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Παρασκευή 7 Δεκεμβρίου 2018

The association between markers of tumor cell metabolism, the tumor microenvironment and outcomes in patients with colorectal cancer

Tumor cell anaerobic metabolism has been reported to be a prognostic factor in colorectal cancer. The present study investigated the association between monocarboxylate transporter (MCT) 1, MCT 2, lactate dehydrogenase (LDH) 1 and LDH 5, the tumor microenvironment, and outcome in patients with colorectal cancer. A cohort of 150 patients with stage I‐III CRC were utilised to assess tumor cell expression of MCT‐1, MCT‐2, LDH‐1 and LDH5 by immunohistochemistry. Expression levels were dichotomised and associations with tumor factors, the tumor microenvironment and survival analysed. Nuclear LDH‐5 associates with poor prognosis (HR 1.68 95% CI 0.99‐2.84, p=0.050) and trends towards increased tumor stroma percentage (TSP, p=0.125). Cytoplasmic MCT‐2 also trends towards increased TSP (p=0.081). When combined into a single score; nuclear LDH‐5+TSP significantly associated with decreased survival independent of stage (HR 2.61 95% CI 1.27‐5.35, p=0.009), increased tumor budding (p=0.002) and decreased stromal T‐lymphocytes (p=0.014). Similarly, cytoplasmic MCT‐2+TSP significantly associated with decreased survival (HR 2.32 95% CI 1.31‐4.11, p=0.003), decreased necrosis (p=0.039), and increased tumor budding (p=0.004). The present study reports that the combination of TSP and nuclear LDH‐5 was significantly associated with survival, increased tumor budding, and decreased stromal T‐lymphocytes. This supports the hypothesis that increased stromal invasion promotes tumor progression via modulation of tumor metabolism. Moreover, MCT‐2 and LDH‐5 may provide promising therapeutic targets for patients with stromal‐rich CRC.

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Erratum: The efficacy and safety of anti‐PD‐1/PD‐L1 antibodies combined with chemotherapy or CTLA4 antibody as a first‐line treatment for advanced lung cancer



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Universal screening for Lynch Syndrome in a large consecutive cohort of Chinese colorectal cancer patients: high prevalence and unique molecular features

The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAF V600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety‐three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAF V600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAF V600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population.

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Mediation of Associations Between Adiposity and Colorectal Cancer Risk by Inflammatory and Metabolic Biomarkers

Inflammation and hyperinsulinemia may drive associations between adiposity and colorectal cancer (CRC) risk, but few studies have examined this hypothesis using mediation analysis. We used inverse odds ratio weighting and logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) for estimated total effects (ORTE) of body mass index, waist circumference, and adult weight gain on CRC risk, and estimated effects operating through seven inflammatory and metabolic biomarkers (natural indirect effect; ORNIE) or through paths independent of these biomarkers (natural direct effect; ORNDE) among 209 CRC cases and 382 matched controls nested within the Health Professionals Follow‐up Study, a prospective cohort of male health professionals. A one‐interquartile range (IQR) increase in body mass index (3.6 kg/m2) was associated with an ORTE of 1.40 (95% CI: 1.13, 1.73), which decomposed into an ORNIE of 1.26 (95% CI: 0.97, 1.52) and an ORNDE of 1.11 (0.87, 1.42), with possibly stronger mediation by these biomarkers for adult weight gain (IQR = 10.4kg; ORTE = 1.32 [95% CI: 1.06, 1.64]; ORNIE = 1.47 [95% CI: 1.01, 1.81]; ORNDE = 0.89 [95% CI: 0.72, 1.11]), but no mediation for waist circumference. Mediation appeared to be stronger for the metabolic biomarkers than the inflammatory biomarkers. Inflammatory and metabolic mechanisms may mediate associations between both body mass index and adult weight gain with CRC risk.

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Citrus fruit intake and gastric cancer: the Stomach cancer Pooling (StoP) project consortium

Diets rich in vegetables and fruit have been associated with reduced risk of gastric cancer, and there is suggestive evidence that citrus fruits have a protective role. This study aimed at evaluating and quantifying the association between citrus fruit consumption and gastric cancer risk. We conducted a one‐stage pooled analysis including 6340 cases and 14,490 controls from 15 case‐control studies from the Stomach cancer Pooling (StoP) Project consortium. Odds ratio (OR) and the corresponding 95% confidence intervals (CI) of gastric cancer across study‐specific tertiles of citrus fruit intake (grams/week) were estimated by generalized linear mixed effect models, with logistic link function and random intercept for each study. The models were adjusted for sex, age, and the main recognized risk factors for gastric cancer. Compared to the first third of the distribution, the adjusted pooled ORs (95% CI) for the highest third was 0.80 (0.73‐0.87). The protective effect of citrus fruits increased progressively until three servings/week and levelled off thereafter. The magnitude of the association was similar between cancer sub‐sites and histotype. The analysis by geographic area showed no association in studies from the Americas. Our data confirm an inverse association between citrus fruit intake and gastric cancer and provide precise estimates of the magnitude of the association. However, the null association found in studies from America and in some previous cohort studies prevent to draw definite conclusions on a protective effect of citrus fruit consumption.

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Leveraging the variable natural history of ductal carcinoma in situ (DCIS) to select optimal therapy

Abstract

Purpose

Ductal carcinoma in situ (DCIS) is a non-obligate precursor to invasive ductal carcinoma. The authors sought to discuss the evidence suggesting that not all DCIS will progress to invasive disease if left untreated.

Results

Four lines of evidence align to suggest that not all of this in-situ disease progresses to invasive cancer: its prevalence on screening mammography, studies of missed diagnoses, incidental findings in autopsy specimens, and large retrospective reviews of those treated with excision alone.

Conclusion

A clearer understanding of the variable history of DCIS coupled with advances in genomic profiling of the disease holds the promise of reducing widespread over-treatment of this non-invasive cancer. Additionally, identification of higher risk of recurrence subsets may select patients for whom more aggressive treatment may be appropriate.



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Integrating self-management into daily life following primary treatment: head and neck cancer survivors’ perspectives

Abstract

Background

Self-management may help cancer survivors to better deal with challenges to their physical, functional, social and psychological well-being presented by cancer and its treatment. Nonetheless, little is known about how people integrate cancer self-management practices into their daily lives. The aim of this study was to describe and characterise the processes through which head and neck cancer (HNC) survivors attempt to integrate self-management into their daily lives following primary treatment.

Methods

Using a purposeful critical case sampling method, 27 HNC survivors were identified through four designated cancer centres in Ireland and participated in face-to-face semi-structured interviews. Interviews were audio-recorded, transcribed and analysed using thematic analysis.

Results

Six themes describing HNC survivors' attempts to integrate self-management into their lives following treatment were identified: grappling with having to self-manage, trying out self-management strategies, becoming an expert self-manager, struggling to integrate self-management strategies into daily life, avoiding recommended self-management and interpreting self-management.

Conclusions

This is the first study to describe HNC survivors' attempts to integrate self-management into their daily lives following primary treatment. The findings indicate that HNC survivors exhibit highly individualised approaches to self-management integration and abandon self-management strategies that fail to meet their own specific needs.

Implications for Cancer Survivors

Survivors may benefit from skills training and structured support to assist their transition between in-patient care and having to self-manage after primary treatment, and/or ongoing support to deal with persistent and recurring challenges such as eating difficulties and fear of recurrence.



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Efficacy and safety of dual-polymer hydroxypropyl guar- and hyaluronic acid-containing lubricant eyedrops for the management of dry-eye disease: a randomized double-masked clinical study

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Scleral buckle surgery in Ghana: a decade comparison of the anatomic and visual outcome

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Circumferential viscodilation of Schlemm’s canal for open-angle glaucoma: ab-interno vs ab-externo canaloplasty with tensioning suture

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Validation of the 2017 European LeukemiaNet classification for acute myeloid leukemia with NPM1 and FLT3‐internal tandem duplication genotypes

Abstract

Background

The revised 2017 European LeukemiaNet (ELN) classification (ELN‐2017) of acute myeloid leukemia (AML) divides patients into 3 prognostic risk categories, with additional factors such as the fms‐like tyrosine kinase 3 (FLT3)–internal tandem duplication (ITD) allele ratio (AR) considered for risk stratification. To the best of the authors' knowledge, the prognostic usefulness of ELN‐2017 in comparison with ELN‐2010 in younger patients with AML has not been validated to date.

Methods

The authors performed a retrospective study on patients aged <60 years who received idarubicin plus cytarabine (IA)–based induction chemotherapy for newly diagnosed AML.

Results

According to ELN‐2017 criteria, the number of patients in the favorable (Fav), intermediate (Int), and adverse (Adv) risk categories was 192 patients (27%), 331 patients (46%), and 192 patients (27%), respectively. Overall survival probabilities at 5 years in the Fav, Int, and Adv groups were 57%, 37%, and 18%, respectively. In comparison, the 5‐year overall survival probabilities in the Fav (169 patients), intermediate (IR)‐1 (80 patients), IR‐2 (306 patients), and Adv (160 patients) ELN‐2010 categories were 59%, 32%, 40%, and 14%, respectively. Although ELN‐2010 historically distinguishes prognosis into IR‐1 and IR‐2 categories in younger patients, this difference was nullified in the current study cohort. When comparing patients with a low FLT3‐ITD AR with those with a high FLT3‐ITD AR, no significant differences in survival were noted among patients with nucleophosmin 1 (NPM1)‐mutated AML (= .28) or wild‐type NPM1 (= .35), and in those treated with IA alone (= .79) or those treated with IA and a FLT3 inhibitor (= .10).

Conclusions

The ELN‐2017 more accurately distinguishes prognosis in patients with newly diagnosed AML. The lack of prognostic significance for the FLT3‐ITD AR needs further evaluation in different treatment settings.



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The prevalence of human papillomavirus in oropharyngeal cancer is increasing regardless of sex or race, and the influence of sex and race on survival is modified by human papillomavirus tumor status

Background

The purpose of this study was to evaluate the influence of sex and race/ethnicity upon prevalence trends of human papillomavirus (HPV) in oropharyngeal cancer (OPC) and survival after OPC.

Method

This was a cohort study of patients included in the United States National Cancer Database who had been diagnosed with OPC between 2010 and 2015. Outcomes were HPV status of tumor specimens and overall survival. Sex‐ and race‐stratified trends in HPV prevalence were estimated using generalized linear modeling. The influence of sex, race, and HPV tumor status on overall survival was compared by Kaplan‐Meier method and Cox Proportional Hazards models.

Results

This analysis included 20,886 HPV‐positive and 10,364 HPV‐negative OPC patients. The prevalence of HPV‐positive tumors was higher among men (70.6%) than women (56.3%) and increased significantly over time at a rate of 3.5% and 3.2% per year among men and women, respectively. The prevalence of HPV‐positive tumors was highest among whites (70.2%), followed by Hispanics (61.3%), Asians (55.8%), and blacks (46.3%). Blacks and Hispanics experienced significantly more rapid increases in prevalence of HPV‐positive tumors over time compared with whites (6.5% vs 5.6% vs 3.2% per year, respectively). In HPV‐positive OPC, neither sex nor race/ethnicity was associated with survival among patients with HPV‐positive OPC. In contrast, for HPV‐negative OPC, risk of death was significantly higher for women versus men (adjusted hazard ratio [aHR], 1.17; 95% confidence interval [CI], 1.08‐1.26) and blacks versus whites (aHR, 1.21; 95% CI, 1.10‐1.33).

