tbuckley/cabot-search huggingface dataset:
MLN0264, an investigational antiguanylyl cyclase C (GCC) antibody-drug conjugate (ADC), in patients (pts) with advanced gastrointestinal (GI) malignancies: Phase I study.
Authors: Cristina Cruz Zambrano, Khaldoun Almhanna, Wells A. Messersmith, Jordi Rodon Ahnert, David P. Ryan, Jason Edward Faris, JungAh Jung, Adedigbo Fasanmade, Tim Wyant, Thea Kalebic
Journal: Journal of Clinical Oncology (2014)

3546 Background: This first-in-human study (NCT01577758) assessed the safety and tolerability, dose limiting toxicities (DLTs), maximum tolerated dose (MTD), pharmacokinetics, and preliminary antitumor activity of MLN0264 in adult patients (pts) with advanced gastrointestianl (GI) malignancies expressing the surface antigen guanylyl cyclase C (GCC). Preclinical studies have shown antitumor activity in GI tumor animal models, including GCC-expressing human colorectal cancer (CRC) xenografts. Methods: Pts received MLN0264 by IV infusion on day 1 of 21-day cycles. Dose escalation proceeded via a Bayesian continual reassessment method in pts with GI malignancies. At the MTD, pts with metastatic CRC were enrolled to an expansion cohort (including ≥ 6 with high GCC expression). Results: As of November 27, 2013, 36 pts have received MLN0264, 19 at 0.3–2.4 mg/kg in the dose-escalation cohorts and 20 (including 3 from dose escalation) in the MTD expansion cohort. Median age was 60 years (30–78); 69% were male; 30 had CRC, two had pancreatic, two had esophageal, one had gastric cancer, and one had small intestine carcinoma. Median time from diagnosis was 37.6 mos. DLTs were seen in four pts: grade 4 neutropenia in two of four pts at 2.1 and the one pt at 2.4 mg/kg (all >MTD), and grade 4 febrile neutropenia in 1 of 6 pts at the MTD of 1.8 mg/kg. Pts received a median of 2 (1–8) cycles. Adverse events (AE) (NCI-CTCAE v4.03) were reported in 86% of pts. Common AEs (all grades) included fatigue (42%), nausea (42%), diarrhea (36%), and decreased appetite (31%); 56% of pts had grade ≥3 AEs, including neutropenia (19%), hypokalemia (11%), diarrhea (8%), and anemia (8%). Four pts discontinued due to AEs. MLN0264 concentration was detectable in all pts in a dose-dependent manner. Antibody drug conjugates (ADC) was detectable in serum at the pre-infusion time of the next cycle (day 21) for pts dosed at ≥1.2 mg/kg. The drug in the ADC, monomethyl auristatin E, was detectable in a dose-dependent manner, with peak concentration occurring approximately 2–3 days after each infusion. One pt (gastric carcinoma, 1.8 mg/kg) had a PR (RECIST 1.1); 13 pts had SD, including three treated for ≥ four cycles. Conclusions: The MTD of MLN0264 was determined as 1.8 mg/kg every three weeks. MLN0264 appeared generally well tolerated; preliminary antitumor activity was seen. Further investigation is warranted. Clinical trial information: NCT01577758.
Inflammatory Abdominal Aortic Aneurysms
Authors: T Cheatle, P Hickman, R P Grimley
Journal: Journal of the Royal Society of Medicine (1987)

About 10% of all abdominal aortic aneurysms are characterized by an exuberant inflammatory reaction consisting of a dense white sheath over the aneurysm with peri-aortic fibrosis. The aetiology is unknown. There are characteristic ultrasonic and CT appearances but the condition is usually diagnosed at laparotomy. Surgery is the best treatment, keeping peri-aortic dissection to a minimum. Steroid therapy may occasionally be indicated where the situation is considered inoperable or when the patient declines surgery. If hydronephrosis is present because of ureteric involvement, surgical ureterolysis, as for retroperitoneal fibrosis, should be considered. We report 8 cases treated surgically over a 3-year period, with good results in 6, one postoperative amputation and one late postoperative death.
Dickkopf-1 promotes prostate cancer cell growth within the bone
Authors: Christopher L. Hall, Anna Bafico, Stuart A. Aaronson, Evan T. Keller
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

