tbuckley/cabot-search huggingface dataset:
Abstract B39: NQO1 as a therapeutic target for atypical teratoid/ rhabdoid tumor
Authors: Julia C. Meade, Zachary R. Moore, Sarai H. Stuart, Agnieszka Cholka, Richard L. Boriack, Jingying Xu, Anat Erdreich-Epstein, Dinesh Rakheja, David A. Boothman, James F. Amatruda, Theodore W. Laetsch
Journal: Cancer Research (2016)

Abstract Atypical Teratoid/ Rhabdoid Tumor (ATRT) is an aggressive cancer that accounts for up to 20% of infant brain tumors. Even with intense chemotherapy and radiation, approximately 75% of children die from their disease at a median of 10 months after diagnosis. We found that the pathognomonic genetic lesion of ATRTs and related malignant rhabdoid tumors (MRTs), loss of the SWI/SNF chromatin remodeling complex member INI1/hSNF5/SMARCB1, is associated with high expression of NAD(P)H:quinone oxidoreductase 1 (NQO1), a two-electron oxidoreductase. Thus, we hypothesized that ATRTs will be vulnerable to drugs such as ß-lapachone (ß-lap, ARQ761 in clinical form) that selectively kill NQO1-expressing cells via mu-calpain mediated cell necrosis. A panel of ATRT cell lines exhibited overall high NQO1 expression and sensitivity to ß-lap (IC50 1.6-4 uM). A two-hour pulse with ß-lap caused a burst of ROS-mediated DNA damage and PARP1 hyperactivation, resulting in NAD+ and ATP depletion. Lack of NQO1 expression or inhibition of NQO1 with dicoumarol abrogated sensitivity to ß-lap. Low expression of NQO1 in normal brain and other pediatric tissues suggests a wide therapeutic window for ß-lap, and a survival advantage was observed after treatment in a heterotopic mouse xenograft model with several mice achieving apparent cures. Furthermore, the mechanism of ß-lap results in synergy with standard of care agents such as ionizing radiation, increasing its potential for clinical applications. Citation Format: Julia C. Meade, Zachary R. Moore, Sarai H. Stuart, Agnieszka Cholka, Richard L. Boriack, Jingying Xu, Anat Erdreich-Epstein, Dinesh Rakheja, David A. Boothman, James F. Amatruda, Theodore W. Laetsch. NQO1 as a therapeutic target for atypical teratoid/ rhabdoid tumor. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B39.
Oxaliplatin and 5-FU/folinic acid (modified FOLFOX6) with or without aflibercept in first-line treatment of patients with metastatic colorectal cancer: the AFFIRM study
Authors: G. Folprecht, C. Pericay, M.P. Saunders, A. Thomas, R. Lopez Lopez, J.K. Roh, V. Chistyakov, T. Höhler, J.-S. Kim, R.-D. Hofheinz, S.P. Ackland, D. Swinson, M. Kopp, D. Udovitsa, M. Hall, T. Iveson, A. Vogel, J.R. Zalcberg
Journal: Annals of Oncology (2016)
Gankyrin has an antioxidative role through the feedback regulation of Nrf2 in hepatocellular carcinoma
Authors: Chun Yang, Ye-xiong Tan, Guang-zhen Yang, Jian Zhang, Yu-fei Pan, Chen Liu, Jing Fu, Yao Chen, Zhi-wen Ding, Li-wei Dong, Hong-yang Wang
Journal: The Journal of Experimental Medicine (2016)

