tbuckley/cabot-search huggingface dataset:
Feasibility and tolerability of the addition of erlotinib to 3D thoracic radiotherapy (RT) in patients (p) with unresectable NSCLC: A prospective randomized phase II study
Authors: E. Martinez, M. Martinez, N. Viñolas, F. Casas, A. de la Torre, F. Valcarcel, J. Minguez, A. Paredes, A. Perez Casas, M. Dómine
Journal: Journal of Clinical Oncology (2008)

7563 Background: RT is the standard treatment for p with unresectable or locally advanced NSCLC. Considering the high frequency of tumor recurrence it is necessary to improve the results of the RT by integrating regimens of chemotherapy and/or targeted therapies into current radiotherapy strategies. Erlotinib is an EGFR TKI that has shown activity in recurrent/metastatic NSCLC. This study aims to evaluate the feasibility of the addition of erlotinib to RT in p with unresectable NSCLC. Methods: P with unresectable stage I-IIIA NSCLC not suitable to receive chemotherapy, ECOG ≤ 2, measurable disease by RECIST were enrolled in this open-label, multicenter, prospective, randomized phase II study. P included in arm A received 3D thoracic RT (66 Gy in 33 fractions during 6 weeks). P assigned to arm B were treated with 3D thoracic RT (66 Gy in 33 fractions during 6 weeks) and concomitant erlotinib 150 mg/day po maintained for 6 months. Primary endpoint is the percentage of grade 3–4 toxicities and secondary endpoints are PFS, time to treatment failure, OS and RR. Results: A total of 30 p have been randomized from March 06 to December 07. Data from 23 p have been included in this analysis (10 Arm A, 13 Arm B). Baseline characteristics were similar in both arms. Esophagitis was observed in 4 p (40%) in arm A and 3 p (23%) in arm B, (no grade 3–4). Radiodermitis occurred in 5 p (50%) in arm A (no grade 3–4 observed) and in 1 p (8%) in arm B, being grade 3. Pneumonitis occurred in 2 p (20%) in arm A (10% grade 3) and 1 p (8%) in arm B (no grade 3–4 observed). Main toxicities related to erlotinib were skin rash (61.5%) and diarrhea (23%) being all cases mild to moderate. 15 p were evaluable for tumor response. Response rate in arm A was 55.5% and 83.3% in arm B. Disease progression is documented in 22.2% of p in arm A and 16.7% of p in arm B. Conclusions: Combination of erlotinib and RT seems to be an active treatment for this p population. The addition of erlotinib does not appear to increase in-field toxicities, being a feasible and well tolerated option for p with unresectable stage I-IIIA NSCLC. Data on survival will be presented. No significant financial relationships to disclose.
Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice
Authors: Antonella Nai, Aude Rubio, Alessandro Campanella, Ophélie Gourbeyre, Irene Artuso, Jessica Bordini, Aurélie Gineste, Chloé Latour, Céline Besson-Fournier, Herbert Y. Lin, Hélène Coppin, Marie-Paule Roth, Clara Camaschella, Laura Silvestri, Delphine Meynard
Journal: Blood (2016)
Screening for Colorectal Cancer
Authors: David A. Lieberman
Journal: New England Journal of Medicine (2009)

A healthy 76-year-old woman presents as a new patient for primary care. She reports having one daily bowel movement and no rectal bleeding. She has no family history of colorectal cancer. She reports having negative stool-card tests during gynecologic examinations, most recently at 65 years of age. Would you advise this patient to undergo colon-cancer screening, and if so, what test would you recommend?
N:NIH(S)II-&lt;italic&gt;nu/nu&lt;/italic&gt; Mice With Combined Immunodeficiency: A New Model for Human Tumor Heterotransplantation&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: H A Azar, C T Hansen, J Costa
Journal: JNCI Journal of the National Cancer Institute (1980)

