Loosening the belt on magnetic sphincter augmentation indications: does body mass index matter?

BACKGROUND: Magnetic sphincter augmentation (MSA) is an effective treatment for gastroesophageal reflux disease (GERD). However, the impact of obesity on MSA outcomes is unknown. The objective of this study was to evaluate the effectiveness of MSA in patients with GERD and obesity. METHODS: A retrospective cohort study was performed of consecutive patients who underwent laparoscopic MSA at three high-volume centers from 2016 to 2019. Patients were grouped into four cohorts according to the World Health Organization body mass index (BMI) classification: BMI < 25 (normal weight), BMI 25-29.9 (overweight), BMI 30-34.9 (obese class I), and BMI > 35 (obese class II-III). Preoperative, operative, and postoperative data were compared between groups. RESULTS: A total of 621 patients underwent laparoscopic MSA during the study period. Follow-up with endoscopy or video esophagram was available for 361 patients (58%) with a median follow-up of 15.4 months. Baseline characteristics of the groups were similar except the BMI > 35 group had more females and a higher preoperative median DeMeester score. There were no significant differences in outcomes between normal weight, overweight, and obese patient groups undergoing MSA. All groups experienced significant reductions in acid suppressive medication use, low GERD-HRQL scores, low DeMeester scores, few intraoperative and postoperative complications, and low rates of hiatal hernia recurrence after MSA. CONCLUSIONS: Magnetic sphincter augmentation is safe and effective in improving GERD symptoms, reducing esophageal acid exposure, and preventing hiatal hernia recurrence, irrespective of patient BMI. MSA should be considered an acceptable treatment option for obese patients with GERD.

MK-2206 causes growth suppression and reduces neuroendocrine tumor marker production in medullary thyroid cancer through Akt inhibition.

BACKGROUND: Development of targeted therapies for medullary thyroid cancer (MTC) has focused on inhibition of the rearranged during transfection (RET) proto-oncogene. Akt has been demonstrated to be a downstream target of RET via the key mediator phosphoinositide-3-kinase. MK-2206 is an orally administered allosteric Akt inhibitor that has exhibited minimal toxicity in phase I trials. We explored the antitumor effects of this compound in MTC. METHODS: Human MTC-TT cells were treated with MK-2206 (0-20 µM) for 8 days. Assays for cell viability were performed at multiple time points with MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide). The mechanism of action, mechanism of growth inhibition, and production of neuroendocrine tumor markers were assessed with Western blot analysis. RESULTS: MK-2206 suppressed MTC cell proliferation in a dose-dependent manner (p ≤ 0.001). Levels of Akt phosphorylated at serine 473 declined with increasing doses of MK-2206, indicating successful Akt inhibition. The apoptotic proteins cleaved poly (ADP-ribose) polymerase and cleaved caspase-3 increased in a dose-dependent manner with MK-2206, while the apoptosis inhibitor survivin was markedly reduced. Importantly, the antitumor effects of MK-2206 were independent of RET inhibition, as the levels of RET protein were not blocked. CONCLUSIONS: MK-2206 significantly suppresses MTC proliferation without RET inhibition. Given its high oral bioavailability and low toxicity profile, phase II studies with this drug alone or in combination with RET inhibitors are warranted.

Multigland disease and slower decline in intraoperative PTH characterize mild primary hyperparathyroidism.

BACKGROUND: Many patients with primary hyperparathyroidism (PHPT) present with less severe biochemical parameters. The purpose of this study was to compare the presentation, operative findings, and outcomes of these patients with "mild" PHPT to patients with "overt" disease. METHODS: A retrospective review of a prospectively collected parathyroid database was performed to identify cases of PHPT undergoing an initial neck operation. Patients were classified as mild when either the preoperative calcium or PTH was within the normal limits. Comparisons were made with the Student's t test, Chi-squared test, or Wilcoxon rank-sum test where appropriate. Kaplan-Meier estimates were plotted for disease-free survival and compared by the log-rank test. RESULTS: Of the 1,429 patients who met inclusion criteria, 1,049 were classified as overt and 388 (27.1 %) were mild. Within the mild group, 122 (31.4 %) presented with normocalcemic PHPT and 266 (68.6 %) had a normal PTH. The two groups had similar demographics and renal function. Interestingly, the mild group had more than double the rate of kidney stones (3.1 vs. 1.3 %, p = 0.02). The mild group was less likely to localize on sestamibi scan (62.4 vs. 78.7 %, p < 0.01). Intraoperatively, more mild patients exhibited multigland disease (34.3 vs. 14.1 %, p < 0.01). When examining intraoperative PTH (IoPTH) kinetics where single adenomas were excised, the IoPTH fell at a rate of 6.9 pg/min in mild patients compared with 11.5 pg/min in the overt group (p < 0.01). Accordingly, 62.2 % of patients in the overt group and 53.3 % in the mild group were cured at 5 min postexcision (p < 0.01). There was no difference in the rates of persistence or recurrence between the groups, and disease-free survival estimates were identical (p = 0.27). CONCLUSIONS: Patients with mild PHPT were more likely to have multigland disease and a slower decline in IoPTH, but these patients can be successfully treated with surgery.

