Prostate cancer: a presentation of clinicopathologic prognosticators among Filipino and American men at radical prostatectomy / 亚洲男科学杂志(英文版)

Lower incidence and mortality rates from prostate cancer (PCa) have been shown in Asian men in general compared to Westerners. This is the first study detailing the clinicopathologic features of resected prostate cancer in Filipino men living in the Philippines (PH). This study investigated the supposed "lower risk" Filipino and "higher risk" American PCa patients from the PH and the United States of America (USA), respectively. We examined 348 (176 from PH, 172 from USA) radical prostatectomy cases. The clinicopathologic features of both groups (age at time of diagnosis, preoperative prostate-specific antigen [pre-op PSA] level, Gleason score [GS], Grade groups [GG], margin involvement, extraprostatic extension [EPE], seminal vesicle invasion [SVI], and regional lymph node [RLN] metastasis) were compared. Six of seven prognosticators examined were more strongly associated with Filipinos than with Americans. Filipinos were older at diagnosis (PH: 64.32 ± 6.56 years vs USA: 58.98 ± 8.08 years) and had higher pre-op PSA levels (PH: 21.39 ± 46.40 ng ml

Multivariate analysis of factors affecting biochemical recurrence after radical prostatectomy

OBJECTIVE@#This study aims to evaluate the effects on biochemical recurrence (BCR) of the followingproposed prognostic factors after radical prostatectomy (RP): patients' clinical T stage, Gleason gradegroup (GG) of RP specimen, technique of operation used (open RP vs. robot-assisted laparoscopicRP), presence of positive surgical margin (PSM), length of PSM, GG at PSM, extraprostatic extension(EPE) at PSM, and presence of detectable PSA at 4-6 weeks after RP. It also aims to identify whichamong the aforementioned variables are independent predictors of risk for BCR.@*PATIENTS AND METHODS@#This is a retrospective study. Included in the study were patients who underwentRP (Open and Robot-assisted Laparoscopic technique) at two tertiary hospital branches of an academicmedical center from April 2009 to December 2015 with histopathology reports read by a singleurologic pathologist and with complete follow- up for at least one year. Excluded were those whounderwent RP but without complete follow- up. Using Pearson chi-square and z-test with level ofsignificance set at 0.05, the clinicopathologic variables including: patients clinical stage, GG of RPspecimen, length of PSM, GG at positive margins, presence of EPE at positive margins, and presenceof detectable PSA after the surgery were assessed in order to know which among these factors werepredictive of BCR. Multinomial regression analysis was also used to identify which among the variableswere independent predictors of risk for BCR.@*RESULTS@#A total of 165 patients underwent RP from April 2009 to December 2015, among which 72patients were eligible for inclusion in the final analysis. Clinical T2 stage was found to be a predictorof BCR with odds ratio of 13.000 (95%CI: 3.705 - 45.620; p < 0.001) as compared to stage T1. GGof final histopathology report of prostatectomy specimen was found to be a predictor of BCR, asthose with grade groups 4 and 5 had significantly increased risk of BCR with odds ratio of 70.778(95%CI: 8.207 - 610.426; p < 0.001) as compared to those with grade groups 1 to 3. Patients withpositive margins had increased risk of BCR, with odds ratio of 13.458 (95%CI: 13.472 - 52.171; p <0.001) compared to those with negative margins. GG at the PSM was found to be a predictor of BCR,with a grade grouping of 4 or 5 at the positive margin predicting BCR with odds ratio of 20.625(95%CI: 2.241 - 189.847; p = 0.008) as compared to grade grouping of 1 or 2 at the margin. DetectablePSA after RP was found to be a predictor of BCR, with odds ratio of 115.000 (95%CI: 19.457 -679.712; p < 0.001) as compared to undetectable PSA after RP. Technique of RP (p = 0.177), measuredlength of PSM (p = 0.713), and EPE at PSM (p = 0.146) were not found to predict BCR. Furthermore,clinical T stage (p = 0.007) and detectable PSA after RP (p < 0.001) were found to be independentpredictors of BCR among the risk factors examined.@*CONCLUSION@#Of the independent variables examined, clinical T stage, GG of RP specimen, presenceof PSM, GG at positive margins, and detectable PSA were found to be significant predictors of BCR. Technique of RP, measured length of PSM, and EPE at PSM were not found to predict BCR.Furthermore, multivariate analysis showed that only clinical T stage and detectable PSA after RPwere independent predictors of BCR. Attentive assessment of these predictors in the preoperativeperiod should aid the urologist in clinical decision-making and in advising patients regarding theirprognosis.