Oxidative stress status has a key role in hepatocellular carcinoma (HCC) development and progression. Normally, reactive oxygen species (ROS) levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors. How HCC cells respond to excessive oxidative stress remains elusive. Here, we identified a feedback loop between gankyrin, an oncoprotein overexpressed in human HCC, and Nrf2 maintaining the homeostasis in HCC cells. Mechanistically, gankyrin was found to interact with the Kelch domain of Keap1 and effectively competed with Nrf2 for Keap1 binding. Increased expression of gankyrin in HCC cells blocked the binding between Nrf2 and Keap1, inhibiting the degradation of Nrf2 by proteasome. Interestingly, accumulation and translocation of Nrf2 increased the transcription of gankyrin through binding to the ARE elements in the promoter of gankyrin. The positive feedback regulation involving gankyrin and Nrf2 modulates a series of antioxidant enzymes, thereby lowering intracellular ROS and conferring a steadier intracellular environment, which prevents mitochondrial damage and cell death induced by excessive oxidative stress. Our results indicate that gankyrin is a regulator of cellular redox homeostasis and provide a link between oxidative stress and the development of HCC.
Femoral-Shaft Fractures Treated by Medullary Nailing
Authors: Edwin F. Cave
Journal: New England Journal of Medicine (1952)

AMERICAN orthopedic surgeons have been skeptical about the use of medullary nailing of long-bone fractures. This, I think, is fortunate, as the slow acceptance of this technic has allowed us to avoid many pitfalls that would have discouraged us as surgeons and would have led to abandonment of a procedure that is one of the great advances in fracture treatment during this century.Medullary nailing of long-bone fractures is not a new procedure. It was used in ancient times in severe compound fractures. Nicolaysen in 18971 proposed such a form of treatment and Hey-Groves2 in 1921 advocated the use of . . .
The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy
Authors: Craig Kollman, Stephen R. Spellman, Mei-Jie Zhang, Anna Hassebroek, Claudio Anasetti, Joseph H. Antin, Richard E. Champlin, Dennis L. Confer, John F. DiPersio, Marcelo Fernandez-Viña, Robert J. Hartzman, Mary M. Horowitz, Carolyn K. Hurley, Chatchada Karanes, Martin Maiers, Carlheinz R. Mueller, Miguel-Angel Perales, Michelle Setterholm, Ann E. Woolfrey, Neng Yu, Mary Eapen
Journal: Blood (2015)
Iodination Defect in the Leukocytes of a Patient with Chronic Granulomatous Disease of Childhood
Authors: Seymour J. Klebanoff, Lon R. White
Journal: New England Journal of Medicine (1969)

In a case of chronic granulomatous disease, the patient's neutrophils, unlike normal neutrophils, did not fix iodine after ingestion of heat-killed Lactobacillus acidophilus or heat-killed or live Serratia marcescens. When live L. acidophilus was employed, iodination did occur, although it was less than normal. The patient's mother had some neutrophils that did not and some neutrophils that did iodinate after ingestion of heat-killed L. acidophilus. Unlike S. marcescens, L. acidophilus was killed as well by the patient's leukocytes as by normal leukocytes. Methimazole inhibited the killing of L. acidophilus by the leukocytes of the patient and the patient's mother but had no significant effect when normal leukocytes were employed. The ability of leukocytes in chronic granulomatous disease to kill certain organisms may depend on bacterial formation of the hydrogen peroxide required for an antimicrobial system in the leukocytes, mediated by myeloperoxidase.
Circulating cytokine and angiogenic factors as predictive biomarkers of glioblastoma response to aflibercept (VEGF Trap)
Authors: Y. Piao, J. V. Heymach, B. Bekele, K. Camphausen, P. Y. Wen, J. Liu, W. K. Yung, J. De Groot
Journal: Journal of Clinical Oncology (2009)

