Feasibility and acceptability of the use of flash glucose monitoring encountered by Indigenous Australians with type 2 diabetes mellitus: initial experiences from a pilot study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is highly prevalent within the Indigenous Australian community. Novel glucose monitoring technology offers an accurate approach to glycaemic management, providing real-time information on glucose levels and trends. The acceptability and feasibilility of this technology in Indigenous Australians with T2DM has not been investigated. OBJECTIVE: This feasibility phenomenological study aims to understand the experiences of Indigenous Australians with T2DM using flash glucose monitoring (FGM). METHODS: Indigenous Australians with T2DM receiving injectable therapy (n = 8) who used FGM (Abbott Freestyle Libre) for 6-months, as part of a clinical trial, participated in semi-structured interviews. Thematic analysis of the interviews was performed using NVivo12 Plus qualitative data analysis software (QSR International). RESULTS: Six major themes emerged: 1) FGM was highly acceptable to the individual; 2) FGM's convenience was its biggest benefit; 3) data from FGM was a tool to modify lifestyle choices; 4) FGM needed to be complemented with health professional support; 5) FGM can be a tool to engage communities in diabetes management; and 6) cost of the device is a barrier to future use. CONCLUSIONS: Indigenous Australians with T2DM had positive experiences with FGM. This study highlights future steps to ensure likelihood of FGM is acceptable and effective within the wider Indigenous Australian community.

Sex differences in the effects of prematurity and/or low birthweight on neurodevelopmental outcomes: systematic review and meta-analyses.

BACKGROUND: Premature birth and/or low birthweight have long-lasting effects on cognition. The purpose of the present systematic review is to examine whether the effects of prematurity and/or low birth weight on neurodevelopmental outcomes differ between males and females. METHODS: Web of Science, Scopus, and Ovid MEDLINE were searched for studies of humans born premature and/or of low birthweight, where neurodevelopmental phenotypes were measured at 1 year of age or older. Studies must have reported outcomes in such a way that it was possible to assess whether effects were greater in one sex than the other. Risk of bias was assessed using both the Newcastle-Ottawa scale and the National Institutes of Health Quality assessment tool for observational cohort and cross-sectional studies. RESULTS: Seventy-five studies were included for descriptive synthesis, although only 24 presented data in a way that could be extracted for meta-analyses. Meta-analyses found that severe and moderate prematurity/low birthweight impaired cognitive function, and severe prematurity/low birthweight also increased internalizing problem scores. Moderate, but not severe, prematurity/low birthweight significantly increased externalizing problem scores. In no case did effects of prematurity/low birthweight differ between males and females. Heterogeneity among studies was generally high and significant, although age at assessment was not a significant moderator of effect. Descriptive synthesis did not identify an obvious excess or deficiency of male-biased or female-biased effects for any trait category. Individual study quality was generally good, and we found no evidence of publication bias. CONCLUSIONS: We found no evidence that the sexes differ in their susceptibility to the effects of severe or moderate prematurity/low birthweight on cognitive function, internalizing traits or externalizing traits. Result heterogeneity tended to be high, but this reflects that one sex is not consistently more affected than the other. Frequently stated generalizations that one sex is more susceptible to prenatal adversity should be re-evaluated.

Early life environmental conditions and adversities affect health into adulthood. For example, it is well-known that premature birth and low birthweight have long-lasting effects on the development and functioning of the brain, affecting various aspects of academic performance, intelligence, and the risk of behavioural problems including depression, anxiety, aggression, impulsivity, and inattention. However, it is not clear if these effects differ between boys and girls. We searched for studies examining the effects of prematurity and/or of low birthweight on cognitive abilities and behavioural problems in children measured at 1 year of age or older, and identified 75 relevant studies. Combining the results of studies found that prematurity/low birthweight decreased measures of intelligence and increased the incidence of behavioural problems, as expected. However, there was no indication that the effects of prematurity/low birthweight consistently differed between males and females, and there were no specific traits where boys appeared to be more or less susceptible to the effects of prematurity/low birthweight than girls. While sex and gender influence health, and in many cases will influence the effects of early life conditions on health, our study shows that prematurity and low birthweight have similar long-term effects on intelligence and behaviour in boys and girls.