Conclusion

The prevalence of HPV‐positive tumors is increasing for all sex and race/ethnicity groups in the United States. Sex and race are independently associated with survival for HPV‐negative but not HPV‐positive OPC.



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A multicenter study of patients with multisystem Langerhans cell histiocytosis who develop secondary hemophagocytic lymphohistiocytosis

Abstract

Background

Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the presence of abnormal CD1a‐positive (CD1a+)/CD207+ histiocytes. Hemophagocytic lymphohistiocytosis (HLH) represents a spectrum of hyperinflammatory syndromes typified by the dysregulated activation of the innate and adaptive immune systems. Patients with LCH, particularly those with multisystem (MS) involvement, can develop severe hyperinflammation mimicking that observed in HLH. Nevertheless, to the authors' knowledge, little is known regarding the prevalence, timing, risk factors for development, and outcomes of children and young adults who develop HLH within the context of MS‐LCH (hereafter referred to LCH‐associated HLH).

Methods

To gain further insights, the authors conducted a retrospective, multicenter study and collected data regarding all patients diagnosed with MS‐LCH between 2000 and 2015.

Results

Of 384 patients with MS‐LCH, 32 were reported by their primary providers to have met the diagnostic criteria for HLH, yielding an estimated 2‐year cumulative incidence of 9.3% ± 1.6%. The majority of patients developed HLH at or after the diagnosis of MS‐LCH, and nearly one‐third (31%) had evidence of an intercurrent infection. Patient age <2 years at the time of diagnosis of LCH; female sex; LCH involvement of the liver, spleen, and hematopoietic system; and a lack of bone involvement each were found to be independently associated with an increased risk of LCH‐associated HLH. Patients with MS‐LCH who met the criteria for HLH had significantly poorer 5‐year survival compared with patients with MS‐LCH who did not meet the criteria for HLH (69% vs 97%; P < .0001).

Conclusions

Given its inferior prognosis, further efforts are warranted to enhance the recognition and optimize the treatment of patients with LCH‐associated HLH.



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A randomized, double‐blind, placebo‐controlled trial of probiotics to reduce the severity of oral mucositis induced by chemoradiotherapy for patients with nasopharyngeal carcinoma

Background

The objective of this study was to evaluate the effect of a probiotic combination on the severity of oral mucositis (OM), which is a common, unpreventable complication induced by radiochemotherapy in patients with nasopharyngeal carcinoma who undergo concurrent radiochemotherapy (CCRT).

Methods

Eligible patients (n = 99) with locally advanced nasopharyngeal carcinoma who were undergoing CCRT were randomly assigned (2:1) to receive a probiotic combination or placebo during radiochemotherapy, and the incidence of severe OM (grade 3 or higher) was the primary endpoint.

Results

Patients taking the probiotic combination showed a significant reduction in the severity of OM. The incidences of grade 0, 1, 2, and 3 OM in the placebo group and the probiotic combination group were 0% and 12.07%, 0% and 55.17%, 54.29% and 17.24%, and 45.71% and 15.52%, respectively. Furthermore, CCRT greatly lowered the number of immune cells, whereas the probiotic combination markedly lowered the reduction rates of CD4+ T cells (76.59% vs 52.85%; P < .05), CD8+ T cells (62.94% vs 29.76%; P < .05), and CD3+ T cells (69.72% vs 45.49%; < .05) in an A‐CCRT‐P (after treatment with radiotherapy plus chemotherapy plus the probiotic combination) group. High‐throughput sequencing results indicated that CCRT had obviously disturbed the intestinal diversity of patients in an A‐CCRT (after treatment with radiotherapy plus chemotherapy plus a placebo) group, whereas the probiotic combination distinctly restored the microbial diversity in the A‐CCRT‐P group toward that of healthy people and a B‐CCRT‐P (before the treatment of radiotherapy plus chemotherapy plus the probiotic combination) group.

Conclusions

A probiotic combination significantly enhances the immune response of patients and reduces the severity of OM through modification of gut microbiota.



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Self‐management intervention for head and neck cancer couples: Results of a randomized pilot trial

Abstract

Background

Patients with head and neck cancer (HNC) experience significant physical and psychological morbidity during radiotherapy (RT) that contributes to treatment interruptions and a poor quality of life. Although spouses/partners can help by encouraging patient self‐management (eg, self‐care) during RT, they often experience high psychological distress rates, lack basic health care knowledge and skills, and report increased marital conflict regarding patient self‐management. The current pilot study examined the feasibility and acceptability of a 6‐session telephone‐based intervention called Spouses coping with the Head And neck Radiation Experience (SHARE), which teaches self‐management, communication, and coping skills to patients with HNC and their spouses. The treatment effects of SHARE compared with usual medical care (UMC) in controlling patient physical symptoms and improving patient/spouse psychological and marital functioning also were examined.

Methods

Thirty patients who initiated RT and their spouses (60 participants; 40% of whom were racial/ethnic minorities) were randomized to SHARE or UMC, and preintervention and postintervention assessments were completed.

Results

Solid recruitment (70%) and low attrition rates (7%) demonstrated feasibility. Strong program evaluations and homework completion rates (72%) supported acceptability. Significant treatment effects (medium in magnitude) were observed for SHARE compared with UMC with regard to HNC‐specific physical symptom burden (Cohen's d, ‐0.89) and symptom interference (Cohen's d, ‐0.86). Medium to large effects favoring SHARE also were found for patient and spouse depressive symptoms (Cohen's d, ‐0.84) and cancer‐specific distress (Cohen's d, ‐1.05).

Conclusions

The findings of the current study support the feasibility, acceptability, and preliminary efficacy of SHARE. They also suggest that programs that empower HNC couples with the necessary skills to coordinate care and manage the challenges of RT together hold great promise for controlling a patient's physical symptoms and improving the psychological functioning of both partners.



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Minimal residual disease–based long‐term efficacy of reduced‐intensity conditioning versus myeloablative conditioning for adult Philadelphia‐positive acute lymphoblastic leukemia

Background

The sensitivity of Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL) to reduced‐intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) versus myeloablative conditioning (MAC) allogeneic HCT by minimal residual disease (MRD) kinetics is not well established.

Methods

This study compared long‐term outcomes based on MRD kinetics for 79 patients with RIC transplants and 116 patients with MAC transplants in first complete remission (CR1) after tyrosine kinase inhibitor–based chemotherapy (median follow‐up, 67.1 months). MRD monitoring was centrally evaluated by real‐time quantitative polymerase chain reaction for all patients.

Results

RIC showed a cumulative incidence of relapse (CIR; 30.6% vs 31.7%), nonrelapse mortality (17.5% vs 14.9%), disease‐free survival (DFS; 51.9% vs 53.4%), and overall survival (61.1% vs 61.4%) comparable to those associated with MAC. In all MRD kinetics–based subgroups, no differences in CIR (early complete molecular response [CMR], 19.3% vs 4.8%; early major molecular response [MMR], 17.0% vs 26.8%; late CMR, 20.0% vs 14.3%; late MMR, 28.3% vs 31.0%; poor molecular response [PMR], 57.9% vs 62.4%) or DFS (early CMR, 71.6% vs 76.2%; early MMR, 66.9% vs 52.1%; late CMR, 50.0% vs 64.3%; late MMR, 50.7% vs 53.7%; PMR, 31.6% vs 34.1%) were observed between RIC and MAC. In a multivariate analysis, the conditioning intensity had no significant impact on transplantation outcomes.

Conclusions

RIC is a valid alternative choice for long‐term disease control and is worthy of further investigation in prospective trials for adult Ph‐positive ALL in CR1.



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C‐reactive protein and its association with depression in patients receiving treatment for metastatic lung cancer

Background

Depression is highly prevalent in lung cancer. Although there is a known association between inflammation and depression, this relationship has not been examined in patients with lung cancer who undergo treatment with immune and other targeted drug therapies. Peripheral blood C‐reactive protein (CRP), a marker of systemic inflammation, may help identify metastatic lung cancer patients with inflammation‐associated depression.

Method

Patients with metastatic lung cancer undergoing treatment were evaluated for depression using the Hospital Anxiety and Depression Scale (HADS). Inflammation (CRP and CRP cutoffs ≥1 and ≥3 mg/mL) and demographic and treatment variables were analyzed for association with depression.

Results

One hundred nine consecutive participants exhibited an average plasma CRP concentration of 1.79 mg/mL (median, 0.75 mg/mL [standard deviation, 2.5 mg/mL), and 20.7% had a CRP concentration of ≥3.0 mg/mL; 23.9% met depression screening criteria (HADS ≥8). A log transformation of CRP was significantly correlated with depression severity (r = 0.47, P < .001). CRP was the only covariate to predict depression severity (= .008) in a multivariate model including lung cancer disease subtype and type of systemic treatment. Receiver operating characteristic analysis indicated that CRP had moderate predictive accuracy in identifying elevated depression (area under the curve = 0.74). A cutoff of CRP ≥3.0 generated high specificity (88%) but identified only 50% of those with elevated depression.

Conclusion

Elevated CRP is associated with depression in patients with metastatic lung cancer. Thus, CRP may identify a subset of lung cancer patients with inflammation‐induced depression and may be useful in predicting response to treatments that target inflammation or its downstream mediators on the brain.



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Medical resource utilization of abiraterone acetate plus prednisone added to androgen deprivation therapy in metastatic castration‐naive prostate cancer: Results from LATITUDE

Background

Abiraterone acetate plus prednisone (AA+P), when added to androgen deprivation therapy (ADT), demonstrated significant improvements in overall survival and disease progression over dual placebos added to ADT in the LATITUDE clinical trial (NCT01715285). The objective of this study was to assess event‐driven medical resource utilization (MRU) of ADT plus AA+P (ADT+AA+P) versus ADT plus dual placebos (ADT+placebos) in LATITUDE.

Methods

Event‐driven MRU data from LATITUDE while patients were on treatment were used for analyses. Types of MRU included overnight hospitalizations and length of stay (LOS), emergency room (ER) visits, radiotherapy, surgery, imaging, and specialist and general practitioner (GP) visits. Rates by treatment (per 100 person‐years) and rate ratios comparing ADT+AA+P with ADT+placebos were estimated with zero‐inflated Poisson regression. The difference in the average hospital LOS between arms was assessed with repeated measures regression analyses. Reasons for hospitalization were explored. Sensitivity analyses were conducted to assess the robustness of the results.

Results

A total of 1199 patients were enrolled in LATITUDE. Significantly lower rates of hospitalization (a 24% reduction), imaging (a 36% reduction), and radiotherapy (a 50% reduction) were observed with ADT+AA+P versus ADT+placebos. There was a nonsignificant trend of lower rates of specialist visits and surgery. The rates of ER and GP visits and the average LOS per hospitalization episode were similar across arms. The most common hospitalization reasons were genitourinary, musculoskeletal, and respiratory tract symptoms/disorders. The results remained consistent in a sensitivity analysis.

Conclusions

Adding AA+P to ADT does not increase MRU and leads to lower rates of hospitalization, imaging, and radiotherapy. This likely reflects the more favorable clinical outcomes with ADT+AA+P therapy.



