tbuckley/cabot-search huggingface dataset:
MEN1 gene mutations with different phenotypic presentations in two families: Is it a time to grade MEN1 mutations as high-risk and low-risk?
Authors: Alexander L. Shifrin, Allen E Bale, Dan Dykas, Angela Musial Fay, Kenneth Belitsis, Svetalna Fomin, Danielle Lann, Ronald Villanueva, Min Zheng, Sushama Govil, Brian Erler, Theodore Matulewicz, Arthur Topilow, Mark Krasna, Jerome Vernick
Journal: Journal of Clinical Oncology (2012)

1540 Background: MEN1 syndrome results from MEN1 gene mutations and is characterized by primary hyperparathyroidism (PHPT), pancreatic endocrine tumors (PET), pituitary adenomas, thymic and other tumors. About 600 different mutations have been reported on Human Gene Mutation Database and 30 of them presented as Familial Isolated Hyperparathyroidism (FIHP); however, no genotype-phenotype correlations have been identified. Methods: We characterized 2 independent families with newly diagnosed MEN1. Mutation analyses were performed in Dept of Genetics Yale University. Diagnostic tests, surgical treatment were implemented. Results: Family 1 has 21 members. 5 presented with early onset of PHPT and no other tumors. 3 ½ parathyroidectomies were performed. A proband had direct sequencing that showed a mutation in Exon 7, consisting of single base insertion in codon 319 (TAC to TTAC)(c1065_1066insT). There were no deaths in the family. Family 2 has 20 members. 7 were tested and showed a mutation in Exon 2, consisting of single base deletion in codon 103 (CTG to _TG)(c417delC). One 1 st generation member died from PET at age 79, three 3 rd generation members had multifocal metatstatic malignant gastrinomas (ages 32, 39, 41). The proband had total pancreatectomy at age 32. Five members had PHPT, angiofibromas. Three 2 nd generation members had thymic carcinomas (ages 20, 54, 60). Conclusions: Phenotypic presentation of MEN1 syndrome may vary with the same mutation suggesting a lack of genotype-phenotype correlation and the effect of modifying factors. On the other hand, these two families—one with a mutation predicted to truncate the menin protein close to its terminus and the other with a truncating mutation early in the coding sequence—have dramatically different severity of the syndrome. Our findings suggest that the exon 7 mutation has a milder effect on protein function resulting in FIHP. The management may be heavily influenced by the predicted clinical phenotype, we are proposing the development of a grading system for MEN1 gene mutations as low-risk and high-risk and to attempt to identify other modifying genetic and environmental factors to improve screening and timing for surgery.
HER2 testing in gastric cancer diagnosis: Insights on variables influencing HER2-positivity from a large, multicenter, observational study in Germany.
Authors: Gustavo Bruno Baretton, Hans Heinrich Kreipe, Peter Schirmacher, Timo Gaiser, Ralf D. Hofheinz, Karl Heinz Berghäuser, Winfried Koch, Britta Holzer, Stefanie Morris, Josef Rüschoff
Journal: Journal of Clinical Oncology (2017)

15 Background: HER2 testing is routine for metastatic gastric or gastroesophageal junction cancer (mGC/GEJC). Differing HER2-positivity rates are considered to be potential indicators of inter- and intra-laboratory deviations in testing quality. The influence of patient-, sample-, or method-related factors on HER2-positivity has not been assessed systematically. Methods: This observational, prospective study collected routine HER2 test result, patient- and tumor-related factors, sample source, and testing method data to identify factors influencing HER2-positivity rates in mGC/GEJC. Influencing factors were identified using stepwise multiple logistic regression and a statistical model was developed to predict probability of HER2-positivity. Institutes with deviations in HER2-positivity rates were identified by comparing 95% confidence intervals (CI) of documented and predicted rates. Results: From Jan 2013 to Dec 2015, data were collected from 2761 mGC/mGEJC routine diagnostic specimens at 50 pathology institutes in Germany. Final analyses included 2033 specimens with HER2 test results (1554 mGC and 479 mGEJC cases). Overall HER2-positivity rates across centers was 19.8% for mGC and 30.5% for mGEJC. Lauren classification showed the highest correlation with HER2-positivity, followed by HER2 testing rate, tumor location, type of sample (resection vs biopsy), and testing method (immunohistochemistry vs fluorescence in situ hybridization) (all P &lt; .05). Four institutes were identified with predicted HER2-positivity rates outside the 95% CI of the documented rate. Conclusions: This is the first study to report on multifactorial parameters that impact HER2-positivity rates in routine mGC/GEJC diagnostics. Results suggest that effective assessment of HER2 testing quality based on positivity rates should consider tumor characteristics, testing rate, type of specimen, and testing method, as they affect HER2-positivity. As therapy options for HER2-positive mGC/GEJC continue to evolve, reliably identifying the right patients is key.
Randomized phase III trial of erlotinib (E) versus docetaxel (D) as second- or third-line therapy in patients with advanced non-small cell lung cancer (NSCLC) who have wild-type or mutant epidermal growth factor receptor (EGFR): Docetaxel and Erlotinib Lung Cancer Trial (DELTA).
Authors: Yoshio Okano, Masahiko Ando, Kazuhiro Asami, Masaaki Fukuda, Hideyuki Nakagawa, Hidenori Ibata, Toshiyuki Kozuki, Tateo Endo, Atsuhisa Tamura, Mitsuhiro Kamimura, Kazuhiro Sakamoto, Michihiro Yoshimi, Yoshifumi Soejima, Yoshio Tomizawa, Shunichi Isa, Minoru Takada, Hideo Saka, Akihito Kubo, Tomoya Kawaguchi
Journal: Journal of Clinical Oncology (2013)

