christine , Poirier Brigitte , Poirier Eric , Boudreau Dominique , Doyle Catherine , Popa Ion , Gagné Isabelle , Hogue Jean-Charles , Lemieux Julie 
Published: September 2018

e13078 Background: Central review of NSABP B-31 showed that some central-review HER2-negative patients benefited from trastuzumab, but survival according to different levels of HER2 expression by immunohistochemistry (IHC) is unknown. The aim of the present study was to examine the survival of trastuzumab-naïve patients with breast cancer according to the level of HER2 expression by IHC. Methods: This was a retrospective study of all women who were treated for an invasive breast cancer at the Centre des maladies du Sein Deschênes-Fabia (Quebec City, Province of Quebec, Canada) between July 1999 and December 2010. Patients were grouped according to the HER2 status by IHC of their primary cancer (0 vs. 1+ vs. 2+ vs. 3+). Survival was obtained from the death registry of the Ministry of Health. Follow-up was censored on December 31st, 2012. Results: During the study period, 2571 patients with invasive breast cancer, with available HER2 status by IHC and survival data, and naïve to anti-HER2 therapy were treated at our center. Both 5- and 9-year overall survival (OS) decreased with increasing HER2 expression by IHC (9-year OS: 0: 86.2% vs. 1+: 71.3% vs. 2+: 73.9% vs. 3+: 69.3%; unadjusted log-rank test: P < 0.0001; adjusted P = 0.04 for 3+). Both 5- and 9-year breast cancer-specific survival (BCSS) decreased with increasing HER2 expression by IHC (9-year BCSS: 0: 90.7% vs. 1+: 81.8% vs. 2+: 77.0% vs. 3+: 75.4%; unadjusted log-rank test: P < 0.0001; adjusted P = 0.04 for 3+). Conclusions: Survival among trastuzumab-naïve breast cancer patients seems to follow a continuum across HER2 expression by IHC.
Mammography use, incidence, and survival of primary breast lymphoma.
Authors: Khudayar Humnah , Fallah Jaleh , Souaid Roy , Olszewski Adam J. 
Published: September 2018

e13087 Background: Breast lymphoma is rare and, unlike in carcinoma, surgery is not the primary treatment modality, so early detection may not contribute to survival. Caon et al. ( Clin Breast Cancer 2012) reported that 85% of aggressive lymphomas are diagnosed by a palpable mass, while 56% of indolent subtypes, by mammography. Our objective was to compare incidence, clinical features, and survival of breast lymphomas according to prevalence of screening mammography. Methods: From the United States SEER registry, we selected primary breast lymphomas diagnosed in 2000-2013 among women ≥40 years old, distinguishing DLBCL, marginal zone (MZL), follicular (FL), and other histologies. Mammography use in county of residence was expressed as % of women ≥40 years old with a mammogram in past 2 years, estimated from the National Cancer Institute’s small-area models. We calculated incidence rates (IR) for each county, and compared them in a Poisson model (with 95% confidence intervals, CI). Head and neck (H&N) lymphomas were used as sensitivity controls. Overall survival (OS, from diagnosis) was compared in a Cox model adjusting for age, race, and median income in the county. Results: We identified 1662 cases of breast lymphoma, with a median age of 69 years. The most common subtypes were DLBCL (39%), MZL (26%), and FL (16%). Stage distribution was: 1 in 62%, 2 in 17%, and 3 or 4 in 21%. Incidence of breast lymphoma increased by 24% for every 10% increase in mammography use (IR ratio, 1.24, 95%CI, 1.15-1.34, P<.0001). This relationship was absent for controls with H&N lymphoma (IR ratio, 1.02, 95%CI 0.97-1.07, P=.43). In breast lymphoma, there was no difference in histologies ( P=.19), stage ( P=.83), or OS by mammography prevalence (hazard ratio 1.01 for every 10% increase, 95%CI, 0.87-1.18, P=.87). OS at 5 years was 60% for DLBCL, 77% for MZL, and 84% for FL. Conclusions: Prevalent mammography use is associated with increased incidence of breast lymphoma, without evident change in stage distribution or survival. Further research will be needed to investigate responsible causal pathways, or potential overdiagnosis. [Table: see text]
Identifying patients according to breast cancer stage and ER/HER2 receptor status using claims data.
Authors: De Luise Cynthia , Beachler Daniel C , Yin Ruihua , Jemison Jamileh , Cochetti Philip T , Gangemi Kelsey , Lanes Stephan 
Published: September 2018

