tbuckley/cabot-search huggingface dataset:
A phase I study of weekly dosing of trastuzumab-DM1 (T-DM1) in patients with advanced HER2+ breast cancer.
Authors: IE Krop, M Mita, HA Burris, M Birkner, S Girish, J Tibbitts, SN Holden, SG Lutzker, S Modi
Journal: Cancer Research (2009)

Abstract Abstract #3136 Background: T-DM1, a novel HER2 antibody-drug conjugate (ADC) in development for HER2+ breast cancer (BC), combines activity of trastuzumab (T) with the targeted delivery of maytansinoid DM1 (potent antimicrotubule agent) to HER2-expressing cells. DM1 binds tubulin competitively with vinca alkaloids, 20-100x more potently than vincristine. It is bound to T by MCC, a linker that is stable with protease activity and under many pH or redox conditions. T-DM1 is the first ADC with an MCC linker to enter clinical trials. Main preclinical AEs were reversible transaminase (TA) elevations, reversible platelet decreases, and neuropathy. A phase I study of T-DM1 every 3 wks (q3w) in patients (pts) with advanced HER2+ BC who progressed on T-containing chemotherapy regimen, the maximum tolerated dose (MTD) was 3.6 mg/kg, with DLT of grade (Gr) 4 thrombocytopenia (TCP); tumor responses were seen in 5 of 9 pts (4 confirmed, 44%) with measurable disease treated at MTD. We undertook this dose escalation study of T-DM1 given once/wk (q1w) to explore pharmacokinetics (PK), safety, and tolerability of more frequent dosing.&amp;#x2028; Methods: Pts with advanced HER2+ BC who had progressed on a T-containing chemotherapy regimen received T-DM1 IV q1w continuously. Dose levels were escalated in successive 3+3 cohorts if DLT was seen in &amp;lt;1/3 of pts within 21 days of Cycle 1 Day 1.&amp;#x2028; Results: As of 19 May 2008, enrollment is complete with 27 pts (15 at the MTD). Data is available for 19 pts [median age 54.0 (range 41-71); all PS 0-1; median number prior metastatic chemo agents 5.0 (range 2-8); median wks of prior trastuzumab 122 (range 29-325)] who have received 246 doses of T-DM1 at 1.2, 1.6, 2.0, 2.4, and 2.9 mg/kg. Common related AEs include fatigue (Gr1, 3 pts; Gr2, 4 pts; Gr3, 1 pt), thrombocytopenia (Gr 1, 4 pts; Gr2, 3 pts; Gr3, 2 pts), nausea (Gr1, 7 pts; Gr 2, 1 pt), TA elevations (Gr1, 1 pt; Gr2, 4 pts; Gr3, 1 pt), vomiting (Gr1, 3 pts; Gr2, 1 pt) and headache (Gr1, 2 pts; Gr2, 1 pt). Dose-limiting toxicity was seen in 2 pts at 2.9 mg/kg (toxicity preventing retreatment on Cycle 1 Day 8, from Gr2-3 thrombocytopenia). No Gr4 AEs or cardiac toxicity were seen. Preliminary PK analyses suggest that steady-state T-DM1 exposure at 2.4 mg/kg q1w will be ∼2x that associated with 3.6 mg/kg q3w. Of 15 pts evaluable for response, 9 had partial responses (8 confirmed, 53%).&amp;#x2028; Conclusions: The MTD of T-DM1 on a weekly schedule is 2.4 mg/kg. Related Gr ≥2 AEs were reversible and manageable. The activity and safety results observed on q1w dosing were consistent with q3w dosing, supporting further study. Three Phase II trials of q3w T-DM1 in advanced HER2+ BC will enroll pts in 2008; preliminary results from the first trial will be reported in 2008. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3136.
Follow-up From Childhood to Adulthood of Individuals With Family History of Brugada Syndrome and Normal Electrocardiograms
Authors: Giulio Conte, Carlo de Asmundis, Giuseppe Ciconte, Justo Julià, Juan Sieira, Gian-Battista Chierchia, Pedro Brugada
Journal: JAMA (2014)