3978 

Prostate cancer (CaP) frequently metastases to the bone where its growth yields mixed lesions that are both osteolytic (increased bone resorption) and osteoblastic (increased bone production). CaP cells produce many factors that are implicated in tumor-induced osteoblastic activity including Wnts. Wnts are cysteine-rich glycoproteins that mediate bone development in the embryo and promote bone production in the adult. We previously demonstrated that blocking canonical Wnts by over-expressing the soluble Wnt inhibitor dickkopf-1 (DKK-1) transforms osteoblastic C4-2B CaP cells into a highly osteolytic tumor in vivo suggesting that Wnts contribute to the osteoblastic component of CaP osseous lesions. We now investi gate the role of DKK-1 as a mediator of CaP induced osteolytic component. To assess a role of DKK-1 in osteolysis, small hairpin RNAs to DKK-1 were over-expressed in DKK-1+, osteolytic PC-3 cells. Two individual clones with greater than 80% reduction in DKK-1 protein were injected into the tibia and subcutis of nude mice (10 mice/group) and followed over six weeks. We show that increasing Wnt activity by reducing DKK-1 expression blocked the development of lesions within the bone compared to shRNA control cells. DKK-1 suppression also reduced the incidence and size of subcutaneous tumors but not attachment dependent growth in vitro suggesting that restoration of Wnt signaling in PC-3 cells had a generalized anti-tumor effect in vivo . Our data on Wnt/DKK-1 activity fits a model of CaP-induced bone remodeling occurring in a continuum composed of an osteolytic phase, mediated by osteolytic factors such as RANKL, PTHRP and DKK-1; a transitional phase, where environmental alterations promote expression of osteoblastic factors (Wnts) and decreases osteolytic factors (i.e., DKK-1); and an osteoblastic phase, in which tumor growth-associated hypoxia results in production of vascular endothelial growth factor and endothelin-1, which have osteoblastic activity. This model suggests that targeting both osteolytic activity and osteoblastic activity will provide efficacy for therapy of CaP bone metastases.
Demographics and disease characteristics of patients with psoriasis enrolled in the <scp>B</scp> ritish <scp>A</scp> ssociation of <scp>D</scp> ermatologists <scp>B</scp> iologic <scp>I</scp> nterventions <scp>R</scp> egister
Authors: I.Y.K. Iskandar, D.M. Ashcroft, R.B. Warren, Z.Z.N. Yiu, K. McElhone, M. Lunt, J.N.W.N. Barker, A.D. Burden, A.D. Ormerod, N.J. Reynolds, C.H. Smith, C.E.M. Griffiths
Journal: British Journal of Dermatology (2015)