Accuracy of the multiparametric magnetic resonance imaging (MRI) and multiparametric MRI ultrasound cognitive fusion biopsy in the detection of prostate cancer among patients at a tertiary hospital

OBJECTIVE@#Image-guided targeted biopsy techniques have been proposed to address problems ofsystematic transrectal ultrasound guided prostate biopsies that lead to the suboptimal cancer detectionrate as well as inaccurate grading of the disease. This study aims to provide local data on the diagnosticaccuracy of multiparametric MRI (MP-MRI) and MP-MRI ultrasound cognitive fusion biopsy inidentifying areas of clinically significant malignancy of the prostate.@*MATERIALS AND METHODS@#This is a validity study involving patients who underwent MP-MRI and MP-MRI ultrasound cognitive fusion biopsy, who eventually underwent robot-assisted laparoscopic radicalprostatectomy (RALRP). Outcome measures included sensitivity, specificity, positive and negativepredictive values of MP-MRI and MP-MRI ultrasound cognitive fusion biopsy. Reference standardused was the final histopathologic report obtained after RALRP.@*RESULTS@#MP-MRI has a sensitivity of 35.5%, specificity of 95.2%, positive predictive value of 97.1%,and negative predictive value of 25%. MP-MRI ultrasound fusion biopsy had similar results, withsensitivity of 34.4%, specificity of 81.0%, positive predictive value of 88.9%, and negative predictivevalue of 21.8%.@*CONCLUSION@#The high specificity and positive predictive value of MP-MRI (95.2% and 97.1%respectively) indicates the necessity for a prostate biopsy and supports the utility of a targeted MP-MRI guided ultrasound cognitive fusion biopsy. However, the low sensitivity and negative predictivevalue (25% and 35% respectively) of 35.5% indicates that MP-MRI guidance does not limit thenumber of biopsy samples only to visible MP-MRI lesions, since negative areas on MP-MRI stillcontains tumors in 75% of cases.

The Effect of Antidepressants on Mesenchymal Stem Cell Differentiation

BACKGROUND: Use of antidepressant medications has been linked to detrimental impacts on bone mineral density and osteoporosis; however, the cellular basis behind these observations remains poorly understood. The effect does not appear to be homogeneous across the whole class of drugs and may be linked to affinity for the serotonin transporter system. In this study, we hypothesized that antidepressants have a class- and dose-dependent effect on mesenchymal stem cell (MSC) differentiation, which may affect bone metabolism. METHODS: Human MSCs (hMSCs) were committed to differentiate when either adipogenic or osteogenic media was added, supplemented with five increasing concentrations of amitriptyline (0.001–10 µM), venlafaxine (0.01–25 µM), or fluoxetine (0.001–10 µM). Alizarin red staining (mineralization), alkaline phosphatase (osteoblastogenesis), and oil red O (adipogenesis) assays were performed at timed intervals. In addition, cell viability was assessed using a MTT. RESULTS: We found that fluoxetine had a significant inhibitory effect on mineralization. Furthermore, adipogenic differentiation of hMSC was affected by the addition of amitriptyline, venlafaxine, and fluoxetine to the media. Finally, none of the tested medications significantly affected cell survival. CONCLUSIONS: This study showed a divergent effect of three antidepressants on hMSC differentiation, which appears to be independent of class and dose. As fluoxetine and amitriptyline, but not venlafaxine, affected both osteoblastogenesis and adipogenesis, this inhibitory effect could be associated to the high affinity of fluoxetine to the serotonin transporter system.