A new "nude" mouse model was developed by successive crossings and backcrossings between athymic nu/nu mice, on an N:NIH(S) background, and female CBA/N mice that have an X-linked immune defect in B-lymphocyte function. The resulting doubly congenic N:NIH(S(II-nu/nu mice maintained the marked thymic hypoplasia and poor development of hair of the nu/nu mice. In contrast to nu/nu and CBA/N mice, in this new mouse model both T-cell zones of lymph nodes and the spleen were depleted of lymphocytes. Lymphocytic follicles were rare and diminutive; not germinal centers were noted. The nodal cortical and paracortical areas were represented principally by connective tissue, endothelial cells, and macrophages, including giant multinucleated cells. No medullary cords were recognized. The mice with combined immunodeficiency supported the growth of human tumor xenografts and were susceptible to murine viral hepatitis.
Adverse childhood experiences reported by adults - five states, 2009.
Authors: L. Bynum, T. Griffin, D. L. Riding, K. S. Wynkoop, R. F. Anda, V. J. Edwards, T. W. Strine, Y. Liu, L. R. McKnight-Eily, J. B. Croft
Journal: MMWR Morbidity and Mortality Weekly Report (2010)
Exosome‐mediated activation of toll‐like receptor 3 in stellate cells stimulates interleukin‐17 production by γδ T cells in liver fibrosis
Authors: Wonhyo Seo, Hyuk Soo Eun, So Yeon Kim, Hyon‐Seung Yi, Young‐Sun Lee, Seol‐Hee Park, Mi‐Jin Jang, Eunjung Jo, Sun Chang Kim, Yong‐Mahn Han, Keun‐Gyu Park, Won‐Il Jeong
Journal: Hepatology (2016)

During liver injury, hepatocytes secrete exosomes that include diverse types of self‐RNAs. Recently, self‐noncoding RNA has been recognized as an activator of Toll‐like receptor 3 (TLR3). However, the roles of hepatic exosomes and TLR3 in liver fibrosis are not yet fully understood. Following acute liver injury and early‐stage liver fibrosis induced by a single or 2‐week injection of carbon tetrachloride (CCl 4 ), increased interleukin (IL)‐17A production was detected primarily in hepatic γδ T cells in wild‐type (WT) mice. However, liver fibrosis and IL‐17A production by γδ T cells were both significantly attenuated in TLR3 knockout (KO) mice compared with WT mice. More interestingly, IL‐17A‐producing γδ T cells were in close contact with activated hepatic stellate cells (HSCs), suggesting a role for HSCs in IL‐17A production by γδ T cells. In vitro treatments with exosomes derived from CCl 4 ‐treated hepatocytes significantly increased the expression of IL‐17A, IL‐1β, and IL‐23 in WT HSCs but not in TLR3 KO HSCs. Furthermore, IL‐17A production by γδ T cells was substantially increased upon coculturing with exosome‐treated WT HSCs or conditioned medium from TLR3‐activated WT HSCs. However, similar increases were not detected when γδ T cells were cocultured with exosome‐treated HSCs from IL‐17A KO or TLR3 KO mice. Using reciprocal bone marrow transplantation between WT and TLR3 KO mice, we found that TLR3 deficiency in HSCs contributed to decreased IL‐17A production by γδ T cells, as well as liver fibrosis. Conclusion : In liver injury, the exosome‐mediated activation of TLR3 in HSCs exacerbates liver fibrosis by enhancing IL‐17A production by γδ T cells, which might be associated with HSC stimulation by unknown self‐TLR3 ligands from damaged hepatocytes. Therefore, TLR3 might be a novel therapeutic target for liver fibrosis. (H epatology 2016;64:616‐631)
The MEK1/2 Inhibitor Pimasertib Enhances Gemcitabine Efficacy—Letter
Authors: Leticia G. Leon, Niccola Funel, Godefridus J. Peters, Amir Avan, Fabio Vistoli, Ugo Boggi, Elisa Giovannetti
Journal: Clinical Cancer Research (2016)

