Deletion of NAD(P)H Oxidase 2 Prevents Angiotensin II-Induced Skeletal Muscle Atrophy

Skeletal muscle atrophy is induced by an imbalance between protein synthesis and degradation. Our previous studies reported that angiotensin II (AII) directly induced muscle atrophy in mice. This study investigated the role of NAD(P)H oxidase 2 (Nox2) activation by AII in the induction of skeletal muscle atrophy. For 4 weeks, either saline (vehicle: V) or AII (1000 ng kg−1 min−1) was infused into male wild-type (WT) and Nox2 knockout (KO) mice via osmotic minipumps. Experiments were performed in the following 4 groups: WT + V, KO + V, WT + AII, and KO + AII. Body weight, muscle weight, and myocyte cross-sectional area were significantly decreased in WT + AII compared to WT + V mice, and these changes were not observed in KO + AII mice. Akt phosphorylation of Ser473 and p70S6K of Thr389 was decreased, gene expression levels of MuRF-1 and atrogin-1 were increased in WT + AII compared to WT + V, and these changes were significantly attenuated in KO + AII mice. The deletion of Nox2 prevented AII-induced skeletal muscle atrophy via improving the balance between protein synthesis and degradation. Therefore, Nox2 may be a therapeutic target for AII-induced skeletal muscle atrophy.

http://ift.tt/2qf0bh8

Epidemiological Profile and Risk Factors for Acquiring HBV and/or HCV in HIV-Infected Population Groups in Nepal

HBV and HCV infections are widespread among the HIV-infected individuals in Nepal. The goals of this study were to investigate the epidemiological profile and risk factors for acquiring HBV and/or HCV coinfection in disadvantaged HIV-positive population groups in Nepal. We conducted a retrospective study on blood samples from HIV-positive patients from the National Public Health Laboratory at Kathmandu to assay for HBsAg, HBeAg, and anti-HCV antibodies, HIV viral load, and CD4+ T cell count. Among 579 subjects, the prevalence of HIV-HBV, HIV-HCV, and HIV-HBV-HCV coinfections was 3.62%, 2.93%, and 0.34%, respectively. Multivariate regression analysis indicated that spouses of HIV-positive migrant labourers were at significant risk for coinfection with HBV infection, and an age of >40 years in HIV-infected individuals was identified as a significant risk factor for HCV coinfection. Overall our study indicates that disadvantaged population groups such as intravenous drug users, migrant workers and their spouses, female sex workers, and men who have sex with HIV-infected men are at a high and persistent risk of acquiring viral hepatitis. We conclude that Nepalese HIV patients should receive HBV and HCV diagnostic screening on a regular basis.

http://ift.tt/2lAVsBY

What happens next? Recurrence Rates for First Unprovoked Seizures in Children

Abstract

Seizures represent approximately 1% of all ED visits in the United States. ¹ Unprovoked first seizures in children commonly present to the Emergency Department (ED), and even after the neurological exam normalizes, the prospect of recurrence can be a source of great anxiety for caregivers. ² Compared to febrile seizures, unprovoked seizures carry a higher rate of recurrence and epilepsy. Previous studies focused on long term recurrence and the cumulative risk of a second seizure was 29%, 37%, 43%, and 46% at 1, 2, 5, and 10 years, respectively. ³ There has been limited information on the short-term risk of recurrence to guide emergency physicians.

This article is protected by copyright. All rights reserved.

http://ift.tt/2Cd5FuB

Dr. Rodgers’ Last Lessons: reflections after the death of a mentor

Abstract

The Indiana University emergency medicine family is grieving. We, the residency program directors, are grieving. The Monday morning before Thanksgiving, Dr. Kevin Rodgers, KRodge, a lifelong educator and mentor to most of us, was killed in his home following his overnight shift. Kevin's death has shaken us deeply and we are tired from crying. As emergency physicians, we're supposed to know about death – we see it regularly; we write about it in our literature; we comfort the families of our dying patients. But when it is one of our own – a father-figure – we don't know how to react. We can't compartmentalize this. As a way to try to find meaning out of the senselessness, we've been reflecting on what it means to be an emergency medicine educator.

This article is protected by copyright. All rights reserved.

http://ift.tt/2CzNX5j

Skin cancer rates in North Rhine-Westphalia, Germany before and after the introduction of the nationwide skin cancer screening program (2000–2015)

Abstract

Germany is the first nation that implemented a nationwide skin cancer screening program in 2008. The aim is to study the effect of the program on skin cancer rates and to estimate the number needed to screen for an unselected and a hypothetical high-risk population in Germany. We used population-based data on skin cancer incidence (2000–2014), mortality, hospitalization and sick leave (2000–2015) from North Rhine-Westphalia, Germany (18 million population). We calculated annual age-standardized rates per 100,000 person years and calculated the relative change of the rates (%) including 95% confidence intervals (95% CI). Between 2007 and 2014, the estimated annual percentage change (EAPC) of the age-standardized incidence rate of skin melanoma was 3.8% among men and women. These increases were accompanied by increases of the age-standardized mortality rates (EAPC men 3.2%, women 2.0%) and age-standardized sick leave rates (EAPC men 11.0%, women 6.1%). Hospitalization rates showed barely any change. All types of rates for nonmelanoma skin cancer showed marked increases. The number needed to screen for skin melanoma death would be 34,000 if the risk reduction due to screening would be 50%. In a hypothetical high-risk approach with 10% of the population at high risk, that is, a relative risk of melanoma death of 4.0, a skin melanoma mortality risk reduction of 50% among these people due to screening would result in a reduction of the skin melanoma mortality by 15% in the total population. However, this reduction would require a number needed to screen of 11,141. Seven years after the introduction of the skin cancer screening program, there is no discernible beneficial effect at population level. The estimated number needed to screen for skin melanoma in an unselected approach is high and a realistic high-risk approach is currently not feasible.

http://ift.tt/2DOmvAu

Hypothetical interventions to prevent stroke: an application of the parametric g-formula to a healthy middle-aged population

