bluuebunny/crossref_metadata_2025_split huggingface dataset:
Challenges in sentinel node (SN) pathology in the era of adjuvant treatment: The risk of over and undertreatment stress the need for expert pathology review.
Authors: Franke Viola , Madu Max Fullah , Bierman Carolien , Klop Willem M.C. , van Houdt Winan J. , Wouters Michel W.J.M. , Van De Wiel Bart A. , Van Akkooi Alexander Christopher Jonathan 
Published: May 2019

9593 Background: With the approval of adjuvant therapy for stage III melanoma, accurate staging in melanoma patients is important more than ever to prevent over- or undertreatment. Sentinel node biopsy (SNB) is an accurate staging tool, yet the presence of capsular nevi (CN) can lead to a false positive diagnosis. We compared positive SNB and CN patient outcomes and aimed to evaluate the cause of false positive SNB and discern diagnostic pitfalls in their evaluation. Methods: Retrospective analysis of AJCC 7th Edition stage IIIA melanoma patients (N1-2a, non-ulcerated primary tumor) who were treated at our institute between 2000 and 2015. SNB slides were reviewed for this study by an expert melanoma pathologist. Baseline characteristics were assessed for SN+ and CN+ patients. Concordance rates for SNB evaluation before and after revision were documented and diagnostic pitfalls were discerned. Results: 169 patients were diagnosed, 10 could not be reviewed due to lack of evaluable slides. Of these 159 cases, 14 patients originally diagnosed with metastatic melanoma were shown to have capsular nevi (8.8%). Another 2 patients were shown to have melanophages that were incorrectly interpreted as metastases (1.3%). Thus, 10.1% was considered false positive after revision. In 14 patients the SN tumor burden was originally reported > 1 mm, but turned out to have < 1 mm SN tumor burden. 4 patients originally reported as SN tumor burden < 1 mm before revision turned out to have > 1 mm SN tumor burden. These 32 patients (20%) might have potentially been over- or undertreated in the current era of adjuvant therapy for stage III melanoma. Conclusions: False positive sentinel node results in melanoma are real, they can occur for a number of reasons, but distinguishing metastatic melanoma from benign capsular nevi and melanophages can be a diagnostic challenge. We plead for an expert pathologists’ review in any case, but certainly when using the SNB+ results to determine treatment consequences for SN+ melanoma patients.
tRNA-derived small RNA fragments (tRFs) as potential biomarkers for doxorubicin resistance in breast cancer.
Authors: Wu Xiaowei , Fu Ziyi , Ge Han , Liu Xiaoan , Xia Yiqin , Li Minghui , Huang Yue , Peng Jinhui , Wang Shui , Xie Hui 
Published: May 2019

e12000 Background: It has been confirmed that tRNA-derived small RNA fragments (tRFs) participate in various kinds of biological activities. However, the function of tRFs in chemotherapy resistance in breast cancer still remains unclear. The purpose of this study is to elucidate the relation between tRFs expression character and chemotherapy resistance in breast cancer. Methods: Drug sensitivity was validated by using Cell Counting Kit-8 in ADR-sensitive breast cancer cells (MCF-7) and ADR-resistant cells (MCF-7/ADR). Next-generation sequencing technology was conducted to identify differentially expressed tRFs between MCF-7 and MCF-7/ADR breast cancer cell lines; quantitative RT-PCR (qRT-PCR) were used to validate the differentially expressed tRFs in MCF-7 and MCF-7/ADR cell lines and the serums of chemotherapy sensitive and resistant patients. Then the dysregulated tRFs were identified through Gene ontology (GO), Pathway analysis and network analysis. Finally, receiver operated-characteristic curve (ROC) analysis was carried out to assess the predictive power of the dysregulated tRFs as biomarkers for chemotherapy resistance.The growth and sensitivity of breast tumor to Adriamycin were assessed by micro-CT in vivo. Results: There were 588 differentially expressed tRFs between MCF-7 and MCF-7/ADR cell lines (fold change > 2).tRF-2023, which was significantly downregulated in chemotherapeutic resistance breast cancer tissues and cells, could induce the sensitivity of breast cancer cells to Adriamycin both in vivo and in vitro. Bio-informatic analysis showed that tRF-2023 was mainly involved in flavonoid glucuronidation and cellular gluuronidation, and the target genes of tRF-2023 were involved in RNA polymerase, purine and pyrimidine metabolism, and p53 signaling pathway, which might illuminate the function of tRF-2023 in chemotherapy resistance of breast cancer. The result of ROC also showed that tRF-2023 was involved in breast cancer resistance. Conclusions: Our study provides a comprehensive analysis of tRFs in breast cancer resistance. It is helpful in revealing the significance of tRFs during the development of chemotherapy resistance in breast cancer. We also identified that tRF-2023 could be a new potential biomarker and therapeutic target for chemotherapy-resistant breast cancer.