Radioguided parathyroidectomy effective in pediatric patients.

BACKGROUND: Radioguided parathyroidectomy (RGP) has been shown to be effective in adult patients with hyperparathyroidism (HPT), but the utility of RGP in pediatric patients has not been systematically examined. It is not known if adult criteria for radioactive counts can accurately detect hyperfunctioning parathyroid glands in pediatric patients. The purpose of our study was to determine the utility of RGP in children with primary HPT. MATERIALS AND METHODS: A retrospective review of our prospectively maintained single-institution database for patients who underwent a RGP for primary HPT identified 1694 adult and 19 pediatric patients aged 19 y or younger. From the adult population, we selected a control group matched three to one for gland weight and gender and compared pre- and postoperative laboratory values, surgical findings, pathology, and radioguidance values between the control and the pediatric groups. RESULTS: Excised glands from pediatric patients were smaller than those in the total adult population (437 ± 60 mg versus 718 ± 31 mg, P = 0.0004). When controlled for gland weight, ex vivo counts as a percentage of background were lower in the pediatric group (51% ± 5% versus 91% ± 11%, P = 0.04). However, ex vivo radionuclide counts >20% of the background were found in 100% of pediatric patients and 95% of the adult-matched control group. CONCLUSIONS: All pediatric patients met the adult detection criteria for parathyroid tissue removal when a RGP was performed, and 100% cure was achieved. We conclude that RGP is a useful treatment option for pediatric patients with primary HPT.

Leflunomide suppresses growth in human medullary thyroid cancer cells.

BACKGROUND: Medullary thyroid cancer (MTC) is a neuroendocrine tumor that arises from the calcitonin-secreting parafollicular cells of the thyroid gland. Leflunomide (LFN) is a disease-modifying antirheumatic drug approved for the treatment of rheumatoid arthritis, and its active metabolite teriflunomide has been identified as a potential anticancer drug. In this study we investigated the ability of LFN to similarly act as an anticancer drug by examining the effects of LFN treatment on MTC cells. METHODS: Human MTC-TT cells were treated with LFN (25-150 µmol/L) and Western blotting was performed to measure levels of neuroendocrine markers. MTT assays were used to assess the effect of LFN treatment on cellular proliferation. RESULTS: LFN treatment downregulated neuroendocrine markers ASCL1 and chromogranin A. Importantly, LFN significantly inhibited the growth of MTC cells in a dose-dependent manner. CONCLUSIONS: Treatment with LFN decreased neuroendocrine tumor marker expression and reduced the cell proliferation in MTC cells. As the safety of LFN in human beings is well established, a clinical trial using this drug to treat patients with advanced MTC may be warranted.

Resistance Training in Patients After Metabolic and Bariatric Surgery: Protocol for a Systematic Review.

BACKGROUND: Resistance training has been consistently shown to have multiple health benefits, especially for patients who have undergone bariatric surgery. Patients who have undergone bariatric surgery are recommended to participate in resistance exercise; however, protocols and guidelines for resistance training remain poorly implemented. OBJECTIVE: This is a protocol for a systematic review and possibly a meta-analysis that will synthesize evidence of the effects of resistance exercise on changes in body composition, muscular strength, overall weight loss or maintenance of weight loss, and quality of life in patients after metabolic and bariatric surgery (MBS). The findings of this study may provide practice recommendations for resistance training among patients who have undergone MBS. METHODS: We registered this systematic review on PROSPERO (CRD42023464928) on September 18, 2023. A systematic search of electronic databases (Embase, PubMed, Scopus, Web of Science, and CINAHL) was conducted on studies published from January 1, 1991, to May 15, 2023, to identify English-language human studies on adult patients who have undergone MBS that include a resistance training intervention and describe outcome measurements of body composition or strength. Screening will be performed using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, and relevant data elements will be extracted. RESULTS: Searches and screenings commenced in May 2023. Data extraction and analyses will be completed by the end of December 2023, after which findings will be synthesized and reported by the end of March 2024. CONCLUSIONS: This systematic review will summarize the evidence regarding resistance training in patients after MBS. The findings from this systematic review and possible meta-analysis may provide practice recommendations for resistance training protocols in this patient population and identify characteristics of protocols with the best adherence and outcomes. With these results, we anticipate that we will gain a deeper understanding of the role of resistance training after MBS. TRIAL REGISTRATION: PROSPERO CRD42023464928; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=464928. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/49513.