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Oligometastatic prostate cancer: Reality or figment of imagination

The term "oligometastatic prostate cancer" refers to a heterogeneous group of disease states currently defined solely on the basis of clinical features. Oligorecurrent disease, de novo oligometastases, and oligoprogressive disease likely have unique biologic underpinnings and natural histories. Evidence suggesting the existence of a subset of patients who harbor prostate cancer with limited metastatic potential currently includes disparate and overwhelmingly retrospective reports. Nevertheless, emerging prospective data have corroborated the "better‐than‐expected," retrospectively observed outcomes, particularly in the setting of oligorecurrent prostate cancer. Improved functional imaging with prostate‐specific membrane antigen‐targeted strategies may enhance the identification of patients with oligometastatic prostate cancer in the short term. In the long term, refinement of the oligometastatic case definition likely will require biologic risk‐stratification schemes. To determine optimal treatment strategies and identify patients most likely to benefit from metastasis‐directed therapy, future efforts should focus on conducting high‐quality, prospective trials with much‐needed molecular correlative studies.



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Early surveillance is associated with less incidence and severity of breast cancer‐related lymphedema compared with a traditional referral model of care

Background

Bioimpedance spectroscopy (BIS) has enabled the early identification of breast cancer‐related lymphedema. In this study, differences in health service metrics and in the incidence of breast cancer‐related lymphedema are evaluated in an early surveillance model of care compared with a traditional referral model of care.

Methods

In a retrospective analysis of data from 753 women who underwent BIS measures between January 1, 2007 and December 31, 2016, 188 women were assigned to the "early surveillance" group if they began lymphedema monitoring presurgery (n = 121) or within 90 days postsurgery (n = 67), and 285 women were assigned to the "traditional referral" group if they began monitoring after 90 days postsurgery. Health service metrics were calculated as the time to the first BIS measure after 90 days postsurgery, the median follow‐up, and the number of health care visits. Lymphedema was diagnosed based on BIS measures.

Results

Women in the early surveillance group received lymphedema care significantly earlier than those in the traditional referral group. However, there was no difference in the number of visits per year to the clinic between groups. Significantly more women in the traditional referral group were diagnosed with clinical lymphedema (stage I‐III, 39 % vs 14%; P < .001) and with greater severity (stage II‐III, 24%) compared with those in the early surveillance group (4%).

Conclusions

The current findings support the adoption of an early prospective surveillance model of care using BIS for the early detection and management of breast cancer‐related lymphedema.



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Tolerance and efficacy of BRAF plus MEK inhibition in patients with melanoma who previously have received programmed cell death protein 1‐based therapy

Abstract

Background

Combined BRAF and MEK inhibition (BRAF‐MEK) is a standard therapy for patients with BRAF V600–mutant melanoma, but to the authors' knowledge, the tolerance, adverse event (AE) profile, and efficacy have not been well defined in the post–programmed cell death protein 1 (PD‐1) setting.

Methods

Patients with BRAF V600–mutant melanoma who received combined BRAF‐MEK after prior PD‐1–based therapy were assembled from 4 tertiary care centers in the United States and Australia. Dose modification was defined as a treatment break, dose reduction, or intermittent dosing. Rates of hospitalization and discontinuation due to AEs were collected, and overall survival (OS) was calculated using Kaplan‐Meier methods from the time of the initiation of BRAF‐MEK therapy.

Results

A total of 78 patients were identified as having received a BRAF‐MEK regimen at a median of 34 days after the last dose of PD‐1–based therapy. The majority of patients (86%) received the combination of dabrafenib and trametinib. Approximately 80% of patients had American Joint Committee on Cancer M1c or M1d disease. Sixty‐five regimens (83%) had ≥1 dose modification. The median time to the first dose modification was 14 days; 86% occurred within 90 days and 71% involved pyrexia. Dose modifications were more common in patients receiving BRAF‐MEK <90 days after the last dose of PD‐1 and who were not receiving steroids. Of the dose modifications, 25 (31%) led to an AE‐related hospitalization. Among 55 BRAF‐naive patients, the median time receiving BRAF‐MEK therapy was 5.8 months and the median OS was 15.6 months.

Conclusions

The majority of patients receiving BRAF‐MEK inhibition after PD‐1 therapy require dose interruptions, and a significant minority require hospitalization for AEs. In this higher risk population, the median time receiving therapy and OS may be inferior to those presented in published phase 3 trials.



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The Effect of PTCH1 on Ovarian Cancer Cell Proliferation and Apoptosis

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.


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Contribution of the OC Sensor ® immunoassay in comparison to the Hemoccult II ® guaiac-test in organized colorectal cancer screening

Abstract

Colorectal cancer (CRC) is a major cause of cancer-related death of worldwide with high incidence and mortality rate, accessible to a screening program in France, first with guaiac- based fecal occult blood test (g-FOBT) then with fecal immunochemical tests (FIT), since 2015, because of better accuracy. The aim of our study was to compare the characteristics of screen-detected lesions in two successive CRC screening campaigns, using two different tests (Hemoccult II® and OC Sensor®) in the department of Maine-et-Loire, and to precise the performance of these tests [participation rate, detection rates (DR), positive predictive value (PPV)]. Participants, invited by CAP SANTE 49, with polyps or cancer at the colonoscopy after a positive screening test between 01/01/2013 and 31/12/2016 were included. A guaiac-based fecal occult blood test (g-FOBT) was used from January 2013 to December 2014 and a FIT was used from June 2015 to December 2016). 2575 participants, 642 in g-FOBT group and 1933 in FIT group had lesions. Participation rate was not different between tests (p = 0.104), whereas DR and PPV were statistically higher in FIT for all lesions (2.61, 95% CI [2.50–2.70] vs 0.93, 95% CI [0.90–1.00], p < 0.0001 and 64.84, 95% CI [63.10–66.60], 50.00, 95% CI [47.30–52.70], p < 0.0001 respectively). FIT detects more precancerous lesions (adenomas, p < 0.001, and advanced adenomas, p < 0.001) than g-FOBT but g-FOBT detects more serrated polyps (p = 0.025). AAs were more in right colon in FIT than g-FOBT (p = 0.035). No different participation rate was detected between FIT and g-FOBT but DR and PPV of all lesions was higher with FIT.



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Correction to: Fulvestrant-Based Combination Therapy for Second-Line Treatment of Hormone Receptor-Positive Advanced Breast Cancer

The article Fulvestrant-Based Combination Therapy for Second-Line Treatment of Hormone Receptor-Positive Advanced Breast Cancer, written by Sarah Sammons, Noah S. Kornblum and Kimberly L. Blackwell, was originally published electronically on the publisher's internet portal (currently SpringerLink).



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A phase II trial of the effect of perindopril on hand–foot skin reaction (HFSR) incidence and severity in patients receiving regorafenib for refractory mCRC

Abstract

Purpose

Regorafenib is an oral multi-kinase inhibitor that offers an OS benefit to patients with mCRC refractory to standard therapy (Grothey et al., in Lancet 381:303–312, 2013), but comes with potential significant toxicities including grade 3 hand–foot skin reaction (HFSR). The pathogenesis of regorafenib-induced HFSR is not well established, but may be related to alterations in the capillary endothelium. We hypothesized that perindopril, an angiotensin-converting enzyme (ACE) inhibitor, indicated for the treatment of hypertension (Ceconi et al., in Cardiovasc Res 73:237–246, 2007), and which plays a role in preventing endothelial dysfunction, may help to prevent or reduce the severity of regorafenib-induced HFSR.

Patients and methods

In this single-center phase II open-label trial, patients with refractory mCRC were treated with both regorafenib (160 mg/day) and perindopril (4 mg/day) for 21 days per 28-day cycle. The primary end point was to assess the proportion of patients with any grade HFSR toxicity. Secondary end points included time to development of worst (grade 3) HFSR, reduction of all grades of hypertension and all grade toxicities, as well as progression-free survival. All toxicities were evaluated using CTCAE v4.03.

Results

A planned interim analysis was performed after ten evaluable patients had completed their first cycle of study treatment. As 50% (5/10) experienced grade 3 HFSR, enrolment was stopped as the addition of perindopril did not lead to a reduced level of HFSR compared with regorafenib alone. Other grade 3 toxicities included hypertension (16.7%) and increased AST (16.7%).

Conclusion

The addition of an ACE inhibitor perindopril to regorafenib did not reduce HFSR incidence or severity in patients with refractory mCRC.



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Vitamin E Reduces Hypobaric Hypoxia-Induced Immune Responses in Male Rats

High Altitude Medicine &Biology, Ahead of Print.


https://ift.tt/2B0SY6N

Yeast Models Of Phosphomannomutase 2 Deficiency, A Congenital Disorder Of Glycosylation

Phosphomannomutase 2 Deficiency (PMM2-CDG) is the most common monogenic congenital disorder of glycosylation (CDG) affecting at least 800 patients globally. PMM2 orthologs are present in model organisms, including the budding yeast Saccharomyces cerevisiae gene SEC53. Here we describe conserved genotype-phenotype relationships across yeast and human patients between five PMM2 loss-of-function missense mutations and their orthologous SEC53 mutations. These alleles range in severity from folding defective (hypomorph) to dimerization defective (severe hypomorph) to catalytic dead (null). We included the first and second most common missense mutations - R141H, F119L respectively- and the most common compound heterozygote genotype - PMM2R141H/F119L - observed in PMM2-CDG patients. Each mutation described is expressed in haploid as well as homozygous and heterozygous diploid yeast cells at varying protein expression levels as either SEC53 protein variants or PMM2 protein variants. We developed a 384-well-plate, growth-based assay for use in a screen of the 2,560-compound Microsource Spectrum library of approved drugs, experimental drugs, tool compounds and natural products. We identified three compounds that suppress growth defects of SEC53 variants, F126L and V238M, based on the biochemical defect of the allele, protein abundance or ploidy. The rare PMM2 E139K protein variant is fully functional in yeast cells, suggesting that its pathogenicity in humans is due to the underlying DNA mutation that results in skipping of exon 5 and a nonfunctional truncated protein. Together, these results demonstrate that yeast models can be used to characterize known and novel PMM2 patient alleles in quantitative growth and enzymatic activity assays, and used as patient avatars for PMM2-CDG drug screens yielding compounds that could be rapidly cross-validated in zebrafish, rodent and human organoid models.



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Most Insured Patients Not Using Online Portals

FRIDAY, Dec. 7, 2018 -- Nearly two-thirds of insured adults with a previous health care visit did not use an online patient portal in 2017, according to a study published in the December issue of Health Affairs. Denise L. Anthony, Ph.D., from the...

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ONECUT2 Is a Key Node and Therapeutic Target in Lethal Prostate Cancer [Research Watch]

The transcription factor ONECUT2 is a core regulator of metastatic castration-resistant prostate cancer.



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Fear Impacts Quality of Life for Young Adults With Type 1 Diabetes

FRIDAY, Dec. 7, 2018 -- Fear of complications and frustration at the amount of time required to manage type 1 diabetes impact the quality of life of young adults with the disease, according to a study published in the December issue of The Diabetes...

