tbuckley/cabot-search huggingface dataset:
PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results.
Authors: Helena Margaret Earl, Louise Hiller, Anne-Laure Vallier, Shrushma Loi, Donna Howe, Helen B Higgins, Karen McAdam, Luke Hughes-Davies, Adrian Nigel Harnett, Mei-Lin Ah-See, Richard Simcock, Daniel William Rea, Janine Mansi, Jean Abraham, Carlos Caldas, Claire Hulme, David Miles, Andrew M. Wardley, David A. Cameron, Janet Dunn
Journal: Journal of Clinical Oncology (2018)

506 Background: Adjuvant trastuzumab has significantly improved outcomes for HER2+ EBC pts, using the 12m duration empirically adopted from the pivotal registration trials. A shorter duration could reduce toxicities and cost whilst providing similar efficacy. No reduced-duration trial to date has demonstrated non-inferiority. Methods: PERSEPHONE is a randomised phase 3 non-inferiority trial comparing 6 to 12m trastuzumab, the largest reduced-duration non-inferiority trial internationally. Mapping onto standard UK practice, all HER2+ EBC pts were eligible. Stratification is by ER status, chemotherapy (CT) type, and CT and trastuzumab timing. The primary endpoint is DFS from diagnosis (first relapse or death from any cause). Randomising 4000 pts (1:1) enabled the trial to assess the non-inferiority of 6m (5% 1-sided significance, 85% power), defining non-inferiority as ‘no worse than 3%’ below the 12m arm’s assumed 80% 4-yr DFS. The pre-planned definitive DFS analysis required 500 events. Results: 4089 pts were randomised from 152 UK sites (Oct’07 – Jul’15). ER+ 69%; CT - 41% anthracycline (A)-based / 49% A and taxane (T)-based / 10% T-based; adjuvant CT 85%; sequential trastuzumab 54%. At 4.9 yrs median follow-up, there were 319 (8%) deaths and 500 (12%) DFS events. With a 4-yr DFS rate of 89% (95%CI 88 – 91) in both arms, the hazard ratio (HR) non-inferiority limit was set at 1.29. The calculated HR was 1.05 (95%CI 0.88 – 1.25, 95th percentile = 1.22) demonstrating non-inferiority (HR < 1.29) of 6m trastuzumab (1-sided p = 0.01). Congruent results were found for overall survival (OS) and for the pre-planned DFS and OS landmark analyses (after 6m of trastuzumab). Heterogeneity was observed in some stratification variables. Cardiac events were reduced in 6m pts (4% v 8% of 12m pts stopping treatment due to cardiotoxicity (p < 0.0001)). Conclusions: PERSEPHONE has demonstrated 6m of trastuzumab as non-inferior to 12m (3% non-inferiority margin). Given cardiac and other toxicities during months 7-12 of treatment, our results would support a reduction of standard trastuzumab duration to 6 months. Clinical trial information: 52968807.
The tumor-immune microenvironment (TME) in HR+/HER2- metastatic breast cancer (mBC): Relationship to non-metastatic (met) tumors and prior treatment (tx) received.
Authors: Adrienne Gropper Waks, Sara M. Tolaney, Stuart J. Schnitt, Deborah Dillon, Evisa Gjini, Sara Abdelrahman, Adrian Marino-Enriquez, Karla Helvie, Lori Marini, Ofir Cohen, Dewey Kim, Seth Andrew Wander, Daniel G. Stover, Scott Rodig, Ian E. Krop, Eric P. Winer, Nancy U. Lin, Nikhil Wagle
Journal: Journal of Clinical Oncology (2018)

