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Presentation of Case. Dr. David K. Rhee (Cardiology): A 65-year-old man was admitted to this hospital because of syncope, dyspnea, and leg edema. The patient had been in his usual health until approximately 1 month before admission, when cough occurred. One week later, his legs became swollen and…
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Bisphosphonates are the first-line medications for treating osteoporosis. The aim of our prospective study was to compare the efficacy of zoledronate with that of alendronate in women with post-menopausal osteoporosis based on the evaluations of bone mineral density (BMD) and serum levels of biochemical markers of bone remodelling.
Chinese women with post-menopausal osteoporosis were randomly assigned to the zoledronate (n = 52) or alendronate (n = 53) group, and were treated with 5 mg zoledronate intravenously once per year and 70 mg alendronate orally once per week, respectively. During a 3-year follow-up period, the lumbar spine, femoral neck and total hip were examined using dual-energy x-ray absorptiometry every 12 months to assess BMD, and the serum levels of amino-terminal propeptide of type I procollagen (P1NP) and carboxy-terminal cross-linked telopeptides of type 1 collagen (CTX) were measured to evaluate bone formation and resorption, respectively.
Greater increases in BMD occurred in the zoledronate group over the 3-year follow-up period, with increases in BMD of 41·3%, 13·5% and 20·0% at the lumbar spine, femoral neck and total hip, respectively, compared with 16·9%, 5·88% and 8·93% in the alendronate group, respectively (P < 0·05 for all). At the 3-year follow-up, P1NP and β-CTX levels were reduced by 42·1% and 50·5% in the zoledronate group, respectively, whereas the levels of each were reduced by 19·5% and 19·4% in the alendronate group, respectively (P < 0·05 for all).
Once yearly zoledronate administered intravenously was more efficacious for improving BMD and reducing the serum levels of P1NP and β-CTX in Chinese women with post-menopausal osteoporosis than alendronate administered orally once per week. The incidence of adverse events after the second and third zoledronate treatments was substantially lower than that in the alendronate group, suggesting a substantially lower risk of adverse events with long-term use of zoledronate in Chinese women, compared with that of alendronate use.
Compared to alendronate, zoledronate medications of women with post-menopausal osteoporosis led to 1) better improvements of lumbar spine, femoral neck and total hip bone mineral densities and 2) was associated with superior reductions of the bone resorption marker P1NP and β-CTX expressions.
Recent progress in the Nerve Growth Factor (NGF) research has shown that this factor acts not only outside its classical domain of the peripheral and central nervous system, but also on non-neuronal and cancer cells. This latter observation has led to divergent hypothesis about the role of NGF, its specific distribution pattern within the tissues and its implication in induction as well as progression of carcinogenesis. Moreover, other recent studies have shown that NGF has direct clinical relevance in certain human brain neuron degeneration and a number of human ocular disorders. These studies, by suggesting that NGF is involved in a plethora of physiological function in health and disease, warrant further investigation regarding the true role of NGF in carcinogenesis. Based on our long-lasting experience in the physiopathology of NGF, we aimed to review previous and recent in vivo and in vitro NGF studies on tumor cell induction, progression and arrest. Overall, these studies indicate that the only presence of NGF is unable to generate cell carcinogenesis, both in normal neuronal and non-neuronal cells/tissues. However, it cannot be excluded the possibility that the co-expression of NGF and pro-carcinogenic molecules might open to different consequence. Whether NGF plays a direct or an indirect role in cell proliferation during carcinogenesis remains to demonstrate.
Interferon-free (IFN-free) therapies for hepatitis C virus (HCV) have been developed to provide more effective, tolerable and safer therapeutic strategies. To date, no network meta-analysis (NMA) evaluating the safety profile of these regimens has been performed. This systematic review and NMA aimed to evaluate safety outcomes of IFN-free treatment options for chronic hepatitis C.
A systematic review was performed according to PRISMA and Cochrane recommendations. A literature search was conducted in PubMed/Medline, Scopus, Cochrane Library, International Pharmaceutical Abstracts and Web of Science electronic databases and included only randomized clinical trials that provided safety outcomes of interest of evaluated second-generation direct-acting antivirals: incidence of any adverse events (AEs) and serious AE. NMA allowed estimating probability for the relative safety of the interventions. A consistency model was used to draw conclusions about relative safety of treatments, presented as odds ratio (OR) and corresponding 95% credible interval (CrI).