8006 Background: E and D are standard cares for previously treated patients with advanced NSCLC. Although E shows significant clinical benefits over best supportive care in the EGFR wild type tumors, it remains unknown whether E or D is more active against the disease. Methods: This is an open-label, multi-center phase III study, sponsored by the Japanese National Hospital Organization. Patients were randomized to E (150 mg, daily), or D (60 mg/m 2 , q3w) by the minimization method according to gender, performance status, histology, and institution. The primary endpoint was progression free survival (PFS), and secondary endpoints included overall survival (OS), response rate, safety, and analyses on EGFR wild type tumors. Eligible patients were those with pathologically proven NSCLC with stage IIIB or IV (AJCC version 6) previously treated with one or two chemotherapy regimens including at least one platinum agent, evaluable or measurable disease, and ECOG PS 0-2. Target sample size was calculated to be 280 based on the assumption that E was superior to D in PFS (3.5 months [m] v 2.5 m, α =0.05 [two sided], β =0.80). Results: From August 2009 to July 2012, 301 patients were accrued from 41 institutions. In the ITT population, 150 and 151 patients were randomly assigned to E and D, respectively, including respective 109 (73%, E) and 89 (59%, D) with EGFR wild type tumors. Median PFS and OS for E v D were 2.0 m (95% CI: 1.3-2.8) v 3.2 m (2.8-4.0, log-rank p=0.092; HR=1.22, 95% CI: 0.97-1.55), and 14.8 m (9.0-19.4) v 12.2 m (9.0-15.5, p=0.527; HR=0.91, 95% CI: 0.68-1.22), respectively. In the EGFR wild type tumors, PFS and OS for E v D were 1.3 m v 2.9 m (p=0.013; HR =1.44, 95% CI: 1.08-1.92), and 9.0 m v 9.2 m (p=0.914; HR =0.98, 95% CI: 0.69-1.39), respectively. Main grade 3/4 toxicities were rash (13.3% [E] v 0.7% [D]) and leukopenia (5.4% [E] v 62.9% [D]). Conclusions: E failed to show better PFS over D. While PFS was significantly longer in D than E in EGFR wild type tumors, the difference did not translate into OS in this pragmatic trial. Clinical trial information: 000002314.
Treatment (tx) patterns and clinical outcomes for patients (pts) with de novo versus recurrent HER2+ metastatic breast cancer (MBC).
Authors: Adam Brufsky, Denise Aysel Yardley, Peter Andrew Kaufman, Marianne Ulcickas Yood, Hope S. Rugo, Musa Mayer, Cheng Seok Quah, Bongin Yoo, Debu Tripathy
Journal: Journal of Clinical Oncology (2013)

