tbuckley/cabot-search huggingface dataset:
Treatment of pediatric lymphocyte predominant Hodgkin lymphoma (LPHL): A report from the Children's Oncology Group.
Authors: Burton Appel, Lu Chen, Robert E. Hutchison, David C. Hodgson, Peter Ehrlich, Louis S. Constine, Cindy L. Schwartz
Journal: Journal of Clinical Oncology (2013)

10000 Background: LPHL, an uncommon subtype of HL, typically presents with low stage disease and responds to regimens used for classical HL. Recurrence is uncommon, but second malignant neoplasms (SMN) or development of non-Hodgkin lymphoma (NHL) can occur. Therefore, reducing radiation exposure may be of benefit. We report the results of a prospective trial in which a selected subset of patients had surgery alone and the remainder were treated with limited chemotherapy +/- involved-field radiation therapy (IFRT). Methods: Patients ages 0-21 years with newly diagnosed, low risk LPHL were eligible for AHOD03P1. Low risk was defined as clinical Stage IA or IIA without bulk disease (mediastinal mass &gt; 1/3 of the thoracic diameter or nodal aggregate &gt; 6 cm). Patients with Stage IA LPHL with an unresected node or more than a single involved node or Stage IIA were treated with 3 cycles of AV-PC (doxorubicin/vincristine/prednisone/cyclophosphamide). Patients with Stage IA LPHL in a single node that was completely resected were initially observed without further therapy; those who recurred after surgery with low risk LPHL received AV-PC x 3. Patients with &lt; complete response (CR) to AV-PC x 3 received 2100 cGY IFRT. Results: 180 eligible patients with low risk LPHL were enrolled and completed study therapy. 52 patients underwent initial surgery alone; their 3 year EFS = 81.5%. 137 patients received AV-PC x 3; 128 were treated at diagnosis and 9 upon relapsing after surgery alone. 11 patients receiving AV-PC had &lt; CR and received IFRT. 12 first events occurred among these 137 patients (11 relapses and 1 SMN, a NHL). One relapse occurred in a patient who received IFRT. The median follow-up among the 125 remaining patients is 39 (range 3 -76) months. Current 4-year EFS estimate is 88.1% (95% CI: 79.5%-93.3%) for these 137 patients. 4 year EFS for the entire cohort of 180 patients = 86.2%; their overall survival (OS) is 100%. Conclusions: Pediatric LPHL patients have an excellent EFS with chemotherapy that is less intensive than standard regimens; &gt;90% of patients can avoid RT. NHL as a first event may be related to the underlying LPHL and not an effect of treatment. The salvage rate for the few relapses is high, and OS to date is excellent. Clinical trial information: NCT00107198.
Integrin β3 inhibition is a therapeutic strategy for supravalvular aortic stenosis
Authors: Ashish Misra, Abdul Q. Sheikh, Abhishek Kumar, Jiesi Luo, Jiasheng Zhang, Robert B. Hinton, Leslie Smoot, Paige Kaplan, Zsolt Urban, Yibing Qyang, George Tellides, Daniel M. Greif
Journal: The Journal of Experimental Medicine (2016)