Fifty-one clinical trials were included (13 089 participants). Most participants had hepatitis C genotype 1 virus (76%) and were treated for 12 weeks. Two NMAs were built to investigate the incidence of AEs and serious AEs, comparing 13 and 10 IFN-free treatment options, respectively. For the outcome incidence of AEs, few significant differences were observed, which were explained by the presence of RBV. Elbasvir with grazoprevir and placebo were both safer than ombitasvir in combination with paritaprevir, ritonavir, daclatasvir plus RBV [ORs with 95% Crl of 4·09 (1·17–14·09) and 2·40 (1·19–4·77), respectively] and sofosbuvir with RBV [ORs with 95% Crl of 0·22 (0·07–0·72) and 2·69 (1·53–4·80), respectively]. Furthermore, elbasvir with grazoprevir was safer than sofosbuvir used with velpatasvir and RBV [OR 0·19 (95% CrI 0·03–0·98)]; ombitasvir in combination with paritaprevir, ritonavir, daclatasvir was safer than the same therapy but combined with RBV [OR 2·14 (95% CrI 1·09–4·44)]; and sofosbuvir used with velpatasvir was safer than sofosbuvir with RBV [OR 2·07 (95% CrI 1·13–3·79)]. Elbasvir with grazoprevir (50%) followed by placebo (28%) had the highest probabilities of less AEs. No significant differences were observed for serious AE outcomes.
This meta-analysis included a large number of therapies. Small differences were observed in any AEs, but not in serious AEs.
It was carried out network meta-analyses to assess safety of IFN-free therapies for hepatitis C. Two outcomes were evaluated: any adverse events and serious adverse events. Small differences were observed in any adverse events network meta-analysis, but not in serious adverse events network meta-analysis. Here it is presented the consistency analysis based on network meta-analysis results for any adverse events. Significant results are presented as odds ratio with 95% credible interval.
This study reports a numerical simulation of the natural convection combined with thermal radiation in a square porous cavity with a thin isothermally heated plate placed horizontally or vertically at its center. The vertical walls of the cavity are cooled while the horizontal ones are adiabatic. The governing equations were solved using a finite volume method on a uniformly staggered grid system. The computational results are presented in the form of isotherm and streamline plots and Nusselt numbers. The effects of the Darcy number ( \(10^{-5} \le \mathrm{Da} \le ~10^{-2})\) , plate length ( \(0.25\le D \le 0.75\) ) and the radiation parameter ( \(0 \le R_{d} \le 2\) ) are investigated for the Rayleigh number Ra = \(10^{7}\) . It is found that the Darcy number, the plate length and the radiation parameter enhance the overall heat transfer rate across the cavity.
Enhanced recovery after surgery is increasingly desired nowadays, and preoperative nutrient intake may be beneficial for this purpose. In this study, we investigated whether the intake of preoperative carbohydrate with amino acid (ONS) solution can improve starvation status and lipid catabolism before the induction of anesthesia.
This randomized, prospective clinical trial included 24 patients who were divided into two groups before surgery under general anesthesia: a control group, comprising patients who fasted after their last meal the day before surgery (permitted to drink only water), and an ONS group, comprising patients who consumed ONS solution 2 h before surgery. Biochemical markers, the respiratory quotient, and psychosomatic scores were assessed at the initiation of anesthesia.
Compared with the control group, the ONS group showed significantly lower serum free fatty acid levels [control group: 828 (729, 1004) µEq/L, ONS group: 479 (408, 610) µEq/L, P = 0.0002, median (25th, 75th percentile)] and total ketone bodies [control group: 119 (68, 440) µmol/L, ONS group: 40 [27, 64] µmol/L, P = 0.037]. In addition, analysis using the Visual Analog Scale showed higher preoperative scores for anxiety, hunger, and thirst for the control group, with no differences in any other measure of subjective well-being between groups.
The results of this study suggest that preoperative ONS intake improves lipid catabolism and starvation status before the induction of anesthesia. Furthermore, it can provide better preoperative mental health compared with complete fasting.
Novel flexible dielectric composites composed of polyvinyl alcohol (PVA), polyethylene glycol (PEG), and graphene oxide (GO) with high dielectric constant and low dielectric loss have been developed using facile and eco-friendly colloidal processing technique. The structure and morphology of the PVA/PEG/GO composites were evaluated using Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, UV-vis spectroscopy (UV-vis), X-ray diffraction (XRD), scanning electron microscopy (SEM), and atomic force microscopy (AFM). The dielectric behavior of PVA/PEG/GO composites was investigated in the wide range of frequencies from 50 Hz to 20 MHz and temperature in the range 40 to 150 °C using impedance spectroscopy. The dielectric constant for PVA and PVA/PEG (50/50) blend film was found to be 10.71 (50 Hz, 150 °C) and 31.22 (50 Hz, 150 °C), respectively. The dielectric constant for PVA/PEG/GO composite with 3 wt% GO was found to be 644.39 (50 Hz, 150 °C) which is 60 times greater than the dielectric constant of PVA and 20 times greater than the dielectric constant of PVA/PEG (50/50) blend film. The PVA/PEG/GO composites not only show high dielectric constant but also show low dielectric loss which is highly attractive for practical applications. These findings underline the possibilities of using PVA/PEG/GO composites as a flexible dielectric material for high-performance energy storage applications such as embedded capacitors.