523 Background: Use of adjuvant trastuzumab (T) in pts with HER2+ early breast cancer is associated with decreased recurrence. As fewer patients relapse, the proportion of pts with de novo metastatic disease in the first-line (1L) setting will increase, which could have implications for the design/interpretation of results from HER2+ MBC trials. To date, little data exist on potential differences in prognosis and outcomes between pts with recurrent vs de novo HER2+ MBC. Methods: registHER is an observational cohort of pts with HER2+ MBC diagnosed ≤6 mo from enrollment and followed until death, disenrollment, or June 2009 (median follow-up: 27 mo). Demographics and 1L tx patterns (using descriptive analyses), as well as clinical outcomes (median PFS and OS estimated by Kaplan-Meier method) were examined for pts with de novo vs recurrent HER2+ MBC. De novo was defined as disease-free interval (DFI) between initial and metastatic diagnosis ≤90 days; recurrent was defined as DFI &gt;90 days. Cox regression analyses were used to generate hazard ratios (HRs). Results: Pts with de novo HER2+ MBC (327 of 1001 enrolled) were more likely to be younger and non-white; have lymph, bone, and/or liver metastases and &gt;4 sites of metastatic disease; less likely to have lung or CNS metastases; and have received 1L regimens of TCH or AC more frequently vs pts with recurrent disease (who received T + vinorelbine more frequently). PFS and OS were longer in the de novo vs recurrent group (Table). Conclusions: Despite presenting with more advanced-stage disease accompanied by higher tumor burdens, pts with de novo HER2+ MBC had more favorable clinical outcomes vs those with recurrent disease. Differences in disease characteristics and tx patterns resulting in more refractory disease (including acquired resistance from adjuvant tx) may account for these observations. Clinical trial information: NCT00105456. [Table: see text]
Comparison of standard versus high dose of paclitaxel with ifosfamide and cisplatin (TIP) in salvage therapy of germ cell tumors (GCTs).
Authors: Jozef Mardiak, Michal Mego, Viera Miskovska, Zuzana Sycova-Mila, Jana Obertova, Patrik Palacka, Vanda Usakova, Jan Rajec, Stefania Liskova, Bibiana Vertakova-Krakovska, Michal Chovanec, Tomas Salek, Maria Reckova
Journal: Journal of Clinical Oncology (2012)

e15028 Background: Currently, TIP with higher dose of paclitaxel (250mg/m 2 ) is considered standard salvage chemotherapy in GCTs with good prognostic features. However, until 2007, we utilized regimen with standard dose of paclitaxel (175mg/m 2 ). The aim of this study was to compare the efficacy of TIP with the standard versus higher dose of paclitaxel as first salvage therapy for patients with relapsed GCTs. Methods: This retrospective study included 64 patients with relapsed GCTs treated with TIP as first salvage therapy between 1998 and 2010 in two major cancer centers in Slovakia. Forty five patients (70%) patients had favorable prognostic features for response (testis primary tumor site and prior complete response to induction chemotherapy regimen). Four cycles of standard dose (175mg/m 2 , 37 patients) or higher dose (250 mg/m 2 , 27 patients) of paclitaxel (day 1) with ifosfamide 1.2 g/m 2 (day 1-5) and cisplatin 20 mg/m 2 (day 1-5) were given 21 days apart with G-CSF support, followed by resection of resectable radiographic residua. Results: Nineteen of 37 (51%) patients treated with standard dose of paclitaxel achieved favourable response (complete remission or partial remission with negative serum tumor markers) compared to 20 of 27 (74%) patients treated with higher dose of paclitaxel (p = 0.07). In median follow-up of 23.9 months 37 patients (58%) experienced disease relapse and 33 (52%) patients died. Patients treated with higher dose of paclitaxel had better progression-free survival (median: not reached vs. 7 months, HR = 0.54, 0.28 - 1.04; p = 0.06) and overall survival (median: not reached vs. 33 months, HR = 0.69, 0.34-1.39; p = 0.31) compared to patients treated with standard dose of paclitaxel. Conclusions: Our data support the hypothesis that higher dose of paclitaxel with ifosfamide and cisplatin is associated with better outcome compared to standard dose of paclitaxel in patients with relapsed GCTs treated in first relapse.
IS AWARENESS OF PREVENTIVE TRAINING ASSOCIATED WITH DECREASED RISK OF INJURY?
Authors: Sten Rasmussen, Rasmus Oestergaard Nielsen
Journal: British Journal of Sports Medicine (2017)