Normal Syncope NP c.[4719C > T] + [ = ] (p.Gly1573Gly); c.[274-24C > T] + [ = ] variant
Supporting TB clinicians managing difficult cases: the ERS/WHO Consilium
Authors: Francesco Blasi, Masoud Dara, Marieke J. van der Werf, Giovanni Battista Migliori
Journal: European Respiratory Journal (2013)

ultidrug-resistant tuberculosis (MDR-TB), defined as active TB cases infected by Mycobacterium tuberculosis strains that are resistant to isoniazid and rifampicin (the two most important anti-TB drugs currently in use), and extensively drug resistant tuberculosis (XDR-TB), defined as active TB cases caused by infection with strains that are resistant to at least one fluoroquinolone and one injectable second-line anti-TB drug in addition to resistance to isoniazid and rifampicin, attract interest at different levels [1][2][3][4][5].In recent years the alarming rates of MDR-or XDR-TB in Eastern Europe and some other parts of the world, have resulted in strong expressions of concern from national and international partners, health authorities, and professional societies.At the media level, the key words MDR-TB and XDR-TB attract spikes of citations and consistent interest, as a simple Google search can testify (fig.1).From the public health point of view, MDR-and XDR-TB is considered a serious threat for TB control and elimination.Therefore, the international community and national governments prioritise monitoring and evaluating prevalence rates and trends of drug resistant TB at both the global and the regional level [2,3].Recent evidence suggests that of the estimated 310,000 MDR-TB cases among notified TB patients with pulmonary TB in 2011, 60% occurred in India, China and the Russian Federation.XDR-TB is, at present, notified in 84 countries, although representative data on these difficult-to-treat cases are only available in 13 of them [2,3].The proportion of MDR-TB cases harbouring XDR-TB strains of M. tuberculosis was highest in Azerbaijan, Belarus, Estonia, Latvia, Lithuania and Tajikistan.
Antibacterial Prophylaxis after Chemotherapy for Solid Tumors and Lymphomas
Authors: Michael Cullen, Neil Steven, Lucinda Billingham, Claire Gaunt, Mark Hastings, Peter Simmonds, Nicholas Stuart, Daniel Rea, Mark Bower, Indrajit Fernando, Robert Huddart, Simon Gollins, Andrew Stanley
Journal: New England Journal of Medicine (2005)

The role of prophylactic antibacterial agents after chemotherapy remains controversial.We conducted a randomized, double-blind, placebo-controlled trial in patients who were receiving cyclic chemotherapy for solid tumors or lymphoma and who were at risk for temporary, severe neutropenia (fewer than 500 neutrophils per cubic millimeter). Patients were randomly assigned to receive either 500 mg of levofloxacin once daily or matching placebo for seven days during the expected neutropenic period. The primary outcome was the incidence of clinically documented febrile episodes (temperature of more than 38 degrees C) attributed to infection. Secondary outcomes included the incidence of all probable infections, severe infections, and hospitalization but did not include a systematic evaluation of antibacterial resistance.A total of 1565 patients underwent randomization (784 to placebo and 781 to levofloxacin). The tumors included breast cancer (35.4 percent), lung cancer (22.5 percent), testicular cancer (14.4 percent), and lymphoma (12.8 percent). During the first cycle of chemotherapy, 3.5 percent of patients in the levofloxacin group had at least one febrile episode, as compared with 7.9 percent in the placebo group (P<0.001). During the entire chemotherapy course, 10.8 percent of patients in the levofloxacin group had at least one febrile episode, as compared with 15.2 percent of patients in the placebo group (P=0.01); the respective rates of probable infection were 34.2 percent and 41.5 percent (P=0.004). Hospitalization was required for the treatment of infection in 15.7 percent of patients in the levofloxacin group and 21.6 percent of patients in the placebo group (P=0.004). The respective rate of severe infection was 1.0 percent and 2.0 percent (P=0.15), with four infection-related deaths in each group. An organism was isolated in 9.2 percent of probable infections.Among patients receiving chemotherapy for solid tumors or lymphoma, the prophylactic use of levofloxacin reduces the incidence of fever, probable infection, and hospitalization.
Is it ethical to hire sherpas when climbing Mount Everest?
Authors: E. A. Largent
Journal: BMJ (2014)