The Role of Consolidation Chemoradiotherapy in Locally Advanced Pancreatic Cancer Receiving Chemotherapy: An Updated Systematic Review and Meta-Analysis / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The role of consolidation chemoradiation (CCRT) after systemic chemotherapy in locally advanced pancreatic cancer (LAPC) is still controversial. We aim to evaluate the effectiveness of CCRT in LAPC using systematic review and meta-analysis of prospective studies. MATERIALS AND METHODS: Prospective clinical trials of LAPC receiving chemotherapy with or without subsequent CCRT were included in the analysis. We systematically searched in PubMed, MEDLINE, Embase, and Web of Science. The primary outcome of interest was 1-year survival. Secondary end-points were median overall survival, progression-free survival, toxicity, and resection rate. RESULTS: Forty-one studies with 49 study arms were included with a total of 1,018 patients receiving CCRT after induction chemotherapy (ICT) and 954 patients receiving chemotherapy alone. CCRT after ICT did not improve 1-year survival significantly in LAPC patients compared with chemotherapy alone (58% vs. 52%). ICT lasted for at least 3 months revealed significantly improved survival of additional CCRT to LAPC patients compared to chemotherapy alone (65% vs. 52%). A marginal survival benefit of consolidation CCRT was noted in studies using maintenance chemotherapy (59% vs. 52%), and fluorouracil-based CCRT (64% vs. 52%), as well as in studies conducted after the 2010 (64% vs. 55%). CONCLUSION: The survival benefit of ICT+CCRT over chemotherapy alone in treating LAPC was noted when ICT lasted for at least 3 months. Fluorouracil-based CCRT, and maintenance chemotherapy were associated with improved clinical outcomes.

Engineering of Anti-CD133 Trispecific Molecule Capable of Inducing NK Expansion and Driving Antibody-Dependent Cell-Mediated Cytotoxicity / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The selective elimination of cancer stem cells (CSCs) in tumor patients is a crucial goal because CSCs cause drug refractory relapse. To improve the current conventional bispecific immune-engager platform, a 16133 bispecific natural killer (NK) cell engager (BiKE), consisting of scFvs binding FcγRIII (CD16) on NK cells and CD133 on carcinoma cells, was first synthesized and a modified interleukin (IL)-15 crosslinker capable of stimulating NK effector cells was introduced. MATERIALS AND METHODS: DNA shuffling and ligation techniques were used to assemble and synthesize the 1615133 trispecific NK cell engager (TriKE). The construct was tested for its specificity using flow cytometry, cytotoxic determinations using chromium release assays, and lytic degranulation. IL-15–mediated expansion was measured using flow-based proliferation assays. The level of interferon (IFN)-γ release was measured because of its importance in the anti-cancer response. RESULTS: 1615133 TriKE induced NK cell–mediated cytotoxicity and NK expansion far greater than that achieved with BiKE devoid of IL-15. The drug binding and induction of cytotoxic degranulation was CD133+ specific and the anti-cancer activity was improved by integrating the IL-15 cross linker. The NK cell–related cytokine release measured by IFN-γ detection was higher than that of BiKE. NK cytokine release studies showed that although the IFN-γ levels were elevated, they did not approach the levels achieved with IL-12/IL-18, indicating that release was not at the supraphysiologic level. CONCLUSION: 1615133 TriKE enhances the NK cell anti-cancer activity and provides a self-sustaining mechanism via IL-15 signaling. By improving the NK cell performance, the new TriKE represents a highly active drug against drug refractory relapse mediated by CSCs.

Lumen apposing metal stents: A review of current uses and outcomes

Lumen-apposing metal stents (LAMS) represent a new innovation in gastrointestinal endoscopy. These devices have a saddle-shaped design and larger inner lumen diameter than either plastic or metal biliary stents, which should decrease the risk of migration and allows for an endoscope to pass into pancreatic fluid collections as well as the ability to perform direct endoscopic necrosectomy. LAMS were originally conceived and designed for transmural pancreatic fluid collection drainage but are currently also being used for many off label indications. There are three different LAMS available at this time around the globe. This manuscript will review the current state of the art with regards to LAMS and their indications, usage, and outcomes.