Abstract

The effects of interventions on multiple lifestyle and metabolic risk factors, initiated in midlife or later in a healthy population, on the long-term risk of first-ever stroke is not known. A particular methodological challenge in observational studies is to estimate the unbiased effect of a time-varying exposure in presence of time-varying confounders, if those confounders are affected by prior exposure. In such cases, the parametric g-formula can be applied to estimate an unbiased effect. We applied the parametric g-formula to estimate the 18-years (1994–2012) cumulative stroke risk under different scenarios of hypothetical interventions on levels of blood pressure, cholesterol, weight, physical activity, smoking and alcohol intake; and compared these to the observed scenario, to calculate the population risk ratios and risk differences. Among 14,796 eligible participants in the prospective, population-based Tromsø study (baseline mean age 46.1 years, 51% women), the observed 18-years stroke risk was 5.9%. A feasible joint hypothetical intervention on six lifestyle and metabolic risk factors would reduce the 18-year stroke risk by 32% (95% confidence interval 16, 44). A combination of more intensive interventions reduced the estimated 18-years stroke risk by 64% (95% confidence interval 40, 80). Blood pressure reduction and quitting smoking significantly reduced the risk when applied separately.

http://ift.tt/2CEG4LS

Differential efficacy of cisplatin plus pemetrexed between L858R and Del-19 in advanced EGFR -mutant non-squamous non-small cell lung cancer

Abstract

Background

LUX-Lung 3 showed afatinib improved progression-free survival (PFS) compared with cisplatin plus pemetrexed in patients with epidermal growth factor receptor (EGFR) mutations. In this study, chemotherapy efficacy tended to differ between patients with Leu858Arg (L858R) point mutation and Exon 19 deletion (Del-19); PFS in L858R patients (8.1 months) was greater than in Del-19 patients (5.6 months). We investigated whether there is any difference in efficacy of cisplatin plus pemetrexed between Del-19 and L858R.

Methods

This study is a multicenter retrospective study. We reviewed medical records of patients who had received cisplatin plus pemetrexed as first line chemotherapy. Efficacies were evaluated between EGFR mutation status: Del-19 and L858R. Wild type cases were reference arm only, and not included in any statistical analysis.

Results

Among 304 patients, 78 (25.7%) harbored EGFR mutations: Del-19 (36/78 patients, 46.2%); and L858R (42/78, 53.8%). Median PFS of L858R group (9.4 months, 95% confidence interval [CI]: 7.0–12.6) was significantly longer than Del-19 group (5.5 months, 95% CI, 3.6–8.6) (p = 0.049). Response rate (RR) and OS presented no significant difference between L858R and Del-19. In multivariate analysis, EGFR mutation status (L858R versus Del-19) was the only significant factor for longer PFS (Hazard ratio [HR]: 0.78, 95% CI: 0.62–0.98) (p = 0.033).

Conclusion

Our study indicated better efficacy of cisplatin plus pemetrexed in L858R than in Del-19 patients. In EGFR-mutant NSCLC, EGFR-TKIs are undoubtedly the premier therapy. However, in second line or later settings, cisplatin plus pemetrexed regimen may confer higher efficacy for L858R patients.

http://ift.tt/2lDwwJR

Heterogeneity of PD-L1 expression in primary tumors and paired lymph node metastases of triple negative breast cancer

Abstract

Background

Programmed cell death ligand 1 (PD-L1) is a potential predictive biomarker of the response to anti-PD-L1/anti- programmed cell death 1 (PD-1) therapy in multiple cancers, including triple negative breast cancer(TNBC). The purpose of this study was to investigate whether PD-L1 expression is homogenous in primary tumors(PTs) and synchronous axillary lymph node metastases(LNMs) of TNBC.

Methods

PD-L1 expression was immunohistochemically evaluated in 101 TNBC patients' PTs and paired LNMs. PD-L1 expression in tumor cells and infiltrating immune cells or node lymphocytes in the PTs and associated LNMs was scored separately and was correlated with patients' clinical parameters and prognoses.

Results

PD-L1 expression exhibited spatial heterogeneity in both the tumor cells and the infiltrating immune cells or node lymphocytes of PTs and LNMs. The PD-L1 expression levels were significantly higher in the lymphocytes and tumor cells of the LNMs than in the PTs. PD-L1 expression was also more frequent among the LNMs. PD-L1 expression was associated with high grade and more stromal tumor-infiltrating lymphocytes(TILs). Furthermore, the disease-free survival and overall survival were similar between the PT- negative/LNM- positive and PT- positive/LNM- positive patients, both of which exhibited worse disease-free survival(DFS) thanPT -negative/LNM -negative patients.

Conclusions

The differential expression of PD-L1 between the PTs and LNMs suggests that LNMs PD-L1 status may be used to indicate whether PD-1/PD-L1-targeted therapy would be suitable for a node-positive TNBC patient in the future.

http://ift.tt/2qaR8y2

Improving zebrafish embryo xenotransplantation conditions by increasing incubation temperature and establishing a proliferation index with ZFtool

Abstract

Background

Zebrafish (Danio rerio) is a model organism that has emerged as a tool for cancer research, cancer being the second most common cause of death after cardiovascular disease for humans in the developed world. Zebrafish is a useful model for xenotransplantation of human cancer cells and toxicity studies of different chemotherapeutic compounds in vivo. Compared to the murine model, the zebrafish model is faster, can be screened using high-throughput methods and has a lower maintenance cost, making it possible and affordable to create personalized therapies. While several methods for cell proliferation determination based on image acquisition and quantification have been developed, some drawbacks still remain. In the xenotransplantation technique, quantification of cellular proliferation in vivo is critical to standardize the process for future preclinical applications of the model.

Methods

This study improved the conditions of the xenotransplantation technique – quantification of cellular proliferation in vivo was performed through image processing with our ZFtool software and optimization of temperature in order to standardize the process for a future preclinical applications. ZFtool was developed to establish a base threshold that eliminates embryo auto-fluorescence and measures the area of marked cells (GFP) and the intensity of those cells to define a 'proliferation index'.

Results

The analysis of tumor cell proliferation at different temperatures (34 °C and 36 °C) in comparison to in vitro cell proliferation provides of a better proliferation rate, achieved as expected at 36°, a maintenance temperature not demonstrated up to now. The mortality of the embryos remained between 5% and 15%. 5- Fluorouracil was tested for 2 days, dissolved in the incubation medium, in order to quantify the reduction of the tumor mass injected. In almost all of the embryos incubated at 36 °C and incubated with 5-Fluorouracil, there was a significant tumor cell reduction compared with the control group. This was not the case at 34 °C.