A medical ethical approach may be useful, but the jury’s still out, writes Emily Largent 

The Everest climbing season that has just ended was marred by the worst accident in the mountain’s history. On 18 April 2014, 16 Nepalese sherpas died in an avalanche, and subsequent climbing expeditions were cancelled.1 2 The deaths of men from poor communities, hired to perform dangerous tasks for the sake of mountain climbing, provoked controversy.3

I used data on deaths above base camps from the Himalayan database,4 and definitions from a prior study.5 The aggregate risk of death for sherpas during a climbing season was 0.8% between 1922 and 2013. Including the recent disaster, 73% of all sherpas’ deaths resulted from objective hazards (avalanche, ice-fall collapse, crevasse fall, or falling rock or ice5) (figure⇓ and table⇓).

View this table:

Causes of death on Mount Everest, 1922-2013





Distribution of deaths on the standard north and south routes on Everest



The question of whether it is acceptable to pay porters to assume risks for the benefit of others is an extreme variant of cases—common in medical ethics—where compensation and assumption of risk coincide. Consider debates about the sale …
Retinal microangiopathy and rapidly fatal cerebral edema in a patient with adult‐onset Still's disease and concurrent macrophage activation syndrome
Authors: Sara Gianella, Dominik J. Schaer, Urs Schwarz, Michael Kurrer, Frank L. Heppner, Jörg Fehr, Jörg D. Seebach
Journal: American Journal of Hematology (2008)

Abstract Hemophagocytic lymphohistiocytosis (HLH) is a complex inflammatory disease with multiple diagnostic and therapeutic pitfalls. The congenital form, referred to as familial hemophagocytic lymphohistiocytosis (FHL), is often associated with cerebromeningeal involvement, whereas neurological complications are not characteristic of the adult form of secondary HLH (sHLH). Here we report the case of a 20‐year‐old woman with adult‐onset Still's disease (AOSD), retinal microangiopathy and concurrent macrophage activation syndrome (MAS), in the context of sHLH. Following treatment with etanercept, ibuprofen, methylprednisolon, and phenylbutazone for 3 weeks, MAS deteriorated and fatal cerebral edema occurred within only 24 h. The clinical signs and neuropathological findings are discussed with special emphasis on possible relationships between the aggravation of MAS and therapeutic interventions for AOSD. In conclusion, even the slightest sign of mental decline in a patient with AOSD must be considered central nervous system MAS which can be rapidly fatal. Am. J. Hematol., 2008. © 2008 Wiley‐Liss, Inc.
Agencies in Haiti switch focus to long term health needs
Authors: J. Zarocostas
Journal: BMJ (2010)