2029 Background: Aflibercept is a recombinant fusion protein that scavenges both vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). In a single-arm phase II study (NABTC06–01; NCT00369590 ), a 22% response rate was seen in recurrent glioblastoma patients receiving aflibercept 4 mg/kg iv every 2 weeks. We performed detailed analyses of circulating and urinary cytokine and angiogenic factors to describe the modulation of markers in response to aflibercept and to identify potential predictive markers. Methods: Plasma samples were collected from 31 of 32 enrolled patients at baseline, 24 hours and every 2–4 weeks until progression. Urine samples were collected at baseline and every 4 weeks. Levels of 41 circulating factors were measured using suspension bead multiplex assays (BioRad) or ELISA. Free VEGF and PlGF levels were determined following sample immunodepletion. Baseline and changes in marker levels over time were correlated with response and progression using logistic regression and Cox proportion hazard models. Results: Treatment with aflibercept resulted in significant increases in total VEGF and PlGF at 24 hours and 28 days (p ≤ 0.001). Free VEGF was rapidly sequestered by 24 hours and remained significantly decreased at 28 days (p = 0.001). However, free PlGF levels rose over time and by 28 days were 45-fold higher than baseline (p &lt; 0.001). Additional modulation of 4 factors at 24 hours included decreases in Groα and MIF (p = 0.001) and increases in urinary VEGF and MIP1β (p ≤ 0.001). At 28 days, levels of IL-18 were significantly decreased (p = 0.02) while SCGFβ and urinary VEGF levels increased (both p &lt; 0.02). Comparing baseline biomarker levels between response groups (PD, SD, and PR), patients with lower levels of GROα, HGF, SCGFβ and higher levels of free VEGF were more likely to have a PR (all p &lt; 0.05). Conclusions: In recurrent glioblastoma, aflibercept resulted in rapid and sustained decreases in free VEGF levels. Although greater than 95% of PlGF remained bound, free PlGF levels significantly increased over time. Treatment significantly modulated multiple cytokine and angiogenic factors with striking increases in MIF and SCGFβ. Potential biomarkers predictive of response to aflibercept include Groα, HGF and SCGFβ. No significant financial relationships to disclose.
The effects of pasireotide (SOM230) on health-related quality of life in patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR
Authors: L. Kvols, J. E. Glusman, E. A. Hahn, E. Wang, K. Öberg, L. Anthony, T. M. O’Dorisio, W. de Herder, C. H. Darby, B. Wiedenmann, G.
Journal: Journal of Clinical Oncology (2007)

4558 Background: Pasireotide is a novel multi-ligand somatostatin analogue with high affinity binding for four of the five somatostatin receptor subtypes (sst 1,2,3 and sst 5 ). This Phase II clinical trial showed that pasireotide is effective in controlling the symptoms of diarrhea and flushing in 27% of patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR. The impact of pasireotide therapy on health-related quality of life (HRQL) was also evaluated. Methods: Patients in this open-label, multicenter study initially received pasireotide 300 μg sc bid which was escalated to a maximum dose of 1,200 μg sc bid until clinical response was achieved. Data are reported for the Functional Assessment of Chronic Illness Therapy-Diarrhea (FACIT-D) instrument. FACIT-D comprises the Functional Assessment of Cancer Therapy-General (FACT-G) score, which measures physical, social, emotional and functional well-being, plus a symptom-specific sub-scale which measures HRQL specific to diarrhea. FACIT-D baseline assessment was obtained on day 1 immediately before dosing, and then monthly thereafter. FACIT-D sub-scale and total scores at baseline and after 1, 2, and 3 months of pasireotide treatment are described by categories of clinical response. Results: 45 patients (mean age 61 years; range 40–83) received treatment, and 44 were eligible for the efficacy and HRQL analyses. Functional well-being scores, symptom-specific scores and total FACIT-D scores of non-responders tended to be lower at baseline and during treatment than those of responders. The three sub-scale and summary FACIT-D scores exhibited relatively stable mean HRQL scores and similar patterns of variability in clinical responders and non- responders through the third month of pasireotide treatment. Conclusions: HRQL was stable during treatment with pasireotide in patients with advanced metastatic disease refractory or resistant to octreotide LAR. Additional work in HRQL study design and evaluation of HRQL endpoints in patients with carcinoid disease is indicated, and will further improve our understanding of quality of life in patients with this disease. [Table: see text]
Medicaid expansion increased low income patients’ coverage and use of healthcare, study finds
Authors: Michael McCarthy
Journal: BMJ (2016)

Adults on low incomes who live in US states that have expanded Medicaid eligibility have reported having higher rates of insurance, improved quality of coverage, and greater use of healthcare services than those who live in states that have not expanded the program, a new study has found.1 They did not, however, report improved health, the researchers said.