Pharmacokinetic (PK) characterization of irinotecan liposome injection in patients (pts) with metastatic breast cancer (mBC).
Authors: Anders Carey K. , Sachdev Jasgit C , Munster Pamela N. , Pedret-Dunn Anna , Maxwell Fiona , Northfelt Donald W. , Han Hyo S. , Ma Cynthia X. 
Published: May 2019

e12003 Background: Irinotecan liposome injection (nal-IRI) uses intraliposomal stabilisation technology to enable high drug load and in-vivo stability. This analysis characterizes the PK profile of nal-IRI in pts with mBC. Methods: The expansion of NCT01770353 enrolled 30 pts with mBC over three cohorts (Cohort 1: ER+ and/or PR+ BC [C-1]; Cohort 2: Triple Negative BC [C-2]; and Cohort 3: BC with active Brain Metastasis [C-3]). Key inclusion criteria: ECOG ≤1; adequate organ function; and >1 and ≤5 prior lines of cytotoxic therapy in metastatic setting. Most pts received nal-IRI 60 mg/m2 salt-based equivalent (50 mg/m2 free base equivalent [FBE]) or 80 mg/m2 (70 mg/m2 FBE) q2w by iv infusion, based on tolerance; 2 pts were treated at 40 mg/m2 (35 mg/m2 FBE). Plasma samples were collected over 360h across cycles 1, 2 &3, and analysed using LC-MS/MS for total irinotecan. Data were analysed by a non-compartmental approach using Phoenix Winnonlin, and were compared with values from studies in other tumor types. Results: 21 patients were evaluable for PK analysis (C-1, n=6; C-2, n=7; and C-3, n=8). No trend for accumulation was observed in cycle 2 or 3, when comparing total irinotecan Cmax & exposure (area under the curve at 168 h [AUC168]) versus cycle 1. At 40-80 mg/m2 (35-70 mg/m2 FBE), Cmax of irinotecan tended to increase proportionally with total dose, and was comparable to studies in other tumour types (see Table). Among 29 pts who received nal-IRI, partial response (per RECIST) was observed in 10 pts. The most related TEAEs (≥ 25%) were diarrhea, nausea, vomiting, hypokalaemia, decreased appetite and fatigue. Stable disease was observed in 5 pts. Conclusions: PK parameters in patients with mBC were comparable to historical studies in patients with other tumour types. The safety profile of nal-IRI monotherapy appeared consistent with gastrointestinal and blood disorders. [Table: see text]
A prognostic nomogram to predict the benefit of adjuvant radiotherapy for resected inﬂammatory breast cancer patients.