We have read with interest the article by Vena and colleagues ([1][1]), on the combination of the MEK1/2 inhibitor pimasertib with gemcitabine in pancreatic ductal adenocarcinoma (PDAC). MEK emerged as a promising target to sensitize gemcitabine therapy through downregulation of the ribonucleotide
A randomized multicenter phase III trial of topotecan monotherapy versus topotecan + etoposide versus topotecan + gemcitabine for second-line treatment of recurrent ovarian cancer
Authors: J. Sehouli, H. Sommer, P. Klare, M. Stauch, A. Zeimet, A. Paulenz, T. Steck, H. Riedel, E. Keil, D. Stengel, A. Kuznik, W. Lichtenegger
Journal: Journal of Clinical Oncology (2006)

5030 Background: Topotecan combined with etoposide (GINECO 1998) and gemcitabine (NOGGO 2001) proved effective for second-line treatment of recurrent ovarian cancer. It is, however, unclear whether combined treatment improves survival and tumor control compared to topotecan alone. Methods: Women with recurrent ovarian cancer after primary surgery and platinum therapy were enrolled in an open-label randomized phase-III trial at 93 German institutions. Stratifying for treatment-free intervals (TFI) of less or more than 12 months, subjects were centrally allocated to topotecan 1.25 mg/m 2 /d (TM), topotecan 1.0 mg/m 2 /d plus oral etoposide 50 mg/d (TE) on day 6–12, or topotecan 0.5 mg/m 2 /d plus gemcitabine (TG) 800 mg/m 2 /d1 and 600 mg/m 2 /d8 every three weeks. Local institutional review boards approved this study, and all patients provided written informed consent. With 145 subjects each arm, this study yielded 90% power to detect a Hazard Ratio (HR) of 0.60 in overall survival (OS) at a two-sided alpha of 0.01. We employed Cox regression for primary endpoint analysis, and addressed progression-free survival (PFS) and toxicity descriptively. Results: Between September 1999 and November 2004, 3036 courses were administered to 505 patients (mean age 60.4 [SD 11.3] years), 208 of whom had a TFI &lt;12 months. Women assigned to TM, TE, and TG received a median of 6.7 (range, 0–10), 6.2 (0–9), and 5.4 (1–42) cycles. Median OS after TM, TE, and TG was 17.8, 17.8, and 15.3 months. Setting TM as the reference, HRs for OS with TE and TG were 1.13 (95% confidence interval [CI] 0.87–1.47) and 1.07 (95% CI 0.80–1.43, p = 0.590). HRs for PFS with TE and TG versus TM were calculated at 0.84 (95% CI 0.66–1.07) each. Subgroup analysis suggested enhanced PFS among subjects with TFI ≥12 months who received TE (HR 0.62, 95% CI 0.42–0.91) or TG (HR 0.68, 95% CI 0.46–1.01) rather than TM. TE produced higher CTC grade 3/4 hematotoxicity than TM or TG, with cumulative incidences of 24.4% (95% CI 20.2–29.0%), 16.0% (95% CI 11.9–20.9%), and 14.7% (10.6–19.5%). Conclusions: This large RCT does not provide evidence that combined treatment performs generally better than topotecan monotherapy in recurrent ovarian cancer. No significant financial relationships to disclose.
Bell’s palsy at high altitude -- an unsuspected finding
Authors: K. V. S. Hari Kumar, K. P. Shijith, F. M. H. Ahmad
Journal: Military Medical Research (2016)

Bell's palsy is a common condition seen in clinical practice. The aetiology of this condition is not clearly defined and neuroimaging is essential to exclude intracranial causes of infra-nuclear facial palsy.We report a young soldier, who presented with Bell's palsy and neuroimaging revealed an unsuspected finding of multiple intracranial calcifications. Detailed evaluation revealed the additional diagnosis of vitamin D deficiency and secondary hyperparathyroidism due to lack of sun exposure at high altitude area.The health care practitioners, looking after the soldiers at high altitude areas should be aware of the measures to prevent vitamin D deficiency. Intracranial calcifications are uncommon in hyperparathyroidism and Bell's palsy.
Soundings: Some diseases must declare themselves
Authors: George Dunea
Journal: BMJ (2001)

When I was a house officer I would regularly see a dishevelled street woman who had numerous bizarre complaints. These she attributed to the dirt she had picked up at a flea market, and she would bring along crumpled bits of paper to prove her point. My chief eventually lost all patience and wrote to the general practitioner asking him not to send “this cantankerous woman” again. Two months later she returned jaundiced, her liver massively enlarged from a cancer of the pancreas.