e13096 Background: Safety analyses of targeted oncology therapies often require cancer stage and receptor status. Automated claims databases offer the largest populations to study rare outcomes, but lack these characteristics. We conducted a validation study of claims data using predictive models to identify two cohorts of women with early-stage and advanced-stage ER+/HER2- breast cancer (ESBC and ASBC, respectively). Methods: Retrospective cohort and validation study using electronic data linkage of a nationwide claims database (HealthCore Integrated Research Database – HIRD) and Anthem’s Cancer Care Quality program (CCQP). The CCQP served as a validation sample. We used claims data to develop two predictive models to estimate breast cancer stage and receptor status. We applied these models to the HIRD to identify ER+/HER2- ESBC and ASBC cohorts. In each cohort we assessed adverse event (AE) rates. Results:: In addition to breast cancer diagnoses, predictive models for ER+/HER2- ESBC and ASBC included 21 and 15 factors, respectively (Table).When compared to an a priori ASBC algorithm developed from clinical experience, the claims-based predictive model for ASBC had better PPV (0.78 v. 0.62) with similar sensitivity (0.39 v. 0.38). For the ASBC cohort, selected AE rates per 100 person-years included: anemia, 26.4; neutropenia, 14.3; pulmonary embolism, 5.7; and leukopenia, 4.0. Conclusions: Identification ofcancer stage and biomarkers using claims data can be improved through predictive modeling. ER+/HER2- ESBC and ASBC cohorts are being utilized for characterizing indications and conducting safety evaluations of targeted therapies. [Table: see text]
Frequency and type of JAK3 variants in adult patients with leukemia.
Authors: Benton Christopher Brent , Assi Rita , Wang Feng , Pierce Sherry , Patel Keyur , Kornblau Steven Mitchell , AlRawi Ahmed , Zhang Jianhua , Hamilton Betty Ky , Takahashi Koichi , Dinardo Courtney Denton , Futreal Andrew , Garcia-Manero Guillermo , Kadia Tapan M. , Kantarjian Hagop M. , Andreeff Michael , Verstovsek Srdan 
Published: September 2018

e13117 Background: Janus kinases (JAK) family members ( JAK1, JAK2, JAK3, TYK2) are involved in tumorigenesis. JAK3 activating variants, including V722I, demonstrably induce cellular transformation in vitro. The prevalence of JAK3 variants/mutations in leukemia, particularly in AML, and their role in leukemogenesis, remains unclear Methods: We retrospectively reviewed leukemia patients (pts) treated at MD Anderson Cancer Center between 2012 and 2016, whose marrow samples were tested for JAK3 variants/mutations by next generation sequencing. We evaluated the type and prevalence of variants, the demographics, laboratory, treatment, and clinical information for JAK3 pts. Results: A total of 28 leukemia pts with JAK3 variants were identified, and included: MDS/MPN (n = 4), CLL (n = 2) and B-cell ALL (n = 1). All 7 non-AML pts had V722I variant (in the pseudokinase domain). Twenty-one AML pts were identified; this included 15 pts with V722I (1.5%) out of total 977 AML pts tested, demonstrating this variant was significantly more prevalent in AML pts than in the general population (1.5 vs 0.9%, P= 0.04). Three pts (0.3%) had P151R (FERM domain), and 1 pt each (0.1%) had V718L (pseudokinase), R925L (kinase), and L940V (kinase), none of which have been previously described. A pt with T815M (between pseudokinase-kinase domains) was identified from outside genetic testing. For AML pts, median allelic frequency for variants was 52% (range, 41-88) and median marrow blasts was 42% (range 21-97); 10% of AML patients had complex karyotype. Concomitant mutations were most commonly found in IDH1/2 (n = 10), TP53 (n = 8), FLT3 (n = 5), NPM1 (n = 5), ASXL1 (n = 5), RUNX1 (n = 4), DNMT3A (3), and TET2 (n = 3). Conclusions: We report the largest survey of JAK3 variants among adult leukemia pts, with detailed and novel variants described for AML. Given allelic frequencies, JAK3 variants may represent germline polymorphisms in most cases; however the activating V722I variant has increased prevalence among AML pts. The existence of an FDA-approved JAK3 inhibitor tofacitinib, and the prevalence and location of JAK3 variants provide a basis for additional investigations.
Virtual brain tumor histopathology and immunohistochemistry with stimulated raman scattering microscopy.
Authors: Lewis Spencer B , Pandian Balaji , Hollon Todd , Niknafs Yashar , Garrard Mia , Camelo-Piragua Sandra , Orringer Daniel A 
Published: September 2018