The aorta is the largest artery in the body, yet processes underlying aortic pathology are poorly understood. The arterial media consists of circumferential layers of elastic lamellae and smooth muscle cells (SMCs), and many arterial diseases are characterized by defective lamellae and excess SMCs; however, a mechanism linking these pathological features is lacking. In this study, we use lineage and genetic analysis, pharmacological inhibition, explant cultures, and induced pluripotent stem cells (iPSCs) to investigate supravalvular aortic stenosis (SVAS) patients and/or elastin mutant mice that model SVAS. These experiments demonstrate that multiple preexisting SMCs give rise to excess aortic SMCs in elastin mutants, and these SMCs are hyperproliferative and dedifferentiated. In addition, SVAS iPSC-derived SMCs and the aortic media of elastin mutant mice and SVAS patients have enhanced integrin β3 levels, activation, and downstream signaling, resulting in SMC misalignment and hyperproliferation. Reduced β3 gene dosage in elastin-null mice mitigates pathological aortic muscularization, SMC misorientation, and lumen loss and extends survival, which is unprecedented. Finally, pharmacological β3 inhibition in elastin mutant mice and explants attenuates aortic hypermuscularization and stenosis. Thus, integrin β3–mediated signaling in SMCs links elastin deficiency and pathological stenosis, and inhibiting this pathway is an attractive therapeutic strategy for SVAS.
Innovative Two-Step Negative Selection of Granulocyte Colony-Stimulating Factor–Mobilized Circulating Progenitor Cells: Adequacy for Autologous and Allogeneic Transplantation
Authors: Alessandro Rambaldi, Gianmaria Borleri, Gianpietro Dotti, Piermario Bellavita, Ricardo Amaru, Andrea Biondi, Tiziano Barbui
Journal: Blood (1998)
Involvement of activation-induced cytidine deaminase in skin cancer development
Authors: Taichiro Nonaka, Yoshinobu Toda, Hiroshi Hiai, Munehiro Uemura, Motonobu Nakamura, Norio Yamamoto, Ryo Asato, Yukari Hattori, Kazuhisa Bessho, Nagahiro Minato, Kazuo Kinoshita
Journal: Journal of Clinical Investigation (2016)

Most skin cancers develop as the result of UV light–induced DNA damage; however, a substantial number of cases appear to occur independently of UV damage. A causal link between UV-independent skin cancers and chronic inflammation has been suspected, although the precise mechanism underlying this association is unclear. Here, we have proposed that activation-induced cytidine deaminase (AID, encoded by AICDA) links chronic inflammation and skin cancer. We demonstrated that Tg mice expressing AID in the skin spontaneously developed skin squamous cell carcinoma with Hras and Trp53 mutations. Furthermore, genetic deletion of Aicda reduced tumor incidence in a murine model of chemical-induced skin carcinogenesis. AID was expressed in human primary keratinocytes in an inflammatory stimulus–dependent manner and was detectable in human skin cancers. Together, the results of this study indicate that inflammation-induced AID expression promotes skin cancer development independently of UV damage and suggest AID as a potential target for skin cancer therapeutics.
Counterregulation between thymic stromal lymphopoietin– and IL-23–driven immune axes shapes skin inflammation in mice with epidermal barrier defects
Authors: Jiagui Li, Juan Manuel Leyva-Castillo, Pierre Hener, Aurelie Eisenmann, Sarra Zaafouri, Nathalie Jonca, Guy Serre, Marie-Christine Birling, Mei Li
Journal: Journal of Allergy and Clinical Immunology (2016)
Poly (ADP-Ribose) Polymerase Inhibitor Hypersensitivity in Aggressive Myeloproliferative Neoplasms
Authors: Keith W. Pratz, Brian D. Koh, Anand G. Patel, Karen S. Flatten, Weijie Poh, James G. Herman, Robert Dilley, Maria I. Harrell, B. Douglas Smith, Judith E. Karp, Elizabeth M. Swisher, Michael A. McDevitt, Scott H. Kaufmann
Journal: Clinical Cancer Research (2016)

