Prognosis after neoadjuvant chemoradiation or chemotherapy for locally advanced gastro-oesophageal junctional adenocarcinoma.

BACKGROUND: Trials typically group cancers of the gastro-oesophageal junction (GOJ) with oesophageal or gastric cancer when studying neoadjuvant chemoradiation and perioperative chemotherapy, so the results may not be fully applicable to GOJ cancer. Because optimal neoadjuvant treatment for GOJ cancer remains controversial, outcomes with neoadjuvant chemoradiation versus chemotherapy for locally advanced GOJ adenocarcinoma were compared retrospectively. METHODS: Data were collected from all patients who underwent neoadjuvant treatment followed by surgery for adenocarcinoma located at the GOJ at a single high-volume institution between 2002 and 2017. Postoperative major complications and mortality were compared between groups using Fisher's exact test. Overall survival (OS) and disease-free survival (DFS) were assessed by log rank test and multivariable Cox regression analyses. Cumulative incidence functions were used to estimate recurrence, and groups were compared using Gray's test. RESULTS: Of 775 patients, 650 had neoadjuvant chemoradiation and 125 had chemotherapy. These groups were comparable in terms of clinical tumour and lymph node categories, although the chemoradiation group had greater proportions of white men, complete pathological response to chemotherapy, and smaller proportions of diffuse cancer, poor differentiation, and neurovascular invasion. Postoperative major complications (20.0 versus 17.6 per cent) and 30-day mortality (1.7 versus 1.6 per cent) were not significantly different between the chemoradiation and chemotherapy groups. After adjustment, type of therapy (chemoradiation versus chemotherapy) was not significantly associated with OS (hazard ratio (HR) 1.26, 95 per cent c.i. 0.96 to 1.67) or DFS (HR 1.27, 0.98 to 1.64). Type of recurrence (local, regional, or distant) did not differ after neoadjuvant chemoradiation versus chemotherapy. CONCLUSION: In patients undergoing surgical resection for locally advanced adenocarcinoma of the GOJ, OS and DFS did not differ significantly between patients who had neoadjuvant chemoradiation compared with chemotherapy.

Treating advanced cancer of the gastro-oesophageal junction (GOJ) poses a challenge given its location in the distal oesophagus and proximal stomach, and whether it should be treated as oesophageal or gastric cancer. Given the indistinct location, it is unclear whether GOJ cancer should be treated with neoadjuvant chemoradiation, which is the treatment of choice for advanced oesophageal cancers, or perioperative chemotherapy, which is the treatment of choice for advanced gastric cancers. Few studies have addressed treatment options specifically for GOJ cancers. This study investigated whether there was a difference in survival between patients with GOJ cancer who were treated with chemoradiation versus chemotherapy.

Tofacitinib in psoriatic arthritis patients: skin signs and symptoms and health-related quality of life from two randomized phase 3 studies.

BACKGROUND: Psoriatic arthritis (PsA) is a chronic, systemic immune-mediated inflammatory musculoskeletal disease. The onset of dermatologic symptoms often precedes rheumatic manifestations. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA that has been shown to improve dermatologic symptoms in patients with PsA. OBJECTIVES: To investigate the efficacy of tofacitinib in improving dermatologic endpoints in adult patients with active PsA. METHODS: This analysis included data from two placebo-controlled, double-blind, phase 3 studies in patients with active PsA and an inadequate response (IR) to ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD) who were tumor necrosis factor inhibitor (TNFi)-naïve (OPAL Broaden; NCT01877668) or an IR to ≥1 TNFi (OPAL Beyond; NCT01882439). Patients had active plaque psoriasis at screening and received a stable dose of one csDMARD during the study. Patients were randomized to tofacitinib 5 mg twice daily (BID), 10 mg BID, adalimumab 40 mg subcutaneous injection once every 2 weeks (OPAL Broaden only) or placebo (to Month 3). Dermatologic endpoints: Psoriasis Area and Severity Index (PASI) total score; PASI90 overall; PASI75 and PASI90 by baseline PASI severity; Physician's Global Assessment of Psoriasis; Nail Psoriasis Severity Index; Dermatology Life Quality Index total and sub-dimension scores; Itch Severity Item; and Patient's Global Joint and Skin Assessment-Visual Analog Scale-Psoriasis question. RESULTS: In patients with active PsA, including those stratified by mild or moderate/severe dermatologic symptoms, greater improvements from baseline and percentage of responders were observed in tofacitinib-treated patients vs. placebo for the majority of analyzed dermatologic endpoints at Months 1 and 3, and improvements were maintained to Month 12 in OPAL Broaden and Month 6 in OPAL Beyond. Similar effects were observed in adalimumab-treated patients vs. placebo in OPAL Broaden across dermatologic endpoints. CONCLUSIONS: Tofacitinib provides a treatment option for patients with active PsA, including the burdensome dermatologic symptoms of PsA.