Trends in All-Cause Mortality during the Scale-Up of an Antiretroviral Therapy Programme: a Cross-Sectional Study in Lusaka; Zambia

Objective To follow the trends in all-cause mortality in Lusaka; Zambia; during the scale-up of a national programme of antiretroviral therapy (ART). Methods Between November 2004 and September 2011; we conducted 12 survey rounds as part of a cross-sectional study in Lusaka; with independent sampling in each round. In each survey; we asked the heads of 3600 households to state the number of deaths in their households in the previous 12 months and the number of orphans aged less than 16 years in their households and investigated the heads' knowledge; attitudes and practices related to human immunodeficiency virus (HIV). Findings The number of deaths we recorded - per 100 person-years - in each survey ranged from 0.92 (95confidence interval; CI: 0.78-1.09) in September 2011; to 1.94 (95CI: 1.60-2.35) in March 2007. We found that mortality decreased only modestly each year (mortality rate ratio: 0.98; 95CI: 0.95-1.00; P = 0.093). The proportion of households with orphans under the age of 16 years decreased from 17 in 2004 to 7 in 2011. The proportions of respondents who had ever been tested for HIV; had a comprehensive knowledge of HIV; knew where to obtain free ART and reported that a non-pregnant household member was receiving ART gradually increased. Conclusion :The expansion of ART services in Lusaka was not associated with a reduction in all-cause mortality. Coverage; patient adherence and retention may all have to be increased if ART is to have a robust and lasting impact at population level in Lusaka

Universal Combination Antiretroviral Regimens to Prevent Mother-to-Child Transmission of HIV in Rural Zambia: a Two-Round Cross-Sectional Study

To evaluate if a pilot programme to prevent mother-to-child transmission (PMTCT) of the human immunodeficiency virus (HIV) was associated with changes in early childhood survival at the population level in rural Zambia.Methods Combination antiretroviral regimens were offered to pregnant and breastfeeding; HIV-infected women; irrespective of immunological status; at four rural health facilities. Twenty-four-month HIV-free survival among children born to HIV-infected mothers was determined before and after PMTCT programme implementation using community surveys. Households were randomly selected and women who had given birth in the previous 24 months were asked to participate. Mothers were tested for HIV antibodies and children born to HIV-infected mothers were tested for viral deoxyribonucleic acid. Multivariable models were used to determine factors associated with child HIV infection or death. Findings In the first survey (2008-2009); 335 of 1778 women (18.8) tested positive for HIV. In the second (2011); 390 of 2386 (16.3) tested positive. The 24-month HIV-free survival in HIV-exposed children was 0.66 (95 confidence interval; CI: 0.63-0.76) in the first survey and 0.89 (95 CI: 0.83-0.94) in the second. Combination antiretroviral regimen use was associated with a lower risk of HIV infection or death in children (adjusted hazard ratio: 0.33; 95 CI: 0.15-0.73). Maternal knowledge of HIV status; use of HIV tests and use of combination regimens during pregnancy increased between the surveys. Conclusion The PMTCT programme was associated with an increased HIV-free survival in children born to HIV-infected mothers. Maternal utilization of HIV testing and treatment in the community also increased

Ranibizumab for idiopathic epiretinal membranes: a retrospective case series

To study the effect of intravitreal ranibizumab on idiopathic epiretinal membranes [ERMs]. A retrospective cohort study on a consecutive series of ranibizumab intravitreal injections for epiretinal membranes was performed. Four cases were identified by reviewing a claims database linked to electronic medical records. All patients received a total of three 0.05 mg/0.05 ml ranibizumab intravitreal injections at a monthly interval. The primary outcome measure was the final best-corrected visual acuity [BCVA] at the end of the injection series, and the final central macular thickness [CMT]. All four patients completed 3 months follow-up after the last ranibizumab injection. The mean baseline CMT was 509 microns [SD = 111]. A trend was noticed for reduction in CMT [delta = 41 microns] P = 0.08. Three patients improved by one line in their BCVA. The remaining patient maintained the same BCVA. No complications were noted. In this study, intravitreal injection of ranibizumab marginally reduced retinal thickness in four patients with minimal improvement in visual acuity. No safety concerns were noticed. Further basic science and clinical studies may be warranted to assess the role of vascular endothelial growth factor and the effect of ranibizumab on idiopathic epiretinal membranes

Implications and limitations of cellular reprogramming for psychiatric drug development

