tbuckley/cabot-search huggingface dataset:
A multicenter, randomized, open-label, phase 2 study of carfilzomib with or without ARRY-520 (filanesib) in patients with advanced multiple myeloma.
Authors: Jeffrey A. Zonder, Noopur S. Raje, Emma Catherine Scott, Craig C. Hofmeister, Nikoletta Lendvai, Larry Don Anderson, Parameswaran Hari, Gregory Joshua Orloff, Jesus G. Berdeja, Seema Singhal, Michael Craig, Jason Neil Valent, Mieke Ptaszynski, Jennifer Schreiber, Roger Aitchison, Saad Zafar Usmani
Journal: Journal of Clinical Oncology (2015)

TPS8612 Background: Immunomodulatory agent (IMiD)/bortezomib (BTZ) combinations are common frontline therapy in patients with multiple myeloma (MM). Despite high initial objective response rates (ORR) and prolonged progression-free survival (PFS), almost all patients eventually relapse. Treatment for relapsed or refractory disease typically includes regimens that maintain IMiDs and/or proteasome inhibitors (PIs) as a foundation. Filanesib is a highly selective, targeted kinesin spindle protein (KSP) inhibitor that has shown promising preliminary activity and manageable toxicity as a single agent and in combination with dexamethasone, BTZ and carfilzomib (CFZ). Due to a distinct mechanism of action, filanesib demonstrates activity in patients with myeloma that has become resistant to IMiDs and PIs, potentially addressing a significant unmet medical need. Methods: This multicenter, randomized (2:1), open-label Phase 2 study is designed to assess the efficacy, safety and pharmacokinetics (PK) of CFZ ± filanesib in 75 patients with measurable MM who have received at least 2 prior treatment regimens (including BTZ and an IMiD) and have disease refractory to their last myeloma therapy (NCT01989325). Patients at community and academic centers in the United States are stratified by BTZ-refractory disease status and randomized to receive CFZ + filanesib (~50 patients) or single-agent CFZ (~25 patients) in continuous 28-day cycles until disease progression or unacceptable toxicity. CFZ (20/27 mg/m2) is administered intravenously (IV) on Days 1, 2, 8, 9, 15 and 16. Filanesib is administered as 1.25 mg/m2/day IV on Days 1, 2, 15 and 16 with prophylactic filgrastim. Crossover from single-agent CFZ to combination treatment is permitted upon confirmed disease progression. The primary endpoint is PFS; secondary endpoints include PFS rate at 6 months, ORR, duration of response, time to best response, clinical benefit rate, disease control rate, safety, and PK. No formal comparisons will be made between treatment arms. Exploratory measurements of alpha 1-acid glycoprotein (AAG), a potential predictive biomarker for filanesib treatment, will be performed. Clinical trial information: NCT01989325.
Ubiquitin E3 ligase FIEL1 regulates fibrotic lung injury through SUMO-E3 ligase PIAS4
Authors: Travis Lear, Alison C. McKelvey, Shristi Rajbhandari, Sarah R. Dunn, Tiffany A. Coon, William Connelly, Joe Y. Zhao, Daniel J. Kass, Yingze Zhang, Yuan Liu, Bill B. Chen
Journal: The Journal of Experimental Medicine (2016)

