Phase I clinical trial of the Src inhibitor dasatinib with dacarbazine in metastatic melanoma.

BackgroundSrc inhibitors sensitise melanoma cells to chemotherapy in preclinical models. The combination of dasatinib and dacarbazine was tested in a phase I trial in melanoma.MethodsPatients had ECOG performance status 0-2 and normal organ function. Dacarbazine was administered on day 1 and dasatinib on day 2 through 19 of each 21-day cycle. Both were escalated from 50 mg b.i.d. of dasatinib and 800 mg m(-2) of dacarbazine. Available pre-treatment biopsies were sequenced for BRAF, NRAS, and C-Kit mutations.ResultsDose-limiting toxicity was reached at dasatinib 70 mg b.i.d./dacarbazine 1000 mg m(-2), and was predominantly haematological. In 29 patients receiving dasatinib 70 mg b.i.d., the objective response rate (ORR) was 13.8%, the clinical benefit rate (ORR+SD) was 72.4%, the 6-month progression-free survival (PFS) was 20.7%, and the 12-month overall survival (OS) was 34.5%. Two out of three patients who were wild type for BRAF, NRAS, and c-KIT mutations had confirmed partial responses, and one had a minor response.ConclusionThe recommended phase II dose is dasatinib 70 mg b.i.d with dacarbazine 800 mg m(-2). PFS and OS data for dasatinib at 70 mg b.i.d. with dacarbazine compared favourably with historical controls. Preliminary data support evaluating tumour mutation status further as a biomarker of response

National Research and Education Networks to Support Telemedicine and Telehealth

National Research and Education Networks (NRENs) worldwide are expanding capacities, including collaboration amongst teams of health scientists to create academic telehealth communities that bridge science, technology, innovation, education, assistance, and federal health authorities to discuss, seek funding and work together. The World Health Organisation promotes Universal Health Coverage (UHC) as a goal for equitable access to health services without pushing people to poverty. UHC has been adopted by the United Nations General Assembly as one of the health targets under Goal 3 on health. Using information and communication technologies to bring healthcare to people in remote areas and to those who need health services most is one of the objectives of UHC. RUTE is the Brazilian Telemedicine University Network programme, coordinated by the NREN RNP (Rede Nacional de Ensino e Pesquisa) . In September 2015 RUTE launched its 118th Telemedicine Unit, all of them located in university and teaching hospitals all over the 27 Brazilian states. Fifty-five special interest groups (SIGs) in health specialties operate over the collaborative network model with 2 to 3 scientific videoconferenced sessions every day, amongst 150 participating institutions. Last year the programme published its second book on its impact in the Brazilian Telehealth initiative as well as in Latin America. As quoted in the foreword: “It is an example of what a country can and has done and what lessons the world can learn from them.” This paper provides insight regarding the development and evaluation of the programme and may provide thoughts and even guidance to policy makers

Renal artery stenosis-when to screen, what to stent?

Renal artery stensosis (RAS) continues to be a problem for clinicians, with no clear consensus on how to investigate and assess the clinical significance of stenotic lesions and manage the findings. RAS caused by fibromuscular dysplasia is probably commoner than previously appreciated, should be actively looked for in younger hypertensive patients and can be managed successfully with angioplasty. Atheromatous RAS is associated with increased incidence of cardiovascular events and increased cardiovascular mortality, and is likely to be seen with increasing frequency. Evidence from large clinical trials has led clinicians away from recommending interventional revascularisation towards aggressive medical management. There is now interest in looking more closely at patient selection for intervention, with focus on intervening only in patients with the highest-risk presentations such as flash pulmonary oedema, rapidly declining renal function and severe resistant hypertension. The potential benefits in terms of improving hard cardiovascular outcomes may outweigh the risks of intervention in this group, and further research is needed

Congenital epulis of the jaw: a series of five cases and review of literature

This article describes five cases of congenital epulis, a rare and benign swelling in the mouth of a newborn, which is not widely known. We present five cases: four cases presented as single pedunculated nodules of the gingiva and in one case two nodules were present. Of all, 50% were located at the maxilla. Excision was performed in four of the five cases and in one case, spontaneous regression was awaited. No recurrence was reported. The characteristic features of congenital epulis are a pedunculated, flesh-pink coloured tumour with a predominant occurrence on the anterior maxillary alveolar ridge in a female newborn. Although the aetiology is unknown, most authors suggest a mesenchymal, rather than an odontogenic, origin. Endogenous hormonal factors might influence growth prenatally. Histological findings include granular cells with eosinophilic cytoplasm and small, eccentric nuclei. Despite the fact that the lesion can be a striking sight, spontaneous regression is possible and can be awaited. Indications for non-radical excision under local anaesthesia are severe upper airway obstruction and interference with feeding technique. In conclusion, we provide clinical and histological information about congenital epulis, so that this entity will be more easily recognised and relevant information given to parent