Conclusions

Our results demonstrate that the proliferation of the injected cells is better at 36 °C and that this temperature is the most suitable for testing chemotherapeutic drugs like the 5-Fluorouracil.

http://ift.tt/2lDwp0T

Identification of fluorescence in situ hybridization assay markers for prediction of disease progression in prostate cancer patients on active surveillance

Abstract

Background

Prostate Cancer (PCa) is the second most prevalent cancer among U.S. males. In recent decades many men with low risk PCa have been over diagnosed and over treated. Given significant co-morbidities associated with definitive treatments, maximizing patient quality of life while recognizing early signs of aggressive disease is essential. There remains a need to better stratify newly diagnosed men according to the risk of disease progression, identifying, with high sensitivity and specificity, candidates for active surveillance versus intervention therapy. The objective of this study was to select fluorescence in situ hybridization (FISH) panels that differentiate non-progressive from progressive disease in patients with low and intermediate risk PCa.

Methods

We performed a retrospective case-control study to evaluate FISH biomarkers on specimens from PCa patients with clinically localised disease (T1c-T2c) enrolled in Watchful waiting (WW)/Active Surveillance (AS). The patients were classified into cases (progressed to clinical intervention within 10 years), and controls (did not progress in 10 years). Receiver Operating Characteristic (ROC) curve analysis was performed to identify the best 3–5 probe combinations. FISH parameters were then combined with the clinical parameters ─ National Comprehensive Cancer Network (NNCN) risk categories ─ in the logistic regression model.

Results

Seven combinations of FISH parameters with the highest sensitivity and specificity for discriminating cases from controls were selected based on the ROC curve analysis. In the logistic regression model, these combinations contributed significantly to the prediction of PCa outcome. The combination of NCCN risk categories and FISH was additive to the clinical parameters or FISH alone in the final model, with odds ratios of 5.1 to 7.0 for the likelihood of the FISH-positive patients in the intended population to develop disease progression, as compared to the FISH-negative group.

Conclusions

Combinations of FISH parameters discriminating progressive from non-progressive PCa were selected based on ROC curve analysis. The combination of clinical parameters and FISH outperformed clinical parameters alone, and was complimentary to clinical parameters in the final model, demonstrating potential utility of multi-colour FISH panels as an auxiliary tool for PCa risk stratification. Further studies with larger cohorts are planned to confirm these findings.

http://ift.tt/2q7N2GE

An inflammation-based cumulative prognostic score system in patients with diffuse large B cell lymphoma in rituximab era

Abstract

Background

Systemic inflammatory parameters are associated with poor outcomes in malignant patients. Several inflammation-based cumulative prognostic score systems were established for various solid tumors. However, there is few inflammation based cumulative prognostic score system for patients with diffuse large B cell lymphoma (DLBCL).

Methods

We retrospectively reviewed 564 adult DLBCL patients who had received rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) therapy between Nov 1 2006 and Dec 30 2013 and assessed the prognostic significance of six systemic inflammatory parameters evaluated in previous studies by univariate and multivariate analysis:C-reactive protein(CRP), albumin levels, the lymphocyte-monocyte ratio (LMR), the neutrophil-lymphocyte ratio(NLR), the platelet-lymphocyte ratio(PLR)and fibrinogen levels.

Results

Multivariate analysis identified CRP, albumin levels and the LMR are three independent prognostic parameters for overall survival (OS). Based on these three factors, we constructed a novel inflammation-based cumulative prognostic score (ICPS) system. Four risk groups were formed: group ICPS = 0, ICPS = 1, ICPS = 2 and ICPS = 3. Advanced multivariate analysis indicated that the ICPS model is a prognostic score system independent of International Prognostic Index (IPI) for both progression-free survival (PFS) (p < 0.001) and OS (p < 0.001). The 3-year OS for patients with ICPS =0, ICPS =1, ICPS =2 and ICPS =3 were 95.6, 88.2, 76.0 and 62.2%, respectively (p < 0.001). The 3-year PFS for patients with ICPS = 0–1, ICPS = 2 and ICPS = 3 were 84.8, 71.6 and 54.5%, respectively (p < 0.001).

Conclusions

The prognostic value of the ICPS model indicated that the degree of systemic inflammatory status was associated with clinical outcomes of patients with DLBCL in rituximab era. The ICPS model was shown to classify risk groups more accurately than any single inflammatory prognostic parameters. These findings may be useful for identifying candidates for further inflammation-related mechanism research or novel anti-inflammation target therapies.

http://ift.tt/2lDwfqj

Positron emission tomography-magnetic resonance imaging (PET-MRI) for response assessment after radiation therapy of cervical carcinoma: a pilot study

Abstract

Background

Advanced stage cervical cancer is primarily treated by radiotherapy. Local tumor control is a prerequisite for cure. Imaging after treatment is controversial. Positron emission tomography (PET) combined with computer tomography (PET-CT) shows great promise for detecting metastases. On the other hand, magnetic resonance imaging (MRI) is superior in depicting anatomical details. The combination of PET-MRI could result in more accurate evaluation of cervical cancer treatment outcome. The aim of this pilot study is to share our initial experience with PET-MRI in the evaluation of treatment response in cervical cancer after radiation treatment.

Methods

Ten patients with cervical carcinoma (FIGO ≥IB2) were prospectively evaluated. Eleven weeks (median; range 8–15 weeks) after radiation therapy, treatment response was evaluated by PET-MRI. The PET, MRI, and combined PET-MRI images were evaluated for the presence of local residual tumor and metastasis. Diagnostic performance was assessed by area under the receiver operator characteristic (ROC) curve for evaluation of local residual tumor. The readers were blinded for outcome data. Local residual disease, metastasis, diagnostic confidence, and change of opinion were scored on a 5-point Likert scale. The reference standard consisted of pathology and/or follow-up according to the clinical guidelines.