In order to reduce the number of Americans without health insurance, the 2010 Affordable Care Act mandated that states open Medicaid—the state run health insurance plan for the poor and disabled—to all adults earning up to 138% of the federal poverty level, about $16 000 (£11 123; €14 084) a year for an individual.

However, in 2012 the Supreme Court gave states the option of not expanding their programs. As a result, when the Medicaid expansion program was implemented in 2014, 24 Republican led states chose not to expand their programs.

This allowed researchers …
Activity of taxane chemotherapy for metastatic breast cancer (MBC) in BRCA1 and BRCA2 mutation carriers compared to sporadic BC patients.
Authors: C. Seynaeve, A. Jager, M. Hooning, C. H. Van Deurzen, M. Bontenbal, J. Blom, M. Collee, A. Ouweland van den, M. Kriege
Journal: Journal of Clinical Oncology (2010)

1020 Background: BRCA1-associated BC is characterized by high differentiation grade and basal-like phenotype, while BRCA2-associated and sporadic BC have similar patterns. Preclinical and small retrospective studies suggest that BC (cells) without functioning BRCA1/2 protein have increased sensitivity to chemotherapy causing dsDNA breaks, and decreased sensitivity to spindle poisons. Clinical data on the activity of taxanes in BRCA1/2-associated BC are scarcely available. Therefore, we assessed the activity of taxane-based chemotherapy in BRCA1- and BRCA2-associated compared to sporadic MBC pts. Methods: From the Family Cancer Clinic database, we selected 32 BRCA1- and 13 BRCA2-associated BC pts treated with taxane chemotherapy for MBC. Sporadic pts (n=90, 1:2 ratio) were matched for year of birth, diagnosis and metastatic disease, and line of chemotherapy. Response rates (RR) were tested by chi-square test, progression-free survival (PFS) was analysed by Kaplan-Meier method. Results: BRCA1 pts significantly more often had ER-negative and contralateral BC, while no significant differences between BRCA2 and sporadic pts were observed. Taxane therapy consisted of docetaxel (n=106), paclitaxel (n=16), or taxane/trastuzumab regimen (n=7). Taxanes were given in first-line therapy n=22, second n=86, or third line setting n=27. Compared to sporadic pts, the RR in BRCA1 pts was worse (overall OR 25% vs. 38%, PD 59% vs. 20%, for second-/third-line: OR 24% vs. 36%, PD 60% vs. 18% (both p<0.001). BRCA2 pts had a better RR than sporadic pts (OR 75% vs. 36%, p=0.02). Median PFS in BRCA1 pts was shorter than in sporadic pts, overall: 2.0 vs. 4.5 mo (p=0.07), for second-/third-line therapy: 2.0 vs. 4.7 mo (p=0.03). Median PFS in BRCA2 and sporadic pts was similar (4.6 vs. 4.7 mo). Both RR and PFS were significantly different between BRCA1 and BRCA2 pts. Similar results were obtained after exclusion of pts receiving a taxane/trastuzumab regimen. Conclusions: Compared to sporadic pts, BRCA1-associated M1BC pts are less sensitive to palliative taxane therapy regarding OR and PFS, which is not observed in BRCA2 pts. In view of potential therapeutic implications, identification of genetic status at BC diagnosis may be(come) important. No significant financial relationships to disclose.
Whole exome sequencing to identify potentially causative gene variants in hereditary gastric cancer.
Authors: Yiqing Huang, Kar Tong Tan, Huiling Yap, Samuel Guan Wei Ow, Henry Yang, Jimmy So, Soo-Chin Lee
Journal: Journal of Clinical Oncology (2015)

