tbuckley/cabot-search huggingface dataset:
Models of Care for Survivors of Childhood Cancer From Across the Globe: Advancing Survivorship Care in the Next Decade
Authors: Emily S. Tonorezos, Dana Barnea, Richard J. Cohn, Monica S. Cypriano, Brice C. Fresneau, Riccardo Haupt, Lars Hjorth, Yasushi Ishida, Jarmila Kruseova, Claudia E. Kuehni, Purna A. Kurkure, Thorsten Langer, Paul C. Nathan, Jane E. Skeen, Roderick Skinner, Nurdan Tacyildiz, Marry M. van den Heuvel-Eibrink, Jeanette F. Winther, Melissa M. Hudson, Kevin C. Oeffinger
Journal: Journal of Clinical Oncology (2018)

With improvements in cancer treatment and supportive care, a growing population of survivors of childhood cancer at risk for significant and potentially life-threatening late effects has been identified. To provide a current snapshot of the models of care from countries with varying levels of resources and health care systems, stakeholders in childhood cancer survivorship clinical care and research were identified from 18 countries across five continents. Stakeholders responded to a survey and provided a brief narrative regarding the current state of survivorship care. Findings indicate that among pediatric-age survivors of childhood cancer (allowing for differences in age cutoffs across countries), resources are generally available, and a large proportion of survivors are seen by a physician familiar with late effects in most countries. After survivors transition to adulthood, only a minority are seen by a physician familiar with late effects. Despite the need to improve communication between pediatric oncology and primary care, only a few countries have existing national efforts to educate primary care physicians, although many more reported that educational programs are in development. These data highlight common challenges and potential solutions for the lifelong care of survivors of childhood cancer. Combining risk-based and patient-oriented solutions for this population is likely to benefit both providers and patients.
Erratum: Corrigendum: Dendritic cell–induced autoimmune heart failure requires cooperation between adaptive and innate immunity
Authors: Urs Eriksson, Romeo Ricci, Lukas Hunziker, Michael O Kurrer, Gavin Y Oudit, Tania H Watts, Ivo Sonderegger, Kurt Bachmaier, Manfred Kopf, Josef M Penninger
Journal: Nature Medicine (2003)
Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström’s Macroglobulinemia
Authors: Meletios A. Dimopoulos, Alessandra Tedeschi, Judith Trotman, Ramón García-Sanz, David Macdonald, Veronique Leblond, Beatrice Mahe, Charles Herbaux, Constantine Tam, Lorella Orsucci, M. Lia Palomba, Jeffrey V. Matous, Chaim Shustik, Efstathios Kastritis, Steven P. Treon, Jianling Li, Zeena Salman, Thorsten Graef, Christian Buske
Journal: New England Journal of Medicine (2018)

Single-agent ibrutinib has shown substantial activity in patients with relapsed Waldenström's macroglobulinemia, a rare form of B-cell lymphoma. We evaluated the effect of adding ibrutinib to rituximab in patients with this disease, both in those who had not received previous treatment and in those with disease recurrence.We randomly assigned 150 symptomatic patients to receive ibrutinib plus rituximab or placebo plus rituximab. The primary end point was progression-free survival, as assessed by an independent review committee. Key secondary end points were response rates, sustained hematologic improvement from baseline, and safety. The mutational status of MYD88 and CXCR4 was assessed in bone marrow samples.At 30 months, the progression-free survival rate was 82% with ibrutinib-rituximab versus 28% with placebo-rituximab (hazard ratio for progression or death, 0.20; P<0.001). The benefit in the ibrutinib-rituximab group over that in the placebo-rituximab group was independent of the MYD88 or CXCR4 genotype. The rate of major response was higher with ibrutinib-rituximab than with placebo-rituximab (72% vs. 32%, P<0.001). More patients had sustained increases in hemoglobin level with ibrutinib-rituximab than with placebo-rituximab (73% vs. 41%, P<0.001). The most common adverse events of any grade with ibrutinib-rituximab included infusion-related reactions, diarrhea, arthralgia, and nausea. Events of grade 3 or higher that occurred more frequently with ibrutinib-rituximab than with placebo-rituximab included atrial fibrillation (12% vs. 1%) and hypertension (13% vs. 4%); those that occurred less frequently included infusion reactions (1% vs. 16%) and any grade of IgM flare (8% vs. 47%). The major hemorrhage rate was the same in the two trial groups (4%).Among patients with Waldenström's macroglobulinemia, the use of ibrutinib-rituximab resulted in significantly higher rates of progression-free survival than the use of placebo-rituximab, both among those who had received no previous treatment and among those with disease recurrence. Atrial fibrillation and hypertension were more common with ibrutinib-rituximab, whereas infusion reactions and IgM flare were more common with placebo-rituximab. (Funded by Pharmacyclics and Janssen Research and Development; ClinicalTrials.gov number, NCT02165397 .).
Abstract 16714: The “Apolipoprotein EBethesda” Variant is a Digenic Phenotype of APOE p.R176C/GALNT2 p.D314A
Authors: Lita A Freeman, Robert D Shamburek, Leslie Biesecker, Alan T Remaley
Journal: Circulation (2016)

