Cachexia is a wasting syndrome associated with elevated basal energy expenditure and loss of adipose and muscle tissues. It accompanies many chronic diseases including renal failure and cancer and is ...an important risk factor for mortality. Our recent work demonstrated that tumor-derived PTHrP drives adipose tissue browning and cachexia. Here, we show that PTH is involved in stimulating a thermogenic gene program in 5/6 nephrectomized mice that suffer from cachexia. Fat-specific knockout of PTHR blocked adipose browning and wasting. Surprisingly, loss of PTHR in fat tissue also preserved muscle mass and improved muscle strength. Similarly, PTHR knockout mice were resistant to cachexia driven by tumors. Our results demonstrate that PTHrP and PTH mediate wasting through a common mechanism involving PTHR, and there exists an unexpected crosstalk mechanism between wasting of fat tissue and skeletal muscle. Targeting the PTH/PTHrP pathway may have therapeutic uses in humans with cachexia.
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•5/6 nephrectomy and LLC tumors trigger cachexia and adipose tissue browning•Elevated circulating PTH and PTHrP stimulate browning through their receptor PTHR•PTHR function in fat is required for adipose tissue browning and wasting•Loss of PTHR in fat tissue also attenuates skeletal muscle atrophy
Kir et al. reveal a role for the PTH/PTHrP pathway in cachexia driven by kidney failure or cancer and show how PTH and PTHrP stimulate adipose tissue browning through their receptor PTHR. Loss of PTHR in adipocytes blocks atrophy of not only fat tissue, but also skeletal muscle in mice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose
To explore whether targeted next generation sequencing (NGS) of liquid biopsy in advanced non-small cell lung cancer (NSCLC) could potentially overcome the innate problems that arise with ...standard tissue biopsy, like intratumoral heterogeneity and the inability to obtain adequate samples for analysis.
Methods
The Scopus, Cochrane Library, and MEDLINE (via PubMed) databases were searched for studies with matched tissue and liquid biopsies from advanced NSCLC patients, analyzed with targeted NGS. The number of mutations detected in tissue biopsy only, liquid biopsy only, or both was assessed and the positive percent agreement (PPA) of the two methods was calculated for every clinically relevant gene.
Results
A total of 644 unique relevant articles were retrieved and data were extracted from 38 studies fulfilling the inclusion criteria. The sample size was composed of 2000 mutations tested in matched tissue and liquid biopsies derived from 1141 patients. No studies analyzed circulating tumor cells. The calculated PPA rates were 53.6% (45/84) for ALK, 53.9% (14/26) for BRAF, 56.5% (13/23) for ERBB2, 67.8% (428/631) for EGFR, 64.2% (122/190) for KRAS, 58.6% (17/29) for MET, 54.6% (12/22) for RET, and 53.3% (8/15) for ROS1. We additionally recorded data for 65 genes that are not recommended by current guidelines for mutational testing. An extra category containing results of unspecified genes was added, with a PPA rate of 55.7% (122/219).
Conclusion
Despite many advantages, liquid biopsy might be unable to fully substitute its tissue counterpart in detecting clinically relevant mutations in advanced NSCLC patients. However, it may serve as a helpful tool when making therapeutic decisions. More studies are needed to evaluate its role in everyday clinical practice.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract Glutathione S-transferases (GSTs) catalyse reactions between glutathione and lipophilic compounds with electrophilic centres, leading to neutralisation of toxic compounds, xenobiotics and ...products of oxidative stress. Controversy exists about whether GST polymorphisms (GSTM1 null/present genotype, GSTT1 null/present genotype, GSTP1 Ile105Val and GSTA1∗A/∗B) represent risk factors for colorectal cancer. This meta-analysis aims to examine the associations between the above-mentioned polymorphisms and colorectal cancer risk. Forty-four studies were eligible for GSTM1 (11,998 colorectal cancer cases, 17,552 controls), 34 studies for GSTT1 (8596 cases, 13,589 controls), 19 studies for GSTP1 (5421 cases, 7671 controls) and four studies for GSTA1 polymorphism (1648 cases, 2039 controls). Pooled odds ratios (ORs) were appropriately derived from fixed-effects or random-effects models. Separate analyses were conducted on Caucasian and Chinese populations. Where appropriate, sensitivity analysis concerning the deviation of genotype frequencies in controls from the Hardy–Weinberg equilibrium was performed. GSTM1 null allele carriers exhibited increased colorectal cancer risk in Caucasian populations (pooled OR = 1.150, 95% confidence interval (CI): 1.060–1.248, random effects); no significant association was detected for Chinese subjects (pooled OR = 1.025, 95% CI: 0.903–1.163, fixed effects). Similarly, GSTT1 null allele carriers exhibited increased colorectal cancer risk in Caucasian populations (pooled OR = 1.312, 95% CI: 1.119–1.538, random effects); the association in Chinese subjects was not significant (pooled OR = 1.068, 95% CI: 0.788–1.449, random effects). Concerning GSTP1 Ile105Val no significant associations were demonstrated in either race. GSTA1∗A/∗B polymorphism was not associated with colorectal cancer risk. GSTM1 and GSTT1 null genotypes confer additional risk for colorectal cancer in Caucasian populations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Metabolic syndrome comprises a cluster of related disorders that includes obesity, glucose intolerance, insulin resistance, dyslipidemia, and fatty liver. Recently, gut-derived chronic endotoxemia ...has been identified as a primary mediator for triggering the low-grade inflammation responsible for the development of metabolic syndrome. In the present study we examined the role of the small intestinal brush-border enzyme, intestinal alkaline phosphatase (IAP), in preventing a high-fat-diet–induced metabolic syndrome in mice. We found that both endogenous and orally supplemented IAP inhibits absorption of endotoxin (lipopolysaccharides) that occurs with dietary fat, and oral IAP supplementation prevents as well as reverses metabolic syndrome. Furthermore, IAP supplementation improves the lipid profile in mice fed a standard, low-fat chow diet. These results point to a potentially unique therapy against metabolic syndrome in at-risk humans.