Results

Three out of ten patients had local residual abnormalities suggestive for tumor residue after radiation treatment. The availability of both PET and MRI resulted in an increase in diagnostic confidence in 80–90% of all patients. Change of opinion was observed in 70% and change of policy in 50%, especially in the group with residual tumor. The diagnostic accuracy increased significantly for the radiologist if PET-MRI was combined (AUC .54 versus .83).

Conclusions

PET-MRI shows promise for evaluation of treatment response after radiation for cervical cancer, especially increasing diagnostic confidence, while potentially increasing diagnostic performance.

http://ift.tt/2lAD2RA

Prognostic parameters of luminal A and luminal B intrinsic breast cancer subtypes of Pakistani patients

Abstract

Background

Prognosis of breast cancer and success of therapeutic interventions largely rely on the clinico-pathologic and biological characteristics of the tumor and vary due to the heterogeneous nature of breast cancers. The aim of this study was to determine the frequency and prognostic parameters of luminal breast cancers in our population to devise targeted and personalized therapeutic regimens tailored to the needs of the loco-regional population.

Methods

A retrospective cross-sectional study including 1951 cases of primary breast cancer treated at Liaquat National Hospital Karachi was conducted during the year 2011–2016. The clinico-pathologic characteristics were observed and semiquantitative immunohistochemical analysis was performed to study the luminal subtypes A and B. The cross-tabulated statistics of the observed characteristics were performed between the two subtypes. The significance level of each characteristic was estimated utilizing the chi-square test.

Results

Luminal cancers comprised 62.7% of the total number of cases diagnosed with breast cancers in the study period. Out of these 1224 cases of luminal cancers, 845 cases (69%) were luminal B, while 379 (31%) cases were of luminal A. Luminal B cancers were significantly more common in younger age groups as compared to luminal A cancers. Comparison of the two subtypes of luminal breast cancers revealed significant differences. Luminal B cancers were associated with higher grade (26% grade III in luminal B compared to 8% in luminal A), micropapillary histology, and high frequency of nodal metastasis (54 vs. 43%).

Conclusions

Luminal B comprised the most frequent subtype of breast cancer in our study and they were found more constantly in a younger age group. Moreover, they were associated with adverse clinico-histologic parameters like higher grade and nodal metastasis. Therefore, we suggest that, despite lack of widespread availability of molecular studies in our setup, IHC-based typing should be done in every case of breast cancer to individualize therapy.

http://ift.tt/2q7EyiM

Feasibility and acceptability of combining cognitive behavioural therapy techniques with swallowing therapy in head and neck cancer dysphagia

Abstract

Background

Head and neck cancer squamous cell carcinoma (HNSSC) patients report substantial rates of clinically significant depression and/or anxiety, with dysphagia being a predictor of distress and poorer quality of life. Evidence-based dysphagia interventions largely focus on the remediation of physical impairment. This feasibility study evaluates an intervention which simultaneously uses a psychological therapy approach combined with swallowing impairment rehabilitation.

Methods

This prospective single cohort mixed-methods study, recruited HNSCC patients with dysphagia, from two institutions. The intervention combined Cognitive Behavioural Therapy with swallowing therapy (CB-EST), was individually tailored, for up to 10 sessions and delivered by a speech and language therapist. Primary acceptability and feasibility measures included recruitment and retention rates, data completion, intervention fidelity and the responsiveness of candidate outcome measures. Measures included a swallowing questionnaire (MDADI), EORTC-QLQH&N35, dietary restrictions scale, fatigue and function scales and the Hospital Anxiety and Depression Scale (HADS), administered pre-, post-CB-EST with three month follow-up and analysed using repeated measures ANOVA. Qualitative interviews were conducted to evaluate intervention processes.

Results

A total of 30/43 (70%) eligible patients agreed to participate and 25 completed the intervention. 84% were male, mean age 59 yrs. Patients were between 1 and 60 months (median 4) post-cancer treatment. All patients had advanced stage disease, treated with surgery and radiotherapy (38%) or primary chemoradiotherapy (62%). Pre to post CB-EST data showed improvements in MDADI scores (p = 0.002), EORTC-QLQH&N35 (p = 0.006), dietary scale (p < 0.0001), fatigue (p = 0.002) but no change in function scales or HADS. Barriers to recruitment were the ability to attend regular appointments and patient suitability or openness to a psychological-based intervention.

Conclusions

CB-EST is a complex and novel intervention, addressing the emotional, behavioural and cognitive components of dysphagia alongside physical impairment. Preliminary results are promising. Further research is required to evaluate efficacy and effectiveness.

http://ift.tt/2qbl2Cl

Incidence of interstitial pneumonitis in non-Hodgkin’s lymphoma patients receiving immunochemotherapy with pegylated liposomal doxorubicin and rituximab

Abstract

Pneumonitis is a rare but severe and potentially fatal adverse effect in chemotherapy of lymphoma. This study is aimed to investigate the incidence of interstitial pneumonitis in non-Hodgkin's lymphoma (NHL) patients receiving immunochemotherapy with pegylated liposomal doxorubicin and rituximab. Lymphoma patients were retrospectively reviewed, and eligible patients were included in this study. According to the chemotherapy regimens, patients were classified in four groups: combination of vincristine, cyclophosphamide, doxorubicin, and prednisone (CHOP group) with rituximab (RCHOP group) and combination of vincristine, cyclophosphamide, pegylated liposomal doxorubicin and prednisone (CDOP group) with rituximab (RCDOP group). Incidence and severity of interstitial pneumonitis were compared among the four groups. Among 757 patients reviewed, 207 patients were included in final analysis. Thirteen patients developed chemotherapy-induced interstitial pneumonitis, and the mean cycle of chemotherapy before the onset of pneumonitis was 4. Incidence rates of pneumonitis were 0, 1.8, 17.4, and 21.1% in CHOP, RCHOP, CDOP, and RCDOP groups, respectively (p < 0.001). The mean grades of pneumonitis were 0, 2, 2.5, and 3 in four groups, respectively (p < 0.001). After adjustment of confounders, chemotherapy regimens (OR 3.491, 95% CI 1.527–7.981, p = 0.003) and neutropenia in previous cycles (OR 2.186, 95% CI 1.281–3.731, p = 0.004) were independently associated with the incidence of pneumonitis. Interstitial pneumonitis should be highlighted in NHL patients who received more than 4 cycles of RCDOP chemotherapy regimen, especially in those who had grade 4 neutropenia in the previous cycles of chemotherapy.