Introduction:  Apolipoprotein E (apoE) is a key protein in lipoprotein metabolism that protects against atherosclerosis. In 1982, a novel apoE protein isoform in a Type III hyperlipidemia patient was described by Brewer and colleagues at NIH. The proband had total cholesterol (TC) and triglyceride (TG) levels up to 550 and 900 mg/dL, respectively, and xanthomas that resolved with treatment. The VLDL-cholesterol to TG ratio, however, remained greater than 0.3. This Type III hyperlipidemia phenotype is generally associated with  APOE  c.526C>T;p.R176C (“apoE2”) homozygosity, but isoelectric focusing suggested the patient was a compound heterozygote for apoE2 and a new apoE isoform, “Apolipoprotein E Bethesda ” (apoE Bethesda,  also known as “apolipoprotein E Bethesda”). These findings suggested that apoE Bethesda  may be coded by a new  APOE  allele. However, sequencing data showed the patient was only heterozygous for apoE2 and no novel “apoE Bethesda ” mutation was ever found. The proband’s son, also a Type III hyperlipidemic patient with both the apoE2 and apoE Bethesda  isoforms, continued to be followed at NIH.   Hypothesis & Methods:  We hypothesized that exome sequencing of the proband’s son would identify the molecular defect in the “ApoE Bethesda ” isoform. Exome sequencing using Illumina TruSeq capture and HiSeq sequencing with standard chemistry was employed.   Results:  Relevant clinical data (on statins, niacin, and natural lipid supplements) were: apoA-I, 174; apoB, 78; TC, 190; TG, 124; HDL-C, 66; LDL-C, 102; BNP, 156; CT- Calcium, 1108. Off medications, TC and TG were 323 and 2030 mg/dL, respectively. The patient was confirmed to be heterozygous for APOE2 but again, no novel “apoE Bethesda ” mutations were found. He was, however, heterozygous for  GALNT2  c.941A>C;p.D314A. GALNT2 is a key enzyme in O-glycosylation.   Conclusion:  We suggest that the “apoE Bethesda ” phenotype is actually the consequence of digenic mutations for  APOE  c.526C>T;p.R176C (APOE2) , coupled with a mutation in  GALNT2,  which causes defective glycosylation of APOE. GALNT2 is known to glycosylate apoC-III and our hypothesis is that APOE or APOE2 is also a substrate for this enzyme. Functional studies are underway to address this hypothesis.
Special Supplemental Nutrition Program for Women, Infants, and Children Program, a Social Experiment on Effective Strategies to Prevent Severe Obesity Among Preschool Children
Authors: Jian Zhang, Andrew R. Hansen
Journal: JAMA Pediatrics (2018)

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Tamoxifen induced ovarian hyperstimulation during hormonal therapy for breast cancer.
Authors: Min Kyoon Kim, Soo Kyung Ahn, Hee-Chul Shin
Journal: Journal of Clinical Oncology (2018)