Outpatient dermatology consultations for oncology patients with acute dermatologic adverse events impact anticancer therapy interruption: a retrospective study.

BACKGROUND: Dermatologic adverse events (dAEs) of anticancer therapies may negatively impact dosing and quality of life. While therapy interruption patterns due to dAEs have been studied in hospitalized cancer patients, similar outcomes in outpatient oncodermatology are lacking. OBJECTIVES: To analyse the therapy interruption patterns, clinico-histopathologic characteristics and management outcomes of outpatient dermatology consultations for acute dAEs attributed to the most frequently interrupted class of oncologic agents. METHODS: We performed a retrospective cohort study of all cancer patients who received a same-day outpatient dermatology consultation for acute dAEs at our institution from 1 January to 30 June 2015. Relevant data were abstracted from electronic medical records, including demographics, oncologic history and explicit recommendations by both the referring clinician and consulting dermatologist on anticancer therapy interruption. Consultations with the most frequently interrupted class of oncologic treatment were characterized according to clinico-histopathologic features, dermatologic management and clinical outcomes. RESULTS: There were 426 same-day outpatient dermatology consultations (median age 59, 60% female, 30% breast cancer), of which 295 (69%) had systemic anticancer therapy administered within 30 days prior. There was weak inter-rater agreement between referring clinicians and consulting dermatologists on interruption of anticancer treatment (n = 150, κ = 0.096; 95% CI -0.02 to 0.21). Seventy-three (25%) consultations involved interruption by the referring clinician, most commonly targeted therapy (24, 33%). Maculopapular rash was commonly observed in 23 consultations with 25 dAEs attributed to targeted agents (48%), and topical corticosteroids were most frequently utilized for management (22, 38%). The majority (83%) of consultations with targeted therapy-induced dAEs responded to dermatologic treatment and 84% resumed oncologic therapy, although three (19%) at a reduced dose. Rash recurred only in two instances (13%). CONCLUSIONS: A high frequency of positive outcomes in the management of targeted therapy-induced dAEs by outpatient consulting dermatologists and low recurrence of skin toxicity suggests impactful reductions in interruption of anticancer therapy.

Long-term prognosis for 1-year relapse-free survivors of CD34+ cell-selected allogeneic hematopoietic stem cell transplantation: a landmark analysis.

CD34+ cell selection significantly improves GvHD-free survival in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, specific information regarding long-term prognosis and risk factors for late mortality after CD34+ cell-selected allo-HSCT is lacking. We conducted a single-center landmark analysis in 276 patients alive without relapse 1 year after CD34+ cell-selected allo-HSCT for AML (n=164), ALL (n=33) or myelodysplastic syndrome (n=79). At 5 years' follow-up after the 1-year landmark (range 0.03-13 years), estimated relapse-free survival (RFS) was 73% and overall survival (OS) 76%. The 5-year cumulative incidence of relapse and non-relapse mortality (NRM) were 11% and 16%, respectively. In multivariate analysis, Hematopoietic Cell Transplantation Comorbidity Index score⩾3 correlated with marginally worse RFS (hazard ratio (HR) 1.78, 95% confidence interval (CI) 0.97-3.28, P=0.06) and significantly worse OS (HR 2.53, 95% CI 1.26-5.08, P=0.004). Despite only 24% of patients with acute GvHD within 1 year, this also significantly correlated with worse RFS and OS, with increasing grades of acute GvHD associating with increasingly poorer survival on multivariate analysis (P<0.0001). Of 63 deaths after the landmark, GvHD accounted for 27% of deaths and was the most common cause of late mortality, followed by relapse and infection. Although prognosis is excellent for patients alive without relapse 1 year after CD34+ cell-selected allo-HSCT, risks of late relapse and NRM persist, particularly due to GvHD.