Background Little is known about the prevalence proportion of sports injuries in Denmark. In addition, the beliefs amongst athletes regarding injury-preventive training regimes and the association with injury risk are lacking. Objective To examine the prevalence proportion of injured athletes in a population-based sample and to describe beliefs regarding their ability to prevent injuries through proper training. Design Population-based sample interviews. Setting Denmark, March 2016. Participants A random sample of 1059 persons from the Danish population above 18 years. Assessment of Risk Factors During the interview, the following questions were asked: Are you sports active? Have you sustained any sports-related injury within the past 3 years that prevented sports activity for a shorter or longer period? Do you know how to train properly to prevent injury? In addition, assessment of demographics included: age, sex, social class, income, education, number of children, county, union member and unemployment fund. Main measurements Sports active, injury within 3 years and prevention knowledge. Results The prevalence proportion of sports active was 60.9% [95% CI: 57.9–63.9]. A majority (61.8% [95% CI: 58.3–65.2]) reported to be aware of proper injury-preventive training, whereas 25.4% [95% CI: 22.0–28.9] sustained an injury within 3 years. Sports activity increased with education (OR=1.17 [95% CI: 1.1–1.23], P=0.0001). Risk of injury decreased with increasing age (OR=0.64 [95% CI: 0.54–0.74], P&lt;0.0001) and female sex (OR=1.61 [95% CI: 1.11–2.35], P=0.013). Knowledge of injury prevention increased with age (OR=1.15 [95% CI: 1.02–1.3], P=0.022) and female sex (OR=1.35 [95% CI: 1.13–1.51], P=0.004). No association of preventive training on injury (OR=1.07 [95% CI: 0.71–1.67]) Conclusions The prevalence proportion of injuries seems to be a public-health issue. A majority believe they know how to train properly to prevent injuries. However, awareness of preventive training was not associated with decreased injury risk.
Synthetic IL-33 DNA as anti-tumor adjuvant in vivo.
Authors: Daniel Villarreal, Megan Wise, Jewell Walters, Jian Yan, Matthew P Morrow, Mark Bagarazzi, Niranjan Sardesai, David Weiner
Journal: Journal of Clinical Oncology (2014)

3098 Background: Antigen specific CD4+ and CD8+ T cell responses have been generated in 78-90% of volunteers in two recent HPV and HIV clinical studies using our highly optimized DNA immunogens delivered using in vivo electroporation. IL-12 DNA was shown to augment T-cell responses in a prophylactic HIV clinical trial as compared to using antigen alone (increase in response rates of 36.4% and 18.6% in the CD4+ and CD8+ T cell compartments respectively) which could prove critical as available FDA-licensed adjuvants are limited, and include aluminum salts, or more recently, LPS formulations and do not improve CD8+T cell immunity. Methods: Here we describe an advance to augment the immune responses of DNA delivered by electroporation in the cancer immunotherapy arena. IL-33 has two different biologically active forms known as full-length IL-33 and mature IL-33. Results: Full-length IL-33 is thought to be the biologically most active form to promote inflammation, while the function of the mature cleaved form of IL-33 in modulating the immune responses remains more elusive. The potential ability of both isoforms to influence the adaptive immune response and act as an adjuvant has not previously been explored. We show that both isoforms of IL-33 are capable of enhancing potent antigen specific effector and memory T cell immunity in vivo when used in a DNA immunotherapy for HPV16. We also show that while both forms of IL-33 drove robust HPV specific IFNy responses (~2000 SFU), neither form drove high secretion of IL-4 (<250 SFU). Moreover, both isoforms augmented polyfunctional CD4+ and CD8+ T cell responses when compared to antigen alone (24-25% vs 18% and 66-67% vs 56%, respectively) and resulted in higher antigen-specific CD8+ degranulation. Co-administration with IL-33 conferred 100% protection against challenge with HPV E6/E7-expressing tumors (TC1 cell challenge). Both the full length and mature IL-33 adjuvant isoforms prevented or delayed the growth of tumors and/or expedited the rate of complete tumor regression and cured 10/10 and 9/10 animals, respectively. Conclusions: The data support that IL-33 DNA can act as a novel adjuvant for HPV-specific DNA immunotherapy, and is a strong candidate to be examined clinically in the context of anti-tumor immune-based therapy.
An open-label, randomized, two-way crossover study to evaluate the potential inhibition of GW572016 metabolism by ketoconazole
Authors: D. A. Smith, C. Bowen, J. M. Herendeen, A. Stead, K. M. Koch, B. P. Andrew
Journal: Journal of Clinical Oncology (2004)