Human-induced pluripotent stem cells (hiPSCs) derived from somatic cells of patients have opened possibilities for in vitro modeling of the physiology of neural (and other) cells in psychiatric disease states. Issues in early stages of technology development include (1) establishing a library of cells from adequately phenotyped patients, (2) streamlining laborious, costly hiPSC derivation and characterization, (3) assessing whether mutations or other alterations introduced by reprogramming confound interpretation, (4) developing efficient differentiation strategies to relevant cell types, (5) identifying discernible cellular phenotypes meaningful for cyclic, stress induced or relapsing-remitting diseases, (6) converting phenotypes to screening assays suitable for genome-wide mechanistic studies or large collection compound testing and (7) controlling for variability in relation to disease specificity amidst low sample numbers. Coordination of material for reprogramming from patients well-characterized clinically, genetically and with neuroimaging are beginning, and initial studies have begun to identify cellular phenotypes. Finally, several psychiatric drugs have been found to alter reprogramming efficiency in vitro, suggesting further complexity in applying hiPSCs to psychiatric diseases or that some drugs influence neural differentiation moreso than generally recognized. Despite these challenges, studies utilizing hiPSCs may eventually serve to fill essential niches in the translational pipeline for the discovery of new therapeutics.

A cone-beam computed tomography evaluation of buccal bone thickness following maxillary expansion

PURPOSE: This study was performed to determine the buccal alveolar bone thickness following rapid maxillary expansion (RME) using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: Twenty-four individuals (15 females, 9 males; 13.9 years) that underwent RME therapy were included. Each patient had CBCT images available before (T1), after (T2), and 2 to 3 years after (T3) maxillary expansion therapy. Coronal multiplanar reconstruction images were used to measure the linear transverse dimensions, inclinations of teeth, and thickness of the buccal alveolar bone. One-way ANOVA analysis was used to compare the changes between the three times of imaging. Pairwise comparisons were made with the Bonferroni method. The level of significance was established at p<0.05. RESULTS: The mean changes between the points in time yielded significant differences for both molar and premolar transverse measurements between T1 and T2 (p<0.05) and between T1 and T3 (p<0.05). When evaluating the effect of maxillary expansion on the amount of buccal alveolar bone, a decrease between T1 and T2 and an increase between T2 and T3 were found in the buccal bone thickness of both the maxillary first premolars and maxillary first molars. However, these changes were not significant. Similar changes were observed for the angular measurements. CONCLUSION: RME resulted in non-significant reduction of buccal bone between T1 and T2. These changes were reversible in the long-term with no evident deleterious effects on the alveolar buccal bone.

Optimized mixture of hops rho iso-alpha acids-rich extract and acacia proanthocyanidins-rich extract reduces insulin resistance in 3T3-L1 adipocytes and improves glucose and insulin control in db/db mice

Rho iso-alpha acids-rich extract (RIAA) from Humulus lupulus (hops) and proanthocyanidins-rich extracts (PAC) from Acacia nilotica exert anti-inflammatory and anti-diabetic activity in vitro and in vivo. We hypothesized that a combination of these two extracts would exert enhanced effects in vitro on inflammatory markers and insulin signaling, and on nonfasting glucose and insulin in db/db mice. Over 49 tested combinations, RIAA:PAC at 5:1 (6.25 microg/mL) exhibited the greatest reductions in TNFalpha-stimulated lipolysis and IL-6 release in 3T3-L1 adipocytes, comparable to 5 microg/mL troglitazone. Pretreatment of 3T3-L1 adipocytes with this combination (5 microg/mL) also led to a 3-fold increase in insulin-stimulated glucose uptake that was comparable to 5 microg/mL pioglitazone or 901 microg/mL aspirin. Finally, db/db mice fed with RIAA:PAC at 5:1 (100 mg/kg) for 7 days resulted in 22% decrease in nonfasting glucose and 19% decrease in insulin that was comparable to 0.5 mg/kg rosiglitazone and better than 100 mg/kg metformin. RIAA:PAC mixture may have the potential to be an alternative when conventional therapy is undesirable or ineffective, and future research exploring its long-term clinical application is warranted.

guideline for the inpatient care of children with pyelonephritis

Febrile urinary tract infections and pyelonephritis are common in children and frequently lead to hospitalization for management, especially in the child who appears toxic. The American Academy of Pediatrics [AAP] practice parameter on the diagnosis, treatment and evaluation of the initial urinary tract infection in febrile infants and young children provides experience and evidence-based guidelines for the practitioner caring for children between the ages of 2 months to 2 years. No established guideline exists for older children and the AAP guideline does not specifically focus on inpatient care. We conducted a comprehensive review of recently published literature and practice guidelines to develop a consensus on the inpatient diagnosis and management of children with pyelonephritis. Eight recommendations are proposed for the diagnosis and management, including revised guidelines for the imaging studies postpyelonephritis on the basis of current best evidence. Proper diagnosis of pyelonephritis, timely initiation of appropriate therapy and identification of children at risk for renal injury will help to reduce immediate as well as long-term complications due to chronic kidney disease

GLUT4's itinerary in health & disease.