DNA repair defects have been previously reported in myeloproliferative neoplasms (MPN). Inhibitors of PARP have shown activity in solid tumors with defects in homologous recombination (HR). This study was performed to assess MPN sensitivity to PARP inhibitors ex vivoHR pathway integrity in circulating myeloid cells was evaluated by assessing the formation of RAD51 foci after treatment with ionizing radiation or PARP inhibitors. Sensitivity of MPN erythroid and myeloid progenitors to PARP inhibitors was evaluated using colony formation assays.Six of 14 MPN primary samples had reduced formation of RAD51 foci after exposure to ionizing radiation, suggesting impaired HR. This phenotype was not associated with a specific MPN subtype, JAK2 mutation status, or karyotype. MPN samples showed increased sensitivity to the PARP inhibitors veliparib and olaparib compared with normal myeloid progenitors. This hypersensitivity, which was most pronounced in samples deficient in DNA damage-induced RAD51 foci, was observed predominantly in samples from patients with diagnoses of chronic myelogenous leukemia, chronic myelomonocytic leukemia, or unspecified myelodysplastic/MPN overlap syndromes.Like other neoplasms with HR defects, MPNs exhibit PARP inhibitor hypersensitivity compared with normal marrow. These results suggest that further preclinical and possibly clinical study of PARP inhibitors in MPNs is warranted. Clin Cancer Res; 22(15); 3894-902. ©2016 AACR.
EGFR targeted nanobody–photosensitizer conjugates for photodynamic therapy in a pre-clinical model of head and neck cancer
Authors: Pieter B.A.A. van Driel, Martin C. Boonstra, Maxime D. Slooter, Raimond Heukers, Marieke A. Stammes, Thomas J.A. Snoeks, Henriette S. de Bruijn, Paul J. van Diest, Alexander L. Vahrmeijer, Paul M.P. van Bergen en Henegouwen, Cornelis J.H. van de Velde, Clemens W.G.M. Löwik, Dominic J. Robinson, Sabrina Oliveira
Journal: Journal of Controlled Release (2016)

Photodynamic therapy (PDT) induces cell death through local light activation of a photosensitizer (PS) and has been used to treat head and neck cancers. Yet, common PS lack tumor specificity, which leads to collateral damage to normal tissues. Targeted delivery of PS via antibodies has pre-clinically improved tumor selectivity. However, antibodies have long half-lives and relatively poor tissue penetration, which could limit therapeutic efficacy and lead to long photosensitivity. Here, in this feasibility study, we evaluate at the pre-clinical level a recently introduced format of targeted PDT, which employs nanobodies as targeting agents and a water-soluble PS (IRDye700DX) that is traceable through optical imaging. In vitro, the PS solely binds to cells and induces phototoxicity on cells overexpressing the epidermal growth factor receptor (EGFR), when conjugated to the EGFR targeted nanobodies. To investigate whether this new format of targeted PDT is capable of inducing selective tumor cell death in vivo, PDT was applied on an orthotopic mouse tumor model with illumination at 1h post-injection of the nanobody-PS conjugates, as selected from quantitative fluorescence spectroscopy measurements. In parallel, and as a reference, PDT was applied with an antibody-PS conjugate, with illumination performed 24h post-injection. Importantly, EGFR targeted nanobody-PS conjugates led to extensive tumor necrosis (approx. 90%) and almost no toxicity in healthy tissues, as observed through histology 24h after PDT. Overall, results show that these EGFR targeted nanobody-PS conjugates are selective and able to induce tumor cell death in vivo. Additional studies are now needed to assess the full potential of this approach to improving PDT.
Prognostic significance of mesenteric tumor nodules in patients with stage III colorectal cancer
Authors: D. S. Lo, A. Pollett, S. Gallinger, L. L. Siu, R. L. Burkes
Journal: Journal of Clinical Oncology (2006)