There has always been a tendency to blame the doctors for such delayed diagnoses. Nowadays the public has become even more demanding, its hopes raised by magazines, newspapers, and television programmes. The medical profession has often also contributed to these raised expectations. By contrast, when I was a student our professors taught that diseases needed time to “declare” themselves; and we were often told that no one would be able to survive a complete examination.

More recently I saw a young woman who had had such an examination. She indeed did not survive, because the opposing street gang had fired two bullets into the back of her head. A complete autopsy disclosed a tiny cancer of the ampulla of Vater that might have taken 30 years to declare itself.

As a renal fellow I once saw a boy who had pain in the back after falling off a diving board. A pyelogram showed unsuspected bilateral congenital hydronephroses and he died of uraemia soon afterwards. Six months earlier he had had a normal college entry physical examination—no hypertension, abdominal masses, not even proteinuria. His mother asked if this tragedy could have been prevented. Perhaps by measuring the blood urea, but there was no indication for doing so.

Then there was the middle aged man who underwent renal biopsy for mild proteinuria: the biopsy specimen revealed a tiny focus of renal carcinoma cells. And in a similar case a minute totally unsuspected renal cancer was found on angiography in a woman hoping to donate a kidney to her brother.

No doubt someday doctors will have the means to diagnose such early diseases. But for the time being we (and the public) need to reconcile ourselves to the idea that many diseases still need time to declare themselves.
Risk factors for short-term outcomes after thoracoscopic lobectomy for lung cancer
Authors: Masataka Irie, Ryoichi Nakanishi, Manabu Yasuda, Yoshihisa Fujino, Kazumi Hamada, Masahiro Hyodo
Journal: European Respiratory Journal (2016)

Few studies have analysed postoperative risk factors in patients undergoing thoracoscopic lobectomy, including assessments of preoperative physical function. The objectives of this study were to identify predictors of postoperative deterioration of performance status and cardiopulmonary complications in cases of thoracoscopic lobectomy. Between June 2005 and October 2012, we retrospectively reviewed 188 consecutive subjects who underwent thoracoscopic lobectomy for preoperative stage I nonsmall cell lung cancer. The demographic and clinical parameters, including physical function, were analysed using a multivariate logistic regression to clarify the determinants. The percent predicted diffusing capacity of the lung for carbon monoxide, quadriceps muscle strength and pathologic stage were independent risk factors for deterioration of performance status after surgery in the multivariate analyses. Chronic obstructive pulmonary disease, 6-min walking distance and pathologic stage were also independent risk factors for postoperative cardiopulmonary complications. Our data suggest that, in addition to a greater pathologic stage, lower diffusing capacity and comorbid chronic obstructive pulmonary disease, poor physical function was associated with worse short-term outcomes after thoracoscopic lobectomy. An evaluation of preoperative quadriceps muscle strength and 6-min walk test is easily performed and may therefore be a useful predictor in cases of thoracoscopic lobectomy.
Mutations in TLR/MYD88 pathway identify a subset of young chronic lymphocytic leukemia patients with favorable outcome
Authors: Alejandra Martínez-Trillos, Magda Pinyol, Alba Navarro, Marta Aymerich, Pedro Jares, Manel Juan, María Rozman, Dolors Colomer, Julio Delgado, Eva Giné, Marcos González-Díaz, Jesús M. Hernández-Rivas, Enrique Colado, Consolación Rayón, Angel R. Payer, Maria José Terol, Blanca Navarro, Victor Quesada, Xosé S. Puente, Ciril Rozman, Carlos López-Otín, Elías Campo, Armando López-Guillermo, Neus Villamor
Journal: Blood (2014)
Phase II study of gemcitabine chemotherapy alone for locally advanced pancreatic carcinoma: JCOG 0506
Authors: H. Ishii, J. Furuse, N. Boku, T. Okusaka, M. Ikeda, S. Ohkawa, A. Fukutomi, Y. Hamamoto, K. Nakamura, H. Fukuda
Journal: Journal of Clinical Oncology (2009)