The E3 small ubiquitin-like modifier (SUMO) protein ligase protein inhibitor of activated STAT 4 (PIAS4) is a pivotal protein in regulating the TGFβ pathway. In this study, we discovered a new protein isoform encoded by KIAA0317, termed fibrosis-inducing E3 ligase 1 (FIEL1), which potently stimulates the TGFβ signaling pathway through the site-specific ubiquitination of PIAS4. FIEL1 targets PIAS4 using a double locking mechanism that is facilitated by the kinases PKCζ and GSK3β. Specifically, PKCζ phosphorylation of PIAS4 and GSK3β phosphorylation of FIEL1 are both essential for the degradation of PIAS4. FIEL1 protein is highly expressed in lung tissues from patients with idiopathic pulmonary fibrosis (IPF), whereas PIAS4 protein levels are significantly reduced. FIEL1 overexpression significantly increases fibrosis in a bleomycin murine model, whereas FIEL1 knockdown attenuates fibrotic conditions. Further, we developed a first-in-class small molecule inhibitor toward FIEL1 that is highly effective in ameliorating fibrosis in mice. This study provides a basis for IPF therapeutic intervention by modulating PIAS4 protein abundance.
Analysis of Expression of Programmed Cell Death 1 Ligand 1 (Pd-L1) in Malignant Pleural Mesothelioma (Mpm)
Authors: S. Cedres, S. Ponce Aix, J. Zugazagoitia, A.B. Anguita, I. Sansano, A. Navarro Mendivil, A. Martinez, P. Martinez, P. Fidalgo, E. Felip
Journal: Annals of Oncology (2014)
Treatment of non-metastatic rhabdomyosarcoma and other non rhabdomyosarcoma soft tissue malignant tumours of childood and adolesence
Authors: S. A. El-Badawy, S. A. El-Badawy
Journal: Journal of Clinical Oncology (2005)

8557 Background: At NCI Egypt, soft tissue sarcomas represent 3.75% of total malignancies & 27.6% of these occur in pediatric age group. Rhabdomyosarcoma (RMS) is the most common type. Methods: This work is a prospective study including 56 children and adolescents, aged 21 years or less treated by upfront chemotherapy and local treatment by surgery or radiotherapy or both after assessment of tumor response at week 9. Children were categorized according to the site, size, type of surgery into 3 risk groups. 54 children received the high risk regimen of chemotherpy consisted of alternating 6 drugs (Ifosfamide 6gm/m2, Adriamycin 75mg/m2, Vincristine 1.5mg/m2, Carboplatin 500mg/m2, Actinomycin-D 1.5m/m2, Etoposide 200mg/m2) for 9 courses. Results: The distribution of primary site of study group was orbit 12.5%, parameningeal sites 12.5%, other head & neck sites 10.7%, extremity 28.6%, trunk 12.5%, bladder & prostate 7.1%, retroperitoneal 7.1% & others 7.2%. The majority of children presented with tumor size more than 5 cm. in 72.5%. Among children with RMS 62% were embryonal, 27% were alveolar. At w 9 evaluation of tumor response revealed 43% complete response, 46% good partial response, 7% partial response, while 2% stationary disease & one child died. The OAS & DFS for the whole group was 73% ± 9%, & 53% ± 9% respectively with a median follow up period of 24 months. Sixteen children relapsed, 7 locoregional, 6 distant failure & 3 chidren both. The DFS was significantly affected by tumor size 93% ± 6% for tumors < 5 cm. versus 42% ± 10% for those >5 cm., P value of 0.03. The local failure free survival was 61% ± 13%. It was significantly affected by the administration of radiotherapy (94% ± 4% for patients received radiotherapy versus 58% ± 15% for those wo did not receive radiotherapy, P=0.02). On multivariate analysis radiotherapy was a significant factor with a P value of 0.04. Regarding the treatment toxicity, one patient died of fungal pneumonia. Conclusion: Chemotherapy regimen used for this study (high risk 54 children out 56) was well tolerated with one mortality. Radiation therpy is effective modality but it should be refined to reduce its late sequale by the use of IMRT & brachytherapy. No significant financial relationships to disclose.
Dermoscopy and<i>in vivo</i>confocal microscopy are complementary techniques for diagnosis of difficult amelanotic and light-coloured skin lesions
Authors: P. Guitera, S.W. Menzies, G. Argenziano, C. Longo, A. Losi, M. Drummond, R.A. Scolyer, G. Pellacani
Journal: British Journal of Dermatology (2016)