3566 Background: Tumor nodules are occasionally found in adjacent mesentery of colorectal cancer specimens, but their prognostic significance is unclear. According to the TNM staging system, mesenteric nodules are classified as part of T or N categories, but clinically they are regarded to reflect a worse prognosis, more like M1. We investigated the clinical significance of mesenteric tumor nodules. Methods: We reviewed 786 patients with stage III colorectal cancer referred between 1995 and 1999. We standardized TNM staging by assigning N status based on number of definite lymph nodes. Mesenteric nodules were considered separately and not assigned to T or N categories. Survival analyses were performed. Results: Mesenteric tumor nodules were found in 116 patients (14.8%); 48 with colon cancer (41.4%) and 68 rectal cancer (58.6%). Mean age at surgery was 62.8±1.0 yrs (SE), and the male: female ratio was 1.2. All tumors were adenocarcinomas with an average size of 4.3±0.1 cm, and the majority were moderately differentiated. Resection margins were clear except in 7 cases. With respect to high risk features, 6 cases (5.2%) had bowel perforation, 12 (10.3%) obstructive symptoms, 41 (35.3%) lymphovascular invasion, and 11 (9.5%) were T4 lesions. Adjuvant chemotherapy was given to 84.8% of colon cancer patients. Two (2.9%) rectal cancer patients received neoadjuvant chemo-radiation, and 63 (92.6%) received adjuvant therapy; chemotherapy, radiation or both. In the cohort with mesenteric nodules, the median time to progression was 23.1 months; the median 5-yr disease free survival was 35%; and the median overall survival (OS) was 47.9 months, with 44% OS at 5 yrs. After TNM standardization, 19 (16.4%) patients were down-staged to either stage I or II, and their 5-yr OS was 60% (SEER Stage II 5 yr survival 82.5%). In the remaining cohort-patients with stage III disease after standardization, the 5-yr OS was 40% (SEER 5yr survival Stage IIIc 44.3%; Stage IV 8.1%). Conclusions: In comparison to SEER survival data, the presence of mesenteric nodules appears to worsen prognosis of any T/N0 disease to that of overall stage III disease. Patients with mesenteric nodules in the setting of any T/N1+ disease had prognosis similar to that of stage IIIC disease, but their prognosis was better than M1 disease. No significant financial relationships to disclose.
Abstract 302: Sex Differences In Nonlinear Dynamics And Their Circadian Variation In Control Dogs And In A New Arrhythmogenic Canine Model Of Heart Failure
Authors: Yujie Zhu, Steven M Pogwizd
Journal: Circulation Research (2014)

Introduction: Females can be more arrhythmogenic than males, and this sex difference can persist with development of chronic heart failure (CHF). The aim of this study was to investigate sex differences in the arrhythmogenic substrate in control dogs and in a new arrhythmogenic canine model of CHF. Methods: CHF was induced in 30 dogs by aortic insufficiency and aortic constriction. Holter monitoring assessed VT and PVCs from 30 dogs, as well as traditional HRV measures and nonlinear dynamics (including correlation dimension (CD), detrended fluctuations analysis α1 (DFAα1), and Shannon entropy (SE)) at baseline, 240 days (240d) and 720 days (720d) after CHF induction. Results: At baseline, females had lower LF/HF (0.27±0.03 vs 0.33±0.02, p=0.04), CD (1.60±0.17 vs 2.21±0.15, p=0.01), DFAα1 (0.62±0.03 vs 0.72±0.03, p=0.03), and SE (2.99±0.02 vs 3.10±0.03, p=0.03 vs males). Females lacked circadian variation in LF/HF, DFAα1, and SE while males had circadian variation in all of these. Of 11 dogs with frequent runs of VT and PVCs, 95% and 91% of total VT runs and total PVCs, respectively, were in females. With CHF, all these linear and nonlinear parameters progressively declined in males and females. CHF females had less decline in LF/HF than males so that by 720 days there was no more sex difference (0.24±0.06, 0.17±0.03 in females vs 0.22±0.05, 0.18±0.01 in males at 240d, 720d). However, for nonlinear parameters of CD, DFAα1, and SE, CHF females had lower values than males (CD: 1.56±0.21, 0.99±0.32 vs 1.87±0.24, 1.50±0.34; DFAα1: 0.51±0.05, 0.43±0.04 vs 0.54±0.07, 0.48±0.04; and SE 2.93±0.08, 2.76±0.08 vs 3.01±0.11, 2.91±0.04 in females vs males at 240d, 720d). With CHF, circadian variation in CD, DFAα1, and SE were lost in both males and females. Conclusions: There are sex differences in the arrhythmogenic substrate in control dogs and in this new arrhythmogenic canine model of moderate CHF. At baseline, females have lower sympathetic stimulation, reduced cardiac chaos, and loss of circadian variation in nonlinear dynamics. With CHF, sex differences in nonlinear dynamics persist; this reflects a loss of complexity and fractal properties that could contribute to increased arrhythmias in female CHF dogs.
Suppression of Substance Abuse Claims in Medicaid Data and Rates of Diagnoses for Non–Substance Abuse Conditions
Authors: Kathryn Rough, Brian T. Bateman, Elisabetta Patorno, Rishi J. Desai, Yoonyoung Park, Sonia Hernandez-Diaz, Krista F. Huybrechts
Journal: JAMA (2016)