e15578 Background: Fluorouracil (5-FU) chemoradiotherapy has been accepted as standard care for locally advanced pancreatic cancer (LAPC); however, it has not been shown to be superior to chemotherapy alone in gemcitabine (Gem) era. The present multicenter phase II study was conducted to evaluate the efficacy and the safety for the screening of Gem monotherapy against LAPC. Methods: Eligibility criteria included the following: patients (pts) with histologically or cytologically proven pancreatic adenocarcinoma or adenosquamous carcinoma, pts with UICC clinical stage III (T4N0–1 and M0), all lesions are assumed to be included in the radiation field of 15 cm square, age 20 or older, no prior treatment for LAPC, ECOG performance status of 0, 1 or 2, and adequate organ function. Gem was given intravenously at a dose of 1,000 mg/m2 over 30 minutes on days 1, 8 and 15, repeated every 4 weeks until disease progression. The primary endpoint was %1-year overall survival. A sample size of 50 was required with one-sided alpha of 0.20, beta of 0.10, expected %1-year survival of 40% and threshold %1-year survival of 25%. Results: Between Jan. 06 and Feb. 07, 50 pts from 14 institutions were registered. Patient characteristics were: median age; 67.5 (45–80), male/female; 35/15, PS 0/1/2; 30/20/0, pancreatic head/body-tail; 26/24. The major grade 3–4 adverse events were neutropenia (62%), leucopenia (32%), thrombocytopenia (18%), fatigue (12%), infection-biliary tree (10%), anorexia (8%), and nausea (6%). Hematological toxicity was mostly transient and there was no episode of infection with grade 3–4 neutropenia. There were no treatment-related deaths during the study. Serum CA 19–9 level was reduced by &gt;50% in 37.5% of 40 pts with baseline CA19–9 &gt;100U/ml. Up to the final follow-up in Apr. 08, the median overall survival was 1.25 years (95% CI, 1.06–1.71 years) with a %1-year survival of 64.8% (95% CI, 49.6–76.4%), and the null hypothesis (%1-y survival=25%) was rejected (p&lt;0.0001). Conclusions: Gem monotherapy demonstrated far better survival than historical data of 5-FU chemoradiotherapy in LAPC pts with mild toxicities. In future randomized trial, we will select Gem chemotherapy as a referential arm to compare with the chemoradiotherapy regimen which is under phase II evaluation for LAPC. No significant financial relationships to disclose.
Soluble CD146 boosts therapeutic effect of endothelial progenitors through proteolytic processing of short CD146 isoform
Authors: Jimmy Stalin, Karim Harhouri, Lucas Hubert, Philippe Garrigue, Marie Nollet, Amel Essaadi, Alexandre Muller, Alexandrine Foucault-Bertaud, Richard Bachelier, Florence Sabatier, Pascale Pisano, Franck Peiretti, Aurélie S. Leroyer, Benjamin Guillet, Nathalie Bardin, Françoise Dignat-George, Marcel Blot-Chabaud
Journal: Cardiovascular Research (2016)