The British Association of Dermatologists Biologic Interventions Register (BADBIR) is a prospective, observational cohort designed to assess the long-term safety of biologic and conventional systemic therapies used for adults with moderate-to-severe psoriasis in the U.K. and Republic of Ireland.To describe the demographics, disease severity and comorbidities of patients with psoriasis on enrolment into BADBIR, and to highlight differences in those commencing biologics compared with those on conventional systemic therapies.Baseline data were collected from 151 dermatology departments in the U.K. and Republic of Ireland. Descriptive analysis was conducted.As of August 2014, 8399 patients were registered with BADBIR; 5065 (60%) received biologics, of whom 52·8% received adalimumab, 24·6% etanercept, 18·7% ustekinumab and 3·9% infliximab. In the comparator cohort 44·1% received methotrexate, 23·1% ciclosporin, 18·0% acitretin and 7·6% fumaric acid esters. Overall 4897 (58%) were male. Patients on biologics had a higher mean ± SD age and disease duration than patients on conventional systemic therapies (46·3 ± 12·7 vs. 44·3 ± 14·3 years and 23·0 ± 12·6 vs. 19·0 ± 13·4 years, respectively; both P < 0·001). Mean body mass index, Psoriasis Area and Severity Index and Dermatology Life Quality Index scores for patients on biologics were higher than for those on conventional systemic therapies (31·0 ± 7·2 vs. 30·1 ± 7·3 kg m(-2) ; 16·4 ± 8·3 vs. 15·5 ± 7·9 and 17·4 ± 7·5 vs. 15·0 ± 7·1, respectively; all P < 0·001). In total 71% of all patients had comorbidities and 47% had more than one comorbidity. The most frequent comorbidities were obesity (42·1%), hypertension (25·7%), depression (22·1%) and psoriatic arthritis (17·1%).BADBIR is an invaluable resource to study the safety and effectiveness of both biologic and conventional systemic therapies. Understanding differences in baseline characteristics between cohorts is crucial in undertaking future pharmacovigilance studies.
Abstract 3566: Elevated Troponin is Associated With Worse Cardiac Structure and Function in Patients With Systemic AL Amyloidosis
Authors: Teimuraz Apridonidze, Richard Steingart, Raymond Comenzo, James Hoffman, Yuliya Goldsmith, Michael Baum, Michelle Johnson, Wendy Schaffer, Howard Weinstein, Jennifer Liu
Journal: Circulation (2009)
Telesleep medicine review - patient and clinician experience
Authors: Phyllis Murphie, Robin Paton, Caroline Scholefield, Neil McIntosh, Stuart Little
Journal: European Respiratory Journal (2014)

NHS Dumfries and Galloway Sleep medicine service has 700 clients living across 2,500 square miles of rural Scotland. Considerable travelling distances, and time are involved for patients attending centralised clinics and clinicians attending peripheral clinics. We have piloted potential Tele-clinic reviews, seeking clients feedback regarding its acceptability.  Aim - Assess the potential for tele-clinic follow-up for patients in a remote and rural sleep service  Methods - Patients were offered choice of tele-clinic or usual review method. Feedback was sought from participations, using a standardised proforma. Video Conferencing was used with the Clinician based in the main centre and the patients attending the nearest community unit.  Results - We have conducted 4 Tele Sleep clinics with 43 clients.  Conclusion: All participants accepted Tele Clinic review. The time saved for clinicians and patients is significant, with reduced clinician time being utilised for additional clinical care. In remote and rural areas Tele-clinic sleep medicine review offers a useful cost-effective, and patient-centred, option, appearing acceptable to patients and clinicians with the addition of potential reduced environmental impact. Our clinical team will now progress the use of this technology for future service delivery and given the increase in long-term conditions requiring some specialist follow-up this might offer potential for other areas of healthcare.
A randomized phase II/III trial of three weekly cisplatin based transarterial chemoembolization (TACE) versus embolization (TAE) alone for hepatocellular cancer (HCC).
Authors: T. Meyer, M. Roughton, D. Yu, N. Davies, E. Williams, S. P. Pereira, D. Hochhauser, J. O’Beirne, D. Patch, A. K. Burroughs
Journal: Journal of Clinical Oncology (2010)