Authors: Ping Yang Jun , Nan Qian Chao 
Published: May 2019

e12007 Background: A nomogram is a convenient and reliable tool for individualizing cancer prognosis. Therefore, the purpose of this study was to construct a clinical nomogram for predicting overall mortality (OM) to help clinicians to make individualized estimates of the potential benefit of adjuvant radiotherapy (RT) for resected inﬂammatory breast cancer (IBC) patients. Methods: We used the Surveillance, Epidemiology, and End Results database to identify 4030 IBS patients treated with surgery between 2004 and 2012, and randomly classified the patients into the discovery (n = 2417) and validation (n = 1613) cohorts. A Cox regression hazards model was used to build a nomogram by determining the prognostic factors for OM in the discovery cohort. The overall accuracy and discriminative ability was measured by Brier score and Harrell's concordance index (c-index). Results: In multivariate analysis, age, race, number of primaries, N stage, estrogen receptor, progesterone receptor status, and marital status, were the independent predictive factors of OM. These variables were selected to generate the nomogram. The calibration curves for 2-, and 5-year OM rate showed excellent agreement between prediction and actual observation. The Brier score and c-index demonstrated the nomogram performed better than the 7th edition TNM staging system for predicting OM possibility. In addition, the nomogram predicted that the magnitude of benefit from adjuvant RT for an individual IBS patient could vary, the certain subgroup of patients (prognostic score: 0-25) would not gain benefit from adjuvant RT, while RT had more pronounced effects in participants with higher prognostic score (prognostic score: ≥25). Conclusions: This nomogram is a reliable prognostic method for predicting OM in IBC patients after surgical resection, which could be used to predict which IBC patients may benefit from adjuvant RT after surgery.
Use of ovarian suppression with endocrine therapy among premenopausal United States women with breast cancer, 2001-2016.
Authors: Mayer Sophie Emma , Lund Jennifer Leigh , Pate Virginia , Reeder-Hayes Katherine Elizabeth 
Published: May 2019

e12010 Background: Clinical trials indicate that adding ovarian suppression (OS) to endocrine therapy (ET) in premenopausal women with non-metastatic breast cancer improves disease-free and overall survival. However, injectable OS may add cost, potential side effect burden, and additional clinic visits to adjuvant therapy. It is not known to what extent OS is being used in contemporary community oncology settings. Methods: We identified women age 18-50 with incident breast cancer based on diagnosis codes from 2001-2016 in the commercial IBM MarketScan database. Eligible patients were continuously enrolled for a year prior to cancer diagnosis and filled at least 1 prescription for oral ET (i.e., tamoxifen, toremifene, anastrozole, letrozole, and/or exemestane) in the year after diagnosis. We classified use of OS as any prescription for a gonadotropin-releasing hormone agonist in outpatient pharmacy claims or procedure code for OS implant or injection 1) in the week prior to ET initiation or 2) following ET initiation and for up to 18 months after diagnosis. We estimated the proportion of women that were OS users in each diagnosis year using linear binomial regression, and examined associations between OS use, age at diagnosis, and geographic region. Results: A total of 26,114 women meeting all inclusion criteria were identified from the MarketScan database, of whom 1,452 (5.6%) were OS users. The most common OS drug was leuprolide or leuprorelin (55.2%), followed by goserelin (46.7%), and triptorelin (1.1%). Risk of OS use varied from 3.2% in 2001 to 9.3% in 2016, peaking at 11.4% in 2015. OS use varied by region (χ2 p = 0.0003), with the highest use observed in the Northeast (6.5%) and the lowest in the South (5.0%). Younger patients were significantly more likely to use OS than older patients, with each additional year of age at diagnosis associated with a 0.57 percentage point lower risk (95% confidence interval [CI]: -0.63, -0.51). After controlling for age group (≤40, 41-44, 45-46, 47-48, 49-50) and region, each additional calendar year was associated with 0.25 percentage point greater risk of OS use (95% CI: 0.19, 0.31). Conclusions: OS use with ET appears to be increasing in US breast oncology practice among women under 50.
Modeling longer-term efficacy of neratinib in the extended adjuvant setting for early-stage breast cancer.
Authors: Danese Mark D. , Halperin Marc , Lalla Deepa , Yao Bin , Crown John , Doan Quan V. 