In response to health and safety questions and concerns regarding particulate matter emissions from equipment used for synthesizing NiFe and TiO2 nanopowders, a study was undertaken to assess their impact on the air quality inside and outside a laboratory where the manufacturing equipment is operated. Elemental concentrations determined by ion beam analysis (IBA) of air particulate matter (PM) samples collected hourly with a StreakerTM sampler were used to identify possible sources and estimate contributions from nanopowder production and other sources. The fugitive nanopowder emissions were the highest at the indoor sampling location when powders were being manufactured. Average fugitive emissions of 210 ng m−3 (1-h average) (maximum 2163 ng m−3 1-h average) represented 2 % (maximum 20 %) of the average PM collected (9359 ng m−3 1-h average). The measured NiFe alloy or TiO2 PM concentrations were much smaller than the 8-h time-weighted average (TWA) workplace exposure standards (WES) for these materials (≥1,000,000 ng m−3). Most PM was found to be from infiltrated outdoor ambient sources. This suggests that nanopowder production in the laboratory is not likely to have adverse health effects on individuals using the equipment, although further improvements can be made to further limit exposure.
Tamoxifen is the most widely used drug to treat women with estrogen receptor α (ERα)-positive breast cancer. Endoxifen is recognized as the active metabolite of tamoxifen in humans. We studied endoxifen effects on ERα-positive MCF-7 breast cancer cells. Estradiol increased the proliferation of MCF-7 cells by two- to threefold and endoxifen suppressed its effects. Endoxifen suppressed c-myc, c-fos and Tff1 oncogene expression, as revealed by RT-PCR. Estradiol increased the activity of ornithine decarboxylase (ODC) and adenosyl methioninedecarboxylase (AdoMetDC), whereas endoxifen suppressed these enzyme activities. Endoxifen increased activities of spermine oxidase (SMO) and acetyl polyamine oxidase (APAO) significantly, and reduced the levels of putrescine and spermidine. These data suggest a possible mechanism for the antiestrogenic effects of tamoxifen/endoxifen, involving the stimulation of polyamine oxidase enzymes. Therefore, SMO and APAO stimulation might be useful biomarkers for the efficacy of endoxifen treatment of breast cancer.
The modification in the third-order nonlinear optical response exhibited by rotating bimetallic Au–Pt nanoparticles in an ethanol solution was analyzed. The samples were prepared by a sol–gel processing route. The anisotropy associated to the elemental composition of the nanoparticles was confirmed by high-resolution transmission electron microscopy and energy-dispersive X-ray spectroscopy measurements. The size of the nanoparticles varies in the range from 9 to 13 nm, with an average size of 11 nm. Changes in the spatial orientation of the nanomaterials automatically generated a variation in their plasmonic response evaluated by UV–Vis spectroscopy. A two-wave mixing experiment was conducted to explore an induced birefringence at 532 nm wavelength with nanosecond pulses interacting with the samples. A strong optical Kerr effect was identified to be the main responsible effect for the third-order nonlinear optical phenomenon exhibited by the nanoparticles. It was estimated that the rotation of inhomogeneous nanostructures can provide a remarkable change in the participation of different surface plasmon resonances, if they correspond to multimetallic nanoparticles. Potential applications for developing low-dimensional gyroscopic systems can be contemplated.
To the Editor: Pembrolizumab and nivolumab, two humanized antibodies against programmed cell death 1 (PD-1) receptor, were recently approved for the treatment of unresectable or metastatic melanoma and for other cancers. We report two cases of severe demyelinating polyradiculoneuropathy that…
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Overweight and obese patients are often asked to lose weight prior to ventral hernia repair (VHR). Improved outcomes are the reasons behind this strategy. Data regarding weight loss targets are scant, and it is not known at what body mass index (BMI) threshold postoperative complications increase. This study aimed to determine the threshold to allow proper patient counseling.
All patients who underwent open VHR at our institution between 2002 and 2015 captured in the NSQIP database were included. The primary outcome was defined as any (≥1) of 18 captured postoperative complications. Patients were divided into five groups based on BMI: group 1 (<25 kg/m2); 2 (25–29.99 kg/m2); 3 (30–34.99 kg/m2); 4 (35–39.99 kg/m2); and 5 (≥40 kg/m2). Multivariable, adjusted logistic regression was performed to evaluate the association between BMI categories and postoperative complications.
Sixty seven of 922 patients (7.3 %) had at least one postoperative complication following VHR. The adjusted odds of complications in group 5 was 2.89 times greater compared to group 1 (OR 2.89; 95 % CI = 1.22–6.84), while there was no significant differences in odds of postoperative complications for groups 2, 3, or 4 compared to group 1. BMI category was also significantly associated with undergoing recurrent VHR, with 28.7 % of patients in group 5 having a recurrent repair compared to 14 % in patients in group 1 (p = 0.03).