Long-term outcome of 487 patients with early-stage extra-nodal marginal zone lymphoma.

BACKGROUND: Localized early-stage extra-nodal marginal zone lymphoma (MZL) presents with heterogeneous organ involvement and is treated with various modalities, including resection, radiotherapy, and systemic therapy. We report the long-term outcome of a large cohort of extra-nodal MZL and assess the impact of patient and disease characteristics, organ site, and treatment strategy on disease control and survival. PATIENTS AND METHODS: We identified 487 consecutive patients with stage IE or IIE MZL referred between 1992 and 2012 to Memorial Sloan Kettering Cancer Center. Pathology was reviewed by hematopathologists at our institution. Patient and disease factors as well as treatment types were analyzed for association with relapse-free survival, overall survival, and cumulative incidence of relapse. RESULTS: Median follow-up after treatment was 4.7 years. Five-year relapse-free survival and overall survival were 60% and 89%, respectively. Cumulative incidence of disease-specific death at 5 years was 1.3%. Radiotherapy alone was the initial treatment in 50% of patients, followed by surgical resection (30%), observation (8%), immunotherapy (4%), and chemotherapy (2%). Initial treatment type, primary disease site, and number of involved sites were significant factors in multivariable analysis of relapse (all P < 0.05). When compared with stomach, MZL originating in other disease sites (HR > 2.0, P ≤ 0.001), except for thyroid, had higher risk of relapse. Strategies such as antibiotics or topical therapies were associated with higher risk of relapse when compared with radiation therapy (P < 0.001). Crude rate of transformation to pathologically confirmed large-cell lymphoma was 2% (11 patients). CONCLUSION: Overall and cause-specific survival are high in early-stage extra-nodal MZL. Curative-intent treatment led to fewer relapses and reduced the need for salvage. Stomach cases had lower risk of relapse than other anatomic primary sites. This study supports the use of local therapies to treat stage IE and IIE MZL.

CT-guided percutaneous core-needle biopsy of pancreatic masses: comparison of the standard mesenteric/retroperitoneal versus the trans-organ approaches.

AIM: To compare the safety and efficacy of percutaneous computed tomography (CT)-guided core-needle biopsy (CNB) of pancreatic masses traversing the gastrointestinal tract or solid viscera versus trans-mesenteric and retroperitoneal approaches. MATERIALS AND METHODS: CT-guided CNB of pancreatic lesions performed between May 2004 and December 2014 were retrospectively analysed at a single centre. Biopsies were performed using 18- or 20-G needles with a coaxial system. CT images, histopathology reports, medical records, and procedural details for all patients were reviewed to evaluate the biopsy route, complications, and diagnostic accuracy. According to the routes, biopsies were divided into trans-mesenteric, retroperitoneal and trans-organ approaches for comparison. RESULTS: A total of 85 patients, who had undergone 89 CNBs for pancreatic masses were reviewed. The overall sensitivity, specificity, and accuracy of CNB for detecting malignancy via various routes were 88.8%, 100%, and 89.9%, respectively, with a complication rate of 20.2%. Trans-organ biopsies of pancreatic masses (n=22) were performed safely via a direct pathway traversing the stomach (n=14), colon (n=3), small bowel (n=2), liver (n=2), and spleen (n=1). The sensitivity, specificity, and accuracy were 90.5%, 100%, and 90.9%, respectively. In the trans-organ biopsy group, three biopsies (13.6%) resulted in minor haematomas, but no major complications occurred. There were no statistically significant differences in the diagnostic efficacy or complication rate among the different biopsy routes. CONCLUSION: Percutaneous CT-guided CNB using a trans-organ approach is a feasible technique for diagnosing pancreatic malignancy; however, as this series was small, more data is required.

AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B.