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Lower RN Staffing Linked to Increased In-Hospital Mortality

FRIDAY, Dec. 7, 2018 -- The risk for in-hospital mortality is increased with lower registered nurse (RN) staffing and higher levels of admissions per RN, according to a study published online Dec. 4 in BMJ Quality & Safety. Peter Griffiths,...

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Ultrarestrictive Opioid Rx Protocol Cuts Postoperative Opioid Use

FRIDAY, Dec. 7, 2018 -- An ultrarestrictive opioid prescription protocol (UROPP) can reduce the number of opioids prescribed to patients after gynecologic and abdominal surgery without negative health consequences, according to a study published...

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American Society of Hematology, Dec. 1-4

The 60th American Society of Hematology Annual Meeting and Exposition The annual meeting of the American Society of Hematology was held from Dec. 1 to 4 in San Diego and attracted approximately 22,000 participants from around the world, including...

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SWI/SNF Mutations Confer Resistance to Ibrutinib plus Venetoclax in MCL [Research Watch]

Biomarker analysis of a phase II trial reveals mechanisms of resistance to BTK and BCL2 inhibition.



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Autophagy Sustains Tumors by Maintaining Serum Arginine Levels [Research Watch]

Impairment of host autophagy reduces circulating arginine and suppresses growth of some tumors.



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The senescence-associated secretory phenotype mediates oncogene-induced senescence in pediatric pilocytic astrocytoma

Purpose: Pilocytic astrocytoma (PA) is the most common childhood brain tumor, characterized by constitutive MAPK activation. MAPK signaling induces oncogene-induced senescence (OIS), which may cause unpredictable growth behavior of PAs. The senescence-associated secretory phenotype (SASP) has been shown to regulate OIS, but its role in PA remains unknown. Experimental Design: The patient-derived PA cell culture model, DKFZ-BT66, was used to demonstrate presence of the SASP and analyze its impact on OIS in PA. The model allows for doxycycline-inducible switching between proliferation and OIS. Both states were studied using gene-expression profiling (GEP), Western blot, ELISA, and cell viability testing. Primary PA tumors were analyzed by GEP and multiplex assay. Results: SASP factors were up-regulated in primary human and murine PA and during OIS in DKFZ-BT66 cells. Conditioned medium induced growth arrest of proliferating PA cells. The SASP factors IL1B and IL6 were up-regulated in primary PA, and both pathways were regulated during OIS in DKFZ-BT66. Stimulation with rIL1B but not rIL6 reduced growth of DKFZ-BT66 cells and induced the SASP. Anti-inflammatory treatment with dexamethasone induced regrowth of senescent cells and inhibited the SASP. Senescent DKFZ-BT66 cells responded to senolytic pan-BCL inhibitors. High IL1B and SASP expression in PA tumors was associated with favorable progression-free survival. Conclusions: We provide evidence for the SASP regulating OIS in pediatric PA, with IL1B as a relevant mediator. SASP expression could enable prediction of progression in PA patients. Further investigation of the SASP driving the unpredictable growth of PAs, and its possible therapeutic application, is warranted.



https://ift.tt/2ElsUY6

Anagrelide for gastrointestinal stromal tumor

Purpose: Gastrointestinal stromal tumor (GIST) is a common type of soft tissue sarcoma. Imatinib, an inhibitor of KIT, PDFGRA and a few other tyrosine kinases, is highly effective for GIST, but advanced GISTs frequently progress on imatinib and other approved tyrosine kinase inhibitors. We investigated phosphodiesterase 3 (PDE3) as a potential therapeutic target in GIST cell lines and xenograft models. Experimental Design: The GIST gene expression profile was interrogated in the MediSapiens IST Online transcriptome database comprising of human tissue and cancer samples, and PDE3A and PDE3B expression was studied using immunohistochemistry on tissue microarrays (TMAs) consisting of 630 formalin-fixed human tissue samples. GIST cell lines were screened for sensitivity to 217 anti-cancer compounds, and the efficacy of PDE inhibitors on GIST was further studied in GIST cell lines and patient-derived mouse xenograft models. Results: GISTs expressed PDE3A and PDE3B frequently compared to other human normal or cancerous tissues both in the in silico database and the TMAs. Anagrelide was identified as the most potent of the PDE3 modulators evaluated. It reduced cell viability, promoted cell death, and influenced cell signaling in GIST cell lines. Anagrelide inhibited tumor growth in GIST xenograft mouse models. Anagrelide was effective also in a GIST xenograft mouse model with KIT exon 9 mutation that may pose a therapeutic challenge, as these GISTs require a high daily dose of imatinib. Conclusions: PDE3A and PDE3B are frequently expressed in GIST. Anagrelide had anti-cancer efficacy in GIST xenograft models, and warrants further testing in clinical trials.



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Activating Mutations in Pik3caContribute to Anal Carcinogenesis in the Presence or Absence of HPV-16 Oncogenes.

Purpose:Over 95% of human anal cancers are etiologically associated with high-risk HPVs, with HPV type 16 (HPV16) the genotype most commonly found. Activating mutations in the catalytic subunit of Phosphatidylinositol (3,4,5)-trisphosphatekinase (PI3K), encoded by the Pik3cagene, are detected in approximately 20% of human anal cancers. Experimental Design: We asked if common activating mutations in Pik3cacontribute to anal carcinogenesis using an established mouse model for anal carcinogenesis in which mice are topically treated with the chemical carcinogen 7,12-Dimethylbenz(a)anthracene (DMBA). Mice expressing in their anal epithelium one of two activating mutations in Pik3cagenes, Pik3caH1047Ror Pik3caE545K, were monitored for anal carcinogenesis in the presence or absence of transgenes expressing the HPV16 E6 and E7 oncogenes. Results:Both mutant forms of Pik3caincreased susceptibility to anal carcinogenesis in the absence of HPV16 oncogenes, and cooperated with HPV16 oncogenes to induce the highest level and earliest onset of anal cancers. The combination of HPV16 oncogenes and Pik3camutations led to anal cancers even in the absence of treatment with DMBA. We further observed that the investigational mTOR1/2 dual inhibitor, TAK-228, significantly reduced the size of anal cancer-derived tumor spheroids in vitroand reduced the growth rates of anal cancer-derived tumor grafts in vivo. Conclusion:These data demonstrate that activating mutations in Pik3cadrive anal carcinogenesis together with HPV16 oncogenes, and that the PI3K/mTOR pathway is a relevant target for therapeutic intervention.



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A “Clearer” View of Pancreatic Pathology: A Review of Tissue Clearing and Advanced Microscopy Techniques

imageAlthough pathologic lesions in the pancreas are 3-dimensional (3D) complex structures, we currently use thin 2D hematoxylin and eosin stained slides to study and diagnose pancreatic pathology. Two technologies, tissue clearing and advanced microscopy, have recently converged, and when used together they open the remarkable world of 3D anatomy and pathology to pathologists. Advances in tissue clearing and antibody penetration now make even dense fibrotic tissues amenable to clearing, and light sheet and confocal microscopies allow labeled cells deep within these cleared tissues to be visualized. Clearing techniques can be categorized as solvent-based or aqueous-based techniques, but both clearing methods consist of 4 fundamental steps, including pretreatment of specimens, permeabilization and/or removal of lipid, immunolabeling with antibody penetration, and clearing by refractive index matching. Specialized microscopes, including the light sheet microscope, the 2-photon microscope, and the confocal microscope, can then be used to visualize and evaluate the 3D histology. Both endocrine and exocrine pancreas pathology can then be visualized. The application of labeling and clearing to surgically resected human pancreatic parenchyma can provide detailed visualization of the complexities of normal pancreatic anatomy. It also can be used to characterize the 3D architecture of disease processes ranging from precursor lesions, such as pancreatic intraepithelial neoplasia lesions and intraductal papillary mucinous neoplasms, to infiltrating pancreatic ductal adenocarcinomas. The evaluation of 3D histopathology, including pathology of the pancreatic lesions, will provide new insights into lesions that previously were seen, and thought of, only in 2 dimensions.

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Gastric-type Adenocarcinoma of the Cervix: Tumor With Wide Range of Histologic Appearances

imageGastric-type endocervical adenocarcinoma (GAS) is a recently described diagnostic entity originally characterized as a tumor with (1) voluminous cytoplasm that is (2) clear or pale eosinophilic, and (3) cells showing distinct cell borders. Since the initial tumor description there has been accumulating experience that the neoplasm, in addition to classic features, may show a wide spectrum of morphologic appearances. This paper describes and illustrates cases of GAS with focal or diffuse findings that include: densely eosinophilic cytoplasm, foamy cytoplasm, goblet cells, glands with elongated, stratified nuclei, glands with small cuboidal cells, glands with flattened cells, papillary growth, single cell infiltration and infiltration with microcystic elongated and fragmented pattern. All these patterns may bring up a differential diagnosis with other cervical malignancies such as usual, intestinal, endometrioid, clear cell, serous, and mesonephric adenocarcinoma. The paper describes the patterns of immunostaining of respective lesions that may aid in the diagnostic process and summarizes the main points of the differential diagnosis. GAS is associated with somatic and germline STK11 mutations and TP53 mutations but is invariably negative for human papilloma virus when tumor only is tested. It shows variation in incidence between countries. Awareness of the spectrum of morphologic appearances in GAS is important for accurate and confident diagnosis. Correct identification of GAS is important due to its propensity for ovarian and other distant metastases, markedly worse prognosis as compared with usual endocervical adenocarcinoma, and its relative resistance to chemotherapy.

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Neoplasms of the Neuroendocrine Pancreas: An Update in the Classification, Definition, and Molecular Genetic Advances

imageThis review focuses on discussing the main modifications of the recently published 2017 WHO Classification of Neoplasms of the Neuroendocrine Pancreas (panNEN). Recent updates separate pancreatic neuroendocrine tumors into 2 broad categories: well-differentiated pancreatic neuroendocrine tumors (panNET) and poorly differentiated pancreatic neuroendocrine carcinoma (panNEC), and incorporates a new subcategory of "well-differentiated high-grade NET (G3)" to the well-differentiated NET category. This new classification algorithm aims to improve the prediction of clinical outcomes and survival and help clinicians select better therapeutic strategies for patient care and management. In addition, these neuroendocrine neoplasms are capable of producing large quantity of hormones leading to clinical hormone hypersecretion syndromes. These functioning tumors include, insulinomas, glucagonomas, somatostatinomas, gastrinomas, VIPomas, serotonin-producing tumors, and ACTH-producing tumors. Although most panNENs arise as sporadic diseases, a subset of these heterogeneous tumors present as parts on inherited genetic syndromes, such as multiple endocrine neoplasia type 1, von Hippel-Lindau, neurofibromatosis type 1, tuberous sclerosis, and glucagon cell hyperplasia and neoplasia syndromes. Characteristic clinical and morphologic findings for certain functioning and syndromic panNENs should alert both pathologists and clinicians as appropriate patient management and possible genetic counseling may be necessary.

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Selected Case From the Arkadi M. Rywlin International Pathology Slide Seminar: Atypical Thymoma With Rhabdomyomatous Differentiation

imageThymic epithelial neoplasms with foci of rhabdomyomatous differentiation are rare. A case is presented of a primary thymic epithelial neoplasm showing the features of an atypical spindle cell thymoma that contained foci of bland-appearing rhabdomyomatous cells. The histologic and immunohistochemical features of this tumor are discussed along with a review of the literature and the comments from the AMR members to the case.