After VHR, complications are most likely to occur in patients with BMI ≥ 40 kg/m2. This subset of patients also had a significantly higher risk of undergoing surgery for a recurrent hernia, suggesting that this group of patients is likely to experience adverse outcomes after VHR and should be counseled to consider bariatric surgery prior to attempts at VHR. VHR at lower BMIs appears appropriate, and delaying therapy to achieve preoperative weight loss will likely offer no advantage.
Presentation of Case. Dr. David K. Rhee (Cardiology): A 65-year-old man was admitted to this hospital because of syncope, dyspnea, and leg edema. The patient had been in his usual health until approximately 1 month before admission, when cough occurred. One week later, his legs became swollen and…
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Digestive Diseases and Sciences
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Obesity Research & Clinical Practice
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Obesity is an epidemic in the USA that continues to grow, becoming a leading cause of premature avoidable death. Bariatric surgery has become an effective solution for obesity and its comorbidities, and one of the most commonly utilized procedures, the sleeve gastrectomy, can lead to an increase in gastroesophageal reflux following the operation. While these data are controversial, sometimes operative intervention can be necessary to provide durable relief for this problem.
We performed an extensive literature review examining the different methods of anti-reflux procedures that are available both before and after a sleeve gastrectomy.
We reviewed several different types of anti-reflux procedures, including those that supplement the lower esophageal sphincter anatomy, such as magnetic sphincter augmentation and radiofrequency ablation procedures. Re-operation was also discussed as a possible treatment of reflux in sleeve gastrectomy, especially if the original sleeve becomes dilated or if a conversion to a Roux-en-Y gastric bypass or biliopancreatic diversion is deemed necessary. Sleeve gastrectomy with concomitant anti-reflux procedure was also reviewed, including the anti-reflux gastroplasty, hiatal hernia repair, and limited fundoplication.
A number of techniques can be used to mitigate the severity of reflux, either by maintaining the normal anatomic structures that limit reflux or by supplementing these structures with a plication or gastroplasty. Individuals with existing severe reflux should not be considered for a sleeve gastrectomy. New techniques that incorporate plication at the time of the index sleeve gastrectomy show some improvement, but these are in small series that will need to be further evaluated. The only proven method of treating intractable reflux after sleeve gastrectomy is conversion to a Roux-en-Y gastric bypass.
Alimentary Pharmacology and Therapeutics
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To the Editor: Pembrolizumab and nivolumab, two humanized antibodies against programmed cell death 1 (PD-1) receptor, were recently approved for the treatment of unresectable or metastatic melanoma and for other cancers. We report two cases of severe demyelinating polyradiculoneuropathy that…
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Overweight and obese patients are often asked to lose weight prior to ventral hernia repair (VHR). Improved outcomes are the reasons behind this strategy. Data regarding weight loss targets are scant, and it is not known at what body mass index (BMI) threshold postoperative complications increase. This study aimed to determine the threshold to allow proper patient counseling.
All patients who underwent open VHR at our institution between 2002 and 2015 captured in the NSQIP database were included. The primary outcome was defined as any (≥1) of 18 captured postoperative complications. Patients were divided into five groups based on BMI: group 1 (<25 kg/m2); 2 (25–29.99 kg/m2); 3 (30–34.99 kg/m2); 4 (35–39.99 kg/m2); and 5 (≥40 kg/m2). Multivariable, adjusted logistic regression was performed to evaluate the association between BMI categories and postoperative complications.
Sixty seven of 922 patients (7.3 %) had at least one postoperative complication following VHR. The adjusted odds of complications in group 5 was 2.89 times greater compared to group 1 (OR 2.89; 95 % CI = 1.22–6.84), while there was no significant differences in odds of postoperative complications for groups 2, 3, or 4 compared to group 1. BMI category was also significantly associated with undergoing recurrent VHR, with 28.7 % of patients in group 5 having a recurrent repair compared to 14 % in patients in group 1 (p = 0.03).
After VHR, complications are most likely to occur in patients with BMI ≥ 40 kg/m2. This subset of patients also had a significantly higher risk of undergoing surgery for a recurrent hernia, suggesting that this group of patients is likely to experience adverse outcomes after VHR and should be counseled to consider bariatric surgery prior to attempts at VHR. VHR at lower BMIs appears appropriate, and delaying therapy to achieve preoperative weight loss will likely offer no advantage.