e12588 Background: Adjuvant endocrine therapy is an integral component of care for endocrine-dependent breast cancer. Tamoxifen is a potent inducer of ovarian function and consequent hyperestrogenism in premenopausal women. However, the incidence rate and risk factors associated this phenomenone were not clarified. Methods: Among consecutive patients who were operated under diagnosis of breast cancer from March 2012 to December 2016 in Chung-Ang university hospital, patients who received post-operative tamoxifen therapy for endocrine-dependent breast cancer (stage 0-III) at age under 60 were selected and retrospectively analysed. Clinicopathologic factors were analyzed between ovarian hyperstimulation group and non-hyperstimulation group by x2 and student t-test. Results: Among 205 patients, 19 patients(9.3%) showed high values of serum estradiol during tamoxifen therapy. They showed 44 times of high estradiol level during follow up period. The serum concentrations of estradiol and FSH were 1047.97638.8pg/mL and 11.57.3 mIu/mL, respectively. The mean duration from the start of the single administration of tamoxifen to the initial detection of a high concentration of estradiol was 666.4+433.1 days. Univariate and multivariate analysis between ovarian hyperstimulation and non-hyperstimulation groups showed younger age( < 40years) and only endocrine therapy without chemotherapy were related to higher prevalence of ovarian hyperstimulation significantly. (p < 0.001, = 0.031 each) Pathologic stages and progesterone receptor expressions on breast tumor were not related to manifestation of ovarian hyperstimulation. Conclusions: The Incidence rate and occurrence time of ovarian hyperstimulation associated with adjuvant tamoxifen treatment in breast cancer patients under age 60 were 9.3% and around 2-year after treatment with tamoxifen. Young age under 40 years old and endocrine treatment without chemotherapy were risk factors predicting occurrence of ovarian hyperstimulation during tamoxifen treatment. Close monitoring of the endocrine parameters during treatment with tamoxifen would be essential.
Analysis of weight trends over time in female survivors with triple negative breast cancer.
Authors: Damien Mikael Hansra, Rebecca Rollins, Karen Rados, Anita Johnson, Johnathan Ramey, Rachel Pannell, John Edward McKnight, Kimberly Randolph, Haritha Pabbathi, Mary Ninan, Ricardo H. Alvarez
Journal: Journal of Clinical Oncology (2018)

28 Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) with unique clinical-pathological &amp; prognostic characteristics. Studies have shown obesity to be risk factor for TNBC. Furthermore, patients (pts) with BC and overweight/obesity have a worse prognosis. Here we investigate body mass index (BMI) &amp; weight trends among BC survivors. Methods: A retrospective review BC pts at Cancer Treatment Centers of America Atlanta from 2012-10/27/17. Definition of a survivor: pts who have completed definitive therapy with no evidence of disease. Survivor BMI &amp; weight gain (kg) calculated from chart review. Weight gain in kg was recorded post chemotherapy, at 3, 6, 9, 12 month follow up. Inclusion: Pts with ER-PR-HER2- (TNBC), adults &gt; 18 yo, pts who completed chemo (neoadjuvant or adjuvant) &amp; surgery +/- radiation. Exclusion: Pts who died, had relapsed local disease or metastatic disease; missing BMI data; currently on chemotherapy; who did not receive chemotherapy; missing continuous BMI data or pathology report; lost to follow up. Results: 1756 BC pts with stage IA-IIIC identified, 300 pts identified as TNBC. A total of 134 patients met full inclusion/exclusion survivorship criteria. Average age of survivors = 52 (range 25-76). Stage: I = 38%; II = 50%, III = 12%. BMI categories: 0% underweight (BMI &lt; 18.5 kg/m2), 15% normal weight (BMI 18.5 to &lt; 25 kg/m2), 18% overweight (BMI 25 to &lt; 30 kg/m2), 55% obese (BMI ≤30 kg/m2), 12% morbid obesity (BMI ≤ 40 kg/m2). Average BMI for all survivors = 32.23 +/-0.59 kg/m2 (range 19-52 kg/m2); post chemotherapy weight change = 0.53 +/-0.41 kg; at 3 month follow up = -0.16 +/-0.51 kg; at 6 month = -0.02 +/-0.54 kg; at 9 month follow up 1.20 +/-0.59 kg; at 12 month follow up = 2.25 +/-0.61 kg. BMI by stage: I = 32.81 +/- 1.00 kg/m2; II = 32.12 +/- 0.91 kg/m2; III = 32.44 +/- 1.27 kg/m2. Conclusions: In our study, female survivors with TNBC present with obesity and gain weight after chemotherapy. Also, weight gain continues at 9 &amp; 12 months post definitive treatment. Survivors with TNBC should be treated with intensive weight loss interventions given that overweight/obesity is a risk factor for recurrence, worse prognosis, &amp; cardiovascular events.
Accurate excision of nonpalpable breast lesions with the new device system.
Authors: Zhongyao Luo
Journal: Journal of Clinical Oncology (2012)