Published: May 2019

e12011 Background: Long-term efficacy in the extended adjuvant setting requires a long follow-up. In the ExteNET trial, neratinib was given for a year and invasive disease-free survival (iDFS) assessed at 2 and 5 years. In women with HER2+ hormone receptor positive (HR+) cancer who initiated neratinib, the observed difference in iDFS between neratinib and placebo at 5 years (4.5%) was greater than at 2 years (3.7%). The objective of these analyses was to extrapolate the effect of neratinib on iDFS beyond 5 years in patients with HER2+/HR+ early stage breast cancer who initiated treatment after receiving adjuvant trastuzumab. Methods: We analyzed the 5-year follow-up of the ExteNET trial using flexible spline-based parametric survival models to project iDFS risk at 10 years. Analyses included only HR+ patients. Several model specifications were explored including various combinations of the following variables: treatment as a time varying covariate, nodal status (0, 1-3, ≥4 nodes), and months from last trastuzumab treatment to randomization. The regression models included different combinations of interaction terms, either a proportional hazards or a proportional odds (PO) link function, and either 2 or 6 knots. The model fit was compared using Akaike Information Criterion (AIC). Results: In general, the fit statistics among the 16 models were comparable; however, the model with the lowest AIC included no interaction terms, 2 knots, and the PO link function. The mean iDFS event rate at 10 years was estimated to be 12.2% for neratinib and 18.9% for placebo for a difference of 6.8% (range across 16 models: 6.8%-7.8%). The recurrence rate and the difference between treatment groups were largest in women with ≥4 positive nodes. Conclusions: Based on these analyses, the projected 10-year difference in iDFS between placebo and neratinib patients seems likely to persist. However, because the data was limited to 5 years, we could not include the effect of hormonal therapy cessation. Also, low event rates in the node negative group may require longer follow-up to evaluate. In absence of longer-term data for neratinib, flexible parametric survival modeling of the iDFS suggests that the effect of neratinib therapy may remain stable.
Stratification of oncotype (ODX) Recurrence Score (RS) by Breast Cancer Index (BCI) and its relation to discordance.
Authors: Cascetta Krystal Pauline , Zimmerman Brittney Shulman , Enson Jenna , Ru Meng , Zubizarreta Nicole J. , Jaffer Shabnam , Tiersten Amy 
Published: May 2019

e12025 Background: ODX is a gene-expression panel predictive of 10-year risk of distant recurrence and has shown prognostic value in both node-negative (LN-) and node-positive (LN+) breast cancer (BC) patients. BCI predicts 10-year risk of recurrence and also identifies those that may benefit from extended adjuvant endocrine therapy (EET). We stratified ODX RS by BCI to compare its precision in predicting recurrence category and its relation to discordance. Methods: 49 women with HR+, LN- and LN+ BC with available ODX and BCI RS with median follow up of 6 years were included. BCI risk groups were evaluated using predetermined cutoffs. RS were stratified by traditional ODX and TAILORx cutoffs and were considered discordant if there was a 1-step or 2-step difference between ODX risk group (low, intermediate, high) and tumor grade (well, moderately and poorly differentiated). N (%) or median (range) were used to describe patients’ characteristics between BCI groups and compared by chi-square test or Fisher’s exact at the confidence level of 5%. Results: Using traditional RS cutoffs, BCI reclassified 42.3% of patients with low RS as intermediate (IR) or high risk (HR). 69% with intermediate RS were reclassified to low risk (LR) and 12% were upgraded to HR by BCI. 27% of low and intermediate RS had a high benefit from EET. 2-step discordance was 14.3%. Using TAILORx RS cutoffs, BCI reclassified 20% of patients with low RS as IR. None were upgraded to HR. In the intermediate RS group, 58% were reclassified as LR and 14% as HR. 24% of intermediate RS had a high benefit from EET. 2-step discordance was 2%. Conclusions: Patients classified as LR by TAILORx RS cutoffs are less likely to be reclassified as high or intermediate risk by BCI. No significant association was found between discordance among ODX RS and tumor grade and BCI prediction of recurrence or benefit of EET.
