Treatment of adult-onset Still's disease: a review

Adult-onset Still's disease (AOSD) is a rare inflammatory disorder that has been recently classified as a polygenic autoinflammatory disorder. The former classification, based on the disease course, seems to be quite dated. Indeed, there is accumulating evidence that AOSD can be divided into two distinct phenotypes based on cytokine profile, clinical presentation, and outcome, ie, a "systemic" pattern and an "articular" pattern. The first part of this review deals with the treatments that are currently available for AOSD. We then present the different strategies based on the characteristics of the disease according to clinical presentation. To do so, we focus on the two subsets of the disease. Finally, we discuss the management of life-threatening complications of AOSD, along with the therapeutic options during pregnancy

Development and Validation of a Bedside Score to Predict Early Death in Cancer of Unknown Primary Patients

BACKGROUND: We have investigated predictors of 90-day-mortality in a large cohort of non-specific cancer of unknown primary patients. METHODS: Predictors have been identified by univariate and then logistic regression analysis in a single-center cohort comprising 429 patients (development cohort). We identified four predictors that produced a predictive score that has been applied to an independent multi-institutional cohort of 409 patients (validation cohort). The score was the sum of predictors for each patient (0 to 4). RESULTS: The 90-day-mortality-rate was 33 and 26% in both cohorts. Multivariate analysis has identified 4 predictors for 90-day-mortality: performance status>1 (OR = 3.03, p = 0.001), at least one co-morbidity requiring treatment (OR = 2.68, p = 0.004), LDH>1.5 x the upper limit of normal (OR = 2.88, p = 0.007) and low albumin or protein levels (OR = 3.05, p = 0.007). In the development cohort, 90-day-mortality-rates were 12.5%, 32% and 64% when the score was [0-1], 2 and [3]-[4], respectively. In the validation cohort, risks were 13%, 25% and 62% according to the same score values. CONCLUSIONS: We have validated a score that is easily calculated at the beside that estimates the 90-days mortality rate in non-specific CUP patients. This could be helpful to identify patients who would be better served with palliative care rather than aggressive chemotherapy

A novel observation of pubic osteomyelitis due to Streptococcus viridans after dental extraction: a case report

<p>Abstract</p> <p>Introduction</p> <p>Pubic osteomyelitis should be suspected in athletic individuals with sudden groin pain, painful restriction of hip movements and fever. It is an infrequent and confusing disorder, which is often heralded by atypical gait disturbance and diffuse pain in the pelvic girdle. The most common pathogen is <it>Staphylococcus aureus </it>but, on occasions, efforts to identify infectious agents sometimes prove negative. Pubic osteomyelitis due to <it>Streptococcus viridans </it>has not been reported previously in the literature.</p> <p>Case presentation</p> <p>We describe the case of a fit 24-year-old athlete, who had a wisdom tooth extracted 2 weeks prior to the presentation, which could have served as a port of entry and predisposed the patient to transient bacteraemia.</p> <p>Conclusion</p> <p><it>S. viridans </it>is well known for causing infective endocarditis of native damaged heart valves, but to the best of the authors' knowledge it has not been reported previously as a cause of pubic osteomyelitis. We believe that this case should alert physicians to the association between dental procedures and osteomyelitis of the pubis secondary to <it>S. viridans</it>.</p

Paclitaxel resistance is associated with switch from apoptotic to autophagic cell death in MCF-7 breast cancer cells