e11557 Background: A histological diagnosis for nonpalpable breast lesions (NPBL) is required to determine suitable therapy. The open-breast biopsy (OBB) is the gold standard to determine the nature of NPBL. However, it is not easy to accurately remove whole breast lesions due to insufficient safe margin of lesions excised. To improve accuracy for removal of NPBL, we designed new tools to assist surgeons to accurately localize and remove NPBL during OBB. Methods: The new device system has two primary parts. First is a set of accurate-resection devices composed of a rotary cutter, a pair of inner and outer tubes, two pairs of concave and convex curved hooks, and a curved incision plate. The second part is the 12 o'clock localization method used to accurately position lesions three-dimensionally after the breast tissue is excised cylindrically. Thus, the exact location of breast lesions removed can be precisely traced back to the original breast tissue location. Results: 100 patients with a total of 149 OBB were studied using the new device system guided with needle localization under ultrasound. 112 out of 149 procedures were identified as nodule. Among 112 cases, 95 were breast fibroadenomas, 10 were mammary adenosis with a trend to form fibroadenoma, 5 were mammary adenosis, and 2 were adipomas. The remaining 37 cases possessed clusters of calcified lesions with small nodule. 32 were benign lesions with calcinosis, and the other 5 lesions were identified as breast cancer. Pathological examination demonstrated that 144 NPBL were accurately resected with accurate-resection devices. However, 19 out of 144 breast lesions were not completely removed the first time. Thus the second surgical procedure was performed for the 19 cases based on 12 o'clock localization method. The results demonstrated that the remaining lesions were accurately and completely eliminated with the second procedure. All patients were followed up with for 2 to 48 months post procedures. These patients treated with accurate resection devices were very satisfied with no breast deformation. Conclusions: The new device system is easy to use and has very low cost. It is very comfortable for the patient and is of great help in accurately localizing and resecting the lesions to the surgeon.
해설논문 : 비알코올지방간염의 발병기전과 치료
Authors: 박상훈 ( Sang Hoon Park )
Journal: Clinical and Molecular Hepatology (2008)

Nonalcoholic fatty liver disease (NAFLD) is characterized by a wide spectrum of liver damage spanning steatosis, nonalcoholic steatohepatitis (NASH), cryptogenic liver cirrhosis, and even to hepatocellular carcinoma. Investigations in the last few years have focused on NASH, a relatively aggressive form of liver disease, due largely to the explosion of information provided by clinical and basic science studies related to the widespread presence of risk factors, such as obesity, type II diabetes mellitus, and dyslipidemia. This is especially important given that obesity and type II diabetes mellitus have recently reached epidemic proportions in Korea. The pathogenesis of NASH is multifactorial, with insulin resistance and increased fatty acid possibly being important factors in the accumulation of hepatocellular fat, and oxidant stress, lipid peroxidation, mitochondrial dysfunction, and dysregulation of variable cytokines possibly being important causes of hepatocellular injury in steatotic liver. Because not all steatotic livers progress to NASH, some other environmental factors or a combination of genetic factors are thought to be required for progression to NASH and fibrosis. Lifestyle modifications continue to be the cornerstone therapy in NAFLD, but some insulin-sensitizing drugs might be more effective in treating NASH. Many pilot trials for antioxidants and lipid-lowering and hepatic protective agents have yielded promising initial results in improving liver enzymes or features of liver histology. However, the efficacy of these agents remains questionable. Despite recent gains in understanding NASH, several issues related to its natural history, pathogenesis, and treatment remain unresolved. (Korean J Hepatol 2008;14:12- 27)
Xenograft tumors derived from malignant pleural effusion of the patients with non-small-cell lung cancer as models to explore drug resistance
Authors: Yunhua Xu, Feifei Zhang, Xiaoqing Pan, Guan Wang, Lei Zhu, Jie Zhang, Danyi Wen, Shun Lu
Journal: Cancer Communications (2018)

Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions show dramatic responses to specific tyrosine kinase inhibitors (TKIs); however, after 10-12 months, secondary mutations arise that confer resistance. We generated a murine xenograft model using patient-derived NSCLC cells isolated from the pleural fluid of two patients with NSCLC to investigate the mechanisms of resistance against the ALK- and EGFR-targeted TKIs crizotinib and osimertinib, respectively.Genotypes of patient biopsies and xenograft tumors were determined by whole exome sequencing (WES), and patients and xenograft-bearing mice received targeted treatment (crizotinib or osimertinib) accordingly. Xenograft mice were also treated for prolonged periods to identify whether the development of drug resistance and/or treatment responses were associated with tumor size. Finally, the pathology of patients biopsies and xenograft tumors were compared histologically.The histological characteristics and chemotherapy responses of xenograft tumors were similar to the actual patients. WES showed that the genotypes of the xenograft and patient tumors were similar (an echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) gene fusion (patient/xenograft: CTC15035EML4-ALK) and EGFR L858R and T790M mutations (patient/xenograft: CTC15063EGFR L858R, T790M)). After continuous crizotinib or osimertinib treatment, WES data suggested that acquired ALK E1210K mutation conferred crizotinib resistance in the CTC15035EML4-ALK xenograft, while decreased frequencies of EGFR L858R and T790M mutations plus the appearance of v-RAF murine sarcoma viral oncogene homolog B (BRAF) G7V mutations and phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha (PIK3C2A) A86fs frame shift mutations led to osimertinib resistance in the CTC15063EGFR L858R, T790M xenografts.We successfully developed a new method of generating drug resistance xenograft models from liquid biopsies using microfluidic technology, which might be a useful tool to investigate the mechanisms of drug resistance in NSCLC.
Detection of residual disease after neoadjuvant chemoradiotherapy for oesophageal cancer (preSANO): a prospective multicentre, diagnostic cohort study
Authors: Bo Jan Noordman, Manon C W Spaander, Roelf Valkema, Bas P L Wijnhoven, Mark I van Berge Henegouwen, Joël Shapiro, Katharina Biermann, Ate van der Gaast, Richard van Hillegersberg, Maarten C C M Hulshof, Kausilia K Krishnadath, Sjoerd M Lagarde, Grard A P Nieuwenhuijzen, Liekele E Oostenbrug, Peter D Siersema, Erik J Schoon, Meindert N Sosef, Ewout W Steyerberg, J Jan B van Lanschot, Michael Doukas, Nanda C Krak, Jan-Werner Poley, Caroline M van Rij, Jaques JGHM Bergman, Suzanne S Gisbertz, Hanneke WM van Laarhoven, Sybren L Meijer, Lucas Goense, Nadia Haj Mohammad, Monique GG Hobbelink, G Johan A Offerhaus, Frank Vleggaar, Wouter L Curvers, Geert-Jan Creemers, Mark J Roef, Maurice JC van der Sangen, Jeroen Buijsen, Robert G Riedl, Wendy MJ Schreurs, Fabienne ARM Warmerdam, MJR Janssen, Chella van der Post, Sandra A Radema, Camiel Rosman, Heidi Rütten
Journal: The Lancet Oncology (2018)
Prevalence of <i>RAS</i> and <i>BRAF</i> mutations in metastatic colorectal cancer (mCRC) patients by tumor location.
Authors: Lauren C Bylsma, Christina Gillezeau, Tamer Garawin, Michael Anthony Kelsh, Jon Fryzek, Laura Sangaré, Kimberly Lowe
Journal: Journal of Clinical Oncology (2018)

681 Background: There is evidence to suggest that tumor biology and pathology differ for right- and left-sided colon tumors which may affect treatment efficacy and clinical outcomes. Therefore, we conducted a systematic review and meta-analysis of the available scientific literature to summarize the prevalence of RAS and BRAF mutations by primary tumor location and to identify potential sources of heterogeneity in mutation prevalence. Methods: This study was conducted in accordance with PRISMA guidelines. Using comprehensive search strings, several medical research databases were queried and relevant variables abstracted including tumor mutation prevalence, study country, metastasis site, tissue source, study design, study dates, median age of the cohort, mutation assessment method, and length of follow-up. Results: Final abstraction was performed on 40 articles, 36 observational studies and 4 randomized trials. Most studies were from Europe (n = 16), followed by Asia (n = 11), USA, (n = 7), Australia (n = 3), and the remaining 3 were conducted in multiple countries. The proportion of males in each study ranged from 37% to 72%, and the mean age ranged from 55 to 76 years. The prevalence of all RAS mutations was significantly higher among right-sided colon tumors than left-sided colon tumors (44%, 95% Confidence Interval [CI]: 38 – 50% vs 34%, 95% CI: 29 – 38%; p = 0.009). BRAF mutation prevalence was also higher in right-sided tumors (16.1%, 95% CI: 13.1 – 19.6% vs 4.4%, 95% CI: 3.4 – 5.8%; p &lt; 0.0001). Conclusions: This systematic review and meta-analysis found that mutation prevalence varied by primary tumor right- or left-sided location among mCRC patients. Some of this variation may be explained by study characteristics such as mutation assessment method, country and length of follow-up. Further research will help to better understand treatment and outcome implications of tumor sidedness and mutation prevalence.