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Circulating Tumor Cells: Overview and Opportunities in Cytology

imageCirculating tumor cells (CTCs) have long been assumed to be the substrate of cancer metastasis. However, only in recent years have we begun to leverage the potential of CTCs found in minimally invasive peripheral blood specimens to improve care for cancer patients. Currently, CTC enumeration is an accepted prognostic indicator for breast, prostate, and colorectal cancer; however, CTC enumeration remains largely a research tool. More recently, the focus has shifted to CTC characterization and isolation which holds great promise for predictive testing. This review summarizes the relevant clinical, biological, and technical background necessary for pathologists and cytopathologists to appreciate the potential of CTC techniques. A summary of relevant systematic reviews of CTCs for specific cancers is then presented, as well as potential applications to precision medicine. Finally, we suggest future applications of CTC technologies that can be easily incorporated in the pathology laboratory, with the recommendation that pathologists and particularly cytopathologists apply these technologies to small specimens in the era of "doing more with less."

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What’s New in Dermatopathology: Inflammatory Dermatoses

imageInflammatory skin diseases encompass a vast array of conditions. The field continues to expand and evolve with resurgence of conditions, through newly recognized medication adverse effects, and via more detailed descriptions of known dermatoses. The importance of clinicopathologic correlation and an up to date knowledge of dermatologic conditions cannot be overstated. This review focuses on an array of recent important developments in the histologic diagnosis of inflammatory conditions that affect the skin.

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Paget’s “Seed and Soil” Theory of Cancer Metastasis: An Idea Whose Time has Come

imageThe concept that the pattern of metastatic spread of cancer is not random and that cancer cells exhibit preferences when metastasizing to organs, dates back to 1889 when Steven Paget published his "seed and soil" hypothesis. He proposed that the spread of tumor cells is governed by interaction and cooperation between the cancer cells (seed) and the host organ (soil). Extensive studies during the last several decades have provided a better understanding of the process of metastatic spread of cancer and several stages such as intravasation, extravasation, tumor latency, and development of micrometastasis and macrometastasis have been defined. Furthermore, recent studies have shown that the target organs may be prepared for metastatic deposits by the development of premetastatic niches. This specialized microenvironment is involved in promoting tumor cell homing, colonization, and subsequent growth at the target organ. The premetastatic niche consists of accumulation of aberrant immune cells and extracellular matrix proteins in target organs. The primary tumor plays a key role in the development of premetastatic niches by producing tumor-derived soluble factors which mobilize bone marrow-derived hematopoietic cells to the premetastatic niche. Exosomes-derived from the primary tumor also contribute to cancer-favorable microenvironment in the premetastatic niches. These changes prime the initially healthy organ microenvironment and render it amenable for subsequent metastatic cell colonization.

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Factors affecting vitamin D deficiency in active inflammatory bowel diseases

Hypovitaminosis D is prevalent in inflammatory bowel disease (IBD) and may be associated with disease activity.

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PTH, FGF23, and Intensive Blood Pressure Lowering in Chronic Kidney Disease Participants in SPRINT

Background and objectives

The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that intensive BP lowering reduced the risk of cardiovascular disease, but increased eGFR decline. Serum parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) concentrations are elevated in CKD and are associated with cardiovascular disease. We evaluated whether intact PTH or intact FGF23 concentrations modify the effects of intensive BP control on cardiovascular events, heart failure, and all-cause mortality in SPRINT participants with CKD.

Design, setting, participants, & measurements

We measured PTH and FGF23 in 2486 SPRINT participants with eGFR<60 ml/min per 1.73 m2 at baseline. Cox models were used to evaluate whether serum PTH and FGF23 concentrations were associated with cardiovascular events, heart failure, and all-cause mortality, and whether PTH and FGF23 modified the effects of intensive BP control.

Results

The mean age of this subcohort was 73 years, 60% were men, and mean eGFR was 46±11 ml/min per 1.73 m2. Median PTH was 48 (interquartile range [IQR], 35–67) pg/ml and FGF23 was 66 (IQR, 52–88) pg/ml. There were 261 composite cardiovascular events, 102 heart failure events, and 179 deaths within the subcohort. The adjusted hazard ratio (HR) per doubling of PTH concentration for cardiovascular events, heart failure, and all-cause mortality were 1.29 (95% confidence interval [95% CI], 1.06 to 1.57), 1.32 (95% CI, 0.96 to 1.83), and 1.04 (95% CI, 0.82 to 1.31), respectively. There were significant interactions between PTH and BP arm for both the cardiovascular (P-interaction=0.01) and heart failure (P-interaction=0.004) end points. Participants with a PTH above the median experienced attenuated benefits of intensive BP control on cardiovascular events (adjusted HR, 1.02; 95% CI, 0.72 to 1.42) compared with participants with a PTH below the median (adjusted HR, 0.67; 95% CI, 0.45 to 1.00). FGF23 was not independently associated with any outcome and did not modify the effects of the intervention.

Conclusions

SPRINT participants with CKD and a high serum PTH received less cardiovascular protection from intensive BP therapy than participants with a lower serum PTH.



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Home-Based Care for CKD for High-Risk Populations



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Sleep Quality and Sleep Duration with CKD are Associated with Progression to ESKD

Background and objectives

Shorter or longer sleep duration and poor sleep quality are risk factors for numerous cardio-metabolic diseases, cardiovascular disease, and mortality in subjects with normal kidney function. The association of sleep duration and sleep quality with health outcomes in patients with CKD remains uncertain.

Design, setting, participants, & measurements

A 4-year prospective cohort study in 17 nephrology centers in Japan, the CKD Japan Cohort (CKD-JAC) Study, assessed an association of self-reported sleep duration and sleep quality, on the basis of the Pittsburgh Sleep Quality Index (PSQI) questionnaire, with incidence of ESKD in 1601 patients with eGFR 10–59 ml/min per 1.73 m2 using multivariable-adjusted Cox proportional hazards models.

Results

Baseline sleep duration and PSQI global score for the 1601 patients were mean±SD 7.0±1.3 hours and median 4 (interquartile range, 3–7), respectively. Poor sleep quality (PSQI global score ≥6) was common (n=588 [37%]). During a median of 4.0 (2.6–4.3) years of the follow-up period, 282 (18%) patients progressed to ESKD. After adjusting for age, sex, eGFR, urinary albumin excretion, smoking status, body mass index, history of diabetes and cardiovascular disease, systolic BP, blockade of the renin-angiotensin system, use of hypnotics, and Beck depression inventory score, both shorter (≤5 hour) and longer (>8 hour) sleep duration were associated with ESKD (adjusted hazard ratios [95% confidence intervals] for ≤5.0, 5.1–6.0, 6.1–7.0, 7.1–8.0, and ≥8.0 hours were 2.05 [1.31 to3.21], 0.98 [0.67 to 1.44], 1.00 [reference], 1.22 [0.89 to 1.66], and 1.48 [1.01 to 2.16]), suggesting a U-shaped relationship between sleep duration and ESKD. PSQI global score ≥6 was also associated with incidence of ESKD (adjusted hazard ratios [95% confidence intervals] for PSQI global score ≤5 and ≥6 were 1.00 [reference] and 1.33 [1.03 to 1.71]).

Conclusions

Shorter (≤5 hour) and longer (>8 hour) sleep duration and poor sleep quality (PSQI global score ≥6) were associated with ESKD in patients with CKD.



https://ift.tt/2Pq6w0w

Adrenocorticotropic Hormone for Childhood Nephrotic Syndrome: The ATLANTIS Randomized Trial

Background and objectives

There is renewed interest in adrenocorticotropic hormone (ACTH) for the treatment of nephrotic syndrome. We evaluated the efficacy and safety of ACTH in children with frequently relapsing or steroid-dependent nephrotic syndrome in a randomized trial.

Design, setting, participants, & measurements

Participants aged 2–20 years old with frequently relapsing or steroid-dependent nephrotic syndrome were enrolled from 16 sites in the United States and randomized 1:1 to ACTH (repository corticotropin injection) or no relapse-preventing treatment. ACTH treatment regimen was 80 U/1.73 m2 administered twice weekly for 6 months, followed by 40 U/1.73 m2 administered twice weekly for 6 months. The primary outcome was disease relapse during the first 6 months. Participants in the control group were offered crossover to ACTH treatment if they relapsed within 6 months. Secondary outcomes were relapse after ACTH dose reduction and treatment side effects.

Results

The trial was stopped at a preplanned interim analysis after enrollment of 31 participants because of a lack of discernible treatment efficacy. Fourteen out of 15 (93%) participants in the ACTH arm experienced disease relapse in the first 6 months, with a median time to first relapse of 23 days (interquartile range, 9–32), compared with 15 out of 16 (94%) participants and at a median of 21 days (interquartile range, 14–51) in the control group. There was no difference in the proportion of relapsed patients (odds ratio, 0.93; 95% confidence interval, 0.05 to 16.40; P>0.99) or time to first relapse (hazard ratio, 1.03; 95% confidence interval, 0.50 to 2.15; P=0.93). Thirteen out of 16 participants in the control group crossed over to ACTH treatment. Three out of 28 participants completed 12 months of ACTH treatment; the others exited the trial because of frequent relapses or side effects. There were no disease relapses after ACTH dose reduction among the three participants. Most side effects were mild and similar to side effects of corticosteroids.

Conclusions

ACTH at 80 U/1.73 m2 administered twice weekly was ineffective at preventing disease relapses in pediatric nephrotic syndrome.



https://ift.tt/2zKNayo

Helping More Patients Receive a Living Donor Kidney Transplant

The best treatment option for many patients with kidney failure is a kidney transplant from a living donor. Countries that successfully increase their rate of living kidney donation will decrease their reliance on dialysis, the most expensive and high-risk form of kidney replacement therapy. Outlined here are some barriers that prevent some patients from pursuing living kidney donation and current knowledge on some potential solutions to these barriers. Also described are strategies to promote living kidney donation in a defensible system of practice. Safely increasing the rate of living kidney donation will require better programs and policies to improve the experiences of living donors and their recipients, to safeguard the practice for years to come.



https://ift.tt/2Pq6uWs

Procurement Biopsies in the Evaluation of Deceased Donor Kidneys

Background and objectives

Biopsies taken at deceased donor kidney procurement continue to be cited as a leading reason for discard; however, the reproducibility and prognostic capability of these biopsies are controversial.

Design, setting, participants, & measurements

We compiled a retrospective, single-institution, continuous cohort of deceased donor kidney transplants performed from 2006 to 2009. Procurement biopsy information—percentage of glomerulosclerosis, interstitial fibrosis/tubular atrophy, and vascular disease—was obtained from the national transplant database. Using univariable, multivariable, and time-to-event analyses for death-censored graft survival, we compared procurement frozen section biopsy reports with reperfusion paraffin-embedded biopsies read by trained kidney pathologists (n=270). We also examined agreement for sequential procurement biopsies performed on the same kidney (n=116 kidneys).