Biguanides such as metformin have previously been shown to antagonize hepatic glucagon-stimulated cyclic AMP (cAMP) signalling independently of AMP-activated protein kinase (AMPK) via direct inhibition of adenylate cyclase by AMP. Here we show that incubation of hepatocytes with the small-molecule AMPK activator 991 decreases glucagon-stimulated cAMP accumulation, cAMP-dependent protein kinase (PKA) activity and downstream PKA target phosphorylation. Moreover, incubation of hepatocytes with 991 increases the Vmax of cyclic nucleotide phosphodiesterase 4B (PDE4B) without affecting intracellular adenine nucleotide concentrations. The effects of 991 to decrease glucagon-stimulated cAMP concentrations and activate PDE4B are lost in hepatocytes deleted for both catalytic subunits of AMPK. PDE4B is phosphorylated by AMPK at three sites, and by site-directed mutagenesis, Ser304 phosphorylation is important for activation. In conclusion, we provide a new mechanism by which AMPK antagonizes hepatic glucagon signalling via phosphorylation-induced PDE4B activation.

A prospective study of total plasma cell-free DNA as a predictive biomarker for response to systemic therapy in patients with advanced non-small-cell lung cancers.

BACKGROUND: While previous studies have reported on the prognostic value of total plasma cell-free deoxyribonucleic acid (cfDNA) in lung cancers, few have prospectively evaluated its predictive value for systemic therapy response. PATIENTS AND METHODS: We conducted a prospective study to evaluate the association between changes in total cfDNA and radiologic response to systemic therapy in patients with stage IIIB/IV non-small-cell lung cancers (NSCLCs). Paired blood collections for cfDNA and computed tomography (CT) assessments by RECIST v1.0 were performed at baseline and 6-12 weeks after therapy initiation. Total cfDNA levels were measured in plasma using quantitative real-time polymerase chain reaction. Associations between changes in cfDNA and radiologic response, progression-free survival (PFS), and overall survival (OS) were measured using Kruskal-Wallis and Kaplan-Meier estimates. RESULTS: A total of 103 patients completed paired cfDNA and CT response assessments. Systemic therapy administered included cytotoxic chemotherapy in 57% (59/103), molecularly targeted therapy in 17% (17/103), and combination therapy in 26% (27/103). Median change in cfDNA from baseline to response assessment did not significantly differ by radiologic response categories of progression of disease, stable disease and partial response (P = 0.10). However, using radiologic response as continuous variable, there was a weak positive correlation between change in radiologic response and change in cfDNA (Spearman's correlation coefficient 0.21, P = 0.03). Baseline cfDNA levels were not associated with PFS [hazard ratio (HR) = 1.06, 95% confidence interval (CI) 0.93-1.20, P = 0.41] or OS (HR = 1.04, 95% CI 0.93-1.17, P = 0.51), neither were changes in cfDNA. CONCLUSIONS: In this large prospective study, changes in total cfDNA over time did not significantly predict radiologic response from systemic therapy in patients with advanced NSCLC. Pretreatment levels of total cfDNA were not prognostic of survival. Total cfDNA level is not a highly specific predictive biomarker and future investigations in cfDNA should focus on tumor-specific genomic alterations using expanded capabilities of next-generation sequencing.

A higher anti-Müllerian hormone level is associated with an increased chance of pregnancy in patients undergoing controlled ovarian stimulation and intrauterine insemination.

Anti-Müllerian hormone (AMH) level has been found to be a useful marker of ovarian reserve, and a predictor of poor and hyper-responses in patients undergoing controlled ovarian stimulation (COS). The study aimed to determine the association of serum AMH level with achieving pregnancy in patients undergoing COS with intrauterine insemination. The cross-sectional study investigated 204 patients who underwent COS with intrauterine insemination at the Obstetrics and Gynecology Department of Taipei Medical University Hospital, from January 2011 to March 2012. The medical records of these patients were reviewed, and serum AMH levels were evaluated for association with successful clinical pregnancy. The AMH level in the patients who achieved clinical pregnancy was significantly higher than in patients who did not (median 2.7 vs 2.0 ng/ml, p = 0.005). Controlling for factors affecting infertility, AMH level had a significant independent influence on outcome; a higher AMH level was associated with a decreased risk of a non-pregnant outcome (odds ratio, OR = 0.895, p = 0.026). In patients undergoing COS and intrauterine insemination, a low AMH level is associated with a decreased chance of a clinical pregnancy, and this association remains irrespective of the presence or absence of endometriosis.

Trans-organ versus trans-mesenteric computed tomography-guided percutaneous fine-needle aspiration biopsy of pancreatic masses: feasibility and safety.