Amelanotic melanomas are often difficult to diagnose.To find and test the best methods of diagnosis using dermoscopy and reflectance confocal microscopy (RCM) tools.We selected consecutive, difficult-to-diagnose, light-coloured and amelanotic skin lesions from three centres (in Australia and Italy). Dermoscopy and RCM diagnostic utility were evaluated under blinded conditions utilizing 45 melanomas (16 in situ, 29 invasive), 68 naevi, 48 basal cell carcinomas (BCCs), 10 actinic keratoses, 10 squamous cell carcinomas (SCCs) and 13 other benign lesions.Sensitivity and specificity for melanoma with dermoscopy pattern analysis by two blinded observers and their 'confidence in diagnosis' were low. The amelanotic dermoscopy method had the highest sensitivity (83%) for a diagnosis of malignancy (melanoma, BCC or SCC), but specificity was only 18%. Multivariate analysis confirmed the utility of RCM features previously identified for the diagnosis of BCC and melanoma (highest odds ratio for melanoma: epidermal disarray, dark and/or round pagetoid cells). RCM sensitivity was 67% and 73% for melanoma and BCC diagnosis, respectively, and its specificity for nonmalignant lesion diagnosis was 56%. RCM reader confidence was higher than for dermoscopy; 84% of melanomas would have been biopsied and biopsy avoided in 47% of benign lesions. All melanomas misclassified by either dermoscopy or RCM were detected by the other tool.Dermoscopy and RCM represent complementary/synergistic methods for diagnosis of amelanotic/light-coloured skin lesions.
Elevated blood pressure is not associated with accelerated glomerular filtration rate decline in the general non-diabetic middle-aged population
Authors: Bjørn O. Eriksen, Vidar T.N. Stefansson, Trond G. Jenssen, Ulla D. Mathisen, Jørgen Schei, Marit D. Solbu, Tom Wilsgaard, Toralf Melsom
Journal: Kidney International (2016)
Effects of Stress on Growth of Transplanted and 7,12-Dimethylbenz[ a ]anthracene-Induced Tumors and Their Modification by Psychotropic Drugs 2
Authors: S. N. Pradhan, Prabhati Ray
Journal: JNCI Journal of the National Cancer Institute (1974)

Journal Article Effects of Stress on Growth of Transplanted and 7,12-Dimethylbenz[a]anthracene-Induced Tumors and Their Modification by Psychotropic Drugs Get access S. N. Pradhan, S. N. Pradhan Search for other works by this author on: Oxford Academic PubMed Google Scholar Prabhati Ray Prabhati Ray 3Department of Pharmacology, Howard University College of Medicine, Washington, D,C. 20001. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 53, Issue 5, November 1974, Pages 1241–1245, https://doi.org/10.1093/jnci/53.5.1241 Published: 01 November 1974 Article history Received: 13 February 1974 Accepted: 06 May 1974 Published: 01 November 1974
Demonstration in vivo of reduced serotonin responsivity in the brain of untreated depressed patients [published erratum appears in Am J Psychiatry 1996 Apr;153(4):588]
Authors: J J Mann, K M Malone, D J Diehl, J Perel, T B Cooper, M A Mintun
Journal: American Journal of Psychiatry (1996)

For over 25 years, it has been hypothesized that major depression is due to a deficiency of available serotonin or subsensitivity of key serotonin receptors in relevant brain regions. Direct evidence supporting this hypothesis has been lacking because of the difficulty in studying regional brain serotonergic function. The authors have developed a method for visualizing in vivo regional brain responses to serotonin release by comparing regional brain glucose metabolism after administration of the serotonin-releasing drug dl-fenfluramine, relative to placebo.Results with healthy subjects (N = 6) were compared to those obtained with drug-free inpatients with moderately severe major depression (N = 6).Healthy subjects had several areas of statistically significant increases in metabolism, mostly in the left prefrontal and temporoparietal cortex, and areas of decreased metabolism, such as in the right prefrontal cortex. In contrast, the depressed patients had no areas of increase or decrease in metabolism, differing significantly from healthy subjects. Results with patients resembled those with healthy subjects (N = 10) who were scanned twice without active drug on either occasion.This study provides the first direct visualization of blunted regional brain responses to serotonin release in the brain of patients with major depression, a finding that supports the hypothesis of impaired serotonergic transmission in depression.
Flavoring Chemicals in E-Cigarettes: Diacetyl, 2,3-Pentanedione, and Acetoin in a Sample of 51 Products, Including Fruit-, Candy-, and Cocktail-Flavored E-Cigarettes
Authors: Joseph G. Allen, Skye S. Flanigan, Mallory LeBlanc, Jose Vallarino, Piers MacNaughton, James H. Stewart, David C. Christiani
Journal: Environmental Health Perspectives (2015)