3071 Background: GW572016 is an oral, dual EGFR/ErbB2 tyrosine kinase inhibitor that blocks signal transduction pathways implicated in cancer growth. In vitro studies indicate that GW572016 is metabolized predominantly by CYP3A4 and CYP3A5, and to lesser extent by CYP2C19. Therefore, the potential for a drug-drug interaction exists when GW572016 is co-administered with drugs that modulate CYP3A4 activity. The objective of this study was to assess the effect of ketoconazole, a potent inhibitor of CYP3A4, on the pharmacokinetics (PK) of GW572016. Methods: This was an open-label, randomized, two-way crossover study in healthy adult subjects. Each treatment period was separated by a 7-day wash-out period. In Treatment A, randomized subjects received a single oral dose of 100 mg GW572016. Subjects randomized to Treatment B received ketoconazole 200 mg BID for 7 days. On Day 4 of Treatment B, a single oral dose of GW572016 was co-administered with ketoconazole. Plasma concentrations of GW572016 were obtained over a 72-hour period during each treatment period. Results: Twenty-two subjects (1 F: 21 M), median age 27.5 years (range 20–55 years) were enrolled in this study. Geometric least square means and 90% confidence interval estimates for AUCinf,Cmax and t1/2 ratios are listed in the table below. Ketoconazole treatment resulted in a 3.6-fold increase in the exposure of GW572016. Conclusion: In conclusion, exposure following a single oral dose of GW572016 was increased after administration of ketoconazole. A decrease in the dose of GW572016 may be necessary to avoid enhanced pharmacodynamic effects and/or adverse events when co-administered with CYP3A4 inhibitors such as ketoconazole. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline
Phase II randomized clinical trial evaluating neoadjuvant chemotherapy regimens with weekly paclitaxel (WP) or eribulin (E) followed by doxorubicin and cyclophosphamide (AC) in women with locally advanced HER2-negative breast cancer (LABC): NSABP FB-9.
Authors: Jame Abraham, Andre Robidoux, Antoinette R. Tan, Marc E. Buyse, Norman Wolmark, Samuel A. Jacobs
Journal: Journal of Clinical Oncology (2014)

1058 Background: Eribulin (E) is a non-taxane, tubulin- and microtubule-targeting agent. In the randomized, phase III EMBRACE trial, disease-free survival and overall survival were prolonged in E versus physician's choice in heavily pretreated patients (pts). In this phase II randomized neo-adjuvant clinical trial, WP or E is followed by AC in patients with HER-2 negative LABC. The primary endpoint was pathologic complete response (pCR) in the breast and nodes. Methods: A total of 50 pts with LABC were accrued between January and August 2013. Median age was 50.5 years (range: 29-70 years). Twenty-three pts had stage IIB, 16 had stage IIIA, 9 had stage IIIB, and 2 had stage IIIC. Four pts had inflammatory breast cancer. Thirty-three were hormone-receptor positive and 17 were triple negative. Pts were randomly assigned (2:1) to receive either E (n= 31) (1.4 mg/m2 day 1 and day 8) every 3 weeks for 4 cycles, or WP (n= 19) (80 mg/m2) for 12 treatments. Both groups received AC (60 mg/m2 and 600 mg/m2) every 3 weeks for 4 cycles before surgery. Pts were evaluated by clinical examination and breast MRI at baseline and after completion of E or WP. MRI clinical partial response was defined as ≥30% decrease in tumor diameter. Results: Significant grade 3 toxicities included diarrhea (2%), febrile neutropenia (2%), mucositis (2%), and thromboembolic events (2%), 1 pt each. No pt experienced grade 3 or higher neuropathy. Baseline and follow-up MRI results are available on 44 pts. In the WP arm, 15/18 (83%) pts had a response (14 PR and 1 CR) and in the E arm, 15/26 (57%) had response (14 PR and 1 CR), either by investigator and/or central review. By central review WP pts had 50% response and E had 45%. Primary endpoint of pCR results will be reported. Conclusions: Both regimens are well tolerated with no unexpected toxicities. Both E and WP had moderate activity as per imaging in this LABC. A full analysis of complete pathological response data is pending. Clinical trial information: NCT01705691.
Low-Density Lipoprotein Measurement Discordance
Authors: Sunny Intwala, Neal J. Stone, Gary J. Balady
Journal: JAMA Cardiology (2017)

A 47-year old man presented with a marked difference between his direct and calculated low-density lipoprotein cholesterol levels and elevated levels of lipoprotein (a). He had been treated with atorvastatin. How do you interpret these results?
Targeting c-FOS and DUSP1 abrogates intrinsic resistance to tyrosine-kinase inhibitor therapy in BCR-ABL-induced leukemia
Authors: Meenu Kesarwani, Zachary Kincaid, Ahmed Gomaa, Erika Huber, Sara Rohrabaugh, Zain Siddiqui, Muhammad F Bouso, Tahir Latif, Ming Xu, Kakajan Komurov, James C Mulloy, Jose A Cancelas, H Leighton Grimes, Mohammad Azam
Journal: Nature Medicine (2017)