AIM: To evaluate the safety and efficacy of computed tomography (CT)-guided percutaneous fine-needle aspiration biopsy (FNAB) of pancreatic masses that traverses the gastrointestinal tract or solid viscera. MATERIALS AND METHODS: From January 2002 to December 2012, 144 patients underwent 165 CT-guided biopsies of pancreatic masses. Biopsies were performed using a 21 or 22 G needle. Cytology reports, medical records, and procedure details for all patients were retrospectively reviewed to evaluate the biopsy route, complications, and diagnostic accuracy. RESULTS: Trans-organ biopsies of pancreatic masses were safely performed via a direct pathway traversing the stomach (n = 45), colon (n = 14), jejunum (n = 4), or liver (n = 5). There were five self-limiting mesenteric haematomas along the biopsy route on immediate post-procedure CT and all patients remained asymptomatic. All haematomas occurred after a trans-mesenteric approach rather than passage through abdominal organs. Three patients had acute pancreatitis. There was no significant difference in complications and diagnostic yields between the groups. The sensitivity, specificity, positive predictive value, and negative predictive value of final FNAB cytology for malignancy were 98.3%, 100%, 100% and 71.4%, respectively. The overall accuracy was 98.4%. CONCLUSION: Percutaneous FNAB using the trans-organ approach is a safe and effective technique to diagnose pancreatic malignancy.

Impact of physician specialty on classification of physician-perceived patient severity for patients with osteoarthritis.

BACKGROUND: Physicians often classify patients' osteoarthritis (OA) severity subjectively. As treatment decisions are influenced by severity classifications, it is important to understand the factors that influence physicians' OA severity ratings. This research sought to empirically identify physician and patient characteristics that lead to a patient being perceived as having more severe OA. METHODS: Data were analyzed from the OA IX Disease Specific Program, a large cross-sectional survey of OA physicians and patients in Germany, the UK, and USA between September 2011 and January 2012. Eligible, consenting physicians completed a Patient Record Form (PRF) for 10 consecutive OA patients. The PRF asked physicians to report the patient's demographics [age, gender, body mass index (BMI), ethnicity], their assessment of the patients' symptom severity, treatment, probability for surgery, to rate their overall OA severity (mild, moderate or severe) and the factors that had influenced the rating. Chi-squared tests and analysis of variance were used to identify patient characteristics that significantly impacted physicians' OA severity ratings. Controlling for the significant patient characteristics, we then examined the impact of physician specialty on physician's OA severity ratings. Finally, we investigated the differences in physician-reported factors that influenced the physicians' rating of patients' severity between physician specialties. RESULTS: Three hundred and sixty-three physicians [220 primary care physicians (PCPs), 48 rheumatologists, 95 orthopedic surgeons] recruited 3561 patients. Patients with greater age and BMI, worse symptoms and greater health care use were given higher OA severity ratings. Controlling for these factors, orthopedic surgeons rated their OA patients as more severe than PCPs and rheumatologists [adjusted odds ratio (OR) 1.8, 95% confidence interval (CI) 1.4-2.4]. Specialists (rheumatologists and orthopedic surgeons) were more likely than PCPs to use joint spaced narrowing based on X-ray and severity of joint deterioration radiographic severity to assess patients' OA severity (joint space narrowing: 79% and 78% vs 55%, P < 0.0001). CONCLUSIONS: Patient age, BMI, presence and severity of symptoms and health care use significantly impacted physicians' OA severity ratings, but radiographic changes appeared to be given greater weight among orthopedic surgeons and rheumatologists than PCPs when assessing patient severity. Whether these differences translate into different treatment recommendations for similar patients is unknown, and warrants study.

Phenethyl isothiocyanate triggers apoptosis in human malignant melanoma A375.S2 cells through reactive oxygen species and the mitochondria-dependent pathways.