<b>Background:</b> Oxidative stress is thought to have a major role in the pathogenesis of airway obstruction. A study was undertaken to determine whether subjects with low levels of antioxidants (serum β-carotene, α-carotene, vitamins A and E) would be at a higher risk of accelerated decline in forced expiratory volume in 1 second (FEV<sub>1</sub>) as their lungs would be less protected against oxidative stress. <b>Methods:</b> 1194 French subjects aged 20–44 years were examined in 1992 as part of the European Community Respiratory Health Survey (ECRHS); 864 were followed up in 2000 and 535 (50% men, 40% lifelong non-smokers) had complete data for analysis. <b>Results:</b> During the 8 year study period the mean annual decrease in FEV<sub>1</sub> (adjusted for sex, centre, baseline FEV<sub>1</sub>, age, smoking, body mass index and low density lipoprotein cholesterol) was 29.8 ml/year. The rate of decrease was lower for the subjects in tertile I of β-carotene at baseline than for those in the two other tertiles (−36.5 <i>v</i> −27.6 ml/year; p = 0.004). An increase in β-carotene between the two surveys was associated with a slower decline in FEV<sub>1</sub>. No association was observed between α-carotene, vitamin A, or vitamin E and FEV<sub>1</sub> decline. However, being a heavy smoker (⩾20 cigarettes/day) in combination with a low level of β-carotene or vitamin E was associated with the steepest decline in FEV<sub>1</sub> (−52.5 ml/year, p = 0.0002 and −50.1 ml/year, p = 0.010, respectively). <b>Conclusions:</b> These results strongly suggest that β-carotene protects against the decline in FEV<sub>1</sub> over an 8 year period in the general population, and that β-carotene and vitamin E are protective in heavy smokers.
THU0210 The comparison of childhood polyarteritis nodosa and cutaneous polyarteritis NODOSA
Authors: E. Demirkaya, T. Turker, N. Ruperto, R. Cuttica, P. Brogan, P. Quartier, J. Anton, N. Ayaz, S. Garay, G. Espada, R. Khubchandani, F. Zulian, A. Bagga, A. Belot, C.A. Silva, S.M. Al-Mayouf, A.I. Estrella, S. Oliveira, C.S. Magalhães, A. Martini, S. Ozen
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Polyarteritis nodosa (PAN) is a predominantly medium size vasculitis characterized by non granulomatous necrotizing vasculitis. In children (c-) the disease may be confined to the skin only (cutaneous involvement-PAN) or may present with systemic involvement (systemic c-PAN) as in adult polyarteritis nodosa. <h3>Objectives</h3> We aimed to evaluate clinical, laboratory and imaging features of cutaneous c-PAN and the systemic c-PAN form in a large international pediatric vasculitis registry available on the PRINTO database. <h3>Methods</h3> We extracted from the PRINTO database all the patients who fulfilled the Ankara 2008-EULAR/PRES/PRINTO criteria for systemic c-PAN. The cutaneous c-PAN patients as per the treating physician diagnosis were also extracted. To define clinical and laboratory characteristics who could help to differentiate cutaneous PAN from cPAN and univariate logistic regression analysis was performed. <h3>Results</h3> There were 109 and 45 patients classified as systemic c-PAN, and cutaneous c-PAN respectively with a mean age at diagnosis of 9.47±3.59 years; and 9.12±3.83 years; respectively. The female/male ratio and ethnicity did not differ in the 2 subtypes. The cutaneous group had significantly less constitutional features and less acute phase reactant levels, as expected. The median values (IQR 25-75%) for the ESR and CRP for cPAN were 78 (48-108) mm/h and 7.36 (2.76-15.03) mg/dL. Musculoskeletal features such as myalgia was present in 82 (75.2%) patients with c-PAN and 18 (40.9%) patients with cutaneous PAN (p&lt;0.001) both groups. As differentiating features skin infarcts were observed in c-PAN only and constitutional features, angiographic abnormalities, and organ involvement was not seen in any of the cutaneous PAN patients. Malaise, fever, severe headache, motor mononeuritis multiplex, sensory peripheral neuropathy, abdominal pain, and hematuria were the most statistically significant clinical characteristics able to differentiate these two entities. <h3>Conclusions</h3> This is the first study comparing the features of childhood PAN and cutaneous PAN in a large group of pediatric patients. Further biological studies are needed to effectively differentiate the two entities. <h3>References</h3> Ozen S, Pistorio A, Iusan SM et al.: EULAR/PRINTO/PRES criteria for Henoch-Schonlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis 2010; 69(5):798-806. <h3>Disclosure of Interest</h3> None Declared
Phase III Randomized Trial of Cisplatin Plus Placebo Compared With Cisplatin Plus Cetuximab in Metastatic/Recurrent Head and Neck Cancer: An Eastern Cooperative Oncology Group Study
Authors: Barbara Burtness, Meredith A. Goldwasser, William Flood, Bassam Mattar, Arlene A. Forastiere
Journal: Journal of Clinical Oncology (2005)