Presentation of Case. Dr. David K. Rhee (Cardiology): A 65-year-old man was admitted to this hospital because of syncope, dyspnea, and leg edema. The patient had been in his usual health until approximately 1 month before admission, when cough occurred. One week later, his legs became swollen and…
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Obesity is an epidemic in the USA that continues to grow, becoming a leading cause of premature avoidable death. Bariatric surgery has become an effective solution for obesity and its comorbidities, and one of the most commonly utilized procedures, the sleeve gastrectomy, can lead to an increase in gastroesophageal reflux following the operation. While these data are controversial, sometimes operative intervention can be necessary to provide durable relief for this problem.
We performed an extensive literature review examining the different methods of anti-reflux procedures that are available both before and after a sleeve gastrectomy.
We reviewed several different types of anti-reflux procedures, including those that supplement the lower esophageal sphincter anatomy, such as magnetic sphincter augmentation and radiofrequency ablation procedures. Re-operation was also discussed as a possible treatment of reflux in sleeve gastrectomy, especially if the original sleeve becomes dilated or if a conversion to a Roux-en-Y gastric bypass or biliopancreatic diversion is deemed necessary. Sleeve gastrectomy with concomitant anti-reflux procedure was also reviewed, including the anti-reflux gastroplasty, hiatal hernia repair, and limited fundoplication.
A number of techniques can be used to mitigate the severity of reflux, either by maintaining the normal anatomic structures that limit reflux or by supplementing these structures with a plication or gastroplasty. Individuals with existing severe reflux should not be considered for a sleeve gastrectomy. New techniques that incorporate plication at the time of the index sleeve gastrectomy show some improvement, but these are in small series that will need to be further evaluated. The only proven method of treating intractable reflux after sleeve gastrectomy is conversion to a Roux-en-Y gastric bypass.
With great interest, we read the paper "GSTT1 and GSTM1 polymorphisms predict treatment outcome for breast cancer: a systematic review and meta-analysis" (by Hu XY et al.), which has reached important conclusions that GSTM1 null and GSTT1/GSTM1 double null polymorphisms might be significantly associated with an increased tumor response in breast cancer. The result is encouraging. Nevertheless, several methodological flaws in this meta-analysis are worth noticing.
Altered expression of microRNAs (miRNAs) has been shown in many types of malignancies including the head and neck squamous cell carcinoma (HNSCC). Although there are many new and innovative approaches in the treatment of HNSCC, a clear marker of this disease is still missing. Three candidate miRNAs (miR-29c-3p, miR-200b-5p and miR-375-3p) were studied in connection with HNSCC using quantitative real-time PCR expression levels in 42 tissue samples of HNSCC patients and histologically normal tumour-adjacent tissue samples of these patients. Primary HNSCC carcinoma tissues can be distinguished from histologically normal-matched noncancerous tumour-adjacent tissues based on hsa-miR-375-3p expression (sensitivity 87.5 %, specificity 65 %). Additionally, a significant decrease of hsa-miR-200b-5p expression was revealed in tumour-adjacent tissue samples of patients with node positivity. Lower expression of hsa-miR-200b-5p and hsa-miR-29c-3p in HNSCC tumour tissue was associated with higher tumour grade. Consequently, survival analysis was performed. Lower expression of hsa-miR-29c-3p in tumour-adjacent tissue was associated with worse overall and disease-specific survivals. Lower expression of miR-29c-3p in tumourous tissue was associated with worse relapse-free survival. hsa-miR-375-3p seems to be a relatively promising diagnostic marker in HNSCC but is not suitable for prognosis of patients. Furthermore, this study highlighted the importance of histologically normal tumour-adjacent tissue in HNSCC progress (significant decrease of hsa-miR-200b-5p expression in tumour-adjacent tissue of patients with node positivity and low expression of hsa-miR-29c-3p in HNSCC tumour-adjacent tissue associated with worse prognosis).
The purpose of this study was to develop a novel index for preoperative, non-invasive prediction of complete primary cytoreduction in patients with FIGO stage IIIC–IV epithelial ovarian cancer. Prospectively collected clinical data was registered in the Danish Gynecologic Cancer Database. Blood samples were collected within 14 days of surgery and stored by the Danish CancerBiobank. Serum human epididymis protein 4 (HE4), serum cancer antigen 125 (CA125), age, performance status, and presence/absence of ascites at ultrasonography were evaluated individually and combined to predict complete tumor removal. One hundred fifty patients with advanced epithelial ovarian cancer were treated with primary debulking surgery (PDS). Complete PDS was achieved in 41 cases (27 %). The receiver operating characteristic curves demonstrated an area under the curve of 0.785 for HE4, 0.678 for CA125, and 0.688 for age. The multivariate model (Cancer Ovarii Non-invasive Assessment of Treatment Strategy (CONATS) index), consisting of HE4, age, and performance status, demonstrated an AUC of 0.853. According to the Danish indicator level, macro-radical PDS should be achieved in 60 % of patients admitted to primary surgery (positive predictive value of 60 %), resulting in a negative predictive value of 87.5 %, sensitivity of 68.3 %, specificity of 83.5 %, and cutoff of 0.63 for the CONATS index. Non-invasive prediction of complete PDS is possible with the CONATS index. The CONATS index is meant as a supplement to the standard preoperative evaluation of each patient. Evaluation of the CONATS index combined with radiological and/or laparoscopic findings may improve the assessment of the optimal treatment strategy in patients with advanced epithelial ovarian cancer.