This study examines the association between implementation of a Centers for Medicare &amp; Medicaid Services policy mandating suppression of substance abuse–related claims in Medicare and Medicaid Research Identifiable Files and rates of diagnoses for non–substance abuse conditions in those data.
Cardio-Oncology
Authors: Carrie G. Lenneman, Douglas B. Sawyer
Journal: Circulation Research (2016)

Through the success of basic and disease-specific research, cancer survivors are one of the largest growing subsets of individuals accessing the healthcare system. Interestingly, cardiovascular disease is the second leading cause of morbidity and mortality in cancer survivors after recurrent malignancy. This recognition has helped stimulate a collaboration between oncology and cardiology practitioners and researchers, and the portmanteau cardio-oncology (also known as onco-cardiology) can now be found in many medical centers. This collaboration promises new insights into how cancer therapies impact cardiovascular homeostasis and long-term effects on cancer survivors. In this review, we will discuss the most recent views on the cardiotoxicity related to various classes of chemotherapy agents and radiation. We will also discuss broadly the current strategies for treating and preventing cardiovascular effects of cancer therapy.
Differential Clinical Impact Of Gene Mutations and Their Combinations In Primary Cytogenetically Normal Acute Myeloid Leukemia (CN-AML)
Authors: Dimitrios Papaioannou, Kati Maharry, Krzysztof Mrózek, Heiko Becker, Klaus H. Metzeler, Jason H. Mendler, Susan P. Whitman, Ann-Kathrin Eisfeld, Sebastian Schwind, Yue-Zhong Wu, Deedra Nicolet, Jonathan E. Kolitz, Maria R. Baer, Bayard L. Powell, Donna Bucci, Michael A. Caligiuri, Andrew J. Carroll, Stefano Volinia, Richard M. Stone, Guido Marcucci, Clara D. Bloomfield
Journal: Blood (2013)
Autolysosomal Formation Is Required for Autophagy-Dependent IL-18 Release from Airway Epithelial Cells
Authors: Hiroki Murai, Shintaro Okazaki, Hisako Hayashi, Akiko Kawakita, Motoko Yasutomi, Sanjiv Sur, Yusei Ohshima
Journal: Journal of Allergy and Clinical Immunology (2016)
Randomized phase III trial of capecitabine/cisplatin (XP) vs. continuous infusion of 5-FU/cisplatin (FP) as first-line therapy in patients (pts) with advanced gastric cancer (AGC): Efficacy and safety results
Authors: Y. Kang, W. K. Kang, D. B. Shin, J. Chen, J. Xiong, J. Wang, M. Lichinitser, M. Philco, T. Suarez, J. Santamaria
Journal: Journal of Clinical Oncology (2006)