We have reported previously that phenethyl isothiocyanate (PEITC) induces apoptosis in human osteosarcoma U-2 OS cells. Cytotoxic activity of PEITC towards other cancer cells such as human malignant melanoma and skin cancer cells has not been reported. In this study, the anticancer activity of PEITC towards human malignant melanoma cancer A375.S2 cells was investigated. To determine the mechanisms of PEITC inhibition of cell growth, the following end points were determined in A375.S2 cells: cell morphological changes, cell cycle arrest, DNA damage and fragmentation assays and morphological assessment of nuclear change, reactive oxygen species (ROS) and Ca(2+) generations, mitochondrial membrane potential disruption, and nitric oxide and 10-N-nonyl acridine orange productions, expression and activation of caspase-3 and -9, B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Bcl-2, poly (adenosine diphosphate-ribose) polymerase, and cytochrome c release, apoptosis-inducing factor and endonuclease G. PEITC induced morphological changes in time- and dose-dependent manner. PEITC induced G2/M phase arrest and induced apoptosis via endoplasmic reticulum stress-mediated mitochondria-dependent pathway. Western blot analysis showed that PEITC promoted Bax expression and inhibited Bcl-2 expression associated with the disintegration of the outer mitochondrial membrane causing cytochrome c release, and activation of caspase-9 and -3 cascade leading to apoptosis. We conclude that PEITC-triggered apoptotic death in A375.S2 cells occurs through ROS-mediated mitochondria-dependent pathways.

Syntaxin 6-mediated Golgi translocation plays an important role in nuclear functions of EGFR through microtubule-dependent trafficking.

Receptor tyrosine kinases (RTKs) are cell surface receptors that initiate signal cascades in response to ligand stimulation. Abnormal expression and dysregulated intracellular trafficking of RTKs have been shown to be involved in tumorigenesis. Recent evidence shows that these cell surface receptors translocate from cell surface to different cellular compartments, including the Golgi, mitochondria, endoplasmic reticulum (ER) and the nucleus, to regulate physiological and pathological functions. Although some trafficking mechanisms have been resolved, the mechanism of intracellular trafficking from cell surface to the Golgi is not yet completely understood. Here we report a mechanism of Golgi translocation of epidermal growth factor receptor (EGFR) in which EGF-induced EGFR travels to the Golgi via microtubule-dependent movement by interacting with dynein and fuses with the Golgi through syntaxin 6-mediated membrane fusion. We also demonstrate that the microtubule- and syntaxin 6-mediated Golgi translocation of EGFR is necessary for its consequent nuclear translocation and nuclear functions. Thus, together with previous studies, the microtubule- and syntaxin 6-mediated trafficking pathway from cell surface to the Golgi, ER and the nucleus defines a comprehensive trafficking route for EGFR to travel from cell surface to the Golgi and the nucleus.

Risk of colorectal cancer in women with pelvic inflammatory disease: a matched cohort study.

OBJECTIVE: Inflammation is an important risk factor for the development of colorectal cancer (CRC). Pelvic inflammatory disease (PID) comprises a spectrum of upper genital tract infections and inflammatory diseases. We aimed to evaluate the association between CRC and PID. DESIGN: Matched cohort study using the National Health Insurance Research Database. SETTING: Women with PID in Taiwan. POPULATION AND SAMPLE: From the Longitudinal Health Insurance Database 2005 (LHID2005) in Taiwan, we obtained data on women from 13 to 45 years of age who were diagnosed with PID. The women with PID were matched 1:4 to selected members of the population without PID based on age and year of first entry into the LHID2005. METHODS: A Cox proportional hazards model was used to evaluate the hazard ratio for CRC during the 5-year follow-up period, after adjusting for sociodemographic characteristics and selected comorbid medical disorders. MAIN OUTCOME MEASURES: Colorectal cancer. RESULTS: Of the 19,029 women with PID, 30 were diagnosed with CRC during the 78,965 person-year follow-up period. Of the 76,116 control women, 66 were diagnosed with CRC. The CRC hazard ratio during the 5-year follow-up period was 2.00 (95% CI 1.30-3.08) for women with PID relative to control women. Similarly, after adjusting for age, Charlson comorbidity index score, urbanisation level and monthly income, the adjusted CRC hazard ratio was 1.71 (95% CI 1.10-2.65) for the women with PID relative to the women in the comparison cohort. CONCLUSIONS: Here we show a weak association between PID and CRC. Additional studies are needed to further evaluate this association and examine plausible mechanisms, including the influence of specific microorganisms.

The dipeptidyl peptidase-4 inhibitor-sitagliptin modulates calcium dysregulation, inflammation, and PPARs in hypertensive cardiomyocytes.