BRCA1 tumor expression and clinical outcome in Uruguayan breast cancer patients diagnosed before the age of 40 years.
Authors: Malvasio Silvina , Camejo Natalia , Castillo Cecilia , Artagaveytia Nora , Di Matteo Carina , Caserta Benedicta , Notejane Roberto , Alonso Maria Isabel , Schiavone Andrea , Delgado Lucia Beatriz 
Published: May 2019

e12028 Background: BRCA1 is one of the main susceptibility genes for breast cancer (BC). While BRCA1 mutations are rare in sporadic tumors, loss or reduction of gene expression have been reported in approximately 30-50% of sporadic BCs in the general population. From the molecular point of view, there is no clear characterization of these tumors in young women and we have found no studies reporting the rate of under-expression of BRCA1 in women with sporadic BC under 40 years of age. Objective: to assess the tumor expression of BRCA1 using immunohistochemistry (IHC) and its prognostic value in Uruguayan women diagnosed with BC before the age of 40 years. Methods: IHQ was used to analyze the tumor expression of BRCA1 in paraffin-embedded tumor samples of 40 BC patients diagnosed before the age of 40 between 01/01/2006 and 12/31/2012. The optimization and determination of the BRCA1 protein by IHC was centralized. The antibodies used were anti BRCA1 MS110 monoclonal antibodies against the N-terminal end and GLK-2 against the C-terminal end (amino acids 1839-1863). Expression was considered positive when >10% of the cells had nuclear and/or cytoplasmic labeling. Overall survival (OS) and disease free survival (DFS) were calculated; the curves were developed using the Kaplan-Meier method and the difference in survival was evaluated through the log rank test. Results: the average age of the 40 patients included was 36 years; 8 patients (20%) had significant family history of BC or ovarian cancer. The distribution by stage (S) was as follows: SI: 9 patients (22.5%); SII: 20 patients (50%); SIII: 10 patients (25%), and SIV: 1 patient. Regarding the biological profile: 17 patients (42.5%) were HER2- and ER/PR+, 13 (32.5%) were HER2+ and the remaining 10 patients (25%) were classified as triple negative. The 5-year OS and DFS were 73% and 60% respectively. The expression of BRCA1 with GLK-2 was ≤10% in 16 of the 40 patients included (40%). The 5-year OS and DFS for patients with ≤10% expression was 56% vs. 85% for patients with >10% (p = 0.015) and 40% vs. 72% (p = 0.034) respectively. The expression of BRCA1 by MS110 was ≤10% in 11 of the 40 patients included (27.5%). No statistically significant differences were found in the 5-year OS or DFS based on the expression of this marker. Conclusions: Decreased BRCA1 tumor expression as assessed by IHC using GLK-2 was found in 40% of young patients included and was associated with unfavorable prognosis.
Comparison of pegfilgrastim (Peg), plinabulin (Plin), and the combination for chemotherapy (Chemo) induced neutropenia (CIN) prevention: Rationale for the combination.