4025 Background: TACE is regarded as the standard of care for intermediate stage HCC but evidence that TACE is superior to TAE is lacking. Methods: Eligible patients had previously untreated HCC based on histology or AASLD criteria; were unsuitable for resection; had multifocal disease or one lesion ≥ 3 cm, PS ≤ 2, Hb ≥ 9g/L, platelets ≥ 50x109/L, INR ≤ 1.5, GFR ≥ 50 mL/min, bilirubin ≤ 100 μ mol/L, and no extrahepatic disease or main branch portal vein occlusion. Patients were randomised to receive TAE with polyvinyl alcohol (PVA) particles alone or TACE in which cisplatin 50 mg was administered intrarterially 4-6 hours before PVA embolization. Treatment was repeated three weekly for a maximum of three treatments. The primary endpoint was overall survival (OS) and secondary endpoints were progression free survival (PFS), toxicity and response. Target sample size for phase II and III was 80 and 322 respectively. Results: Eighty-five patients were randomised (41 TAE, 44 TACE). Median age 62 years (range 30-80); 87% men; 81% Child-Pugh A cirrhosis; 82% PS 0/1, 64% multifocal disease. Etiology was Hep B in 16%, Hep C in 36% and alcohol in 20%. Currently 58% (TAE) and 57% (TACE) patients have received all three planned treatments. There was no significant difference in toxicity, with 24 (TAE) and 28 (TACE) patients reporting at least one grade 3/4 toxicity. Response rates according to RECIST for TAE vs. TACE were; PR 10% vs. 25%, SD 37% vs. 36%, PD 17% vs. 7% (p = 0.165). Eight vs. 9 patients subsequently had a liver transplant following treatment and were censored for survival at the date of surgery. Median PFS was 6.9 (TAE) vs 7.8 months (TACE) (p = 0.64) and median OS was 16.2 vs. 15.9 months (p = 0.82). When transplanted patients were excluded, the median survival was 14.6 vs 12.7 months (p = 0.76). Conclusions: Based on these results, the chance of seeing a survival difference of > 2 months between TACE and TAE in a phase III trial was < 20%. The trial was therefore terminated at phase II. No significant financial relationships to disclose.
Antidepressants for old people
Authors: R C Baldwin, P. Haddad, R H McAllister-Williams, C. Gordon, M. G Livingston, H. M Livingston
Journal: BMJ (1999)

Cancellation of debt must ensure maximum benefit to vulnerableEditor-It should be difficult for any doctor to ignore Abbasi's recent article on "third world" debt. 1 The state of health care available to families in between half and two thirds of the world is unacceptable, and the great differences in quality of health care between rich and poor countries are unethical. 2However, the experiences of our aid agency in trying to develop hospital care for children in disadvantaged countries leads us to be cautious about advocating simply a cancellation of debts.We have witnessed that an input of money alone to countries which are poorly governed, and where corruption is a way of life, may fail to reach the most vulnerable and needy within the community.Our agency's view is that all debt to poor and disadvantaged countries should be cancelled but in a more sustainable way than by releasing states from their repayments.Money earmarked for debt repayment should be retrieved but ploughed back fully and immediately into the country's healthcare and education systems.We suggest that this is implemented through the appointment in each repaying country of carefully chosen advocates for women and children.Ideally, partners appointed from within the United Nations should support these local delegates.A committee formed between the UN partners and delegates from the country repaying the debt should thereby ensure that all the money that has been repaid to rich countries is used for health care and education.Such a system would be more difficult to organise than simple cancellation of debt.Care would have to be taken to ensure that existing levels of finance for health care and education are maintained in addition to money resulting from debt repayment.The repayment of debts by the "third world" to rich countries who have prospered from earlier exploitation clearly represents an evil.However, our response to this should be "street wise" and should ensure that the abolition of debt results in maximum benefit to the most vulnerable members of disadvantaged countries.
Ultrasound guided forceps biopsy of the pleura
Authors: Yousef Ahmed, Gamal Agmy, Lamiaa Shahban, Nermin Kamel
Journal: European Respiratory Journal (2012)

Background: Ultrasound guided forceps biopsy of the pleura is a technique that can cover the diagnostic yield gap between the needle biopsy of the pleura and thoracoscopy or thoracotomy. This technique enables the operator to take biopsy from multiple pleural sites.

Study Objectives: (1) To describe the ultrasound guided forceps biopsy of the pleura as a technique that is not in common use in our practice to obtain pleural biopsy. (2) To evaluate the diagnostic yield of this technique in undiagnosed exudative pleural effusion.

Design: Prospective interventional study.

Setting: Ultrasound Unit- Chest Department- Assiut University Hospital - Egypt.