e13511 Background: Stimulated Raman scattering (SRS) microscopy is a label-free optical technique which uses the chemical composition of fresh tissue to generate image contrast. Prior work has demonstrated exceptional correlation between SRS images and H&E microscopy for detecting brain tumor infiltration ex vivo. However, SRS has not previously been suitable for a clinical environment. Further, SRS has utilized structural, rather than chemical, diagnostic features. We present the first clinical validation of SRS, as well as our work towards mutation-targeted SRS imaging. Methods: Implementation of SRS with a fiber laser source allowed sufficient stability for clinical deployment. Unprocessed specimens from 200 neurosurgical cases were imaged at the CH2 and CH3 vibrational modes, then processed to mimic the appearance of H&E staining. 30 cases were trialed in a simulated intraoperative consultation to assess concordance between SRS and cryosection microscopy. A multi-layer perceptron (MLP) model was then used to predict brain tumor diagnosis based on quantified image attributes. To explore the potential for chemically specific SRS, isogenic lines of normal human astrocyte were prepared, differing by the presence or absence of the R132H mutation in the isocitrate dehydrogenase 1 (IDH1) gene. IDH1 R132H cells accumulate high concentrations of the oncometabolite 2-hydroxyglutarate and display predictably altered metabolism. 200 Raman spectra were collected from 50 wild type (WT) and 50 R132H cells with the aim of detecting these changes. Each cell line was then submitted for targeted metabolomic analysis. Results: Excellent concordance was observed between SRS and frozen section histology ( κ >0.89). The MLP diagnosed brain tumor subtype with 90% accuracy. A robust spectral difference was observed between wild type and R132H cells, which showed concordance with metabolomic data. Conclusions: The diagnostic capability, ease of use and speed of SRS make it well-suited for integration into the operative workflow. Further, because SRS amplifies the Raman signal with no resonant background, the spectral differences observed may allow rapid differentiation of IDH1 WT and R132H cells with SRS.
Clinical implications of next-generation sequencing in the treatment of brain cancer at a large academic institution.
Authors: Mariotti Veronica , Gonzalez Velez Miguel , Parrondo Ricardo Daniel , Leslie Lori Ann 
Published: September 2018