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Abstract Background The incidence of symptomatic biliary disease during pregnancy ranges from 0.05 to 8%. Cholecystectomy is one of the common operations performed during pregnancy and laparoscopic ...approach has gained popularity as an attractive alternative to open surgery. Methods In order to evaluate the safety, feasibility, outcomes and technical aspects of laparoscopic cholecystectomy during pregnancy a comprehensive search of Medline and Cohrane Library databases was conducted. Results Fifty-one studies were deemed eligible, in which laparoscopic cholecystectomy was attempted in 590 patients. The majority of the procedures (70.7%) were performed during the second trimester. Intraoperative and postoperative complications were observed in 3.5% and 4% of the study population. Conversion rate to open surgery was 2.2%. Fetal loss rate and preterm delivery rate were 0.4% and 5.7% respectively. Conclusion Laparoscopic cholecystectomy seems to be a safe alternative to open surgery during pregnancy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background An incision less than 3 cm in length in the neck is the main feature that discriminates the minimally invasive thyroidectomy and parathyroidectomy from traditional procedures. Smaller neck ...scars are assumed to yield better patient satisfaction, although no established data support this. In this analysis, we evaluated the satisfaction of patients who had undergone both procedures, while examining the effects of sociodemographic and surgical characteristics. Methods We analyzed data from 691 patients who underwent a thyroidectomy or parathyroidectomy between January 2000 and March 2010. We assessed the satisfaction of patients who underwent conventional compared to minimally invasive procedures, using the validated Patient Scar Assessment Questionnaire (PSAQ). We included both the appearance and the consciousness subscales. Results Overall, patients were satisfied with their neck scars, as indicated by the low scores in appearance (13.3; range, 9 to 31) and consciousness (8.5; range, 6 to 24) subscales. The degree of satisfaction improved with increased time since surgery ( P < .001). Patient satisfaction was similar regardless of the procedure used, implying that smaller scars do not provide better patient satisfaction. Most patients (81.2%) reported that they would not have preferred a transaxillary procedure over the procedure they received. Conclusion A smaller incision in the neck was not associated with better patient satisfaction. New surgical approaches aimed at maximizing cosmesis while minimizing scar size should be evaluated for cost-effectiveness and clinical outcomes, as well as patient satisfaction, before becoming the standard of care.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Papillary thyroid carcinoma (PTC) is increasing in incidence while mortality is unchanged. Identifying patients with higher risk of recurrence and death is essential. Case series identify the hobnail ...variant of PTC (HVPTC), which is characterized by micropapillary architecture, apocrine features, and loss of cellular polarity. Herein, we describe the clinical course, pathologic features, and mutational profile of patients at our institution with HVPTC.
A query into the surgical pathologic database (2009-2012) was performed, and clinicopathologic data were collected on all patients carrying the diagnosis of HVPTC. BRAF(V600E) testing was performed on paraffin-embedded blocks using SNaPshot mutational analysis.
Twelve patients with HVPTC were identified, with an average age of 54.1±18.8 years. Seven patients (63.6%) were AJCC Stage III or IV at presentation. Tumors were large (3.7±2.0 cm), some were multifocal (33.3%), and frequently with extrathyroidal extension (58.3%), lymphovascular invasion (41.7%), and lymph node metastasis (75%). Forty percent of the patients had concomitant tall cell features (TCF), and two had small foci of undifferentiated (anaplastic) thyroid carcinoma (ATC). Eighty percent of tumors undergoing mutational analysis had the BRAF(V600E) mutation, and the remaining 20% harbored a RET/PTC1 gene rearrangement. No other known thyroid cancer mutations were identified on SNaPshot analysis. At median follow-up of 26 months, four patients had recurrent or persistent disease, one of whom died from the disease one year after surgery.
The hobnail variant of PTC has an aggressive behavior, with a high incidence of infiltrative tumors and metastatic disease. Strikingly, all tumors in our series harbored a PTC-associated genetic abnormality, either a BRAF(V600E) mutation (80%) or a RET/PTC1 rearrangement (20%). This histologic variant warrants further study, and patients with this diagnosis should be observed closely for recurrence.
Objective Most patients presenting with carotid body tumors (CBTs) seek medical attention when tumors have grown to exceed Shamblin I stage, rendering surgery a challenging undertaking and the ...associated morbidity a continuing threat to the clinical outcome. This study examined the availability, applicability, and overall clinical efficacy of adjunct endovascular interventions performed alongside CBT surgery and their potential in clinical decision making and clinical practice. Methods Studies reporting the feasibility, applicability, and clinical efficacy of adjunct endovascular interventions in the surgical management of CBTs were thoroughly searched using the Medline database from January 1967 to August 2013. Results There were no randomized studies on the efficacy of endovascular interventions in CBT surgery. Sixty studies met our inclusion criteria, reporting 465 patients (526 CBTs) with a mean age of 39.8 years. The treated CBTs were a mean size of 4.9 cm. Patients treated with surgery with the use of adjunct endovascular interventions had a mean blood loss of 368.4 mL (range, 25-to 2000 mL). There were 57 cranial nerve injuries, of which 28 (49.1%) were permanent. Cerebrovascular accident occurred in nine patients, of which one died. Hospital stay was a mean of 4.4 days (range, 2-17 days). Conclusions Preoperative selective endovascular embolization in patients with Shamblin II and Shamblin III CBTs may be beneficial when competently performed by interventional physicians proficient in neurovascular microcatheterization/embolization procedures.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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