Metastatic disease accounts for more than 90% of cancer deaths. For example, the life expectancy of women who have breast cancer has dramatically improved over the past 10 years, but women with metastatic disease have a 5-year survival rate of only 20%. Approximately 30% of women without evidence…
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To quantify the hepatic safety of pazopanib and comparator anti-vascular endothelial growth factor (VEGF) therapies in clinical practice among renal cell carcinoma (RCC) patients.
A population-based cohort study of new anti-VEGF users was conducted in two US healthcare databases, Department of Veterans Affairs (VA) and an oncology practice network (Altos), and the PHARMO Database Network in The Netherlands. A common protocol was used to collect liver chemistry (LC) data from anti-VEGF initiation through 4 years of follow-up. In the VA population, suspected drug-induced liver injury (DILI) outcomes were investigated via chart review, with adjudication by hepatologists.
In Altos and VA, respectively, the total RCC patients were: pazopanib (156, 243), bevacizumab (122, 99), sorafenib (82, 249) and sunitinib (285, 751). PHARMO contained too few patients to be included. Few cases of alanine aminotransferase (ALT) ≥8× the upper limit of normal were seen across the anti-VEGF cohorts; incidence rates (per 100 person-years) ranged from 0 (sunitinib) to 8.2 (pazopanib) in Altos and from 0 (bevacizumab and sorafenib) to 2.1 (pazopanib) among VA patients. No cases of Hy's law identified by combination LC elevations were seen in patients treated with pazopanib or bevacizumab; one case was observed in those treated with sorafenib, and two cases were found among sunitinib users. One case of adjudicated DILI was observed in a sunitinib-treated patient; none were found among patients treated with pazopanib, bevacizumab or sorafenib.
Severe liver injury occurred infrequently during exposure to pazopanib and other anti-VEGF therapies in a population-based setting.
Rectal cancer surgery is accompanied with high morbidity and poor long term functional outcome. Screening programs have shown a shift towards more early staged cancers. Patients with early rectal cancer can potentially benefit significantly from rectal preserving therapy. For the earliest stage cancers, local excision is sufficient when the risk of lymph node disease and subsequent recurrence is below 5 %. However, the majority of early cancers are associated with an intermediate risk of lymph node involvement (5–20 %) suggesting that local excision alone is not sufficient, while completion radical surgery, which is currently standard of care, could be a substantial overtreatment for this group of patients.
In this multicentre randomised trial, patients with an intermediate risk T1-2 rectal cancer, that has been locally excised using an endoluminal technique, will be randomized between adjuvant chemo-radiotherapylimited to the mesorectum and standard completion total mesorectal excision (TME). To strictly monitor the risk of locoregional recurrence in the experimental arm and enable early salvage surgery, there will be additional follow up with frequent MRI and endoscopy. The primary outcome of the study is three-year local recurrence rate. Secondary outcomes are morbidity, disease free and overall survival, stoma rate, functional outcomes, health related quality of life and costs. The design is a non inferiority study with a total sample size of 302 patients.
The results of the TESAR trial will potentially demonstrate that adjuvant chemoradiotherapy is an oncological safe treatment option in patients who are confronted with the difficult clinical dilemma of a radically removed intermediate risk early rectal cancer by polypectomy or transanal surgery that is conventionally treated with subsequent radical surgery. Preserving the rectum using adjuvant radiotherapy is expected to significantly improve morbidity, function and quality of life if compared to completion TME surgery.
NCT02371304, registration date: February 2015
We aimed to evaluate the prognostic value of quality of life (QOL) for predicting survival among disease-free survivors of surgically-treated lung cancer after the completion of cancer treatment.
We administered the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), the Quality of Life Questionnaire Lung Cancer Module (QLQ-LC13), Hospital Anxiety and Depression Scale (HADS), and Posttraumatic Growth Inventory (PTGI) to 809 survivors who were surgically-treated for lung cancer at two hospitals from 2001 through 2006. We gathered mortality data by linkage to the National Statistical Office through December 2011. We used Cox proportional hazard models to compute adjusted hazard ratios (aHRs) and 95 % confidence intervals (CIs) to estimate the relationship between QOL and survival.