There are > 7,000 e-cigarette flavors currently marketed. Flavoring chemicals gained notoriety in the early 2000s when inhalation exposure of the flavoring chemical diacetyl was found to be associated with a disease that became known as "popcorn lung." There has been limited research on flavoring chemicals in e-cigarettes.
Efficacy of Lipegfilgrastim (Lipeg) and Pegfilgrastim (Peg) in Breast Cancer Patients Receiving Chemotherapy (Ctx) Stratified By Status, Age, and Disease Stageby Status, Age, and Disease Stage
Authors: C. Volovat, P. Bias, U. Müller, A. Buchner
Journal: Annals of Oncology (2014)
Oxaliplatin and 5-fluorouracil in heavily pretreated patients with ovarian carcinoma: A well tolerated and efficient treatment
Authors: D. D. Rosa, A. Awada, F. Cardoso, T. Gil, F. Lebrun, M. S. Mano, J. Selleslags, M. J. Piccart, V. D'Hondt
Journal: Journal of Clinical Oncology (2007)

16028 Background: Recurrent ovarian cancer is an incurable disease. The prognosis of patients with platinum refractory disease is dismal. We present data from heavily pretreated patients with recurrent ovarian cancer to whom the Folfox regimen was administered. Methods: Patients with recurrent, resistant or refractory, pretreated ovarian carcinoma were eligible for this compassionate use program of oxaliplatin (85 mg/m 2 in 2 hours) and leucovorin (200 mg/m 2 in 1 hour) on day 1, followed by a continuous infusion of 5FU (2,600 mg/m 2 in 48 hours), every 2 weeks. The objectives of the study were primarily to assess response rate and secondarily to evaluate the safety profile. Results: Fourteen patients were treated. Median age: 56 years (49–70). Performance status: 0 (n=4) and 1 (n=10). Median number of previous chemotherapy regimens: 5 (3–10) and previous platinum-based regimens: 2 (1–3). Median chemotherapy-free interval: 9.5 weeks (1–39). Median administered cycles of Folfox/patient: 8 (2–11 cycles). Responses according to RECIST criteria: 2 CR (14.5%), 2 PR (14.5%), 4 SD (29%) and 6 PD (43%). Responses according to CA125 Rustin's criteria: 4 CR (29%), 2 PR (14.5%), 5 SD (35.5%) and 3 PD (21%). Grade 1/2 and 3 peripheral neuropathy: 10 (71%) and 2 (14.5%), respectively. There were no grade 4 adverse events or deaths due to the treatment. Conclusions: Folfox is a valuable option for heavily pre-treated patients with ovarian cancer, with an overall response rate of 29% (95% CI 15.2% to 41.8%), disease stabilization in an additional 29%, and a manageable toxicity profile. These results support the use of Folfox as salvage treatment for patients with ovarian carcinoma. No significant financial relationships to disclose.
Amrubicin (Amr) Versus Docetaxel (Dtx) As Second- or Third-Line Treatment for Non-Small Cell Lung Cancer (Nsclc): a Randomized Phase III Trial
Authors: N. Katakami, H. Yoshioka, H. Okamoto, Y. Iwamoto, T. Seto, T. Takahashi, N. Sunaga, S. Kudoh, K. Chikamori, M. Harada, H. Tanaka, H. Saka, K. Takeda, N. Nogami, N. Masuda, T. Harada, N. Yamamoto, K. Nakagawa
Journal: Annals of Oncology (2014)