LBA4018 Background: The oral fluoropyrimidine capecitabine has proven efficacy and safety in colorectal and breast cancer. Phase II data in AGC suggested that XP would show comparable efficacy to a standard FP regimen, with potential safety and convenience advantages. This phase III study evaluated XP vs. FP in first-line AGC. Methods: Pts with previously untreated measurable AGC received either oral capecitabine (1000mg/m 2 bid d1–14) + cisplatin (80mg/m 2 i.v. d1) q3w (XP arm) or 5-FU (800mg/m 2 /d continuous infusion, d1–5) + cisplatin (80mg/m 2 i.v. d1) q3w (FP arm). XP requires 1 day per 3 weeks in hospital; FP requires 5 days. Pts were treated until disease progression or unacceptable toxicity. Primary endpoint: non-inferiority (NI) in progression-free survival (PFS), defined as upper limit of 95% CI of hazard ratio (HR) &lt;1.4 (first test) and &lt;1.25 (second test). Results: From Apr 03 to Jan 05, 316 pts were enrolled in 46 centers/13 countries. Arms were well balanced: median age (years, range) XP (56, 26–74), FP (56, 22–73); median Karnofsky PS 80 (range 70–100) in both arms; male/female (%): XP (64/36) FP (69/31). Median no. of cycles was 5 (XP and FP). Median follow-up is 22.1 months. Primary endpoint was met: HR 0.81 (95% CI 0.63–1.04). XP was superior to FP in terms of overall response rate (ORR, RECIST). Efficacy is presented in the table. Most common treatment-related grade 3/4 adverse events (XP vs. FP) were: neutropenia (16 vs. 19%), vomiting (7 vs. 9%), stomatitis (2 vs. 7%), diarrhea (5 vs. 5%), and anemia (5 vs. 3%). Other grade 3/4 events occurred in &lt;5% of pts. The rate of all-grade hand-foot syndrome was low (22 vs. 4%). Conclusions: XP showed highly significant non-inferiority for PFS and significant superiority for ORR vs. FP with similar safety. These findings suggest that capecitabine should become the fluoropyrimidine of choice for AGC, given the efficacy, reduced hospitalization time and simplified regimen. No significant financial relationships to disclose. [Table: see text]
Influence of reviewers’ clinical backgrounds on interpretation of confocal laser endomicroscopy findings
Authors: Masakuni Kobayashi, Helmut Neumann, Shoryoku Hino, Michael Vieth, Seiichiro Abe, Yousuke Nakai, Kiyokazu Nakajima, Ralf Kiesslich, Shinichi Hirooka, Kazuki Sumiyama
Journal: Endoscopy (2016)

<b>Background and study aims:</b> Substantial differences in endoscopic strategy for gastric cancer exist between Western and Eastern countries, owing to clinicoepidemiological diversity, including differences in the prevalence of gastric cancer. This international multicenter study involved German and Japanese institutions and aimed to evaluate the influence of reviewers' clinical backgrounds on interpreting probe-based confocal laser endomicroscopy (pCLE) findings for diagnosis of superficial gastric lesions. <b>Patients and methods:</b> 39 reviewers answered questionnaires about their clinical background and then reviewed 30 sets of white light endoscopy (WLE) and pCLE video clips via an online questionnaire. For each set of clips, reviewers were asked to classify lesions as neoplastic or non-neoplastic. Results of video reviews were compared with the final histopathological diagnosis for each lesion. The accuracy of diagnosis based on WLE + pCLE was compared with that based on WLE alone for each aspect of clinical background. <b>Results:</b> The overall accuracy of diagnosis based on WLE + pCLE was higher than that based on WLE alone (73.93 % vs. 65.64 %, <i>P</i> = .0002). Outcomes of expert gastroenterologists were better than those of pathologists (<i>P</i> = .038 for WLE, <i>P</i> = .002 for WLE + pCLE) and outcomes of reviewers at Japanese institutions were better than those of reviewers at German institutions (<i>P</i> = .001 for WLE, <i>P</i> < .001 for WLE + pCLE). <b>Conclusions:</b> Reviewers from Japanese institutions and expert gastroenterologists performed well in the pCLE interpretation. Substantial experience in conventional endoscopy is important for interpreting pCLE images for the diagnosis of gastric cancer. University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; <ext-link href="http://www.umin.ac.jp/ctr/index.htm">www.umin.ac.jp/ctr/index.htm</ext-link>) number UMIN 000013437).
Doctors are urged to limit opioid prescribing
Authors: Michael McCarthy
Journal: BMJ (2016)

Doctors should use non-steroidal anti-inflammatory drugs and physical therapy instead of opioids when treating patients with chronic, non-cancer pain, the US Centers for Disease Control and Prevention has said in new guidelines that were released on 15 March.1

However, if opioids are used, the CDC said, clinicians should prescribe the lowest effective dosages, monitor their patients closely to reduce the risk of adverse events and overdose, and consider alternative treatments if there is no meaningful improvement in their patients’ pain and function.

The guidelines, which were released as a draft in December 2015,2 are part of an effort by US health officials to deal with a prescription opioid overdose crisis, which since 1999 has been responsible …