Analyses of QOL items adjusted for age, sex, stage, body mass index, and physical activity showed that scores for poor physical functioning, dyspnea, anorexia, diarrhea, cough, personal strength, anxiety, and depression were associated with poor survival. With adjustment for the independent indicators of survival, final multiple proportional hazard regression analyses of QOL show that physical functioning (aHR, 2.39; 95 % CI, 1.13–5.07), dyspnea (aHR, 1.56; 95 % CI, 1.01–2.40), personal strength (aHR, 2.36; 95 % CI, 1.31–4.27), and anxiety (aHR, 2.13; 95 % CI, 1.38–3.30) retained their independent prognostic power of survival.
This study suggests that patient-reported QOL outcomes in disease-free survivors of surgically-treated lung cancer after the completion of active treatment has independent prognostic value for long-term survival.
The chemokine CXCL12 and its corresponding receptor CXCR4 are key players in the development of several cancers. Therefore, we hypothesized that there is a functional causality between CXCL12 expression and tumor progression in patients with esophageal squamous cell carcinoma (ESCC).
We performed an immunohistochemical analysis in 79 consecutive patients with ESCC. We performed in vitro and in vivo cell proliferation assays using ESCC cell lines and a newly established transfectant stably overexpressing CXCL12.
Immunohistochemistry revealed positive CXCR4 and CXCL12 expression in 48 (61 %) and 62 (78 %) patients, respectively. Additionally, the expression levels did not significantly correlate with any clinicopathological factors. The MIB-1 proliferation index was markedly higher in ESCC with a positive expression of CXCR4 or CXCL12. Positive CXCL12 expression was significantly correlated with lower recurrence-free survival (RFS, p = 0.02). Cox's hazard models revealed CXCL12 expression as an independent predictive factor for recurrence. In vitro, CXCL12 exposure or overexpression enhanced ESCC proliferation; and AMD3100, a specific inhibitor of CXCR4, equally decreased proliferation irrespective of CXCL12 exposure or overexpression. In the mouse model, AMD3100 significantly decreased ESCC tumor size (p = 0.03).
CXCL12 stimulates ESCC proliferation, and its expression levels are related to lower RFS in patients with ESCC. Our findings indicate that positive CXCL12 expression may be a useful marker for predicting the outcome in patients with ESCC and is a potentially new therapeutic target for ESCC.
With great interest, we read the paper "GSTT1 and GSTM1 polymorphisms predict treatment outcome for breast cancer: a systematic review and meta-analysis" (by Hu XY et al.), which has reached important conclusions that GSTM1 null and GSTT1/GSTM1 double null polymorphisms might be significantly associated with an increased tumor response in breast cancer. The result is encouraging. Nevertheless, several methodological flaws in this meta-analysis are worth noticing.
Altered expression of microRNAs (miRNAs) has been shown in many types of malignancies including the head and neck squamous cell carcinoma (HNSCC). Although there are many new and innovative approaches in the treatment of HNSCC, a clear marker of this disease is still missing. Three candidate miRNAs (miR-29c-3p, miR-200b-5p and miR-375-3p) were studied in connection with HNSCC using quantitative real-time PCR expression levels in 42 tissue samples of HNSCC patients and histologically normal tumour-adjacent tissue samples of these patients. Primary HNSCC carcinoma tissues can be distinguished from histologically normal-matched noncancerous tumour-adjacent tissues based on hsa-miR-375-3p expression (sensitivity 87.5 %, specificity 65 %). Additionally, a significant decrease of hsa-miR-200b-5p expression was revealed in tumour-adjacent tissue samples of patients with node positivity. Lower expression of hsa-miR-200b-5p and hsa-miR-29c-3p in HNSCC tumour tissue was associated with higher tumour grade. Consequently, survival analysis was performed. Lower expression of hsa-miR-29c-3p in tumour-adjacent tissue was associated with worse overall and disease-specific survivals. Lower expression of miR-29c-3p in tumourous tissue was associated with worse relapse-free survival. hsa-miR-375-3p seems to be a relatively promising diagnostic marker in HNSCC but is not suitable for prognosis of patients. Furthermore, this study highlighted the importance of histologically normal tumour-adjacent tissue in HNSCC progress (significant decrease of hsa-miR-200b-5p expression in tumour-adjacent tissue of patients with node positivity and low expression of hsa-miR-29c-3p in HNSCC tumour-adjacent tissue associated with worse prognosis).