Following the discovery of insulin 85 yr ago and the realization thereafter that in some individuals, tissues lose their responsiveness to this hormone, an enormous world-wide effort began to dissect the cellular mechanisms of insulin action and define abnormalities in the insulin-resistant state. A clear goal through the years has been to unravel the insulin signal transduction network regulating glucose transport. This line of investigation has provided tremendous insight into the physiology and pathophysiology surrounding the cellular processes controlled by insulin. Between the plasma membrane insulin receptor and the intracellularly sequestered insulin-responsive glucose transporter GLUT4, many events participate in the transduction of the insulin signal. In this review, we detail our current state of knowledge on the intricate insulin signaling network responsible for glucose transport in peripheral adipose and skeletal muscle tissues. In particular, we identify signaling connections spanning the insulin receptor and GLUT4. In addition, we discuss cytoskeletal mechanics and membrane docking and fusion mechanisms pertinently involved in the cellular redistribution of GLUT4 to the plasma membrane. On the whole, this review highlights the considerable progress in our understanding of insulin signaling in health and disease as we rapidly approach the centennial anniversary of insulin's discovery.

The Effect of 7.5% Hypertonic Saline Resuscitation and Normal Saline Resuscitation on Acute Lung Injury after Hemorrhagic Shock

PURPOSE: To investigate the hypothesis that resuscitation with hypertonic saline (HTS) in hemorrhagic shock (HS) will improve the pulmonary function and inflammatory changes in post-hemorrhage induced acute lung injury. METHODS: HS was induced in anesthetized Swiss-Webster mice by removing 0.025cc blood/g. body weight via the carotid artery while under blood pressure monitoring. Mice were divided into 5 groups: Group I (n=12) were cannulated but not bled (sham); Group II (n=12) were bled and received 4mL/kg 7.5% HTS; Group III (n=10) were bled and received 3 times their shed blood (SB) volume of normal saline (NS); Group IV (n=11) were bled and received SB and 4mL/kg 7.5% HTS; Group V (n=9) were bled and received SB and two times their SB volume of NS after 30 minutes shock. Serum lactates (LA) were evaluated at the end of the shock period and after resuscitation. Pulmonary function was measured by whole-body plethysmography prior to any instrumentation and again 24hr, 48hr and 72hr after resuscitation. Pulmonary inflammation was assessed by quantifying bronchoalveolar lavage neutrophil infiltration (BALN) and myeloperoxidase (MPO) activity after 72hr of observation. RESULTS: There were no differences in baseline BP, shock BP, shock LA and LA after resuscitation in each shock group. The survival rates were as follows: Group I, 75.0%; Group II, 33.3%; Group III, 60%; Group IV, 81.8%; and Group V, 88.8% (p=0.046). There were no significant differences in the changes of airway resistance after resuscitation in each group. BALN and MPO activity in Group III were increased. CONCILUSION: HTS resuscitation alone was associated with higher mortality. HTS was decreased pulmonary inflammation but it did not alter respiratory function.

Prevención de adherencias en cirugía de infertilidad / Prevention of adhesions in infertility surgery

Se reporta el caso clínico de una paciente de 26 años, gravida 0, para 0 que presenta un útero aumentado de tamaño, sonográficamente se confirma la presencia de un fibromioma. Se realiza una laparotomía y una miomectomía. La incisión uterina se sutura en tres planos y para prevenir la formación de adherencias, se utiliza una membrana de polytetrafluoreethylene, Gore-Tex. Un año después una laparoscopia muestra la ausencia de adherencias en el útero. Dos meses después la paciente se embaraza naciendo posteriormente vía operación cesárea un niño de término sano. A pesar que el útero se expandió, la membrana se mantuvo en su posición sin la formación de adherencias