The allopurinol metabolite, oxypurinol, drives oligoclonal expansions of drug-reactive T cells in resolved hypersensitivity cases and drug-naïve healthy donors.

Allopurinol (ALP) is a successful drug used in the treatment of gout. However, this drug has been implicated in hypersensitivity reactions that can cause severe to life-threatening reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Individuals who carry the human leukocyte antigen (HLA)-B*58:01 allotype are at higher risk of experiencing a hypersensitivity reaction (odds ratios ranging from 5.62 to 580.3 for mild to severe reactions, respectively). In addition to the parent drug, the metabolite oxypurinol (OXP) is implicated in triggering T cell-mediated immunopathology via a labile interaction with HLA-B*58:01. To date, there has been limited information regarding the T-cell receptor (TCR) repertoire usage of reactive T cells in patients with ALP-induced SJS or TEN and, in particular, there are no reports examining paired αßTCRs. Here, using in vitro drug-treated PBMCs isolated from both resolved ALP-induced SJS/TEN cases and drug-naïve healthy donors, we show that OXP is the driver of CD8+ T cell-mediated responses and that drug-exposed memory T cells can exhibit a proinflammatory immunophenotype similar to T cells described during active disease. Furthermore, this response supported the pharmacological interaction with immune receptors (p-i) concept by showcasing (i) the labile metabolite interaction with peptide/HLA complexes, (ii) immunogenic complex formation at the cell surface, and (iii) lack of requirement for antigen processing to elicit drug-induced T cell responsiveness. Examination of paired OXP-induced αßTCR repertoires highlighted an oligoclonal and private clonotypic profile in both resolved ALP-induced SJS/TEN cases and drug-naïve healthy donors.

The Community Rehabilitation Assessment: patient and clinician-reported outcomes in ambulatory rehabilitation.

Objectives: The interRAI Community Rehabilitation Assessment (CRA) is a comprehensive health assessment designed to collect essential health and function information for rehabilitation care planning, benchmarking, and evaluation of clinic and home-based programs. A portion of the CRA is completed through patient self-report. The objective of this study was to demonstrate how the CRA can be used to describe the baseline clinical characteristics of patients participating in ambulatory rehabilitation programs and measure change across numerous domains of function, health, and wellbeing over time. Design: Cohort study. Setting and participants: In total, 709 patients were assessed with the CRA across 25 ambulatory clinics in Ontario, Canada between January 1st, 2018, to December 31st, 2018. We examined sub-groups of patients receiving rehabilitation following stroke (n = 82) and hip or knee total joint replacement (n = 210). Methods: Frequency responses and means were compared between admission and discharge from the ambulatory rehabilitation programs. Measures of interest included self-reported difficulty in completing instrumental activities of daily living, locomotion, fear of falling, and pain. Results: Significant improvement relative to at admission was detected for the overall cohort and both sub-samples on individual instrumental activities of daily living, stair difficulty, use of mobility aides, distance walked, fear of falling, and pain. Conclusions and implications: The standardized and comparable information collected by the CRA is expected to provide clinicians, clinic, and health system administrators with essential health and function information that can be used for care planning, benchmarking, and evaluation.

Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss.

SMARCA4 (BRG1) and SMARCA2 (BRM) are the two paralogous ATPases of the SWI/SNF chromatin remodeling complexes frequently inactivated in cancers. Cells deficient in either ATPase have been shown to depend on the remaining counterpart for survival. Contrary to this paralog synthetic lethality, concomitant loss of SMARCA4/2 occurs in a subset of cancers associated with very poor outcomes. Here, we uncover that SMARCA4/2-loss represses expression of the glucose transporter GLUT1, causing reduced glucose uptake and glycolysis accompanied with increased dependency on oxidative phosphorylation (OXPHOS); adapting to this, these SMARCA4/2-deficient cells rely on elevated SLC38A2, an amino acid transporter, to increase glutamine import for fueling OXPHOS. Consequently, SMARCA4/2-deficient cells and tumors are highly sensitive to inhibitors targeting OXPHOS or glutamine metabolism. Furthermore, supplementation of alanine, also imported by SLC38A2, restricts glutamine uptake through competition and selectively induces death in SMARCA4/2-deficient cancer cells. At a clinically relevant dose, alanine supplementation synergizes with OXPHOS inhibition or conventional chemotherapy eliciting marked antitumor activity in patient-derived xenografts. Our findings reveal multiple druggable vulnerabilities of SMARCA4/2-loss exploiting a GLUT1/SLC38A2-mediated metabolic shift. Particularly, unlike dietary deprivation approaches, alanine supplementation can be readily applied to current regimens for better treatment of these aggressive cancers.