1054 Background: HR+/HER2- primary breast tumors demonstrate less anti-tumor immune activity than HER2+ or triple-negative BC. However, minimal data exist about the TME of HR+/HER2- met tumors, particularly in the tx-refractory setting. Prior analyses also have not looked at macrophages (macs), which may be important in HR+ BC. Methods: We obtained met tumor biopsies (bx) from HR+/HER2- mBC patients (pts) on a prospective tissue collection protocol. Tumor-infiltrating lymphocytes (TILs) were scored histologically, and cytokeratin, CD68, CD163, and PD-L1 on tumor cells (tPD-L1) were assessed by multiplex immunofluorescence (IF). Correlation between biomarkers and prior lines of tx was assessed by Spearman coefficient. A previously presented cohort of HR+/HER2- non-met tumors is included for comparison. Biomarker differences between non-mBC and mBC samples were assessed by Wilcoxon rank sum (TILs) and chi2 (tPD-L1) tests. Results: 33 HR+/HER2- mBC bx were analyzed from 30 pts (31 assessed for TILs, 21 by IF). Bx sites were 17 (52%) liver, 8 (24%) breast, and 8 (24%) other. Bx were obtained after a mean of 3.9 (range 0-10) lines of tx. Median TILs were 1% (range 0-20%). Ratio of M2 (CD68+CD163+) to M1 (CD68+CD163-) macs was ≥1 in 19/21 samples, suggesting dominance of M2 (immunosuppressive) macs. tPD-L1 was < 1% in 20/21 (95%) pts. There was no significant correlation between level of any cell type (TILs, M1 or M2 macs) and lines of hormonal tx, chemotx, or both received before bx. There was a trend toward lower TILs and lower tPD-L1 in mBC bx compared to a separate cohort (N = 55) of HR+/HER2- non-mBC (Table). Analysis of additional samples, IF stains, and RNA/exome sequence is in process and will be presented. Conclusions: HR+/HER2- mBC tumors show a trend toward lower TILs and tPD-L1 than unmatched non-met bx, which may help explain low response rates to checkpoint inhibitors. Immune biomarker levels did not change significantly based on a tumor's degree of pre-tx. Value Non-mBC (N (%)) mBC (N (%)) Test of difference TILs Median 5% 1% p= 0.068 0-5% 19 (38%) 17 (55%) ≥5-10% 22 (44%) 8 (26%) ≥10% 9 (18%) 6 (19%) tPD-L1 < 1% 40 (78%) 20 (95%) p= 0.082 ≥1-5% 6 (12%) 1 (5%) ≥5% 5 (10%) 0
From smartphone to EHR: a case report on integrating patient-generated health data
Authors: Nicholas Genes, Samantha Violante, Christine Cetrangol, Linda Rogers, Eric E. Schadt, Yu-Feng Yvonne Chan
Journal: npj Digital Medicine (2018)

Patient-generated health data (PGHD), collected from mobile apps and devices, represents an opportunity for remote patient monitoring and timely interventions to prevent acute exacerbations of chronic illness-if data are seen and shared by care teams. This case report describes the technical aspects of integrating data from a popular smartphone platform to a commonly used EHR vendor and explores the challenges and potential of this approach for disease management. Consented subjects using the Asthma Health app (built on Apple's ResearchKit platform) were able to share data on inhaler usage and peak expiratory flow rate (PEFR) with a local pulmonologist who ordered this data on Epic's EHR. For users who had installed and activated Epic's patient portal (MyChart) on their iPhone and enabled sharing of health data between apps via HealthKit, the pulmonologist could review PGHD and, if necessary, make recommendations. Four patients agreed to share data with their pulmonologist, though only two patients submitted more than one data point across the 4.5-month trial period. One of these patients submitted 101 PEFR readings across 65 days; another submitted 24 PEFR and inhaler usage readings across 66 days. PEFR for both patients fell within predefined physiologic parameters, except once where a low threshold notification was sent to the pulmonologist, who responded with a telephone discussion and new e-prescription to address symptoms. This research describes the technical considerations and implementation challenges of using commonly available frameworks for sharing PGHD, for the purpose of remote monitoring to support timely care interventions.
Outcome of everolimus based therapy in hormone receptor positive metastatic breast cancer patients after progression on palbociclib combination.
Authors: Ajay Dhakal, Roby Antony Thomas, Ellis Glenn Levine, Adam Brufsky, Matthew G Hanna, Austin Miller, Thaer Khoury, Kazuaki Takabe, Amy P. Early, Tracy O'Connor, Mateusz Opyrchal
Journal: Journal of Clinical Oncology (2018)