http://ift.tt/2C622GH

Safety of avoiding systemic corticosteroid administration for grade II acute graft-versus-host disease limited to the skin

Abstract

We hypothesized that systemic corticosteroid administration would be safely avoided not only in grade I acute graft-versus-host disease (GVHD) but also in selected patients with grade II acute GVHD limited to the skin (grade IIs GVHD). We retrospectively evaluated risk factors for subsequent GVHD progression, defined as the involvement of other organs or progression to grade III to IV GVHD, in 50 patients with acute GVHD of grade IIs at its onset. Sixteen patients received systemic corticosteroid administration before GVHD progression. The cumulative incidence of GVHD progression at 28 days from the onset of grade IIs GVHD was 24%. Twenty-five patients did not require systemic corticosteroid administration throughout the entire episode of acute GVHD. Systemic corticosteroid administration before GVHD progression did not affect GVHD progression, chronic GVHD, or non-relapse mortality. Early onset (less than 26 days from transplantation) of grade IIs GVHD was identified as the only statistically significant risk factor for GVHD progression (hazard ratio 6.73, 95% confidence interval 1.5–31.1, P = 0.01). In conclusion, avoiding systemic corticosteroid administration for selected patients with grade IIs GVHD before GVHD progression did not compromise the transplantation outcomes. Patients with early-onset grade IIs GVHD were at high risk for GVHD progression.

http://ift.tt/2CAJPSU

MYC-dependent downregulation of telomerase by FLT3 inhibitors is required for their therapeutic efficacy on acute myeloid leukemia

Abstract

The somatic mutation of FLT3 occurs in 30% of acute myeloid leukemia (AML), with the majority of mutations exhibiting internal tandem duplication (ITD). On the other hand, the induction of telomerase reverse transcriptase (hTERT) and the activation of telomerase is a key step in AML development. Here, we sought to determine whether FLT3ITD regulates hTERT expression in AML cells and whether hTERT expression affects FLT3 inhibitors' therapeutic efficacy on AML. FLT3ITD-harboring AML cell lines and primary cells treated with the FLT3 inhibitor PKC412 displayed a rapid decline in the levels of hTERT mRNA and telomerase activity. Moreover, PKC412 inhibited hTERT gene transcription in a c-MYC-dependent manner. The ectopic expression of hTERT significantly attenuated the apoptotic effect of PKC412 on AML cells. Mechanistically, hTERT enhanced the activity of FLT3 downstream effectors or alternative RTK signaling, thereby enhancing AKT phosphorylation, in AML cells treated with PKC412. Collectively, PKC412 downregulates hTERT expression and telomerase activity in a MYC-dependent manner and this effect is required for its optimal anti-AML efficacy, while hTERT over-expression confers AML cells resistance to a targeted therapeutic agent PKC412. These findings suggest that the functional interplay between FLT3ITD and hTERT contributes to the AML pathogenesis and interferes with the efficacy of FLT3ITD-targeted therapy.

http://ift.tt/2C9quao

Factors influencing platelet transfusion refractoriness in patients undergoing allogeneic hematopoietic stem cell transplantation

Abstract

Hematopoietic stem cell transplantation has been considered a risk factor for development of platelet transfusion refractoriness. The objective of this study was to assess the platelet transfusion refractoriness rate in patients undergoing allogeneic hematopoietic stem cell transplantation from different sources. We retrospectively reviewed the charts and transfusion records of patients who underwent allogeneic stem cell transplantation at our institution between 2013 and 2015. The evaluation of post-transfusion platelet count was assessed for each transfusion given, from day of progenitor infusion to day 30 after transplantation. Of 167 patients included in this study, 101 received peripheral blood stem cell transplantation (PBSCT) and 66 received umbilical cord blood transplantation (UCBT). Overall, the percentage of platelet transfusions with a 14-h CCI lower than 5000 was 59.3%, being these data significantly higher for UCBT (67.6%) than for PBSCT (31.0%). Seventy-eight percent of patients underwent UCBT become refractory, while 38.6% of patients who received PBSCT were refractory. Factors associated to platelet refractoriness were lower CD34+ cell dose infused, higher number of antibiotics used, presence of anti-HLA I antibodies, and reduced-intensity conditioning regimen. Platelet refractoriness is a frequent and complex adverse event and remains a therapeutic challenge in the management of patients undergoing HSCT. There is a higher rate of platelet refractoriness in patients who received UCBT as compared to patients who received PBSCT.

http://ift.tt/2CAJH5S

Diagnosis and management of gastrointestinal complications in adult cancer patients: 2017 updated evidence-based guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO)

Abstract

Cancer patients frequently suffer from gastrointestinal complications. In this manuscript, we update our 2013 guideline on the diagnosis and management of gastrointestinal complications in adult cancer patients by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO). An expert group was put together by the AGIHO to update the existing guideline. For each sub-topic, a literature search was performed in PubMed, Medline, and Cochrane databases, and strengths of recommendation and the quality of the published evidence for major therapeutic strategies were categorized using the 2015 European Society for Clinical Microbiology and Infectious Diseases (ESCMID) criteria. Final recommendations were approved by the AGIHO plenary conference. Recommendations were made with respect to non-infectious and infectious gastrointestinal complications. Strengths of recommendation and levels of evidence are presented. A multidisciplinary approach to the diagnosis and management of gastrointestinal complications in cancer patients is mandatory. Evidence-based recommendations are provided in this updated guideline.

http://ift.tt/2C8590H

PD1 blockade with low-dose nivolumab in NK/T cell lymphoma failing l -asparaginase: efficacy and safety

http://ift.tt/2CzmAs3

Transformed follicular lymphoma

Abstract

Follicular Lymphoma (FL) is the second most common type of non-Hodgkin lymphoma and is considered to be the prototype of indolent lymphomas. Histologic transformation into an aggressive lymphoma, which is expected to occur at a rate of 2 to 3% each year, is associated with rapid progression, treatment resistance, and poor prognosis. Recent modifications to the physiopathologic mechanism of transformed follicular lymphoma (t-FL) have been proposed, including genetic and epigenetic mechanisms as well as a role for the microenvironment. Although t-FL is considered a devastating complication, as it is associated with treatment-refractory disease and a dismal outcome, recent data in the rituximab era have suggested that not only is the prognosis less severe than reported in the previous literature but the risk of transformation is also lower. Thus, this study aimed to review the most recent research on t-FL in an attempt to better understand the clinical meaning of transformation from FL to diffuse large B cell lymphoma (DLBCL) and the impact of current treatment strategies on the curability of this intriguing subentity of lymphoma.