Results

For kidneys on which more than one procurement biopsy was performed (n=116), category agreement was found in only 64% of cases (=0.14). For all kidneys (n=270), correlation between procurement and reperfusion biopsies was poor: overall, biopsies were classified into the same category (optimal versus suboptimal) in only 64% of cases (=0.25). This discrepancy was most pronounced when categorizing percentage of glomerulosclerosis, which had 63% agreement (=0.15). Interstitial fibrosis/tubular atrophy and vascular disease had agreement rates of 82% (=0.13) and 80% (=0.15), respectively. Ninety-eight (36%) recipients died, and 56 (21%) allografts failed by the end of follow-up. Reperfusion biopsies were more prognostic than procurement biopsies (hazard ratio for graft failure, 2.02; 95% confidence interval, 1.09 to 3.74 versus hazard ratio for graft failure, 1.30; 95% confidence interval, 0.61 to 2.76), with procurement biopsies not significantly associated with graft failure.

Conclusions

We found that procurement biopsies are poorly reproducible, do not correlate well with paraffin-embedded reperfusion biopsies, and are not significantly associated with transplant outcomes.



https://ift.tt/2zNZzS1

Pharmacology behind Common Drug Nephrotoxicities

Patients are exposed to numerous prescribed and over-the-counter medications. Unfortunately, drugs remain a relatively common cause of acute and chronic kidney injury. A combination of factors including the innate nephrotoxicity of drugs, underlying patient characteristics that increase their risk for kidney injury, and the metabolism and pathway of excretion by the kidneys of the various agents administered enhance risk for drug-induced nephrotoxicity. This paper will review these clinically relevant aspects of drug-induced nephrotoxicity for the clinical nephrologist.



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Still Asking "Which Rate Is Right?" Years Later



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Intravenous Fluids: Finding the Right Balance



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Health Insurance in the First 3 Months of Hemodialysis and Early Vascular Access

Background and objectives

Patients without Medicare who develop ESKD in the United States become Medicare eligible by their fourth dialysis month. Patients without insurance may experience delays in obtaining arteriovenous fistulas or grafts before obtaining Medicare coverage.

Design, setting, participants, & measurements

In this retrospective cohort study, we used a national registry to compare uninsured patients starting in-center hemodialysis with a central venous catheter between 2010 and 2013 with similar patients with Medicare or Medicaid. We evaluated whether insurance status at dialysis start influenced the likelihoods of switching to dialysis through an arteriovenous fistula or graft and hospitalizations involving a vascular access infection. We used multivariable logistic and Cox regression models and transformed odds ratios to relative risks using marginal effects.

Results

Patients with Medicare or Medicaid were more likely to switch to an arteriovenous fistula or graft by their fourth dialysis month versus uninsured patients (Medicare hazard ratio, 1.63; 95% confidence interval, 1.14 to 2.43; Medicaid hazard ratio, 1.23; 95% confidence interval, 1.12 to 1.38). There were no differences in rates of switching to arteriovenous fistulas or grafts after all patients obtained Medicare in their fourth dialysis month (Medicare hazard ratio, 1.17; 95% confidence interval, 0.97 to 1.42; Medicaid hazard ratio, 1.01; 95% confidence interval, 0.96 to 1.06). Patients with Medicare at dialysis start had fewer hospitalizations involving vascular access infection in dialysis months 4–12 (hazard ratio, 0.60; 95% confidence interval, 0.37 to 0.97).

Conclusions

Insurance-related disparities in the use of arteriovenous fistulas and grafts persist through the fourth month of dialysis, may not fully correct after all patients obtain Medicare coverage, and may lead to more frequent vascular access infections.



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Novel Models for Health Care Delivery for CKD for Disadvantaged Populations



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Monoclonal Gammopathies and Kidney Disease: Searching for Significance



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Lung Ultrasonography in the Acutely Dyspneic Hemodialysis Patient



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Treatment of Drug-Induced Acute Tubulointerstitial Nephritis: The Search for Better Evidence



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Prevalence of Opioid, Gabapentinoid, and NSAID Use in Patients with CKD



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Does What Goes Around Always Come Around?



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Acute Kidney Injury among Hospitalized Children in China

Background and objectives

High-quality epidemiologic data on AKI in children are particularly lacking in developing countries. This study aimed to assess the epidemiology and clinical correlates of AKI among hospitalized children in China.

Design, setting, participants, & measurements

We performed a multicenter study, in a cohort of hospitalized children aged 1 month to 18 years, from 25 general and children's hospitals in China during 2013–2015. We obtained patient-level data from the electronic hospitalization information system and laboratory databases of all children who had at least two serum creatinine tests within any 7-day window during their first 30 days of hospitalization. We identified AKI events according to the creatinine criteria of Kidney Disease Improving Global Outcomes. The in-hospital outcomes of AKI, including mortality, kidney recovery, and length of stay, were assessed. We estimated the corresponding hazard ratios using a Cox proportional hazard model, with adjustment for age, sex, comorbidities, and clinical procedures.

Results

A total of 19,908 (20%) patients with AKI were identified among 101,836 pediatric inpatients, of which 7220 (7%) were community acquired and 12,688 (13%) were hospital acquired. Up to 96% of these AKI events were not diagnosed on the discharge records. The cumulative incidence of AKI in infants (28%) was twice that in adolescents (12%). The profiles of risk factors differed between community-acquired and hospital-acquired AKI and varied with age. Diarrhea and sepsis were the top risk factors for community-acquired AKI, each contributing 6% of the risk. Congenital heart disease/cardiac surgery was the major risk factor for hospital-acquired AKI, contributing to 19% of cases. Exposure to nephrotoxic drugs, mostly nonsteroidal anti-inflammatory drugs and proton pump inhibitors, was common in hospitalized children and was associated with a higher risk of AKI. Death occurred in 842 out of 19,908 patients (4%) with AKI versus 450 out of 81,478 children (0.5%) without AKI. The risk of in-hospital death was higher among children with severe AKI, shock, and respiratory failure. Pediatric AKI was associated with longer hospital stay and higher daily cost, even after adjustment for covariates.

Conclusions

Pediatric AKI is common and is substantially underdiagnosed in China.



https://ift.tt/2PmNJDD

Home-Based Kidney Care, Patient Activation, and Risk Factors for CKD Progression in Zuni Indians: A Randomized, Controlled Clinical Trial

Background and objectives

The burden of CKD is greater in ethnic and racial minorities and persons living in rural communities, where access to care is limited.

Design, setting, participants, & measurements

A 12-month clinical trial was performed in 98 rural adult Zuni Indians with CKD to examine the efficacy of a home-based kidney care program. Participants were randomized by household to receive usual care or home-based care. After initial lifestyle coaching, the intervention group received frequent additional reinforcement by community health representatives about adherence to medicines, diet and exercise, self-monitoring, and coping strategies for living with stress. The primary outcome was change in patient activation score, which assesses a participant's knowledge, skill, and confidence in managing his/her own health and health care.

Results

Of 125 randomized individuals (63 intervention and 62 usual care), 98 (78%; 50 intervention and 48 usual care) completed the 12-month study. The average patient activation score after 12 months was 8.7 (95% confidence interval, 1.9 to 15.5) points higher in the intervention group than in the usual care group after adjusting for baseline score using linear models with generalized estimating equations. Participants randomized to the intervention had 4.8 (95% confidence interval, 1.4 to 16.7) times the odds of having a final activation level of at least three ("taking action") than those in the usual care group. Body mass index declined by 1.1 kg/m2 (P=0.01), hemoglobin A1c declined by 0.7% (P=0.01), high-sensitivity C-reactive protein declined by 3.3-fold (P<0.001), and the Short-Form 12 Health Survey mental score increased by five points (P=0.002) in the intervention group relative to usual care.

Conclusions

A home-based intervention improves participants' activation in their own health and health care, and it may reduce risk factors for CKD in a rural disadvantaged population.



https://ift.tt/2zMeex8

Association of Monoclonal Gammopathy with Progression to ESKD among US Veterans

Background and objectives

Whether patients with monoclonal protein are at a higher risk for progression of kidney disease is not known. The goal of this study was to measure the association of monoclonal protein with progression to ESKD.

Design, setting, participants, & measurements

This was a retrospective cohort study of 2,156,317 patients who underwent serum creatinine testing between October 1, 2000 and September 30, 2001 at a Department of Veterans Affairs medical center, among whom 21,898 had paraprotein testing within 1 year before or after cohort entry. Progression to ESKD was measured using linked data from the US Renal Data System.

Results

Overall, 1,741,707 cohort members had an eGFR≥60 ml/min per 1.73 m2, 283,988 had an eGFR of 45–59 ml/min per 1.73 m2, 103,123 had an eGFR of 30–44 ml/min per 1.73 m2 and 27,499 had an eGFR of 15–29 ml/min per 1.73 m2. The crude incidence of ESKD ranged from 0.7 to 80 per 1000 person-years from the highest to lowest eGFR category. Patients with low versus preserved eGFR were more likely to be tested for monoclonal protein but no more likely to have a positive test result. In adjusted analyses, a positive versus negative test result was associated with a higher risk of ESKD among patients with an eGFR≥60 ml/min per 1.73 m2 (hazard ratio, 1.67; 95% confidence interval, 1.22 to 2.29) and those with an eGFR of 15–29 ml/min per 1.73 m2 (hazard ratio, 1.38; 95% confidence interval, 1.07 to 1.77), but not among those with an eGFR of 30–59 ml/min per 1.73 m2. Progression to ESKD was attributed to a monoclonal process in 21 out of 76 versus seven out of 174 patients with monoclonal protein and preserved versus severely reduced eGFR at cohort entry.

Conclusions

The detection of monoclonal protein provides little information on ESKD risk for most patients with a low eGFR. Further study is required to better understand factors contributing to a positive association of monoclonal protein with ESKD risk in patients with preserved and severely reduced levels of eGFR.



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Correction



https://ift.tt/2zNZzBv

Diagnostic sensitivity of electrophysiology and ultrasonography in ulnar neuropathies of different severity

Ulnar neuropathy is the second most common mono-neuropathy after carpal tunnel syndrome. It usually results from focal nerve abnormality around the elbow, with an estimated incidence of 24.7/105/year (Mondelli et al., 2005). It presents with paraesthesia or sensory loss in the little and ring fingers and weakness of ulnar innervated muscles. Untreated ulnar neuropathy can progress to cause severe disability. However, despite its relatively high incidence, diagnosis and management of ulnar neuropathy at the elbow can be still challenging.

https://ift.tt/2RIzhaO

Cognitive and motor event-related potentials in Tourette syndrome and tic disorders: a systematic review

Tourette syndrome (TS) is a neurodevelopmental psychiatric disorder involving motor and phonic tics. Tics are conceptualized as involuntary motor contractions or vocalizations (American Psychiatric Association, 2013). These tics can be either simple or complex. Simple motor tics are the most frequent ones, and may take the form or eyeblinks, nose twitches, or head jerks, among others. While simple motor tics only involve one group of muscles, complex motors tics involve multiple groups of muscles in a coordinated sequence.

https://ift.tt/2QnmGNX

Persistent intestinal metaplasia after endoscopic eradication therapy of neoplastic Barrett’s esophagus increases the risk of dysplasia recurrence: meta-analysis

Endoscopic eradication therapy (EET) is the main treatment for dysplastic Barrett's esophagus and intramucosal adenocarcinoma. Although the goal of EET is to achieve complete remission of intestinal metaplasia (CRIM), treatment might achieve complete remission of dysplasia (CR-D) only, without achieving CRIM. Persistent intestinal metaplasia after eradication of dysplasia might carry a higher risk for progression into advanced neoplasia.