1064 Background: BOLERO 2 trial showed improved progression free survival (PFS) with everolimus (EV) + exemestane combination over exemestane alone in hormone receptor positive, HER2 non-amplified metastatic breast cancer patients (HR+ HER2- MBC) who progressed on an aromatase inhibitor (AI). Recent studies have established CDK 4/6 inhibitors (CDKI) as front line therapy in HR+ HER2- MBC. There are no clinical outcome data of HR+ HER2- MBC on EV after they progress on CDKI. Objective of our study is to analyze clinical outcomes of HR+ HER2- MBC on EV after progression on palbociclib (PA) & compare them with BOLERO 2 results. Methods: This is a retrospective, two-institute review of HR+ HER2- MBC from Jan 2015-July 2017 treated with EV after progression on PA. Women who received EV or PA < 4 weeks were excluded. PFS was defined as the time from the initiation of EV to the date of progression as determined by treating physician based on radiological, biochemical and/or clinical criteria. Response rates were determined based on available radiological data. Results: 26 women with median age 61 (33-70) were identified. 76% had prior sensitivity to endocrine therapy, 69% had adjuvant chemo/hormonal therapy, 54% had visceral disease, 23% had 3 or more metastatic sites, 100% had ECOG performance status 0 or 1, 92% had prior AI, 65% had received chemotherapy, 35% had received chemotherapy for metastatic disease, 81% had 3 or more lines of prior therapy. Kaplan Meier estimate showed median PFS (95% CI) of 4.4 months (3.3-6.1) and median overall survival (OS) of 18.7 months (9.0- not reached). Median PFS and OS of EV cohort of BOLERO 2 (EV BOL) were 6.9 months (6.4-8.1) and 31.0 months (28.0-34.6). Fisher’s exact test comparing current study cohort vs. EV BOL showed significant difference in objective response (complete + partial responses) of 6/26 (23%) vs. 46/485 (9.5%), p = 0.04. Conclusions: EV showed shorter PFS and OS but significantly higher objective response in HR+ HER2- MBC who have progressed on PA compared to EV BOL. This small study, for the first time, suggests that EV has evidence of clinical benefit after progression on PA in HR+ HER2- MBC. Larger studies are needed to confirm the results.
MICMIC: identification of DNA methylation of distal regulatory regions with causal effects on tumorigenesis
Authors: Yin Tong, Jianlong Sun, Chi Fat Wong, Qingzheng Kang, Beibei Ru, Ching Ngar Wong, April Sheila Chan, Suet Yi Leung, Jiangwen Zhang
Journal: Genome biology (2018)

Aberrant promoter methylation is a common mechanism for tumor suppressor inactivation in cancer. We develop a set of tools to identify genome-wide DNA methylation in distal regions with causal effect on tumorigenesis called MICMIC. Many predictions are directly validated by dCas9-based epigenetic editing to support the accuracy and efficiency of our tool. Oncogenic and lineage-specific transcription factors are shown to aberrantly shape the methylation landscape by modifying tumor-subtype core regulatory circuitry. Notably, the gene regulatory networks orchestrated by enhancer methylation across different cancer types are seen to converge on a common architecture. MICMIC is available on https://github.com/ZhangJlab/MICMIC .
Prognostic value of the detection of lympho-vascular invasion in hormone receptor positive early breast cancer in the era of molecular profiling.
Authors: Raz Mutai, Hadar Goldvaser, Aaron Sulkes, Tzippy Shohat, Idit Peretz, Rinat Yerushalmi
Journal: Journal of Clinical Oncology (2018)