BACKGROUND: Hypertension induces cardiac dysfunction, calcium (Ca(2+)) dysregulation, and arrhythmogenesis. Dipeptidyl peptidase (DPP)-4 inhibitors, an antidiabetic agent with anti-inflammation and anti-hypertension potential, may regulate peroxisome proliferator-activated receptors (PPARs)-α, -γ, and -δ and Ca(2+) homeostasis. OBJECTIVE: The purpose of this study was to investigate whether DPP-4 inhibitor, sitagliptin, can modulate PPARs and Ca(2+) handling proteins in hypertensive hearts. METHODS: A Western blot analysis was used to evaluate protein expressions of myocardial PPAR isoforms, tumor necrosis factor (TNF)-α, interleukin (IL)-6, sarcoplasmic reticulum ATPase (SERCA2a), Na(+)-Ca(2+) exchanger (NCX), ryanodine receptor (RyR), voltage-dependent Ca(2+) (CaV1.2), slow-voltage potassium currents (Kvs), angiotensin II type 1 receptor (AT1R), and receptor of advanced glycated end-products (RAGE) from Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR), and SHR treated with sitagliptin (10mg/kg for 4weeks). Conventional microelectrodes were used to record action potentials (APs) in the ventricular myocytes from each group. RESULTS: Compared to the control group, SHR had lower cardiac PPAR-α and PPAR-δ protein expressions, but had greater cardiac PPAR-γ levels, and TNF-α, IL-6, RAGE, and AT1R protein expressions, which were ameliorated in the sitagliptin-treated SHR. SHR had prolonged QT interval and AP duration with less SERCA2a and RyR, and greater CaV1.2 expressions, which were also attenuated in sitagliptin-treated SHR. CONCLUSIONS: Sitagliptin significantly changed the cardiac electrophysiological characteristics and Ca(2+) regulation, which may have been caused by its effects on cardiac PPARs, proinflammatory cytokines, and AT1R.

Profiles of circulating endothelial cells and serum cytokines during adjuvant chemoradiation in rectal cancer patients.

INTRODUCTION: This research aimed to demonstrate the correlation of circulating endothelial cells (CECs) count and serum cytokine levels with side effects and prognosis in rectal cancer patients receiving adjuvant chemoradiation. METHODS: Eleven patients received proctectomy, chemoradiotherapy and follow-up for 4 years. Fifty-five blood samples were taken before radiation and during the course. The quantities of CECs were estimated by flow cytometry, and serological factors were measured by ELISA. RESULTS: The CEC level in patients without tumor recurrence was significantly lower than in patients with tumor recurrence (p < 0.01). The IL-6 and TGF-ß1 levels exhibited a similar profile (p < 0.01). For morbidity, the mean CEC level in patients with grade 3 diarrhea was significantly greater than patients with grades 1 (p < 0.001) and 2 diarrhea (p < 0.005). CONCLUSIONS: Levels of CECs, serum IL-6, TGF-ß1 and TNF-α during post-operative chemoradiation in rectal cancer patients might be candidate biomarkers for prognosis and morbidity (NCT00325871).

Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from 5 years of follow-up.

BACKGROUND: Long-term safety evaluations of biologics are needed to inform patient management decisions. OBJECTIVES: To evaluate the safety of ustekinumab in patients with moderate-to-severe psoriasis treated for up to 5 years. METHODS: Safety data were pooled from four studies of ustekinumab for psoriasis. Rates of adverse events (AEs), serious AEs (SAEs) and AEs of interest [infections, nonmelanoma skin cancers (NMSCs), other malignancies and major adverse cardiovascular events (MACE)] per 100 patient-years (PY) of follow-up were analysed by ustekinumab dose (45 or 90 mg) and by year of follow-up (years 1-5) to evaluate the dose response and impact of cumulative exposure. Observed rates of overall mortality and other malignancies were compared with those expected in the general U.S. population. RESULTS: Analyses included 3117 patients (8998 PY) who received one or more doses of ustekinumab, with 1482 patients treated for ≥4 years (including 838 patients ≥5 years). At year 5, event rates (45 mg, 90 mg, respectively) for overall AEs (242·6, 225·3), SAEs (7·0, 7·2), serious infections (0·98, 1·19), NMSCs (0·64, 0·44), other malignancies (0·59, 0·61) and MACE (0·56, 0·36) were comparable between dose groups. Year-to-year variability was observed, but no increasing trend was evident. Rates of overall mortality and other malignancies were comparable with those expected in the general U.S. population. CONCLUSIONS: No dose-related or cumulative toxicity was observed with increasing duration of ustekinumab exposure for up to 5 years. Rates of AEs reported in ustekinumab psoriasis trials are generally comparable with those reported for other biologics approved for the treatment of moderate-to-severe psoriasis.