ABSTRACT   Aim: DTX is one of the standard drugs for patients (pts) with previously treated NSCLC. However, its efficacy seems insufficient. The efficacy of AMR for NSCLC has been previously reported. Thus, we conducted a randomized phase III trial comparing AMR to DTX, sponsored by Dainippon Sumitomo Pharma Co., Ltd.  Methods: We enrolled pts with NSCLC, Eastern Cooperative Oncology Group Performance Status 0-1, undergoing second- or third-line treatment, and aged 20–74 years. Pts were classified by histology, prior treatment, and institution into 2 groups and then randomly assigned (1:1 ratio) to treatment with AMR (35 mg/m2/day i.v., on days 1–3, q3w) or DTX (60 mg/m2/day i.v., on day 1, q3w). We planned a sample size of 100 patients per group, with a 2-sided alpha of 5% and power of 90%. We hypothesized a median progression-free survival (PFS) time of 3.3 and 2.0 months for AMR and DTX, respectively. The primary endpoint was PFS; secondary endpoints included overall survival (OS), overall response rate (ORR), disease control rate (DCR), and adverse events according to Common Terminology Criteria for Adverse Events v 4.03.  Results: From October 2010 to June 2012, 202 pts were enrolled from 32 institutions. Patient characteristics were well balanced between both groups. OS was measured after a median follow-up of 13.5 months. Median PFS was 3.6 and 3.0 months with AMR and DTX, respectively (adjusted Hazard Rate (HR) 0.96, 95% Confidence Interval (CI) 0.69–1.34, p = 0.831). Median OS was 14.6 and 13.5 months with AMR and DTX, respectively (adjusted HR 1.02, 95% CI 0.72–1.43, p = 0.933). ORR was 14.8% and 18.8% with AMR and DTX, respectively (p = 0.544). DCR was 55.7% for both AMR and DTX (p = 1.000). The most frequent adverse events (≥grade 3) for AMR and DTX were neutropenia (82.7% and 78.8%, respectively) and leukopenia (63.3% and 70.7%, respectively). Two treatment-related deaths occurred in the DTX arm: a case of interstitial pneumonia and another of drowning in a bath.  Conclusions: We were not able to demonstrate superiority of AMR over DTX for PFS, despite the 20-day PFS prolongation. Our results suggest that AMR may become a treatment option for patients with previously treated NSCLC.  Disclosure: All authors have declared no conflicts of interest.
Life-Threatening Cutaneous Bleeding in Childhood Klippel-Trenaunay Syndrome Treated With Oral Sirolimus
Authors: Didier Bessis, Hélène Vernhet, Michèle Bigorre, Isabelle Quéré, Jochen Rössler
Journal: JAMA Dermatology (2016)

For our patient, sirolimus provided rapid and effective control of the cutaneous bleeding complicating a combined venous and lymphatic cutaneous malformation.The drug's efficacy in treating the cutaneous lymphatic malformation appears obvious from the striking regression in the turgidity and hemorrhagic component of the lymphatic vesicles.However, a potentially antiangiogenic action on the lateral thigh vein cannot be excluded.This case report suggests that sirolimus may be an alternative medical treatment for bleeding induced by venous and lymphatic malformation associated with KTS.
Correlation Between Clinical Features, CRLF2 Expression and Copy Number Alterations In Acute Lymphoblastic Leukemia
Authors: Juan Carlos Ponce Jarquin, Rosa M. Ayala, Ana Belen Dueñas Perez, Daniel Rueda, María Luisa Martin Ramos, José Luis Vivanco, Pilar Martinez Sánchez, Rafael Alberto Alonso Fernandez, Florinda Gilsanz Rodriguez, Joaquin Martinez -Lopez
Journal: Blood (2013)
More patients are facing “devastating consequences” from premature discharge, says watchdog
Authors: Gareth Iacobucci
Journal: BMJ (2016)

A health services watchdog has highlighted the “devastating consequences” faced by vulnerable NHS patients who are discharged from hospital too early or without adequate support to return home.