Patients and Methods: All recruited patients (96) had exudative pleural effusion with first pleural tapping undiagnostic. Patients with bleeding tendency or blood coagulation defects were excluded. The procedure was performed under local anesthesia (Xylocaine 2%) and aseptic condition. The patients were premedicated by analgesic (Ketorolac thromethamine 20mg). Three to five biopsy fragments were obtained from each case and sent in 10% formaldehyde to the pathology laboratory. The diagnostic yield was compared with that of thoracoscopy.

Results: Compared to thoracoscopy the sensitivity in diagnosis of malignant and tuberculous lesions was 85% and 88% respectively. The technique was absolutely specific in diagnosis of malignant and tuberculous lesions.

Conclusions: Ultrasound – guided forceps biopsy of the pleura is a simple, efficient, and safe procedure. It can be carried out easily and safely even in sick and obese patients. On the other hand, the procedure appears similar to the thoracoscopy in obtaining adequate pleural tissue specimens. Yet, it is simpler and less traumatic.
Abstract 1861: Myocardial Assistance by Grafting a New Bioartificial Upgraded Myocardium (MAGNUM Clinical Trial): One Year Outcome
Authors: Juan Chachques, Jorge Trainini, Miguel Cortes-Morichetti, Olivier Schussler, Alain Carpentier
Journal: Circulation (2007)

Objectives Cell transplantation for myocardial regeneration is limited by poor graft viability and low cell retention. In addition, in ischemic cardiomyopathy the extracellular matrix is deeply altered. Therefore it could be important to associate a procedure aiming at regenerating myocardial cells and restoring the extracellular matrix function. We evaluated intrainfarct stem cell therapy associated with a cell-seeded collagen scaffold grafted onto infarcted ventricles. Methods In 15 patients (aged 54.2±3.8 years) presenting LV postischemic myocardial scars (age of the infarcts 8.2±3.5 months) and with indication for a single OP-CABG, bone marrow was collected by aspiration from the iliac crest. The cell suspension was loaded on Ficoll-Paque density gradient and 300 ± 28 million mononuclear bone marrow cells (BMC) were implanted during surgery in the scar. A type I collagen matrix seeded with the same number of BMC (300 ± 28 million cells) was added on top of the scarred area and fixed onto the epicardium by 6 single PDS sutures and covered by a second non-cellularized matrix. Results There was no mortality and any related adverse events (follow-up 15±4.2 months), no malignant cardiac arrhythmias were reported, no patient was lost to follow-up. NYHA FC improved from 2.3±0.5 to 1.4±0.3 (p=0.005). LV end-diastolic volume evolved from 142±24 to 117±21mL (p=0.03), LV filling deceleration time improved from 162±7ms to 196±8ms (p=0.01). Scar area thickness progress from 6±1.4 to 9±1.5mm (p=0.005). EF improved from 25±7 to 33±5% (p=0.04). Conclusions Simultaneous intramyocardial injection of BMC and fixation of a cell seeded matrix onto the epicardium is feasible and safe. The cell seeded collagen matrix seems to increase the thickness of the infarct scar with viable tissues and help to normalize cardiac wall stress in injured regions, thus limiting ventricular remodelling and improving diastolic function. Functional improvements can not be conclusively related to the cells and matrix due to the association of CABG. Cardiac tissue engineering seems to be a promising way for the creation of “bioartificial myocardium”. Efficacy and safety of this approach should be evaluated in a large randomized controlled trial.
Doctors need more training in care of the dying, experts say
Authors: Nigel Hawkes
Journal: BMJ (2015)

The recent draft guideline from the National Institute for Health and Care Excellence on care of the dying is a good summary of evidence but not much help at the bedside, two experts on palliative care have said.