Necrotizing pneumonia caused by nanC-carrying serotypes is associated with pneumococcal haemolytic uraemic syndrome in children.

Streptococcus pneumoniae infection is a leading cause of morbidity and mortality worldwide. One of the most severe complications of invasive pneumococcal disease (IPD) is haemolytic uraemic syndrome (HUS). This study was undertaken to determine the risk factors and role of pneumococcal neuraminidases in HUS in children with IPD. Eighteen cases of HUS and 54 patients with IPD without HUS were identified. The controls were patients with culture-confirmed IPD without HUS. Clinical and laboratory characteristics of the two groups of patients were compared. Bacterial isolates from both groups were serotyped, sequence typed and examined for their carriage of three neuraminidase genes. Necrotizing pneumonia and serotype 3 infection were significantly associated with HUS in children with IPD, suggesting that a severe pulmonary suppurating disease increase the risk of HUS. Serotype 14 was associated with necrotizing pneumonia but not HUS. Children with HUS were more likely to require surgery and had a longer duration of hospitalization. The study identified a significantly higher carriage of a neuraminidase gene, nanC, in the causative pneumococcal isolates from patients with HUS (89% versus 41%, p 0.001). The sensitivity and specificity of nanC to predict HUS were 89% and 59%, respectively. In conclusion, necrotizing pneumonia, serotype 3 infection and neuraminidase gene nanC were associated with HUS in children with IPD. The result suggests that NanC could provide an additive effect to NanA and NanB in the overall activity of pneumococcal neuraminidases to expose Thomsen-Friedenreich antigen on various cells in patients with HUS.

Effects of herpes simplex virus type 1 infection on immune functions of human neutrophils.

BACKGROUND AND OBJECTIVE: Herpesviruses may play roles in the development of periodontal diseases. This study analyzed the effects of herpes simplex virus type 1 (HSV-1) infection on neutrophil function. The effects of lipopolysaccharide (LPS) from the periodontal pathogen, Porphyromonas gingivalis, during HSV-1 infection were also determined. MATERIAL AND METHODS: Purified HSV-1 was pretreated with buffer containing no serum, with HSV-1 immunoglobulin G (IgG)-positive serum (HSV-1 antiserum) or with control serum. Neutrophils were mock-infected or infected with the pretreated HSV-1. Viral binding and phagosome formation were detected using immunostaining. Intracellular reactive oxygen species (ROS) were determined using 2',7'-dichlorofluorescin diacetate and fluorometry. Leukotriene B(4) (LTB(4)) and interleukin-8 (IL-8) were detected using enzyme immunoassays. Release of matrix metalloproteinase-9 (MMP-9) was examined using gelatin zymography. Phosphorylation of Akt/glycogen synthase kinase-3 (GSK-3) was determined using western blotting. RESULTS: HSV-1 bound directly to neutrophils and enhanced the release of MMP-9. HSV-1 immune complexes, formed in the HSV-1 antiserum, bound neutrophils and induced the formation of early phagosome more effectively than did HSV-1 alone. The relative levels of ROS and phosphorylation of Akt/GSK-3 were increased significantly in neutrophils after infection with HSV-1 immune complexes. Infection with HSV-1 and HSV-1 immune complexes also stimulated the production of inflammatory mediators, LTB(4) and IL-8. Moreover, LPS enhanced the HSV-1-stimulatory production of IL-8. CONCLUSION: This study demonstrated differences in neutrophils infected with HSV-1 alone or with HSV-1 immune complexes, suggesting that opsonization of HSV-1 might enhance its effects on neutrophils. The in vitro findings suggest that HSV-1 infection may induce the inflammatory response and affect periodontal health.