Endothelial colony-forming cells (ECFC) constitute an endothelial progenitor fraction with a promising interest for the treatment of ischaemic cardiovascular diseases. As soluble CD146 (sCD146) is a new factor promoting angiogenesis, we examined whether sCD146 priming could improve the therapeutic potential of ECFC and defined the involved mechanism. We investigated the effects of sCD146 priming on regenerative properties of ECFC in vivo . In a mouse model of hindlimb ischaemia, the homing of radiolabelled cells to ischaemic tissue was assessed by SPECT-CT imaging. Soluble CD146 priming did not modify the number of engrafted ECFC but improved their survival capacity, leading to an enhanced revascularization. The mechanism of action of sCD146 on ECFC was studied in vitro. We showed that sCD146 acts in ECFC through a signalosome, located in lipid rafts, containing angiomotin, the short isoform of CD146 (shCD146), VEGFR1, VEGFR2, and presenilin-1. Soluble CD146 induced a sequential proteolytic cleavage of shCD146, with an extracellular shedding followed by an intramembrane cleavage mediated by matrix metalloprotease (MMP)/ADAM and presenilin-1, respectively. The generated intracellular part of shCD146 was directed towards the nucleus where it associated with the transcription factor CSL and modulated the transcription of genes involved in cell survival ( FADD , Bcl-xl ) and angiogenesis ( eNOS ). This effect was dependent on both VEGFR1 and VEGFR2, which were rapidly phosphorylated by sCD146. These findings establish that activation of the proteolytic processing of shCD146, in particular by sCD146, constitutes a promising pathway to improve endothelial progenitors' regenerative properties for the treatment of cardiovascular diseases.
Abstract 9171: An Increase in Late Sodium Current Causes Junctional Tachycardia in Mice Expressing an LQT3 SCN5A Mutant Na+ Channel
Authors: Lin Wu, Gongxin Liu, Bo Yang, Hong Li, Kirsten Hoyer, John C Shryock, Luiz Belardinelli
Journal: Circulation (2011)

Background: Junctional tachycardia (JT) is predominantly seen in young patients, where it is associated with significant morbidity and mortality and poor response to drug therapy. We documented JT ...
Skeletal Muscle Mitochondrial Content, Oxidative Capacity, and Mfn2 Expression Are Reduced in Older Patients With Heart Failure and Preserved Ejection Fraction and Are Related to Exercise Intolerance
Authors: Anthony J.A. Molina, Manish S. Bharadwaj, Cynthia Van Horn, Barbara J. Nicklas, Mary F. Lyles, Joel Eggebeen, Mark J. Haykowsky, Peter H. Brubaker, Dalane W. Kitzman
Journal: JACC Heart Failure (2016)
Cervical sarcomas: An analysis of treatment and outcome
Authors: J. D. Wright, K. Rosenblum, D. G. Mutch, J. S. Rader, M. A. Powell, P. C. Huettner, R. K. Gibb
Journal: Journal of Clinical Oncology (2005)

5178 Background: Cervical sarcomas are exceedingly rare neoplasms associated with a poor prognosis. The objective of this study was to examine the treatment and outcome of women with cervical sarcomas. Methods: A hospital based tumor registry was searched to identify all patients with cervical sarcomas treated between 1986 and 2003. The medical records of all patients were reviewed. All pathologic specimens were reviewed by a single pathologist. Results: Among 1583 patients with cervical cancer, 11 cervical sarcomas were identified. Three patients were excluded after review found the histology to be inconsistent with sarcoma (2 poorly differentiated carcinomas, 1 sarcomatoid carcinoma). Cervical sarcomas thus accounted for 0.005% of all cervical tumors. The mean age of the 8 patients was 54 years. All initially presented with vaginal bleeding. A cervical mass was noted in all 8 patients, the mean size was 5.1 cm. The lesions were clinically staged as IB1 (2), IB2 (4), IIIA (1), and IIIB (1). Five of the tumors were carcinosarcomas, of which 3 were heterologous and 2 homologous. Other histologies included sarcoma NOS (12.5%), leiomyosarcoma (12.5%), and endometrial stromal sarcoma (12.5%). Initial treatment included surgery in 5 patients, radiation in 2 and chemoradiation in 1. Six (75%) patients were treated with curative intent, 5 received adjuvant therapy. While both patients treated palliatively died from progressive disease, the other 6 patients remain alive after a mean follow-up of 2.5 years. Two patients have recurred. One patient underwent a thoracotomy for an isolated pulmonary metastasis and is alive with no evidence of disease. The second patient developed pulmonary metastases and is alive eight months after recurrence. No locoregional recurrences have been noted. Conclusions: Cervical sarcomas are rare neoplasms. Most patients present with vaginal bleeding and a palpable cervical mass. While the optimal management of these tumors is uncertain, aggressive primary therapy can result in prolonged survival and cure. In this series all patients treated with curative intent were alive at the time of last follow-up. No significant financial relationships to disclose.