e12539 Background: Lympho-vascular invasion (LVI) is considered a negative prognostic factor in early breast cancer, but its value in clinical decisions regarding adjuvant chemotherapy is unclear in the current era of molecular profiling. This study sought to evaluate the association of LVI status with the recurrence score (RS) on the multigene Oncotype DX (ODX) assay and its impact on outcome. Methods: Patients with early estrogen-receptor-positive breast cancer who underwent ODX analysis in 2005-2012 were retrospectively identified from the database of a tertiary medical center. Clinical, treatment, and outcome data were collected from the medical records. Cox proportional hazard ratio was used to determine the recurrence rate and disease-free survival. The prognostic significance of LVI was evaluated by competing risks analysis. Results: LVI was detected in 38 of 657 patients (6%). LVI was not associated with the ODX RS (p = 0.225). However, it was significantly associated (p≤0.05) with other known prognostic factors (high tumor grade, low estrogen and progesterone receptors staining intensity, positive lymph nodes, large tumors) and with worse 5-year disease-free survival (HR 2.93, 95% CI 1.02-8.39, p = 0.04). Overall survival analysis according to the ODX subgroups showed that the presence of LVI was associated with worse 5-year overall survival (p = 0.04) only in the intermediate-risk group (ODX RS 18-30), while LVI had no effect in low (RS < 18) or high (RS > 30) risk groups. Conclusions: Although LVI was not significantly associated with a higher ODX RS, it may infer a worse outcome. Accordingly, LVI may serve as an independent prognostic factor in early breast cancer, especially in ODX intermediate-risk patients. Further studies are warranted to clarify the role of LVI status in treatment decisions in early breast cancer.
Serum amyloid P component therapeutically attenuates atherosclerosis in mice via its effects on macrophages
Authors: Dan Xi, Jinzhen Zhao, Kai Guo, Lu Hu, Hui Chen, Weijun Fu, Wenyan Lai, Zhigang Guo
Journal: Theranostics (2018)

Background: A hallmark of atherosclerosis is the formation of macrophage-derived foam cells.Serum amyloid P component (SAP), a member of the pentraxin family of proteins, is known to affect macrophage activation.However, the role of SAP in atherosclerosis is still unclear.Methods: Apolipoprotein E-deficient (Apoe -/-) mice fed a high-fat diet were given intraperitoneal injections of SAP (6 mg/kg) every other day for a total of 2 weeks to characterize atherosclerosis development. Results:We showed that intraperitoneal injection of SAP attenuated atherosclerosis in Apoe -/- mice.Immunostaining of aortic roots indicated that SAP was up-taken by the lesion area.In SAP-treated mice, serum paraoxonase1 (PON1) activity was increased whereas high-density lipoprotein inflammatory index (HII) was reduced.The cholesterol efflux rate in macrophages was elevated along with the expression of cholesterol efflux proteins.Through bioinformatics analysis followed by experimental validation, we found that proline/serine-rich coiled-coil protein 1 (Psrc1) was an important downstream effector of SAP in macrophages.Conclusions: Our findings reveal an anti-atherosclerotic role of SAP and extend the current knowledge regarding this molecule as a marker for atherosclerosis.
Veterans Health Administration Home-Based Programs and Cardiac Rehabilitation
Authors: Eric Y. Chang, Anam Umar
Journal: JAMA Internal Medicine (2018)

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포스터 전시 : 뇌량병변(corpus callosum)에 의한 실어증을 동반한 급성 간성혼수 환자 3예
Authors: 김세환, 정인권, 김은수, 이종협, 조창민, 권영오, 김성국, 최용환
Journal: Clinical and Molecular Hepatology (2003)