1525 Background: Gastric cancer is the leading cause of death in Asia where a small proportion is hereditary. While some causative genes like CDH1 and mismatch repair genes have been well characterized, many remain unidentified. Methods: We performed whole exome sequencing on peripheral blood DNA of gastric cancer patients suspected to have an underlying hereditary predisposition, defined as young onset cancer diagnosed at or below age forty, and/or strong family history of cancers. Potentially causative mutations were identified using ANNOVAR, the CADD algorithm and HGMD database. Sanger sequencing was performed to confirm mutations identified. Results: Twenty subjects (18 Chinese and 2 Malays) were studied. 70% were males. Median age at cancer diagnosis was 36 (range 24-68). 75% had poorly differentiated adenocarcinomas and 50% had signet ring cells. 9 subjects had young onset cancer without family history, 6 had young onset cancer with family history and 5 had gastric cancer after age 40 but had family history of gastric or Lynch syndrome related cancers. Potentially deleterious germline mutations that may cause hereditary gastric cancer were identified in 9/20 (45%) of subjects. Seven subjects carried 8 deleterious mutations in genes known to cause familial gastric cancer, including CDH1 (n = 1: c.1888C > G(L630V)), MLH1 (n = 2: 428T > A(V143D), n = 1: 2101C > A(Q701K)), MSH6 (n = 2: c.4071_4072insGATT, n = 1: 3205G > C(G1069R)) and TP53 (n = 1: 679G > T(G227X)). A probably deleterious mutation was identified in 1 novel gene, ABCA10 (1328_1331del), in 2 patients with young onset gastric cancer without family history; this variant is present in less than 1% of Asians. Five of the 7 distinct deleterious mutations identified were novel. In addition, 6 subjects carried two PLCE-1 variants (T1469I, H1619R), while another 6 subjects carried a MLL3 S3660L variant, all of which have been reported to be possible low-penetrance variants that increase gastric cancer risk by 1.4 and 2.5 fold respectively. Conclusions: In this cohort of Asian gastric cancer patients suspected to have hereditary gastric cancer, potentially causative rare high penetrance and common low penetrance genetic variants were identified.
The British Columbia Cancer Agency (BCCA) Compassionate Access program (CAP); A web-based submission process for all non-standard treatment regimens
Authors: J. Venkatesh, J. Barnett, L. Kovacic, S. Taylor, K. S. Wilson
Journal: Journal of Clinical Oncology (2008)

17533 Background: Access to new and expensive cancer treatments is a major contemporary issue in both private and public health care systems. Implementation and public funding of new chemotherapy protocols at BCCA is subject to approval by the Priorities and Evaluation Committee (PEC) and Systemic Therapy Program (STP). Reports of new therapies lead to evaluation by BCCA Tumour Groups who advance protocols to PEC for approval and STP for funding. In the period of data evolution, or prior to STP approval, funding for these therapies may be requested through CAP via province-wide online access. Methods: CAP submissions are required for non-STP approved therapies: where standard therapies are contra-indicated, being used for different indications, being prolonged or substantially modified: or to confirm eligibility for expensive STP-approved regimens. The original CAP paper process has been transformed to a web-based secure data entry form with links to BC Cancer Information System (CAIS) for patient demographics, diagnosis and stage, and to currently approved protocols. Online demonstration will be available for presentation. Results: From its inception in July 2006 to Dec. 2007, 5816 CAP requests from 203 physicians have been processed with 5000 (86%) approved. Median and mean outcome response times were 1 and 1.4 days. Infrequent users (<10 CAP requests) had lower approval rates than frequent users (77% vs 88%). CAP utilisation varied widely due to physician specialty (eg use of FOLFOX, FOLFIRI-Bevacizumab, sorafenib, maintenance rituximab), practice volumes and oncologists’ philosophies of care. 5% of physicians made 29% of all CAP requests. Representative subgroup outcome analyses have been published (alemtuzumab in CLL [ASCO 2007 abstract 8098]: esophago-gastric cancer [ASCO 2007 abstract 15158]). Conclusions: The BCCA web-based CAP request system is a novel electronic process with rapid turnaround, linking to CAIS, and linkable to outcome data bases (breast, colorectal cancer, lymphoma). Drug utilisation is monitored for patient eligibility, cost and budgetary implications. Prospective collection of response and serious adverse event data by CAP would facilitate outcome analyses of patient subgroups. No significant financial relationships to disclose.
Natriuretic Effect of Calcitonin in Man
Authors: Olav L. M. Bijvoet, Jaap van der Sluys Veer, Henk R. de Vries, Alphons T. J. van Koppen
Journal: New England Journal of Medicine (1971)