https://ift.tt/2Ppouk4

FibroScan detects cardiovascular damage in patients with NAFLD



https://ift.tt/2zOuoGf

Universal screening for hepatitis C: an important step in virus elimination



https://ift.tt/2PqN97A

Concomitant Use of Aminosalicylates Is Not Associated with Improved Outcomes in Patients with Ulcerative Colitis Escalated to Vedolizumab



https://ift.tt/2zOaACV

Nimesulide effects on the blood pro-oxidant–antioxidant status in lipopolysaccharide-challenged mice

Abstract

The maintenance of the pro-oxidant–antioxidant equilibrium between ROS production and antioxidant protection systems is an important element of systemic defence and requires efficient control. The aim of the study was to monitor the dynamics of antioxidants and lipid peroxidation in mice challenged intraperitoneally with Escherichia coli (O111:B4) lipopolysaccharide (LPS) and to evaluate the antioxidant potential of the non-steroidal anti-inflammatory drug nimesulide. Albino mice were divided into three groups (n = 36). Group I received a single intraperitoneal (i.p.) injection with 25 μg/0.5 mL LPS. Thirty minutes before LPS, group II received orally (p.o.) 100 mg/kg nimesulide. The preparation was administered for 4 days. Group III received only nimesulide at the indicated dose for 4 days. The blood parameters were analysed at hour 0 (prior to treatment applied to each group), post treatment hours 6 and 24, and days 3, 5 and 9. Assayed parameters included catalase, reduced glutathione, albumin, glucose, ferric reducing ability of plasma (FRAP), malondialdehyde and oxidative stress index. LPS induced continuous hypoglycaemia, decreased catalase activity and reduced glutathione, but FRAP and albumin were preserved. The application of nimesulide alone did not alter oxidative stress index and enhanced FRAP. Its co-administration with LPS normalised reduced glutathione, decreased catalase and increased malondialdehyde concentrations and oxidative stress index. The application of nimesulide as antioxidant requires objective evaluation of associated benefits and risks.



https://ift.tt/2PliSY1

Vitality Measured as Self-reported Energy Level and Clinical Outcomes in Hemodialysis Patients: The Japanese Dialysis Outcomes and Practice Pattern Study (J-DOPPS)

The infrequent assessment of vitality in clinical practice may be partially due to an inadequate understanding of vitality and the lack of a concise method of assessing it. This study aimed to examine the association of a simple 1-item "vitality" question measuring self-reported energy level with clinical outcomes.

https://ift.tt/2UwovGG

Acute Thrombotic Microangiopathy and Cortical Necrosis Following Administration of Alemtuzumab: A Case Report

Alemtuzumab, a humanized monoclonal antibody that targets CD52 antigens on lymphocytes and monocytes, has shown efficacy in preventing relapse in relapsing-remitting multiple sclerosis. Despite known severe (yet rare) renal side effects such as anti-glomerular basement membrane disease and membranous glomerulopathy, to our knowledge, alemtuzumab has never been documented to cause drug-induced thrombotic microangiopathy. We describe a 39-year-old woman with relapsing-remitting multiple sclerosis who developed acute kidney injury requiring renal replacement therapy after 1 dose of alemtuzumab, as well as microangiopathic hemolytic anemia and thrombocytopenia.

https://ift.tt/2BacQob

Nonconvulsive Seizure Detection by Reduced-Lead Electroencephalography in Children with Altered Mental Status in the Emergency Department

To evaluate the proportion of children presenting to the emergency department (ED) with altered mental status who demonstrate nonconvulsive seizures on reduced-lead electroencephalography (EEG), and to further investigate the characteristics, treatment, and outcomes in these patients compared with patients without nonconvulsive seizures.

https://ift.tt/2zKIwQY

Characterization of Post-Thrombotic Syndrome in Children with Cardiac Disease

To assess the validity of existing clinical scales assessing the presence of physical and functional abnormalities for diagnosing post-thrombotic syndrome (PTS) in children, including specific evaluation of use in children with congenital heart disease (CHD).

https://ift.tt/2Ppk4cY

Comparison of 30-Day Serious Adverse Clinical Events for Elderly Patients Presenting to the Emergency Department With Near-Syncope Versus Syncope

Controversy remains in regard to the risk of adverse events for patients presenting with syncope compared with near-syncope. The purpose of our study is to describe the difference in outcomes between these groups in a large multicenter cohort of older emergency department (ED) patients.

https://ift.tt/2BWn4K6

Treatment-Related Outcomes in Paget–Schroetter Syndrome—A Cross-Sectional Investigation

To investigate treatment-related outcomes, namely radiological clot resolution, post-thrombotic syndrome (PTS), and health related quality-of-life (HRQoL) scores, in children with Paget–Schroetter syndrome (PSS) undergoing multidisciplinary management, including anticoagulation and decompressive rib-resection surgery, with or without thrombolytic therapy.

https://ift.tt/2PoAMch

Dynamic Cerebellar Tonsils in Chiari Malformation

A 5-year-old asymptomatic boy had apparent optic nerve head elevation on routine ophthalmology examination. Magnetic resonance (MR) imaging of the brain revealed a previously undiagnosed Chiari I malformation with crowding of the foramen magnum and low-lying cerebellar tonsils (Figure, A). Cine phase sagittal MR imaging (Video; available at www.jpeds.com) showed altered cerebrospinal fluid egress through the foramen magnum. It also demonstrated dynamic motion of the cerebellar tonsils that correlated with the cardiac cycle.

https://ift.tt/2PrdS3V

Research Pioneers in Emergency Medicine—Reflections on Their Paths to Success and Advice to Aspiring Researchers: A Qualitative Study

Research in basic, translational, and clinical emergency medicine has made great strides since the formalization of emergency medicine as a specialty. Our objective is to identify and analyze strategies used by emergency medicine research pioneers to inform further advancement of research in emergency medicine, particularly for aspiring researchers and those in emerging areas, using emergency medicine medical education as one example.

https://ift.tt/2E5BglH

Do Glucocorticoids Improve Symptoms and Reduce Return Visits or Admission Rates Among Children With Croup?

Authors included 43 randomized controlled trials comprising 4,565 patients from an initial 79 studies discovered during the literature search. Of these, 21 (48.8%) evaluated ED patients, 21 (48.8%) evaluated hospitalized patients, and 1 (2.3%) evaluated patients presenting to a physician outpatient office. Twenty-nine studies (67.4%) measured croup scores; of these, 17 (58.6%) used the Westley score, 11 (37.9%) used author-created scales, and 1 (3.4%) used the Downes score. Compared with placebo, glucocorticoids improved symptoms of croup as measured by standardized mean difference at intervals from medication administration at 2 hours (standardized mean difference –0.65; 95% CI –1.13 to –0.18) to 24 hours (standardized mean difference –0.86; 95% CI –1.40 to –0.31).

https://ift.tt/2EbZDyj

Acceleration Index Predicts Efficacy of Orthostatic Training on Vasovagal Syncope in Children

To explore the value of the acceleration index as a predictor of therapeutic response to orthostatic training in children with vasovagal syncope (VVS).

https://ift.tt/2zKItEM

Prematurity Does Not Increase Early Childhood Fracture Risk

To evaluate the impact of prematurity on fracture by age 5, controlling for medications and comorbidities of prematurity.

https://ift.tt/2zKu7nF

Revisiting code status in patients undergoing GI endoscopy with a “do not resuscitate” order

Patients with a do not resuscitate (DNR) order may go through relatively invasive procedures such as surgery or endoscopy for symptom control. Although there is a robust body of literature on revisiting DNR orders before surgical procedures, there is a scarcity of literature discussing this issue for endoscopy.1,2 We identified this gap after a clinical ethics consultation with the GI clinic team at one of the healthcare institutions affiliated with the Centre for Clinical Ethics.

https://ift.tt/2BY3n4Q

miR-192-5p silencing by genetic aberrations is a key event in hepatocellular carcinomas with cancer stem cell features

Various cancer stem cell (CSC) biomarkers have been identified for hepatocellular carcinoma (HCC), but little is known about the implications of heterogeneity and shared molecular networks within the CSC population. Through miRNA profile analysis in a HCC cohort (n=241) for five groups of CSC+ HCC tissues, i.e., EpCAM+, CD90+, CD133+, CD44+, and CD24+ HCC,we identified a 14-miRNA signature commonly altered among these five groups of CSC+ HCC. MiR-192-5p, the top ranked CSC-miRNA, was liver -abundant and -specific and markedly downregulated in all five groups of CSC+ HCC from two independent cohorts (n=613). Suppressing miR-192-5p in HCC cells significantly increased multiple CSC populations and CSC-related features through targeting PABPC4. Both TP53 mutation and hyper-methylation of the mir-192 promoter impeded transcriptional activation of miR-192-5p in HCC cell lines and primary CSC+ HCC. This study reveals the circuit from hyper-methylation of the mir-192 promoter through the increase in PABPC4 as a shared genetic regulatory pathway in various groups of primary CSC+ HCC. This circuit may be the driver that steers liver cells toward hepatic CSC cells, leading to hepatic carcinogenesis.

https://ift.tt/2L79d6Y

Meds Taken Do Not Vary With ADL Impairment in Heart Failure

FRIDAY, Dec. 7, 2018 -- For individuals with heart failure, those with impairment in activities of daily living (ADL) take as many medications as those without ADL impairment, according to a study published online Nov. 29 in the Journal of the...

https://ift.tt/2E6uhZH

Pregnant Women Commonly Refuse Vaccines

FRIDAY, Dec. 7, 2018 -- Pregnant women commonly refuse vaccines, including influenza vaccine and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine, according to research published online Dec. 4 in Obstetrics &...

https://ift.tt/2QIUGDu

Rural Residence, Poverty Are Risk Factors for COPD

FRIDAY, Dec. 7, 2018 -- Rural residence and poverty are risk factors for chronic obstructive pulmonary disease (COPD), according to a study recently published in the American Journal of Respiratory and Critical Care Medicine. Sarath Raju, M.D., from...

https://ift.tt/2E9Gm0q

Minimally Invasive Surgery Works Well for Detached Retina

FRIDAY, Dec. 7, 2018 -- A minimally invasive treatment for retinal detachment leads to favorable outcomes, according to a study published online Nov. 20 in Ophthalmology. Roxane J. Hillier, M.B.Ch.B., from St. Michael's Hospital and the University...

https://ift.tt/2QHB4Qd

Chronic Kidney Disease Burden Increasing in the United States

FRIDAY, Dec. 7, 2018 -- The burden of chronic kidney disease (CKD) increased in the United States between 2002 and 2016, although there was variability by state, according to a study published online Nov. 30 in JAMA Network Open. Benjamin Bowe,...

https://ift.tt/2QDuQ3N

Botox Injections Explored to Cut Postop A-Fib in Cardiac Surgery

FRIDAY, Dec. 7, 2018 -- Intraoperative botulinum toxin (BTX) injections show promise as a way to reduce the risk for postoperative atrial fibrillation (AF) following cardiac surgery, according to two studies recently published in Heart...

https://ift.tt/2E8UOFS

Breast Screening Linked to Lower Risk for Breast Cancer Death

FRIDAY, Dec. 7, 2018 -- Women who have participated in mammography screening have a lower risk for dying from breast cancer within 10 and 20 years after diagnosis, according to a study recently published in Cancer. László Tabár, M.D., from Falun...

https://ift.tt/2E7Clt5

Patient Education Can Improve Chronic Disease Management

FRIDAY, Dec. 7, 2018 -- An educational intervention can improve patients' ability to self-manage their chronic diseases, according to a study published in the November issue of the Journal of the American Osteopathic Association. Alexis M. Stoner,...

https://ift.tt/2QHB4jb

Lack of Peds Preventive Care Ups Unplanned Hospital Admissions

FRIDAY, Dec. 7, 2018 -- A lack of preventive care in infants and children is associated with an increased rate of unplanned hospital admissions, according to a study recently published in BMC Medicine. Elizabeth Cecil, Ph.D., from Imperial College...

https://ift.tt/2E9zBf3

Secondhand Smoke Exposure Saw Big Drop From 1988 to 2014

FRIDAY, Dec. 7, 2018 -- Secondhand smoke exposure declined substantially among U.S. nonsmokers from 1988 through 2014, according to research published in the Dec. 7 issue of the U.S. Centers for Disease Control and Prevention Morbidity and Mortality...

https://ift.tt/2QAUwyb

Gender Bias Sways How We Perceive Competence in Faces

Faces that are seen as competent are also perceived as more masculine, according to research published in Psychological Science, a journal of the Association for Psychological Science.