배경/목적 : 급성 간성혼수는 만성간질환에서 진행성 가면, 의식혼탁, 혼수로 진행하는 정신착란으로 특징지워지며, 만성간질환이 급성 간성혼수의 가장 흔한 원인이지만 다양한 감염, 독물, 간문맥 우회로등이 원인이될 수 있다. 대부분의 급성 간성혼수 환자에서 혈액 및 뇌척수액에서의 암모니아는 증가된 소견을 보이며, 증가된 암모니아에 의한 일차적 손상뿐만 아니라 뇌척수압 상승에 의한 뇌부종이 중요한 기전으로 알려져 있다. 한편 현재까지 만성 간성혼수에 의한 기저핵병변, 급성 간성혼수에 의한 대뇌피질병변등은 보고된 바 있으나, 급성 간성혼수에 의한 뇌량병변의 예는 보고된 바 없었다. 이에 연자등은 급성 간성혼수에서 뇌량병변에 의한 실행증, 실어증등의 임상증상을 동반한 환자들을 경험하였기에 보고하는 바이다. 증례 1: 10년전 B형 간염에 의한 간경변증으로 진단을 받은 66세 여자환자로 2일 동안의 갑작스런 의식변화를 주소로 내원하였다. 이전에 간성혼수의 과거력은 없었고, 내원당시 침밷기, 의식혼미등의 비정상적 행위와 구음장애, 불면, 구간운동실조등의 증상이 있었으며, 이학적소견상 복부팽만, 신경학적 소견상 경한 의식혼미, 경한 구음장애를 동반한 단음절 어휘구사(monotonous speech), 실행증, 실어증등이 있었다. 뇌척수액 소견는 정상이었으며, 그 외 검사실 소견은 표1과 같았다. 뇌자기공명영상상 양측성으로 뇌량, 전방 백질, 적핵, 치상핵의 조영증가 소견을 보였다. 환자는 만성 B형 간염에 의한 간경변증 및 급성 간성혼수로 치료도중 의식의 악화와 무도병 양상의 운동이상이 생기고 간부전으로 진행하면서 가망없는 퇴원을 하였다. 증례 2: 9년전 B형 간염에 의한 간경변증으로 진단받은 48세 여자로 갑작스런 복부팽만, 열감을 주소로 내원하여 이학적 소견상 복부팽만, 공막황달,함몰부종이 있었고, 검사실 소견은 표1과 같았다. 입원후 복수천자술상 감염소견을 보여 항생제 치료도중 경한 구음장애, 구간운동실조가 있어 시행한 뇌자기공명영상상 양측성으로 뇌량, 피각, 담창구, 적핵, 치상핵, 흑질의 조영증가 소견을 보였다. 환자는 만성 B형 간염에 의한 간경변증 및 급성 간성혼수, 윌슨씨병 진단하에 치료후 증상의 호전이 있어서 퇴원하였다. 증례 3: 5년전 B형 간염에 의한 간경변증으로 본원 외래에 다니던중 내원 2개월전 간암을 진단받고 고주파열치료술을 시행받았던 59세 여자환자로 내원 3일전부터의 의식혼미를 주소로 내원하였다. 내원당시 신체검사상 공막황달, 복부팽만, 신경학적 소견상 의식혼미, 경한 구음장애를 동반한 단음절 어휘구사, 실어증, 수평형 안구진탕등이 있었다. 검사실 소견은 표1과 같았고, 뇌자기공명영상상 양측성으로 뇌량, 뇌실주위 백질, 중뇌, 뇌교, 기저핵의 조영증가 소견을 보였다. 환자는 입원후 급성 간성혼수에 대한 치료도중 사망하였다. 결론: 급성 간성혼수 환자에서 뇌자기공명영상상 뇌량병변을 가지면서 뇌량병변에 의한 실어증,실행증을 동반한 3예를 경험하였기에 보고하는 바이다. 표1: 검사실 소견 (표) :
Implementation of a survivorship clinic in a medically underserved comprehensive community cancer center.
Authors: Carrie Lopez, Abhinav Chandra, Mary Sweigart
Journal: Journal of Clinical Oncology (2018)