http://ift.tt/2CBtTjg

Incidence, clinical characteristics, and outcome of interstitial pneumonia in patients with lymphoma

Abstract

Interstitial pneumonia (IP) is a lethal complication in lymphoma patients undergoing chemotherapy. A total of 2212 consecutive patients diagnosed with lymphoma between 2009 and 2014 were enrolled in the present study. IP was defined as diffuse pulmonary interstitial infiltrate found on computed tomography scans. IP was observed in 106 patients. Of these, 23 patients were excluded from the study. Finally, 83 patients with IP were included in this study. The incidence of IP was 3.9% (7/287) in Hodgkin lymphoma and 2.4% (76/1925) in non-Hodgkin lymphoma (P = 0.210). The median number of chemotherapy cycles before IP was 3. The median time from the cessation of chemotherapy to IP was 17 days. Eighty-two (98.8%) patients recovered after the treatment with glucocorticoids. Sixty-six (79.5%) patients had a delay in chemotherapy, and 14 (16.9%) patients had premature termination of chemotherapy. Sixty-nine patients were re-treated with chemotherapy after remission from IP, of which 22 (31.9%) experienced IP recurrence. The incidence of IP recurrence was significantly higher in patients re-treated with a similar regimen than in those re-treated with an alternative regimen (65.4 vs. 11.6%, P < 0.001). In a multivariate Cox regression analysis, B symptoms and a history of drug allergies were identified as risk factors for IP. In conclusion, IP is a life-threatening complication in lymphoma patients. Glucocorticoid therapy with continuous monitoring of chest radiographic changes may be a favourable strategy for treating IP. However, IP may recur, especially in patients re-treated with a similar chemotherapy regimen.

http://ift.tt/2C7tfcc

Incidence and impact of atrial arrhythmias on thrombotic events in MPNs

Abstract

Atrial arrhythmias (AA) induce a high rate of thromboses and require vitamin K antagonists (VKA) or direct anticoagulants (DOAC) prescriptions. Essential thrombocythemia (ET) and polycythemia vera (PV) are also pro-thrombotic diseases. The prevention of thromboses is based on the association of cytoreductive drug and low-dose aspirin (LDA). We studied the incidence and complications of AA among patients with ET or PV. We identified 96/713 patients (13.5%) carrying AA. These patients were older (median 72.1 vs. 61.3 years old, p < 0.0001). In a case-control analysis, we observed that patients with AA had a higher frequency of cardiovascular risk factors (77/96, 80% vs. 61/96, 61%; p = 0.01). A higher incidence of thromboses before and after myeloproliferative neoplasm (MPN) diagnosis was seen in this group: 26/96, 27.1% vs. 14/96, 14.6% (p = 0.03) and 34/96, 35% vs. 18/96, 18.8% (p = 0.009). Most of the events were arterial (82 vs. 61%, p = 0.09). This translates into a shorter thrombosis-free survival (11.0 vs. 21.6 years, p = 0.01). Continuation of LDA in this situation exposed patients to more thrombotic events (p = 0.04) but VKA did not seem to be good anticoagulant drugs either. The association of AA and MPN is more frequent than expected. AA clearly increased the thrombotic risk of these patients. Anticoagulant drugs should be carefully managed between cardiologists and hematologists. Association of LDA and VKA or the role of DOAC in such population should be rapidly discussed to reduce the thrombotic rate.

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Approach to Richter transformation of chronic lymphocytic leukemia in the era of novel therapies

Abstract

Chronic lymphocytic leukemia (CLL) has a highly variable clinical course. About 2–10% of CLL patients develop aggressive histological transformation, most commonly to diffuse large B cell lymphoma (DLBCL), historically called Richter transformation (RT). Clinical features suggestive of RT include elevated LDH and non-specific symptoms such as fever, weight loss, and lymphadenopathy. 18-fluorodeoxyglucose (18-FDG) uptake is increased on PET scan (standardized uptake value max most commonly ≥ 10). PET/CT study can identify optimal site for excisional biopsy, which is the gold standard for RT diagnosis, as well as aid in disease staging and prognostication. In addition to clinical prognostic features such lactate dehydrogenase level, platelet count, and performance status, important predictors of poor outcome in RT are TP53 disruption and clonal relationship of DLBCL to underlying CLL. Chemoimmunotherapy constitutes the standard treatment for RT, followed by stem cell transplant (SCT) in eligible patients. However, the majority of patients do not proceed to allogeneic SCT, either due to inadequate disease control with initial therapy, poor performance status, or lack of donor availability. Overall outcome is dismal. Some novel agents under investigation, particularly PD-1 inhibitors, are showing clinical activity in Phase I and II trials. An ongoing incidence of RT has been noted in studies of previously treated patients receiving targeted therapies such as ibrutinib and venetoclax; the frequency of RT in patients initially treated with novel agents rather than chemoimmunotherapy will be important to determine with longer follow-up. This review focuses on the development, clinicopathologic features, and treatment of RT in the context of novel therapies.