Therapy of recurrent/metastatic squamous cell carcinoma of the head and neck results in median progression-free survival (PFS) of 2 months. These cancers are rich in epidermal growth factor receptor (EGFR). We wished to determine whether the addition of cetuximab, which inhibits activation of EGFR, would improve PFS.Patients with recurrent/metastatic squamous cell carcinoma of the head and neck were randomly assigned to receive cisplatin every 4 weeks, with weekly cetuximab (arm A) or placebo (arm B). Tumor tissue was assayed for EGFR expression by immunohistochemistry. The primary end point was PFS. Secondary end points of interest were response rate, toxicity, overall survival, and correlation of EGFR with clinical end points.There were 117 analyzable patients enrolled. Median PFS was 2.7 months for arm B and 4.2 months for arm A. The hazard ratio for progression of arm A to arm B was 0.78 (95% CI, 0.54 to 1.12). Median overall survival was 8.0 months for arm B and 9.2 months for arm A (P = .21). The hazard ratio for survival by skin toxicity in cetuximab-treated patients was 0.42 (95% CI, 0.21 to 0.86). Objective response rate was 26% [corrected] for arm A and 10% [corrected] for arm B (P = .03). Enhancement of response was greater for patients with EGFR staining present in less than 80% of cells.Addition of cetuximab to cisplatin significantly improves response rate. There was a survival advantage for the development of rash. Progression-free and overall survival were not significantly improved by the addition of cetuximab in this study.
Captopril for correcting diuretic induced hypotension in pulmonary oedema after scorpion sting.
Authors: D. R. Karnad, A. M. Deo, N. Apte, A. S. Lohe, S. Thatte, G. H. Tilve
Journal: BMJ (1989)

caused by wax or condensation may be easily identified as the tubing is transparent.Residents who were considered to have a hearing loss that affected them socially were followed up to see whether matters had improved after their hearing problems had been dealt with by IC or their general practitioners or at the audiology clinic.The table shows the results.Half of the hearing aids already fitted were not functioning, nine because of flat batteries and 16 because of blockage by wax.Although Findings in 304 residents whose hearing was assessed informally Finding No of residents Already fitted with an aid 49 Aid non-functioning 25 Aid functioning 24 Dementia not improved by amplification 11 Referred to audiology-hearing aid clinic for first time 42 Received hearing aid 27 Died before seen in clinic 6 Hearing improved after wax removal 2 Required no action 4 Admitted to hospital for reasons unconnected with ENT 3 Refused offer of referral to audiology department 17 Known to have hearing loss but uncooperative 13 Use of personal amplifier recommended 7* Found to have severely disabling tinnitus 5 Required wax removal 79 Referred to general practitioner but no action taken 15 Required no action 132 * Patients too ill to travel to hospital.ENT=Ear, nose, and throat.
The retroverted gravid uterus and its effect on the outcome of pregnancy.
Authors: A R Weekes, R D Atlay, V A Brown, E C Jordan, S M Murray
Journal: BMJ (1976)

Among 1954 pregnant women who booked before the end of the 14th week of gestation the uterus was retroverted in 220 (11.2%). The incidence of bleeding in early pregnancy and spontaneous abortion was significantly higher in the retroverted group. Only three patients (1.4%) with a retroverted gravid uterus developed acute retention of urine. Patients with retroverted uteri did not have a higher incidence of previous infertility, nor any increase in the incidence of common obstetric abnormalities.
Overexpression of Gi-proteins precedes the development of DOCA-salt-induced hypertension: relationship with adenylyl cyclase
Authors: J Marcil
Journal: Cardiovascular Research (1998)