Evolution of pediatric thyroid surgery at a tertiary medical center.

BACKGROUND: Thyroidectomy in the pediatric population is often avoided due to perceived risks in children. With growing subspecialization and establishment of high volume endocrine surgery centers, the indications for thyroid surgery and extent of resection continue to change. We examined the evolution of pediatric thyroid surgery at a high volume tertiary medical center. METHODS: From our prospectively collected database, we reviewed medical records of individuals younger than 19 y who underwent thyroidectomy at our institution from 1994 to 2009. Patients were divided into two groups: (1) before establishment of our endocrine surgery center (1994-2001) and (2) since establishment of the center (2002-2009). RESULTS: We identified 78 operations performed on 74 patients with a median age of 15 (range 3-18) y. We found that the number of patients doubled in the later time period, with 26 operations in group 1 and 52 in group 2. The age of patients and percentage of females were similar between groups. After establishment of the endocrine surgery center, there was a significant increase in total thyroidectomies for all indications, including significantly more for benign disease. Overall, 9% of the patient population experienced transient complications, with no permanent complications or long-term sequelae. CONCLUSIONS: Pediatric thyroid surgery is extremely safe, especially when performed at a high volume endocrine surgery center. We more often select surgical treatment for benign disease and choose total thyroidectomy over limited resection. This may reflect increasing confidence in the safety and efficacy of surgery and reliability of thyroid hormone replacement.

A sequence-oriented comparison of gene expression measurements across different hybridization-based technologies.

Over the last decade, gene expression microarrays have had a profound impact on biomedical research. The diversity of platforms and analytical methods available to researchers have made the comparison of data from multiple platforms challenging. In this study, we describe a framework for comparisons across platforms and laboratories. We have attempted to include nearly all the available commercial and 'in-house' platforms. Using probe sequences matched at the exon level improved consistency of measurements across the different microarray platforms compared to annotation-based matches. Generally, consistency was good for highly expressed genes, and variable for genes with lower expression values as confirmed by quantitative real-time (QRT)-PCR. Concordance of measurements was higher between laboratories on the same platform than across platforms. We demonstrate that, after stringent preprocessing, commercial arrays were more consistent than in-house arrays, and by most measures, one-dye platforms were more consistent than two-dye platforms.

Connexin 43 suppresses human glioblastoma cell growth by down-regulation of monocyte chemotactic protein 1, as discovered using protein array technology.

Previously, we demonstrated that connexin 43 (cx43) suppressed the growth of human glioblastoma cells. To investigate the molecular mechanisms involved in tumor suppression by cx43, we developed a human cytokine array system, which simultaneously detects the expression of 43 cytokines. By using this new technology, we analyzed the cx43-regulated genes in cx43-transfected cells. The cytokine arrays showed that expression of monocyte chemotactic protein-1 (MCP-1) was profoundly reduced in cx43-transfected cells. RT-PCR, immuno-Western blot, and cDNA microarrays further confirmed this observation. Addition of conditioned medium from control-transfected cells and recombinant MCP-1 to cx43-transfected cells significantly enhanced cx43-transfected cell proliferation and colony formation in soft agar. In contrast, addition of neutralization antibody against MCP-1 significantly inhibited cell proliferation in control-transfected cells. Our results suggested that MCP-1 is involved in the suppression of human glioblastoma cell growth by cx43.

Parathyroid conditions in childhood.

This review of parathyroid surgery in children will briefly discuss parathyroid gland embryology and anatomy before focusing on the pathophysiology, clinical presentation, and treatment of hyperparathyroidism in children. Hyperparathyroidism (HPT) is the overproduction of PTH and it is rare in children, with an incidence of 2-5 per 100,000. This rarity means that the principles of caring for children with parathyroid disease are largely extrapolated from the richer adult experience; however, the unique pediatric aspects of parathyroid problems and their surgical treatment, including presentation, imaging, operative approach, and complications, will be considered.

Early-phase technetium-99m sestamibi scintigraphy can improve preoperative localization in primary hyperparathyroidism.