Abstract Porcine calcitonin was given to eight patients by continuous infusion for six to 39 days. Renal sodium and water excretion increased for 48 hours, and 0.5 to 1.6 kg of body weight was lost. A new steady state followed, with body weight below, sodium excretion the same as, and aldosterone secretion rate and plasma renin activity above, control levels. After the calcitonin infusion was stopped, there was sodium retention, and body weight returned to control values. Contamination or species difference as an explanation of these effects was unlikely because in short-term studies, porcine and synthetic human calcitonin had identical effects. The absence of a simultaneous increase in the excretion of cyclic adenosine-3′,5′-monophosphate suggests that the increase of sodium excretion was not due to a secondary increase of parathyroid-hormone secretion. Plasma calcitonin concentration achieved during continuous infusion suggests that calcitonin in physiologic amounts causes sufficient sodium and water lo...
Local Adverse Reaction Rates Decreased over Time during Treatment with Recombinant Human Hyaluronidase-Facilitated Subcutaneous Infusion of Immunoglobulin G (IGHy) in Patients with Primary Immunodeficiency Disorders in the IGHy Phase 3 Studies
Authors: Mark R. Stein, Richard L. Wasserman, Isaac Melamed, Sudhir Gupta, Lisa J. Kobrynski, Arye Rubinstein, Christopher J. Rabbat, Werner Engl, Barbara McCoy, Heinz Leibl, Leman Yel
Journal: Journal of Allergy and Clinical Immunology (2016)
Treatment of Kaposi's Sarcoma of the Lower Extremity by Extracorporeal Perfusion with Chemotherapeutic Agents
Authors: Anthony P. Monaco, W. Gerald Austen
Journal: New England Journal of Medicine (1959)

KAPOSI'S sarcoma, or "idiopathic multiple hemorrhagic sarcoma," was first described as a clinical entity by Kaposi in 1872. The disease is progressive, and it exhibits a wide range of clinical and histologic variations. It has a singular propensity for the male Jewish and Italian population of Eastern Europe, is common in the African Negro, but rarely affects the female.1 2 3 4 Although the disease is reported in adolescence,1 its onset is usually in persons over forty, with a progressively increasing incidence in succeeding decades.The initial lesion is most often found on the hands and feet, and it takes the form of . . .
Case 22-2006
Authors: Gilmore N. O'Neill, R. Gilberto Gonzalez, Didier P. Cros, Robert H. Ackerman, Robert H. Brown, Anat Stemmer-Rachamimov
Journal: New England Journal of Medicine (2006)

A 77-year-old man had difficulty walking that progressed rapidly during four months. For approximately 14 months, he had had a series of medical problems that prevented him from carrying out his usually brisk physical activities. On examination, motor strength and sensation were normal, and a neurologist noted mild hyperreflexia and bilateral Babinski signs. Despite physical therapy, his symptoms worsened and additional physical signs developed. A diagnostic procedure was performed.