Taxanes remain first line chemotherapy in management of metastatic breast cancer and have a key role in epithelial ovarian cancer, with increasingly common use of weekly paclitaxel dosing regimens. However, their clinical utility is limited by the development of chemoresistance. To address this, we modelled in vitro paclitaxel resistance in MCF-7 cells. We show that at clinically relevant drug doses, emerging paclitaxel resistance is associated with profound changes in cell death responses and a switch from apoptosis to autophagy as the principal mechanism of drug-induced cytotoxicity. This was characterised by a complete absence of caspase-mediated apoptotic cell death (using the pan-caspase-inhibitor Z-VAD) in paclitaxel-resistant MCF-7TaxR cells, compared with parent MCF-7 or MDA-MB-231 cell lines on paclitaxel challenge, downregulation of caspase-7, caspase-9 and BCl2-interacting mediator of cell death (BIM) expression. Silencing with small interfering RNA to BIM in MCF-7 parental cells was sufficient to confer paclitaxel resistance, inferring the significance in downregulation of this protein in contributing to the resistant phenotype of the MCF-7TaxR cell line. Conversely, there was an increased autophagic response in the MCF-7TaxR cell line with reduced phospho-mTOR and relative resistance to the mTOR inhibitors rapamycin and RAD001. In conclusion, we show for the first time that paclitaxel resistance is associated with profound changes in cell death response with deletion of multiple apoptotic factors balanced by upregulation of the autophagic pathway and collateral sensitivity to platinum

Specific β-Tubulin Isotypes Can Functionally Enhance or Diminish Epothilone B Sensitivity in Non-Small Cell Lung Cancer Cells

Epothilones are a new class of microtubule stabilizing agents with promising preclinical and clinical activity. Their cellular target is β-tubulin and factors influencing intrinsic sensitivity to epothilones are not well understood. In this study, the functional significance of specific β-tubulin isotypes in intrinsic sensitivity to epothilone B was investigated using siRNA gene knockdown against βII-, βIII- or βIVb-tubulins in two independent non-small cell lung cancer (NSCLC) cell lines, NCI-H460 and Calu-6. Drug-treated clonogenic assays showed that sensitivity to epothilone B was not altered following knockdown of βII-tubulin in both NSCLC cell lines. In contrast, knockdown of βIII-tubulin significantly increased sensitivity to epothilone B. Interestingly, βIVb-tubulin knockdowns were significantly less sensitive to epothilone B, compared to mock- and control siRNA cells. Cell cycle analysis of βIII-tubulin knockdown cells showed a higher percentage of cell death with epothilone B concentrations as low as 0.5 nM. In contrast, βIVb-tubulin knockdown cells displayed a decrease in epothilone B-induced G2-M cell cycle accumulation compared to control siRNA cells. Importantly, βIII-tubulin knockdowns displayed a significant dose-dependent increase in the percentage of apoptotic cells upon treatment with epothilone B, as detected using caspase 3/7 activity and Annexin-V staining. Higher concentrations of epothilone B were required to induce apoptosis in the βIVb-tubulin knockdowns compared to control siRNA, highlighting a potential mechanism underlying decreased sensitivity to this agent. This study demonstrates that specific β-tubulin isotypes can influence sensitivity to epothilone B and may influence differential sensitivity to this promising new agent

Detection of primary sites in unknown primary tumors using FDG-PET or FDG-PET/CT

<p>Abstract</p> <p>Background</p> <p>Carcinoma of unknown primary tumors (CUP) is present in 0.5%-9% of all patients with malignant neoplasms; only 20%-27% of primary sites are identified before the patients die. Currently, 18F-fluorodeoxy-glucose positron-emission tomography (18F-FDG PET) or PET combined with computed tomography (PET/CT) is widely used for the diagnosis of CUP. However, the diagnostic yield of the primary site varies. The aim of this study was to determine whether PET or PET/CT has additional advantages over the conventional diagnostic workup in detecting the primary origin of CUP.</p> <p>Findings</p> <p>Twenty patients with unknown primary tumors that underwent PET or PET/CT were included in this study. For all patients, the conventional diagnostic workup was unsuccessful in detecting the primary sites. Among 20 patients, 11 had PET scans. The remaining nine patients had PET/CT. In all 20 patients, neither the PET nor PET/CT identified the primary site of the tumor, including six cases with cervical lymph node metastases. The PET and PET/CT revealed sites of FDG uptake other than those associated with known metastases in seven patients, but these findings did not influence patient management or therapy. Two patients had unnecessary invasive diagnostic procedures due to false positive results on the PET or PET/CT.</p> <p>Conclusions</p> <p>Although it is inconclusive because of small sample size of the study, the additional value of PET or PET/CT for the detection of primary sites in patients with CUP might be less than expected; especially in patients that have already had extensive conventional diagnostic workups. Further study is needed to confirm this finding.</p

Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: fundamentals of care for uveitis (focus) initiative

Topic: An international, expert-led consensus initiative to develop systematic, evidence-based recommendations for the treatment of noninfectious uveitis in the era of biologics. Clinical Relevance: The availability of biologic agents for the treatment of human eye disease has altered practice patterns for the management of noninfectious uveitis. Current guidelines are insufficient to assure optimal use of noncorticosteroid systemic immunomodulatory agents. Methods: An international expert steering committee comprising 9 uveitis specialists (including both ophthalmologists and rheumatologists) identified clinical questions and, together with 6 bibliographic fellows trained in uveitis, conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol systematic reviewof the literature (English language studies from January 1996 through June 2016; Medline [OVID], the Central Cochrane library, EMBASE,CINAHL,SCOPUS,BIOSIS, andWeb of Science). Publications included randomized controlled trials, prospective and retrospective studies with sufficient follow-up, case series with 15 cases or more, peer-reviewed articles, and hand-searched conference abstracts from key conferences. The proposed statements were circulated among 130 international uveitis experts for review.Atotal of 44 globally representativegroupmembersmet in late 2016 to refine these guidelines using a modified Delphi technique and assigned Oxford levels of evidence. Results: In total, 10 questions were addressed resulting in 21 evidence-based guidance statements covering the following topics: when to start noncorticosteroid immunomodulatory therapy, including both biologic and nonbiologic agents; what data to collect before treatment; when to modify or withdraw treatment; how to select agents based on individual efficacy and safety profiles; and evidence in specific uveitic conditions. Shared decision-making, communication among providers and safety monitoring also were addressed as part of the recommendations. Pharmacoeconomic considerations were not addressed. Conclusions: Consensus guidelines were developed based on published literature, expert opinion, and practical experience to bridge the gap between clinical needs and medical evidence to support the treatment of patients with noninfectious uveitis with noncorticosteroid immunomodulatory agents

Insulin Storage and Glucose Homeostasis in Mice Null for the Granule Zinc Transporter ZnT8 and Studies of the Type 2 Diabetes–Associated Variants

International audienceObjective. Zinc ions are essential for the formation of hexameric insulin and hormone crystallisation. Correspondingly, a non-synonymous single nucleotide polymorphism rs13266634 in the SLC30A8 gene, encoding the secretory granule zinc transporter ZnT8, is associated with type 2 diabetes. Here, we describe the effects of deleting the ZnT8 gene in mice and explore the action of the at-risk allele. Research Design and Methods. Slc30a8 null mice were generated and backcrossed at least twice onto a C57BL/6J background. Glucose and insulin tolerance were measured by intraperitoneal injection, or euglycemic clamp, respectively. Insulin secretion, electrophysiology, imaging, and the generation of adenoviruses encoding the low- (W325) or elevated- (R325) risk ZnT8 alleles, were undertaken using standard protocols. Results. ZnT8(-/-) mice displayed age, sex and diet-dependent abnormalities in glucose tolerance, insulin secretion and body weight. Islets isolated from null mice had reduced granule zinc content, and showed age-dependent changes in granule morphology, with markedly fewer dense cores but more rod-like crystals. Glucose-stimulated insulin secretion, granule fusion and insulin crystal dissolution, as assessed by total internal reflection fluorescence microscopy, were unchanged or enhanced in ZnT8(-/-) islets. Insulin processing was normal. Molecular modelling revealed that residue-325 was located at the interface between ZnT8 monomers. Correspondingly, the R325 variant displayed lower apparent Zn(2+) transport activity than W325 ZnT8 by fluorescence-based assay. Discussion and conclusions. ZnT8 is required for normal insulin crystallisation and insulin release in vivo but not, remarkably, in vitro. Defects in the former processes in carriers of the R allele may increase type 2 diabetes risk