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Langerhans cell histiocytosis and Erdheim-Chester disease overlap syndrome with bone marrow involvement and type 2 diabetes mellitus

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ALK expression plays different roles in anaplastic large-cell lymphomas and outcome of crizotinib use in relapsed/refractory ALK+ patients in a Chinese population

Abstract

The prognostic value of anaplastic lymphoma kinase (ALK) expression in patients with anaplastic large-cell lymphoma (ALCL) remains controversial. Data on the clinical features of ALCL in a Chinese population are limited. We retrospectively reviewed 1293 patients with pathologically diagnosed lymphoma at Guangdong General Hospital from June 2007 through August 2016. We evaluated the incidence of ALCL, clinical characteristics, survival status, and outcome of crizotinib use in four relapsed/refractory ALK-positive patients. Among the 1293 patients, 1193 (92.3%) were non-Hodgkin's lymphoma, and 53 (4.4%) of whom were ALCL. Of the 50 ALCL patients, with a median age of 34 years, were evaluated. Among them, 33 (66.0%) were ALK-positive and 17 (34.0%) were ALK-negative. Significantly, more patients younger than 40 years old were ALK-positive than ALK-negative (66.7 vs. 23.5%; P = 0.003). The 5-year progression-free survival (PFS) for ALK-positive and ALK-negative patients were 61 and 11%, and the 5-year overall survival (OS) were 70 and 22%, respectively. Median PFS and OS were significantly better for patients with ALK-positive than ALK-negative (60.1 vs. 9.4 months, P = 0. 017; not reached vs. 32.7 months, P = 0.021). Multivariate analyses identified ALK expression, stage, and bone marrow involvement as independent prognostic factors for PFS and OS. Four relapsed ALK-positive patients were treated with crizotinib and two died. Our results suggest that ALK expression has different prognostic significance in patients with ALCL. Mechanisms underlying early relapse after chemotherapy and resistance to crizotinib need further investigation.

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Efficacy of intermediate-dose cytarabine in central nervous system-relapsed wild-type BRAF Erdheim-Chester disease

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Redistribution of cell cycle by arsenic trioxide is associated with demethylation and expression changes of cell cycle related genes in acute promyelocytic leukemia cell line (NB4)

Abstract

PML-RARα perturbs the normal epigenetic setting, which is essential to oncogenic transformation in acute promyelocytic leukemia (APL). Transcription induction and recruitment of DNA methyltransferases (DNMTs) by PML-RARα and subsequent hypermethylation are components of this perturbation. Arsenic trioxide (ATO), an important drug in APL therapy, concurrent with degradation of PML-RARα induces cell cycle change and apoptosis. How ATO causes cell cycle alteration has remained largely unexplained. Here, we investigated DNA methylation patterns of cell cycle regulatory genes promoters, the effects of ATO on the methylated genes and cell cycle distribution in an APL cell line, NB4. Analysis of promoter methylation status of 22 cell cycle related genes in NB4 revealed that CCND1, CCNE1, CCNF, CDKN1A, GADD45α, and RBL1 genes were methylated 60.7, 84.6, 58.6, 8.7, 33.4, and 73.7%, respectively, that after treatment with 2 μM ATO for 48 h, turn into 0.6, 13.8, 0.1, 6.6, 10.7, and 54.5% methylated. ATO significantly reduced the expression of DNMT1, 3A, and 3B. ATO induced the expression of CCND1, CCNE1, and GADD45α genes, suppressed the expression of CCNF and CDKN1A genes, which were consistent with decreased number of cells in G1 and S phases and increased number of cells in G2/M phase. In conclusion, demethylation and alteration in the expression level of the cell cycle related genes may be possible mechanisms in ATO-induced cell cycle arrest in APL cells. It may suggest that ATO by demethylation of CCND1 and CCNE1 and their transcriptional activation accelerates G1 and S transition into the G2/M cell cycle arrest.

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Early stage primary cranial vault lymphoma in a 50-year-old man: presenting as only sclerosis and mimicking osteoma

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The Reliability and Validity of a Modified Squat Test to Predict Cardiopulmonary Fitness in Healthy Older Men

Background. Shortcomings are noted in currently available cardiopulmonary field tests for the older adult and thus relevant research is still ongoing. Purpose. The purpose of this study was to investigate the reliability and validity of a modified squat test and to establish a regression model for predicting aerobic fitness in the older adult. Methods. Twenty-five healthy men aged 60 to 75 years completed this study. Each subject performed two modified squat tests with a prototype testing equipment and a maximal exercise test to determine maximal oxygen consumption. Recovery heart rates (HR) (0~30, 60~90, and 120~150 seconds) were measured following the modified squat tests. The fitness indexes included the sum of recovery HR, recovery HR index, age-adjusted recovery HR index, and immediate HR. Results. The results revealed that the age-adjusted recovery HR index fitness had the highest intraclass correlation coefficients (ICC) of 0.9 and Pearson's correlation coefficients of 0.71, which suggested the modified squat test can reasonably assess cardiopulmonary fitness for the older adult. The regression equation for estimating aerobic power was = 16.781 + 16.732 × (age-adjusted recovery HR index) + 0.02467 × (physical activity level). Conclusion. The modified squat test is a valid and reliable field test and thus can be an option to assess the cardiopulmonary fitness level of healthy older men in clinics or communities.

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HISTOLOGIC FEATURES IN PEDIATRIC ILEITIS: IS IT POSSIBLE TO TIP THE BALANCE TOWARDS CROHN’S DISEASE?

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Application of RNAi and Heat-shock-induced Transcription Factor Expression to Reprogram Germ Cells to Neurons in C. elegans

This protocol describes how to study cellular processes during cell fate conversion in Caenorhabditis elegans in vivo. Using transgenic animals,allowing heat-shock promoter-driven overexpression of the neuron fate-inducing transcription factorCHE-1 and RNAi-mediated depletion of the chromatin-regulating factor LIN-53germ cell to neuron reprogramming can be observed in vivo.

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A Protocol for Decellularizing Mouse Cochleae for Inner Ear Tissue Engineering

The goal of this protocol is to demonstrate an effective method to decellularize and decalcify mouse cochleae for utilization as scaffolds for tissue engineering applications.

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Recording Synaptic Plasticity in Acute Hippocampal Slices Maintained in a Small-volume Recycling-, Perfusion-, and Submersion-type Chamber System

This protocol describes the stabilization of the oxygen level in a small volume of recycled buffer and methodological aspects of recording activity-dependent synaptic plasticity in submerged acute hippocampal slices.

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Detecting Estrogenic Ligands in Personal Care Products using a Yeast Estrogen Screen Optimized for the Undergraduate Teaching Laboratory

This article presents an optimized yeast estrogen screen for quantifying ligands in Personal Care Products (PCPs) that bind estrogen receptors alpha (ERα) and/or beta (ERβ). The method incorporates two colorimetric substrate options, a six-day refrigerated incubation for use in undergraduate courses, and statistical tools for data analysis.