Authors: Blayney Douglas W. , Ogenstad Stephan , Shi Yuankai , Zhang Qingyuan , Feng Jifeng , Sun Tao , Du Lihua , Huang Lan , Mohanlal Ramon 
Published: May 2019

e12030 Background: Peg is used for prevention of CIN. Plin, a novel non-GSF small molecule with anti-cancer activity has equal efficacy against CIN as Peg; Plin does not cause bone pain and mitigates thrombocytopenia and the immune suppressive hematologic profile (Blayney ASCO, ESMO, SITC 2018). Plin has a mechanism of action (MoA) consistent with IL-6 -dependent granulocyte progenitor cell expansion, increased neutrophil demargination and transit from the bone marrow (Suwa, Am J Physiol 2000; Blayney SLB/IEIIS 2018). In single agent (SA) Peg and Plin phase (Ph) 2 data, CIN with Peg occurs in the 1st week (~day (D) 7) post Chemo, and with Plin in the 2nd week (~ D15) post Chemo, presumably due to different MoAs (NCT03102606, NCT03294577). We evaluated whether combining these two agents/MoAs would protect against CIN throughout the entire Chemo cycle (C). Methods: Early stage Breast Cancer Ph 2 patients received high febrile neutropenia (FN) risk TAC (docetaxel, doxorubicin, cyclophosphamide) and either SA standard dose Peg 6 mg (Peg; n=22) or SA Plin (20 mg/m2; n= 15), or Peg 6mg combined with Plin 20 mg/m2 (Peg/Plin; n=16). Peg was given ~24 hrs after TAC, and Plin ~30 min after TAC. Blood draws for ANC were taken daily from predose to Day (D)15, and validated bone pain assessments were done from predose D1 to D8 in C1. Results: On D7 (week 1) of C1, Plin but not Peg maintained mean ANC within normal; P<0.0001 for Plin vs Peg mean ANC. On D15 (week 2 of C1) Peg, but not Plin maintained ANC within normal; P<0.0001 for Peg vs Plin mean ANC. Plin added to Peg maintained mean and median ANC within normal throughout C1. (ANC normal range is 1.5 - 8 x10E9/L.) Frequency of Grade (Gr) 4 and 3/4 CIN was ~35 % lower (P<0.05 for Gr3/4) and median ANC nadir was 2 times higher (1.00 vs 0.46) in Peg/Plin vs Peg in C1. FN occurred in 1 pt each with Peg and Peg/Plin. Incidence of bone pain was 95% vs 6% with Peg vs Peg/Plin (P<0.0001). Conclusions: Adding Plin to standard dose Peg offers superior CIN protection throughout the entire high FN risk Chemo cycle, while almost eradicating bone pain vs Peg alone. Clinical trial information: NCT03294577 .[Table: see text]
The Neat-HER Virtual Registry: A novel registry following HER2+ ESBC patients receiving neratinib in the extended adjuvant setting.
Authors: Tripathy Debu , Vidal Gregory A. , Lalla Deepa , Bryce Richard , Hanson Gillian , Brammer Melissa , Xu Feng , Rugo Hope S. 
Published: May 2019

e12035 Background: While data from traditional registries are limited to patients (pts) treated at study sites, virtual registries can enroll a more diverse real-world population. Neat-HER is a US-based, non-interventional pilot virtual registry through PicnicHealth that will enroll 100 pts with HER2+ BC receiving neratinib as extended adjuvant therapy. Methods: Neat-HER will evaluate the feasibility of enrolling pts & answering research questions using this novel methodology. Eligibility includes receipt of neratinib, signed informed consent for medical record retrieval/data abstraction & > 18 years age at study consent. Pts who fail to complete enrollment procedures, are participating in a clinical trial, have metastatic disease, or who lack adequate medical records will be excluded. For each pt discontinuing neratinib within 60 days of starting treatment, an additional pt will be recruited, but all pts will be included in the analysis. Pts are recruited through multiple mechanisms incl. private social media groups, treating clinicians & pts enrolled in the Puma texting program. PicnicHealth will collect & structure medical records from medical practices in the United States for ~7 years prior to enrolment up to 1 year after enrolment. Research questions focus on descriptive pt characteristics & demographics, breast cancer history [(neo)adjuvant treatment/outcomes], use of diarrhea prophylaxis, incidence of diarrhea & duration of neratinib. Results: Enrollment began in 12/2018 with target completion in 4/2019. As of 2/2019, 42 pts have initiated enrolment. Of these, 19 pts completed enrolment & 69,750 data points have been extracted from medical records. Descriptive statistics will be used to characterize the pt cohort. Duration of treatment, receipt & type of prophylaxis, incidence of diarrhea, treatment discontinuation & reasons for discontinuation will be summarized for all pts. Conclusions: A virtual registry allows assessment of medication use & outcomes in a diverse population in a rapid timeframe. Neat-HER will provide comprehensive information on clinical history & treatment patterns in a real-world cohort of pts receiving extended adjuvant neratinib.