e13521 Background: The use of next-generation sequencing (NGS) in clinical practice has increased the treatment (tx) options for cancer patients (pts). The expansion of genomic libraries used by NGS databases has resulted in increased identification of targetable genomic alterations (GAs). The aim of this study was to identify the clinical implications of genomic library expansion in the detection of GAs in pts with brain cancer at a large academic institution. Methods: We retrospectively analyzed 71 consecutive pts with brain cancer at the John Theurer Cancer Center that had NGS performed between 02/2014 and 09/2016. GAs were identified using the FoundationOne assay (Foundation Medicine, Cambridge, MA). GAs, number (n) of available genomic-directed tx and n of clinical trials were reviewed. The NGS assay interrogated 236 genes and introns of 19 genes until 09/2014, and subsequently was expanded to include 315 genes and introns of 28 genes. We compared median survival, n of GAs found, n of available trials, and n of tx available in pts who received NGS until 09/2014 (G1, n = 33) with pts who received NGS after 9/2014 (G2, n = 38). Results: Median survival was 30 months (range 19.9-40.1), median age was 62 years (range 26-82), the median n of GAs/sample was 5 (range 1-11). There was a significant positive correlation between n of GAs/sample and n of available trials and tx (r = .5, p = .00 and r = .3, p = .00, respectively). There was a negative correlation between survival and n of GAs (r = -.3, p = .02). G1 harbored 142 GAs with a median n of 4 GAs/sample (range 1-10), while G2 harbored 170 GAs with a median n of 5.5 GAs/sample (range 0-11). There was an absolute increase of 19.7% in GAs in G2 compared to G1. There was no difference in median overall survival. Conclusions: The expansion of genomic libraries increased the detection of GAs, and was positively correlated with the n of tx and clinical trials available for brain cancer pts. Survival was not affected by the expansion of the genomic library, but higher n of GAs was correlated with shorter survival. Expansions of NGS databases lead to increased n of potential tx options for brain cancer pts. Further studies are needed to investigate the impact of NGS targeted tx on survival.
Novel domain-targeted anti-Trop-2 monoclonal antibodies to elicit therapeutic synergy against multiple human cancers.
Authors: Alberti Saverio , Trerotola Marco , Relli Valeria , Pedicone Chiara , D' Amore Antonella , Dini Francesca , Fratarcangeli Silvia , Guerra Emanuela 
Published: September 2018

e14002 Background: Trop-2 is a calcium signal transducer that drives tumor cell growth. Trop-2 is overexpressed in the majority of carcinomas, where it associates with worse prognosis. The Trop-2 extracellular domain contains a N-terminal cysteine-rich globular domain followed by a stem-like cysteine-less region that connects to the transmembrane domain. Trop-2 engages in homophylic interactions between adjacent cells and interacts with tight-junction proteins, which may severely affect accessibility by therapeutic monoclonal antibodies (mAb). Available anti-Trop-2 mAb mostly recognize a single immunodominant epitope between the globular and stem regions, and have limited or no therapeutic efficacy. In order to untap the potential of anti-Trop-2 immunotherapy we generated novel anti-Trop-2 mAb with tailored specificity towards the globular versus stem regions. Methods: Balb-C mice were immunized with soluble human Trop-2 produced in human 293 and murine L cell lines and in baculovirus expression system. Domain-targeted anti-Trop-2 mAb were selected by flow cytometry using live 293 transfectants.Therapeutic potential was assessed in human cancer xenografts in murine models. mAb mode of action was investigated by Western blot, live-cell imaging and in vitro ADCC and cancer cell growth inhibition assays. Results: mAb were identified that were differentially directed against the Trop-2 stem versus globular regions. These mAb efficiently bound Trop-2 expressing cancer cells and inhibited cell growth in vitro. In vivo, naked anti-globular OX-G64 and anti-stem OX-S55 mAb were most effective in inhibiting the growth of colon, ovary, breast and prostate cancers as xenografts in nude mice. NSG mice and in vitro mechanism profiling indicated efficient ADCC, together with efficient internalization for ADC development. Differential efficacy for established tumors versus isolated-cell models of metastatic dissemination was shown. Most remarkably, OX-G64/OX-S55 co-administration demonstrated sinergic growth inhibition in vivo. Conclusions: The OX-G64 and OX-S55 anti-Trop-2 mAb are novel domain-targeted, sinergic therapeutic mAb for game-changing anti-cancer immunotherapy.
Evaluation of carboplatin toxicities and efficacy using different body weight descriptors in the Calvert formula.
Authors: Jhaveri Tulip A , Gil Brigitte , Zou Mei , Hartwell Nathan , Sands Jacob 
Published: September 2018