A case repot of Merkel cell carcinoma on chronic lymphocytic leukemia: differential diagnosis of coexisting lymphadenopathy and indications for early aggressive treatment

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a monoclonal disorder, characterized by a progressive proliferation of functionally incompetent B lymphocytes. There is increased evidence of association between CLL and skin cancers, including the uncommon Merkel cell carcinoma (MCC). CASE PRESENTATION: A case report of an 84-year old male, who presented with an aggressively recurrent form of MCC on the lower lip, on the background of an 8-year history of untreated CLL. During the recurrences of MCC, coexisting regional lymphadenopathy, posed a problem in the differential diagnosis and treatment of lymph node involvement. Histopathology and immunoistochemistry showed that submandibular lymphadenopathy coexisting with the second recurrence of MCC, was due to B-cell small lymphocytic lymphoma. The subsequent and more aggressive recurrence of the skin tumor had involved the superficial and deep cervical lymph nodes. Surgical excision followed by involved field radiation therapy has been proven effective for both malignancies. CONCLUSION: MCC has a high incidence of regional lymphadenopathy at presentation (12–45%) and even when it arises on the background of chronic leucemia, lymphadenopathy at presentation should be managed agressively with elective lymph node dissection. We overview the postulated correlation between Merkel tumor and CCL, the differential diagnosis of regional lymphadenopathy during the recurrences of the skin tumor and the strategies of treatmen

Risk of classic Kaposi sarcoma with exposures to plants and soils in Sicily

<p>Abstract</p> <p>Background</p> <p>Ecologic and in vitro studies suggest that exposures to plants or soil may influence risk of Kaposi sarcoma (KS).</p> <p>Methods</p> <p>In a population-based study of Sicily, we analyzed data on contact with 20 plants and residential exposure to 17 soils reported by 122 classic KS cases and 840 sex- and age-matched controls. With 88 KS-associated herpesvirus (KSHV) seropositive controls as the referent group, novel correlates of KS risk were sought, along with factors distinguishing seronegatives, in multinomial logistic regression models that included matching variables and known KS cofactors - smoking, cortisone use, and diabetes history. All plants were summed for cumulative exposure. Factor and cluster analyses were used to obtain scores and groups, respectively. Individual plants and soils in three levels of exposure with <it>P</it>_trend≤ 0.15 were retained in a backward elimination regression model.</p> <p>Results</p> <p>Adjusted for known cofactors, KS was not related to cumulative exposures to 20 plants [per quartile adjusted odds ratio (OR_adj) 0.96, 95% confidence interval (CI) 0.73 - 1.25, <it>P</it>_trend= 0.87], nor was it related to any factor scores or cluster of plants (<it>P </it>= 0.11 to 0.81). In the elimination regression model, KS risk was associated with five plants (<it>P</it>_trend= 0.02 to 0.10) and with residential exposure to six soils (<it>P</it>_trend= 0.01 to 0.13), including three soils (eutric regosol, chromic/pellic vertisol) used to cultivate durum wheat. None of the KS-associated plants and only one soil was also associated with KSHV serostatus. Diabetes was associated with KSHV seronegativity (OR_adj4.69, 95% CI 1.97 - 11.17), but the plant and soil associations had little effect on previous findings that KS risk was elevated for diabetics (OR_adj7.47, 95% CI 3.04 - 18.35) and lower for current and former smokers (OR_adj0.26 and 0.47, respectively, <it>P</it>_trend= 0.05).</p> <p>Conclusions</p> <p>KS risk was associated with exposure to a few plants and soils, but these may merely be due to chance. Study of the effects of durum wheat, which was previously associated with cKS, may be warranted.</p

History of adversity, health and psychopathology among prisoners: comparison between men and women