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Circulating CD3+CD4+CD161+ Cells Are Associated with Early Complications after Autologous Stem Cell Transplantation in Multiple Myeloma

The aim of this study was to explore if measurement of pretransplant circulating CD161-expressing cells, in addition to clinical risk factors, could predict mucositis and infections in patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (ASCT). To determine if CD161-expressing cells are likely to predict early complications, namely, mucositis (≥grade 3), infections, and cytomegalovirus (CMV) reactivation, we prospectively examined CD161-expressing cells (CD3+CD4+CD161+ and CD3+CD8+CD161+) in peripheral blood samples from 108 patients with MM undergoing ASCT. After adjusting for factors identified by univariate analysis that predicted mucositis (≥grade 3), infection before engraftment, and CMV reactivation, multivariate analyses revealed that the low proportion of CD3+CD4+CD161+ cells in peripheral blood was an independent predictor of mucositis (≥grade 3) (), infections before engraftment (), and CMV reactivation (). In addition, we found that female sex and decreased glomerular filtration rate were independent factors for predicting mucositis. Female sex and severe pulmonary comorbidity were independent factors for predicting infection before engraftment. We found that the proportion of circulating CD3+CD4+CD161+ cells is useful for predicting the occurrence of early complications, including mucositis and infections, after ASCT in patients with MM.

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Major Success for Gene Therapy for Factor IX Deficiency: near elimination of bleeding and factor use

Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant: the researchers infused a single-stranded adeno-associated viral (AAV) vector consisting of a bioengineered capsid, liver-specific promoter and factor IX Padua (factor IX–R338L) transgene in 10 men with hemophilia B who had factor IX coagulant activity of 2% or less of the normal value.

They found sustained therapeutic expression of factor IX coagulant activity after gene transfer in the 10 participants with hemophilia who received the same vector dose. Transgene-derived factor IX coagulant activity enabled the termination of baseline prophylaxis and the near elimination of bleeding and factor use.

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Isolation and Identification of Compounds from Bioactive Extracts of Taraxacum officinale Weber ex F. H. Wigg. (Dandelion) as a Potential Source of Antibacterial Agents

Currently, the most effective treatment for recurrent urinary tract infections in women is antibiotics. However, the limitation for this treatment is the duration and dosage of antibiotics and the resistance that bacteria develop after a long period of administration. With the aim of identifying mainly novel natural agents with antibacterial activity, the present study was undertaken to investigate the biological and phytochemical properties of extracts from the leaves Taraxacum officinale. The structural identification of compounds present in hexane (Hex) and ethyl acetate (AcOEt) extracts was performed by mass spectrometry (GC-MS) spectroscopic techniques and nuclear magnetic resonance (NMR) with the major compounds corresponding to different sesquiterpene lactones (α-santonin, glabellin, arborescin, and estafiatin), monoterpene (9,10-dimethyltricycle [4.2.1.1 (2,5)]decane-9,10-diol), phytosterol (Stigmasta-5,22-dien-3-ol acetate), terpenes (lupeol acetate, pregn-5-en-20-one-3-acetyloxy-17-hydroxy, 2-hydroxy-4-methoxy benzaldehyde), and coumarin (benzofuranone 5,6,7,7-a-tetraaldehyde-4,4,7a-trimethyl). The results obtained show that the Hex extract was highly active against Staphylococcus aureus showing a MIC of 200 g/mL and moderately active against Escherichia coli and Klebsiella pneumoniae with MIC values of 400 g/mL and 800 g/mL for the other Gram-negative strains tested with Proteus mirabilis as uropathogens in vitro. Therefore, the effective dandelion extracts could be used in the development of future products with industrial application.

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Electroacupuncture Improved the Function of Myocardial Ischemia Involved in the Hippocampus-Paraventricular Nucleus-Sympathetic Nerve Pathway

We investigated the hippocampus-paraventricular nucleus- (PVN-) sympathetic nerve pathway in electroacupuncture (EA) at the heart meridian for the treatment of myocardial ischemia by observing PVN neuronal discharge, sympathetic nerve discharge, and hemodynamics parameters. Sprague Dawley (SD) rats were equally divided into four groups: Sham, Model, Model + EA, and Model + EA + Lesion. The model rat was established by ligating the left anterior descending branch of the coronary artery. Changes in the sympathetic nerve discharge and hemodynamic parameters were observed. The Model + EA exhibited a significantly lower discharge frequency of PVN neurons compared with the Model. The Model + EA + Lesion had a significantly higher discharge frequency compared with the Model + EA. The total discharge frequency of PVN neurons and interneurons were positively correlated with the sympathetic nerve discharge. The total discharge frequency of PVN neurons was positively correlated with heart rate (HR) and negatively correlated with mean arterial pressure (MAP) and rate pressure product (RPP). The discharge frequency of interneurons was positively correlated with HR and negatively correlated with MAP and RPP. The hippocampus-PVN-sympathetic nerve pathway is involved in electroacupuncture at the heart meridian and interneurons are the key neurons in PVNs.

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Saccharomyces cerevisiae-Derived Mannan Does Not Alter Immune Responses to Aspergillus Allergens

Severe asthma with fungal sensitization predominates in the population suffering from allergic asthma, to which there is no cure. While corticosteroids are the mainstay in current treatment, other means of controlling inflammation may be beneficial. Herein, we hypothesized that mannan from Saccharomyces cerevisiae would dampen the characteristics of fungal allergic asthma by altering the pulmonary immune responses. Using wild-type and transgenic mice expressing the human mannose receptor on smooth muscle cells, we explored the outcome of mannan administration during allergen exposure on the pathogenesis of fungal asthma through measurement of cardinal features of disease such as inflammation, goblet cell number, and airway hyperresponsiveness. Mannan treatment did not alter most hallmarks of allergic airways disease in wild-type mice. Transgenic mice treated with mannan during allergen exposure had an equivalent response to non-mannan-treated allergic mice except for a prominent granulocytic influx into airways and cytokine availability. Our studies suggest no role for mannan as an inflammatory regulator during fungal allergy.

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