BACKGROUND: In hyperparathyroidism, dual-phase technetium-99m sestamibi scintigraphy is important for parathyroid adenoma localization. We hypothesized that reviewing early-phase scans can increase localization in patients with primary hyperparathyroidism (PHPT). METHODS: We reviewed our prospectively maintained database for patients with sestamibi scans before parathyroidectomy for PHPT from 2001 to 2011. Early-phase scans were read and compared with the location of the gland(s) removed at operation. RESULTS: Of 902 patients identified, radiologists read 693 scans as positive. Of 209 negative scans, 141 (67%) were positive in the early phase; 135 (96%) correctly identified the side of the adenoma. Using radiologist reads, 35% of patients with negative scans and 41% of patients with falsely localized glands required bilateral exploration compared with 5% of patients with correctly localized glands. CONCLUSIONS: A review of early scans in patients with negative imaging increases accurate adenoma localization and allows for minimally invasive operations in more patients.

Octreotide-functionalized and resveratrol-loaded unimolecular micelles for targeted neuroendocrine cancer therapy.

Medullary thyroid cancer (MTC) is a neuroendocrine tumor (NET) that is often resistant to standard therapies. Resveratrol suppresses MTC growth in vitro, but it has low bioavailability in vivo due to its poor water solubility and rapid metabolic breakdown, as well as lack of tumor-targeting ability. A novel unimolecular micelle based on a hyperbranched amphiphilic block copolymer was designed, synthesized, and characterized for NET-targeted delivery. The hyperbranched amphiphilic block copolymer consisted of a dendritic Boltorn® H40 core, a hydrophobic poly(l-lactide) (PLA) inner shell, and a hydrophilic poly(ethylene glycol) (PEG) outer shell. Octreotide (OCT), a peptide that shows strong binding affinity to somatostatin receptors, which are overexpressed on NET cells, was used as the targeting ligand. Resveratrol was physically encapsulated by the micelle with a drug loading content of 12.1%. The unimolecular micelles exhibited a uniform size distribution and spherical morphology, which were determined by both transmission electron microscopy (TEM) and dynamic light scattering (DLS). Cellular uptake, cellular proliferation, and Western blot analyses demonstrated that the resveratrol-loaded OCT-targeted micelles suppressed growth more effectively than non-targeted micelles. Moreover, resveratrol-loaded NET-targeted micelles affected MTC cells similarly to free resveratrol in vitro, with equal growth suppression and reduction in NET marker production. These results suggest that the H40-based unimolecular micelle may offer a promising approach for targeted NET therapy.

Array-based multiplexed screening and quantitation of human cytokines and chemokines.

HydroGel-coated slide is a porous substrate based on a polymer matrix that provides a three-dimensional hydrophilic environment similar to free solution suitable for biomolecular interactions. This substrate has been used to develop fluorescence-based multiplexed cytokine immunoassays. Forty-three monoclonal antibodies (mAb) of cytokines and chemokines were printed at a volume of 350 pL per spot using a Packard BioChip Arrayer. For each probe, four replicates were printed at a pitch of 500 microm in the layout of a 13 x 16 pattern on a 12 x 12 mm2 HydroGel pad. Cytokines and chemokines that are captured by the arrayed mAbs are detected by using another biotinylated mAb, following by the addition of a Texas Red-conjugated streptavidin. The fluorescent images of arrays were recorded using a Packard ScanArray 5000 confocal slide scanner and quantitated using Packard QuantArray software. Experiments demonstrated that 43 cytokines and chemokines could be simultaneously screened and quantitated in conditioned culture media, cell lysates, and human plasma. Using this chip, we have examined cytokine expression in breast cancer cells and identified the chemokines associated with human cervical cancers.

Antibody microarray profiling of human prostate cancer sera: antibody screening and identification of potential biomarkers.

We developed a practical strategy for serum protein profiling using antibody microarrays and applied the method to the identification of potential biomarkers in prostate cancer serum. Protein abundances from 33 prostate cancer and 20 control serum samples were compared to abundances from a common reference pool using a two-color fluorescence assay. Robotically spotted microarrays containing 184 unique antibodies were prepared on two different substrates: polyacrylamide based hydrogels on glass and poly-1-lysine coated glass with a photoreactive cross-linking layer. The hydrogel substrate yielded an average six-fold higher signal-to-noise ratio than the other substrate, and detection of protein binding was possible from a greater number of antibodies using the hydrogels. A statistical filter based on the correlation of data from "reverse-labeled" experiment sets accurately predicted the agreement between the microarray measurements and enzyme-linked immunosorbent assay measurements, showing that this parameter can serve to screen for antibodies that are functional on microarrays. Having defined a set of reliable microarray measurements, we identified five proteins (von Willebrand Factor, immunoglobulinM, Alpha1-antichymotrypsin, Villin and immunoglobulinG) that had significantly different levels between the prostate cancer samples and the controls. These developments enable the immediate use of high-density antibody and protein microarrays in biomarker discovery studies.