Objective: In the present studies, we have investigated if aorta, like heart from deoxycorticosterone acetate (DOCA)-salt hypertensive rats, (HR) also exhibit enhanced expression of G-protein levels and if these alterations occur before or after the development of blood pressure. Methods: Sprague–Dawley rats treated with DOCA-salt or vehicle for 1, 2, 3 and 4 weeks were used for these studies. The levels of inhibitory guanine nucleotide regulatory proteins (Giα-2, Giα-3) and Gβ proteins were determined by immunoblotting, whereas the levels of Giα-2 and Giα-3 and adenylyl cyclase type V enzyme mRNA were determined by Northern-blotting techniques. Results: The blood pressure was significantly increased in DOCA-salt-treated rats as compared to sham-operated rats after 2 to 4 weeks of treatment; whereas no change in blood pressure was observed after 1 week of treatment (prehypertensive state). However, the levels of Giα-2, Giα-3 and Gβ proteins and Giα-2 and Giα-3 mRNA were significantly enhanced in hearts and aorta from DOCA-salt treated rats after 1 week of treatment and remained elevated up to 4 weeks of treatment. In addition, the Gi-mediated inhibitions of adenylyl cyclase by Angiotensin II (Ang II) and C-ANF4-23 were also greater in DOCA-salt-treated rats as compared to sham-operated rats after 1 week and longer periods of treatments (2 to 4 weeks). On the other hand, the levels of Gsα were not altered up to 2 weeks of DOCA-salt treatment but significantly decreased in rats treated for 3 and 4 weeks. Furthermore, the stimulatory effects of guanine 5′-[γ-thio]triphosphate (GTPγS), isoproterenol and forskolin on adenylyl cyclase were decreased in both hearts and aorta from DOCA-salt-treated rats after 1 to 4 weeks of treatment as compared to sham-operated rats. The mRNA levels of adenylyl cyclase, type V enzyme in hearts from DOCA-salt treated rats were significantly decreased after 3 and 4 weeks of DOCA-salt treatment but not in rats treated for 1 or 2 weeks. Conclusions: These results indicate that the enhanced expression of Giα-2 and Giα-3 precedes the development of blood pressure in DOCA-salt-induced hypertension. It can thus be suggested that the increased levels of Gi proteins and resulting decreased levels of cAMP may be one of the factors that contribute to the impaired cardiac contractility and increased vascular tone in DOCA-salt hypertension.
Genetic variations of<i>NLRP1</i>: susceptibility in psoriasis
Authors: A.-K. Ekman, D. Verma, M. Fredrikson, C. Bivik, C. Enerbäck
Journal: British Journal of Dermatology (2014)

Background NACHT, LRR and PYD domain-containing protein (NLRP)1 is part of the inflammasome multiprotein complex involved in the production of interleukin (IL)-1β and IL-18, two cytokines strongly implicated in psoriasis pathogenesis. Genetic variations in NLRP1 are associated with a predisposition for chronic inflammatory conditions. Objectives The aim of the study was to investigate the role of genetic variation in the NLRP1 inflammasome in psoriasis susceptibility. Material and methods Four haplotype-tagging single-nucleotide polymorphisms (SNPs) (rs6502867, rs8079034, rs878329 and rs12150220) were investigated by TaqMan allelic discrimination in a patient sample comprising 1847 individuals from 478 families and 802 healthy controls. Results Using the transmission disequilibrium test, a significant increase in the transmission of the NLRP1 rs8079034C and rs878329C alleles to patients with psoriasis was demonstrated (P = 0·006 and P = 0·033, respectively). Furthermore, homozygosity for the rs878329C allele correlated with a younger age of onset. We also observed an increase in the expression of NLRP1 mRNA in the peripheral blood cells of patients with psoriasis. This was accompanied by a higher level of circulating IL-18 and appeared to be associated with the rs878329C allele. Conclusions Our data support the involvement of NLRP1 and the NLRP1 inflammasome in psoriasis susceptibility and further support the role of innate immunity in psoriasis.