The purpose of this study was to develop a novel index for preoperative, non-invasive prediction of complete primary cytoreduction in patients with FIGO stage IIIC–IV epithelial ovarian cancer. Prospectively collected clinical data was registered in the Danish Gynecologic Cancer Database. Blood samples were collected within 14 days of surgery and stored by the Danish CancerBiobank. Serum human epididymis protein 4 (HE4), serum cancer antigen 125 (CA125), age, performance status, and presence/absence of ascites at ultrasonography were evaluated individually and combined to predict complete tumor removal. One hundred fifty patients with advanced epithelial ovarian cancer were treated with primary debulking surgery (PDS). Complete PDS was achieved in 41 cases (27 %). The receiver operating characteristic curves demonstrated an area under the curve of 0.785 for HE4, 0.678 for CA125, and 0.688 for age. The multivariate model (Cancer Ovarii Non-invasive Assessment of Treatment Strategy (CONATS) index), consisting of HE4, age, and performance status, demonstrated an AUC of 0.853. According to the Danish indicator level, macro-radical PDS should be achieved in 60 % of patients admitted to primary surgery (positive predictive value of 60 %), resulting in a negative predictive value of 87.5 %, sensitivity of 68.3 %, specificity of 83.5 %, and cutoff of 0.63 for the CONATS index. Non-invasive prediction of complete PDS is possible with the CONATS index. The CONATS index is meant as a supplement to the standard preoperative evaluation of each patient. Evaluation of the CONATS index combined with radiological and/or laparoscopic findings may improve the assessment of the optimal treatment strategy in patients with advanced epithelial ovarian cancer.
Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease that presents with cerebellar ataxia and motor learning defects. Previous studies have indicated that the pathology of SCA1, as well as other ataxic diseases, is related to signalling pathways mediated by the metabotropic glutamate receptor type 1 (mGluR1), which is indispensable for proper motor coordination and learning. However, the functional contribution of mGluR signalling to SCA1 pathology is unclear. In the present study, we show that SCA1 model mice develop a functional impairment of mGluR signalling which mediates slow synaptic responses, dendritic Ca2+ signals and short- and long-term synaptic plasticity at parallel fibre (PF)-Purkinje cell (PC) synapses in a progressive manner from the early disease stage (5 postnatal weeks) prior to PC death. Notably, impairment of mGluR-mediated dendritic Ca2+ signals linearly correlated with reduction of PC capacitance (cell surface area) in the disease progression. Enhancement of mGluR signalling by baclofen, a clinically available GABAB receptor agonist, led to an improvement of motor performance in SCA1 mice and the improvement lasted ∼1 week after a single application of baclofen. Moreover, the restoration of motor performance in baclofen-treated SCA1 mice matched the functional recovery of mGluR-mediated slow synaptic currents and mGluR-dependent short- and long-term synaptic plasticity. These results suggest that impairment of synaptic mGluR cascades is one of the important contributing factors to cerebellar ataxia in early and middle stages of SCA1 pathology, and that modulation of mGluR signalling by baclofen or other clinical interventions may be therapeutic targets to treat SCA1.
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Greener synthesis of a series of novel indolizine analogues have been achieved by the cyclization of aromatic cycloimmoniumylides with electron deficient alkynes in presence of water as the base and solvent at 80 °C. Yield of the title compounds was good and reactions performed were eco-friendly. The structures of these newly synthesized compounds have been confirmed by spectroscopic techniques such as FTIR, NMR, LC-MS and elemental analysis. Characterized title compounds were evaluated for larvicidal activity against Anopheles arabiensis by standard WHO larvicidal assay using Temephos as standard at 4 μg/mL. Title compounds 2e, 2f and 2g emerged as promising larvicidal agents.
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The title compounds 2a-j have been synthesized by two step chemical reaction, purified by recrystallization method at 69-83% yield. Larvicidal results revealed that, title compounds 2e and 2g emerged as promising larvicidal agents compared to standard compound.
The C-terminal sequences of porcine thrombin encode a series of peptides with the characteristics of net positive charge and hydrophobicity, suggesting antimicrobial potential. In this study, we synthesized truncated C-terminal peptides to explore their antimicrobial potency and structure-activity relationship. The results showed that some peptides exerted antimicrobial activity against Gram-positive and Gram-negative bacteria, with selectivity for microbial membranes. The antimicrobial potency of the peptides increased with the extension of chain length. Considering toxicity to red blood cells, the 21-mer peptide T-6 displayed the highest therapeutic index of 43.4, suggesting its higher cell selectivity. Typical α-helical conformations were observed upon binding to a bacteria-mimicking environment. The derivatives tended to interact preferentially with negatively charged vesicles compared to zwitterionic vesicles. Flow cytometry and electron microscopy revealed that the peptides targeted bacterial cell membranes and disrupted cytoplasmic membrane integrity, thereby causing the release of cellular contents leading to cell death. Peptide-membrane interaction experiments provided evidence that the peptides killed bacteria via a membrane-mediating mechanism. In summary, the C-terminal sequence of porcine thrombin has antimicrobial functions.
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A series of short antimicrobial peptides were obtained from C-terminus of porcine thrombin to investigate their antimicrobial potency, structure-activity relationship and mechanism. The 21-residue peptide T-6 exhibited a considerably higher level of cell selectivity with TI of 43.4. T-6 demonstrated a typical α-helix structure in membrane-mimetic environment and rapidly disrupted the microbial membrane, leading to leakage of the intracellular content and eventual cell death at its MIC.