Adversity in childhood, risk behaviors and psychopathology are highly prevalent phenomena in inmate populations and have a strong impact on health. Knowing the differences in these variables between the sexes is most important in order to develop appropriate intervention strategies in a prison context. By administering the Socio-demographic and Life History Questionnaire and the Brief Symptoms Inventory, we sought to characterize adverse childhood experiences and relate them to risk behaviors and to psychopathological symptoms, and study the differences between the 65 male and 42 female detainees in Portuguese prison establishments. Men and women report a complex web of adversity in childhood. In a range of ten possible categories, a medium value of 5.05 (DP = 2.63) in total adversity for women and 2.63 (DP = 2.18) for men was encountered, with the prevalence being significantly higher within the female population (Z = -4.33; p = .000). A high prevalence of risk behaviors and psychopathological symptoms was found in both groups, the latter being higher among females. We concluded that the differences between men and women calls for in depth studies in order to provide guidelines for intervention projects in specific populations.Adversidade na infância, comportamentos de risco e psicopatologia são fenómenos muito prevalentes na população reclusa e com forte impacto na saúde. Conhecer as diferenças entre sexos, no que diz respeito a tais variáveis, é de elevada importância no sentido de adequar estraté- gias de intervenção em contexto prisional. Utilizando o Questionário Sociodemográfico e Histó- ria de Vida, o Questionário de Adversidade na Infância e o Brief Symptons Inventory, procuramos caracterizar a adversidade na infância, os comportamentos de risco e as dimensões psicopatológicas, e averiguar as diferenças entre 65 homens e 42 mulheres reclusos em estabelecimentos prisionais Portugueses. Homens e mulheres relatam um quadro complexo de adversidade na infância. Num total possível de dez categorias, verificamos uma média de adversidade total de 5.05 (DP = 2.63) para as mulheres e de 2.63 (DP = 2.18) para os homens, sendo a prevalência significativamente mais elevada junto da população feminina (Z = -4.33; p = .000). Foi ainda encontrada uma elevada prevalência de comportamentos de risco e de sintomatologia psicopatológica em ambos os grupos, sendo esta última superior nas mulheres. Concluímos que as diferenças entre sexos devem ser estudadas para guiarem a adequação dos projetos

In Vivo Depletion of Lymphotoxin-Alpha Expressing Lymphocytes Inhibits Xenogeneic Graft-versus-Host-Disease

Graft-versus-host disease (GVHD) is a major barrier to successful allogeneic hematopoietic cell transplantation and is largely mediated by activated donor lymphocytes. Lymphotoxin (LT)-α is expressed by subsets of activated T and B cells, and studies in preclinical models demonstrated that targeted depletion of these cells with a mouse anti-LT-α monoclonal antibody (mAb) was efficacious in inhibiting inflammation and autoimmune disease. Here we demonstrate that LT-α is also upregulated on activated human donor lymphocytes in a xenogeneic model of GVHD and targeted depletion of these donor cells ameliorated GVHD. A depleting humanized anti-LT-α mAb, designated MLTA3698A, was generated that specifically binds to LT-α in both the soluble and membrane-bound forms, and elicits antibody-dependent cellular cytotoxicity (ADCC) activity in vitro. Using a human peripheral blood mononuclear cell transplanted SCID (Hu-SCID) mouse model of GVHD, the anti-human LT-α mAb specifically depleted activated LT-expressing human donor T and B cells, resulting in prolonged survival of the mice. A mutation in the Fc region, rendering the mAb incapable of mediating ADCC, abolished all in vitro and in vivo effects. These data support a role for using a depleting anti-LT-α antibody in treating immune diseases such as GVHD and autoimmune diseases

Intracellular insulin in human tumors: examples and implications

Insulin is one of the major metabolic hormones regulating glucose homeostasis in the organism and a key growth factor for normal and neoplastic cells. Work conducted primarily over the past 3 decades has unravelled the presence of insulin in human breast cancer tissues and, more recently, in human non-small cell lung carcinomas (NSCLC). These findings have suggested that intracellular insulin is involved in the development of these highly prevalent human tumors. A potential mechanism for such involvement is insulin's binding and inactivation of the retinoblastoma tumor suppressor protein (RB) which in turn is likely controlled by insulin-degrading enzyme (IDE). This model and its supporting data are collectively covered in this survey in order to provide further insight into insulin-driven oncogenesis and its reversal through future anticancer therapeutics