54 Background: Historically, preparation of Survivorship Care Plans (SCPs) had been a cumbersome challenge that resulted in a limited number of plans delivered to eligible patients. In 2015, eleven breast SCPs were prepared and delivered by an RN. Upon review, it was determined the process of preparation and delivery of SCPs required refinement. Methods: Initially, we identified the barriers to our practice, which included limited knowledge, process, personnel, and software interfacing. We implemented a quality improvement project with the goal of delivery of SCPs to an increased number of cancer survivor patients. The project targeted staff education to identify eligible patient populations, create awareness of the Commission on Cancer accreditation requirements, and the knowledge necessary to create a SCP. We coordinated with the information technology department to attempt interfacing software programs, track the delivery of plans, and use provider notes to export data. We increased communication between departments to identify eligible patient populations. A nurse practitioner was assigned the responsibility for preparation and delivery of the document during a scheduled appointment, which focused on review and education in relation to the patient’s diagnosis, treatment plan, sequelae and recommended surveillance. Results: Through close coordination of interdisciplinary teams, we were able to implement strategies to develop a streamlined process to create and deliver SCPs. These interventions resulted in the Survivorship Clinic going from 11 breast cancer SCPs delivered in 2015 to 98 and counting, of all types of cancer, delivered in 2016. Patients requested follow up visits to the Survivorship clinic. Conclusions: We have successfully developed a Survivorship Clinic within a federally designated medically underserved community setting. Implementation of best practices resulted in nine-fold increase in delivery of SCPs. Most importantly, we have increased patient education and satisfaction. Our practices can be replicated by other programs and thereby curb the disparity of cancer survivorship care in rural areas.
Fifteen-year results of the randomised EORTC trial 22922/10925 investigating internal mammary and medial supraclavicular (IM-MS) lymph node irradiation in stage I-III breast cancer.
Authors: Philip Poortmans, Sandra Collette, Henk Struikmans, Karin De Winter, Erik Van Limbergen, Carine Kirkove, Volker Budach, Karine Peignaux-Casasnovas, Ernest Vonk, Desiree D.Vandenbongard@Umcutrecht.Nl, Sofia Rivera, Daniel Zips, Geertjan Van Tienhoven, Matthias Guckenberger, Roxolyana Abdah-Bortnyak, Alain Fourquet, Harry G. M. Bartelink
Journal: Journal of Clinical Oncology (2018)

504 Background: EORTC trial 22922-10925 investigates whether internal mammary and medial supraclavicular (IM-MS) lymph nodes (LN) irradiation improves outcome for stage I-III breast cancer patients (Clinicaltrials.gov NCT00002851). The 10 years analysis showed an improvement of 3.0% in metastases free survival (p = 0.02) and of 1.6% in overall survival (p = 0.056). Toxicity was limited and no increased lethal side effects were seen. This is the second of 3 scheduled analyses, at 15-year follow-up. Methods: Eligible patients had involved axillary nodes and/or a medially located primary tumour. Randomisation was to irradiate or not the IM-MS. The final trial design aimed at detecting a 4% increase in 10-year overall survival (OS) (from 75 to 79%, HR = 0.82) with 2-sided unadjusted Log-rank test at the 5% significance level. Secondary endpoints are disease-free survival (DFS), metastases-free survival (MFS) and cause of death. Two long-term analyses were planned, at respectively 15 and 20 years of follow-up. Results: Between 1996 and 2004, 4004 patients were randomized in 43 centres. Median age was 54 years; 59.0% were postmenopausal; 55.6% had involved axillary LN; 33.8%, 52.0% and 14.2% had stage I, II and III, respectively. Nearly all LN-positive (99.0%) and 66.3% of LN-negative patients received adjuvant systemic treatment. At a median follow-up of 15.7 years, 1117 patients died. At 15 years, overall survival was 73.2% in the nodal-irradiation group and 70.8% in the control group (HR IM-MS RT vs. control = 0.95; 95%CI, 0.84-1.06;P = 0.358).). Regional recurrences in IM-MS LN occurred in 1.8% vs. 3.1% of patients. Distant disease-free survival rate was 70.1% vs. 68.1% (HR = 0.92; 95%CI, 0.83-1.04; P = 0.178), breast-cancer mortality was 15.8% vs. 19.7% (HR = 0.81; 95%CI, 0.69-0.94; P = 0.005). Probability of breast cancer recurrence was 24.5% vs. 27.1% (HR = 0.87; 95%CI, 0.77-0.98; P = 0.024. No difference was observed in the incidence of second malignancies, contralateral breast cancer or cardiovascular deaths. Conclusions: The 15-years results show a significant reduction of breast cancer mortality and breast cancer recurrence by internal mammary and medial supraclavicular lymph node irradiation in stage I-III breast cancer. However, this is not converted in improved overall survival without a clear explanation for this. Subgroup analyses and continued follow-up will be performed to better define patients that may benefit from this treatment and define the causes of death. Clinical trial information: NCT00002851.