e14017 Background: Carboplatin dosing is calculated using the Calvert formula that includes glomerular filtration rate (GFR). In practice, GFR is often substituted by creatinine clearance (CrCl) with the Cockcroft-Gault (CG) equation. However, there is no standardization of which body weight descriptors should be utilized. Data suggest use of total body weight (TBW) may overestimate CrCl in overweight patients, while adjusted body weight may better estimate CrCl. The primary objective is to determine the impact of using different weight descriptors (DWD) in place of TBW for carboplatin dosing. Methods: This was a single-center, retrospective cohort study. Patients over 18 who were intended to receive at least 6 cycles of carboplatin with target area under the curve (AUC) of 5 or 6 and paclitaxel 175 to 225 mg/m2 were included. DWD included: adjusted body weight for overweight and obese patients, ideal body weight for normal weight patients and TBW for underweight patients. Primary endpoint was the composite of grade 3 or 4 anemia, thrombocytopenia and neutropenia (hematologic toxicity). Secondary endpoints included individual parameters of the primary endpoint, dose delays, dose reductions, progression-free survival, overall survival and objective response rate. Results: A total of 117 patients were included (DWD: n = 39; TBW: n = 78). Results on survival analysis, anemia and dose reductions are pending. Conclusions: To our knowledge, this is the first evaluation of patient outcomes specifically comparing carboplatin dosing calculations. Although there is a trend toward decreased grade 3 and 4 hematologic toxicities in the DWD group, there is no statistically significant difference in this under powered cohort. However, there was a significant decrease in treatment delays and days of treatment delay (p < 0.001) in the DWD group. Further studies are needed to evaluate the impact of DWD on carboplatin dosing. [Table: see text]
An easy-to-handle DPD deficiency test in saliva to identify patients at high-risk for life-threatening toxicity due to fluoropyrimidine therapy.
Authors: Schwartsmann Gilberto , Antunes Marina Venzon , Galarza Andres , Hahn Roberta Zilles , Raymundo Suziane , da Silva Anne Caroline Cezimbra , Staggemeier Rodrigo , Spilki Fernando R , Longhinoti Lidia B , Anjos Gabriel M , Franzoi Maria Alice B , Linden Rafael 
Published: September 2018

e14019 Background: Severe dihydropyrimidine dehydrogenase (DPD) deficiency can be lethal in 0.5-3.0% of patients receiving fluoropyrimidines. Unfortunately, there is no routine test in medical practice to identify high-risk patients. Here, we evaluated the use of plasma and saliva uracil (U) to dihydrouracil (UH2) metabolic ratio and DPYD genotyping, as a means to identify patients with DPD deficiency and fluoropyrimidine toxicity. In addition, we report on a functional test using UH2/U metabolic ratio in dried saliva spots (DSS). Methods: Prior to fluoropyrimidine therapy, plasma and saliva samples were obtained from 60 patients with GI cancer. U and UH2 levels were measured by LC-MS/MS in plasma and saliva. Patients were also genotyped for DPYD (*7/*2A/*13/Y186C). WHO grading were used to report treatment toxicity. Results: In 21 patients (35%) toxicity was documented. For those, no variant allele carrier for DPYD was identified. The UH2/U metabolic ratios were 0.1-26.7 in plasma and 0.1-24.0 in saliva, with a higher correlation with toxicity grade in saliva as compared to plasma (rs 0.52 vs 0.28). Median metabolic ratios were lower in patients with severe toxicity as compared to those with no toxicity (0.59 vs 2.83 saliva; 1.62 vs 6.75 plasma, P < 0.01). A cut-off of 1.16 for the salivary UH2/U ratio was set (AUC 0.84) with 86% sensitivity and 77% specificity for the identification of grade 3-4 toxicity. A plasma cut-off of 4.0 (AUC 0.75) revealed a 71% sensitivity and 76% specificity. Moreover, saliva of 21 patients were applied to filter paper to obtain DSS and sent to the laboratory by regular mail. U and UH2 were stable in DSS stored at 45°C up to 7 days. In this set of patients, grade 3-4 toxicity was documented in 3/21 cases (14%), all three cases had metabolic ratios below 1.16 in DSS, confirming our prior results. Conclusions: DPYD genotyping failed to identify severe DPD deficiency, but the UH2/U metabolic ratios in saliva showed enough sensitivity and specificity to deserve further evaluation. DSS samples allowed medical oncologists working at distant sites to send us samples by post, with results available within a week. This test is being validated in a larger sample population.