Since the demise of the Liverpool care pathway, acute trusts have been left to their own devices over adult palliative care, Jonathan Koffman and Katherine Sleeman, from the Cicely Saunders Institute in London, told journalists at the Science Media Centre, London, on 3 September. They said that NICE’s 266 page guideline,1 which is out for public consultation until 9 …
Smoking cessation for COPD patients: preliminary results of the SMOKE study.
Authors: Lieke C.A. Christenhusz, Marcel E. Pieterse, J. van der Palen, E.R. Seydel, P.I. van Spiegel, F.J.W.M. Smeenk, P.D.L.P.M. van der Valk
Journal: European Respiratory Journal (2004)
Application of intracellular cytokine flow cytometry in the diagnosis of active tuberculosis
Authors: Jaehee Lee, Eun Jin Kim, Seung Soo Yoo, Shin Yup Lee, Seung Ick Cha, Jae Yong Park, Chang Ho Kim
Journal: European Respiratory Journal (2012)

Background:  Intracellular cytokine flow cytometry (ICCFC) has been introduced to detect the T cell response to  M. tuberculosis  antigen (MTB Ag) to overcome the limits shown by whole-blood interferon-gamma (IFN-γ) release assays (IGRA). Given the important role of CD4+T cells as well as IFN-γ and TNF-α in pathogenesis of TB, we compared the diagnostic accuracy between ICCFC measuring frequencies of MTB-specific Ag stimulated IFN-γ+TNF-α+CD4+T cells and IGRA to confirm the usefulness of application of ICCFC for TB diagnosis in clinical practice.   Methods:  Both QuantiFERON  ®   TB Gold In-Tube (QFT-IT) test and ICCFC analysis were performed in 80 patients who were suspected of having pulmonary TB or TB pleurisy and 10 controls with no known exposure to TB.   Results:  (1) Sixty one and 19 out of total 80 patients were diagnosed with active TB and non-TB, respectively. (2) Double IFN-γ+TNF-α+CD4+T cells among all T cell subsets analyzed by ICCFC showed the highest sensitivity (90%) for diagnosis of TB. (3) Sensitivity of QFT-IT test and ICCFC assay were 77% and 90%, respectively (p = 0.021). (4) Specificity of QFT-IT and ICCFC assay were 73.7% and 89.5%, respectively. (5) There was a good correlation between the quantitiy of IFN-γ, as detected by the QFT-IT test, and the freqeunceis of IFN-γ+TNF-α+CD4+T cell measured by the ICCFC assay in TB patients (p=0.012). (6) The frequencies of IFN-γ+TNF-α+CD4+T cells were significantly decreased after 6 months of treatment compared with pretreatment (p=0.026).   Conclusions:  The ICCFC assay with T cells stimulation by MTB-specific Ag may be a useful additional tool for the diagnosis of active TB, although further study is needed for more convincing data.
Alpha-interferon in superficial bladder cancer: a Northern California Oncology Group Study.
Authors: F M Torti, L D Shortliffe, R D Williams, W C Pitts, R L Kempson, J C Ross, J Palmer, F Meyers, M Ferrari, J Hannigan
Journal: Journal of Clinical Oncology (1988)

Thirty-five patients with superficial transitional carcinoma of the bladder were treated intravesically with escalating doses of recombinant alpha-2-interferon administered weekly for 8 weeks. Of the 19 patients with high-grade intraepithelial neoplasia (17 carcinoma in situ [CIS], two severe dysplasia, all cytology positive), six (32%) had complete resolution of all histologic and cytologic evidence of disease (complete response). An additional three patients (16%) had complete resolution of CIS, but the interval appearance of a low-grade transitional cell neoplasm. Five (26%) had a partial response (complete resolution of all evidence of CIS on multiple bladder biopsies but persistently positive cytologic preparations). Sixteen patients with recurrent papillary tumors and extensive prior therapy were also treated. Four (25%) had a complete response. Twenty-three of the 35 patients had prior intravesical therapy. Seven of the 23 (30%) patients with prior intravesical chemotherapy or immunotherapy had a complete or partial response to interferon, while eight of the 12 patients (67%) without prior intravesical treatment responded. These responses were achieved with minimal local and systemic toxicity. Of the ten complete responders, five remain in continuous unmaintained remission for 18+ to 37+ months. Intracavitary alpha-2-interferon is an effective new treatment for some patients with bladder cancer.