The warning from the Office of the Parliamentary and Health Service Ombudsman came after a new report showed that it investigated 221 complaints about hospital discharge in England in 2014-15, a 36% increase from the previous year.1

The ombudsman upheld or partly upheld over half of these complaints in 2014-15, a significantly higher proportion than the average …
Acute rotator cuff tendinopathy: does ice, low load isometric exercise, or a combination of the two produce an analgaesic effect?
Authors: Phillip J Parle, Diane L Riddiford-Harland, Chris D Howitt, Jeremy S Lewis
Journal: British Journal of Sports Medicine (2016)

Rotator cuff tendinopathies are the most commonly diagnosed musculoskeletal shoulder conditions and are associated with pain, weakness and loss of function.1 Tendon swelling may be associated with tendinopathy and may result from acute overload.2–3 An increase in tendon cells (tenocytes) and upregulation of large molecular weight proteoglycans, such as aggrecan, may increase tendon water content.2 There is uncertainty as to whether the swelling is related to the pain or is instead an observed but unrelated phenomenon. Weakness detected clinically may be due to pain inhibition.4–5

Early treatment of acute rotator cuff tendinopathy involves patient education and relative rest, and may include non-steroidal anti-inflammatory drugs (NSAIDs) to reduce pain, swelling and inflammation. Subacromial corticosteroid injections are also used to achieve the same purpose. These techniques show low to moderate evidence of reducing short-term pain but they do not improve function.6 The medications have side effects such …
T-DM1 for HER2 positive advanced breast cancer: a single institution, “real life” experience
Authors: I. Bertolini, I. Ferrarini, S. Fancelli, C. De Angelis, A. Fontana, B. Salvadori, E. Landucci, A. Michelotti, A. Falcone
Journal: Annals of Oncology (2015)
Relationship between PD-L1 expression and clinical outcomes in patients (Pts) with advanced gastric cancer treated with the anti-PD-1 monoclonal antibody pembrolizumab (Pembro; MK-3475) in KEYNOTE-012.
Authors: Kei Muro, Yung-Jue Bang, Veena Shankaran, Ravit Geva, Daniel Virgil Thomas Catenacci, Shilpa Gupta, Joseph Paul Eder, Raanan Berger, Edward J. Gonzalez, Archana Ray, Marisa Dolled-Filhart, Kenneth Emancipator, Kumudu Pathiraja, Jared K. Lunceford, Jonathan D. Cheng, Minori Koshiji, Hyun Cheol Chung
Journal: Journal of Clinical Oncology (2015)

3 Background: Tumors use the PD-1 pathway to evade immune surveillance. Pembrolizumab, an anti-PD-1 monoclonal antibody, has shown antitumor activity in advanced cancers. We assessed the safety and efficacy of pembrolizumab in patients with advanced gastric cancer in KEYNOTE-012 (Clinicaltrials.gov identifier NCT01848834). Methods: Archival tumor samples from patients from Asia-Pacific (AP) and rest of the world (ROW) with recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction were screened for PD-L1 expression using a prototype IHC assay with the 22C3 antibody. Only patients with distinctive stromal or ≥1% tumor nest cell PD-L1 staining were eligible. Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 24 months or until complete response, progression, or unacceptable toxicity. Imaging was performed every 8 weeks. Primary efficacy end point is ORR assessed per RECIST v1.1 by independent central review. Secondary end points include duration of response, PFS, and OS. Results: Of the 162 patientts screened, 65 (40%) were PD-L1 + . Of these 65 patients, 39 enrolled (19 from AP, 20 from ROW; median age, 63 years [range 33-78]). The number of prior therapies for advanced disease ranged from 0 to 5; 67% received ≥2 prior therapies. Median follow-up duration was 8.8 months (range 6.2-12.6); 13 patients (33%) remain on therapy. Four patients experienced 5 total grade 3-5 drug-related adverse events: peripheral sensory neuropathy, fatigue, decreased appetite, hypoxia, and pneumonitis (n = 1 each). There was 1 drug-related death (hypoxia). ORR was 22% (95% CI 10-39) by central review and 33% (95% CI 19-50) by investigator review. Median time to response was 8 weeks (range 7-16), with a median response duration of 24 weeks (range 8+ to 33+). PD-L1 expression level was associated with ORR (1-sided P = 0.10). The 6-month PFS rate was 24%. The 6-month OS rate was 69%. Conclusions: Pembrolizumab demonstrated manageable toxicity and promising antitumor activity in advanced gastric cancer. These results support the ongoing development of pembrolizumab for gastric cancer. Clinical trial information: NCT01848834.