"Our research sheds light on the pernicious gender bias in how we perceive others — we judge masculine looking people as competent, a judgment that can affect our leadership choices," explains psychology researcher DongWon Oh of Princeton University, first author on the research.

Oh and coauthors Elinor A. Buck and Alexander Todorov were interested in identifying the "visual ingredients" that influence how we perceive competence from individuals' appearance.

To do this, the researchers used a computational model of competence that they had established in previous research. Using participant ratings of many different faces, the researchers identified the parameters that were most reliably associated with impressions of competence. They then built a model that allowed them to digitally alter face stimuli according to these specific parameters, producing faces that varied in perceived competence.

In one online experiment, the researchers used this model to present 33 participants with face stimuli that varied in competence. Some participants rated how competent the faces were, while others rated their attractiveness. The results showed that the faces designed to look more competent were rated as such, and they were also rated as more attractive, consistent with the "attractiveness halo" found in previous research.

But Oh and colleagues suspected that there were probably other components of appearance that signal competence.

"Using the computational methods we developed for visualizing appearance stereotypes, we can literally remove the attractiveness of the competent-looking faces," says Oh. "We can then test whether 'competent' faces still appear competent and inspect what visual properties other than attractiveness drive the competence impressions."

Using this new model, the researchers found that participants perceived more competent faces as more confident and more masculine, impressions that are not explained by attractiveness.

Another online experiment revealed a clear gender bias: When participants were asked to identify faces as either or female, they tended to rate more competent faces as male and less competent faces as female.

Together, these findings suggest that competence and masculinity are correlated components of first impressions based on appearance.

To investigate whether this relationship operates similarly for male faces and female faces, the researchers manipulated photorealistic images of male and female faces so that they varied in masculinity. They randomly assigned 250 online participants to rate the competence of either male faces or female faces.

Again, the data suggested a gender bias in first impressions: As male faces increased in masculinity, so did their perceived competence. For female faces, this relationship only held up to a point, after which more masculine female faces were actually perceived as less competent.

This is noteworthy because impressions of competence influence who we choose as our leaders: Research has shown that individuals with more competent-looking faces are more likely to be elected as high-ranking politicians such as US senators and as the heads of large companies.

"Problematically, how competent someone appears does not guarantee their actual competence," Oh notes. "Needless to say, these gender biases pose a threat to social justice, creating unfair environments for everyone."

The researchers hope to expand on this research, exploring the origins of this gender bias and how the bias might be mitigated. In addition, they are investigating whether there are systematic differences in the impressions we have of male and female faces.

All data and materials have been made publicly available via the Open Science Framework. This article has received the badges for Open Data and Open Materials.



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Targeted Treatment for Rare Digestive Tract Cancers May Extend Survival

In an early-phase trial, dabrafenib plus trametinib shrank tumors in patients with biliary tract cancer and adenocarcinoma of the small intestine whose tumors had a specific mutation in the BRAF gene.



https://ift.tt/2G5W4w0

Immunosuppressive {beta}ig-h3 links tumour stroma and dysfunctional T cells in pancreatic cancer

Recent FDA approval of anti-PD-1 antibody pembrolizumab as a site-agnostic therapy for mismatch repair (MMR)–deficient solid tumours has highlighted the importance of CD8+ T cell responses and the potential of immunotherapy, even in tumour entities that are traditionally considered poor candidates for immune-based therapies, such as pancreatic carcinoma.1 Clearly, the old dogma of immunologically cold pancreatic carcinoma has to be refined.

It has been known for long that higher levels of intratumoural CD8+ cytotoxic T lymphocytes (CTLs) correlate with better survival of patients with pancreatic carcinoma.2 3 However, in most pancreatic carcinomas, endogenous CD8+ T cells are relatively sparse.4 Moreover, intratumoural macrophages, myeloid-derived suppressor cells and regulatory T cells (Tregs) dominate even the earliest phases of pancreatic cancer development, and predominance of these immunosuppressive cell populations persists through invasive cancer. This immune privilege of pancreatic cancer is characterised by a comparatively low mutational burden resulting in fewer...



https://ift.tt/2Uq3Hk4

Comparing Eye-tracking Data of Children with High-functioning ASD, Comorbid ADHD, and of a Control Watching Social Videos

This is a qualitative comparative case study analysis of eye-tracking data on the first moments of social video scenes as viewed by three participants: one with autism spectrum disorder, one with comorbid attention deficit-hyperactive disorder, and one neurotypical control.

https://ift.tt/2E9xc42

ASO Author Reflections: Management of the Nipple Margin After Mastectomy: A Trend Toward a more Minimally Invasive Approach



https://ift.tt/2PpEi64

Completion Thyroidectomy: Revisited a Quarter of a Century Later



https://ift.tt/2zKmmOM

Impact of Long-Course Neoadjuvant Radiation on Postoperative Low Anterior Resection Syndrome and Quality of Life in Rectal Cancer: Post Hoc Analysis of a Randomized Controlled Trial

Abstract

Background

Neoadjuvant radiation is recommended for locally advanced rectal cancer, with proven benefit in local control but not in disease-free survival. However, the impact of long-course radiation on postoperative bowel function and quality of life (QOL) remains controversial. This study aimed to investigate the impact of long-course neoadjuvant radiation on bowel function and QOL, and to identify risk factors for severe bowel dysfunction.

Methods

Patients who underwent long-course neoadjuvant chemoradiotherapy (nCRT) or chemotherapy (nCT) followed by radical low anterior resection for locally advanced rectal cancer were recruited from the FOWARC randomized controlled trial. Low anterior resection syndrome (LARS) score and European Organisation for Research and Treatment of Cancer (EORTC) C30/CR29 questionnaires were used to assess bowel function and QOL, respectively.

Results

Overall, 220 patients responded after a median follow-up of 40.2 months, of whom 119 (54.1%) reported major LARS, 74 (33.6%) reported minor LARS, and 27 (12.3%) reported no LARS. Compared with the nCT group, the nCRT group reported more major LARS (64.4% vs. 38.6%, p < 0.001) and worse QOL. Long-course neoadjuvant radiation (OR 2.20, 95% CI 1.24–3.91; p = 0.007), height of anastomosis (OR 0.74, 95% CI 0.63–0.88; p < 0.001), and diverting ileostomy (OR 2.59, 95% CI 1.27–5.30; p = 0.009) were independent risk factors for major LARS.

Conclusions

Long-course neoadjuvant radiation, along with low anastomosis, are likely independent risk factors for postoperative bowel function and QOL. Our findings might have implications for alleviating LARS and improving QOL by informing selection of neoadjuvant treatment.



https://ift.tt/2zKmopS

Should 911 dispatchers be considered first responders?

Our co-hosts talk about the reclassification possibility and also consider the idea of a national certification for all dispatchers

https://ift.tt/2rrqezG

Recovery after stroke: not so proportional after all?

Abstract
The proportional recovery rule asserts that most stroke survivors recover a fixed proportion of lost function. To the extent that this is true, recovery from stroke can be predicted accurately from baseline measures of acute post-stroke impairment alone. Reports that baseline scores explain more than 80%, and sometimes more than 90%, of the variance in the patients' recoveries, are rapidly accumulating. Here, we show that these headline effect sizes are likely inflated. The key effects in this literature are typically expressed as, or reducible to, correlation coefficients between baseline scores and recovery (outcome scores minus baseline scores). Using formal analyses and simulations, we show that these correlations will be extreme when outcomes are significantly less variable than baselines, which they often will be in practice regardless of the real relationship between outcomes and baselines. We show that these effect sizes are likely to be over-optimistic in every empirical study that we found that reported enough information for us to make the judgement, and argue that the same is likely to be true in other studies as well. The implication is that recovery after stroke may not be as proportional as recent studies suggest.

https://ift.tt/2QKmgAA

Corrigendum

Emily O. Garnett, Ho Ming Chow, Alfonso Nieto-Castañón, Jason A. Tourville, Frank H. Guenther, Soo-Eun Chang. Anomalous morphology in left hemisphere motor and premotor cortex of children who stutter. Brain 2018; 141: 2670–2684. doi:10.1093/brain/awy199.

https://ift.tt/2QHrZa2

Progression of myelopathy in males with adrenoleukodystrophy: towards clinical trial readiness

Abstract
Males with adrenoleukodystrophy develop progressive myelopathy causing severe disability later in life. No treatment is currently available, but new disease-modifying therapies are under development. Knowledge of the natural history of the myelopathy is of paramount importance for evaluation of these therapies in clinical trials, but prospective data on disease progression are lacking. We performed a prospective observational cohort study to quantify disease progression over 2 years of follow-up. Signs and symptoms, functional outcome measures and patient-reported outcomes were assessed at baseline, 1 and 2 years of follow-up. We included 46 male adrenoleukodystrophy patients (median age 45.5 years, range 16–71). Frequency of myelopathy at baseline increased with age from 30.8% (<30 years) to 94.7% (>50 years). Disease progression was measured in the patients who were symptomatic at baseline (n = 24) or became symptomatic during follow-up (n = 1). Significant progression was detected with the functional outcome measures and quantitative vibration measurements. Over 2 years of follow-up, Expanded Disability Status Score increased by 0.34 points (P = 0.034), Severity Scoring system for Progressive Myelopathy decreased by 2.78 points (P = 0.013), timed up-and-go increased by 0.82 s (P = 0.032) and quantitative vibration measurement at the hallux decreased by 0.57 points (P = 0.040). Changes over 1-year follow-up were not significant, except for the 6-minute walk test that decreased by 19.67 meters over 1 year (P = 0.019). None of the patient-reported outcomes were able to detect disease progression. Our data show that progression of myelopathy in adrenoleukodystrophy can be quantified using practical and clinically relevant outcome measures. These results will help in the design of clinical trials and the development of new biomarkers for the myelopathy of adrenoleukodystrophy.

https://ift.tt/2E4TALL