Targeted inhibition of FGF19/FGFR cascade improves antitumor immunity and response rate in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common liver cancer globally, claiming nearly 1 million lives each year. The overexpression of fibroblast growth factor (FGF) receptors (FGFRs) signaling cascade has been shown to contribute to tumorigenesis, metastasis, and poor prognosis in HCC. Therefore, targeted inhibition of the FGF/FGFR cascade may represent a new treatment strategy for HCC patients. METHODS: HCC patient-derived xenograft (PDX) models were implanted into either severe combined immunodeficient (SCID) or CD34+hu-NSG (humanized) mice and subsequently treated with vehicle, infigratinib (FGFR1-3 inhibitor), FGF401 (FGFR4 inhibitor), or the combination of infigratinib and FGF401. Tumor progressions, overall survival of mice, lung metastasis, and drug resistance were monitored, and samples collected at the end of the treatment cycle were subjected to Western blot analyses and immunohistochemistry. RESULTS: HCC PDX models expressing high levels of FGF19/FGFR4 or FGFR2/3 showed favorable initial treatment response to FGF401 and infigratinib, respectively. However, progressive disease due to acquired resistance was observed. Combination infigratinib/FGF401 augmented the antitumor activity, response rate, and overall survival of mice. This combination significantly increased the infiltration of B cells, macrophages, CD8+ T cells, and CD4+ T cells associated with granzyme-B-mediated apoptosis, delayed onset of resistance, and inhibited metastasis by potently inhibiting several critical signaling pathways involved in proliferation and metastasis. CONCLUSIONS: Our findings suggest that HCC patients with high FGFR2/3 or FGF19/FGFR4 expressing tumors might benefit from a combination infigratinib/FGF401; thus, supporting its evaluation in clinical trials.

Upregulation of the ErbB family by EZH2 in hepatocellular carcinoma confers resistance to FGFR inhibitor.

PURPOSE: Hepatocellular carcinoma (HCC), the most common manifestation of liver cancer, is one of the leading causes of cancer-related mortality worldwide with limited treatment options. Infigratinib, a pan-FGFR inhibitor, has shown a potent antitumour effect in HCC. However, drug resistance is often observed in long-term treatment. In this study, we examined the potential feedback mechanism(s) leading to infigratinib and explored a combination therapy to overcome resistance in HCC. METHODS: Patient-derived xenograft (PDX) tumours were subcutaneously implanted into SCID mice and were subsequently treated with infigratinib. Tumour growth was monitored over time, and tumour samples were subjected to immunohistochemistry and Western blotting. For drug combination studies, mice were treated with infigratinib and/or varlitinib. Gene overexpression and knockdown studies were conducted to investigate the relationship between EZH2 and ErbB activity in infigratinib resistance. RESULTS: Infigratinib-resistant tumours exhibited higher levels of p-ErbB2 and p-ErbB3, concomitant with an increase in EZH2 expression. Gene overexpression and knockdown studies revealed that EZH2 directly regulates the levels of p-ErbB2 and p-ErbB3 in acquired resistance to infigratinib. The addition of varlitinib effectively overcame infigratinib resistance and prolonged the antitumour response, with minimal toxicity. CONCLUSION: The upregulation of the ErbB family by EZH2 appears to contribute to infigratinib resistance. The combination of infigratinib and varlitinib showed a potent antitumour effect and did not result in additional toxicity, warranting further clinical investigation.

Diagnosis and management of pharyngoesophageal stenosis: A comprehensive approach to prophylactic, endoscopic, and reconstructive treatment options.

BACKGROUND: Pharyngoesophageal stenosis (PES) is a serious complication that substantially impacts functional outcomes and quality of life (QOL) for up to a third of head and neck cancer patients who undergo radiotherapy. Dysphagia is often multifactorial in nature and is a devastating complication of treatment that impacts patients' QOL, general health and overall wellbeing. The authors detail the clinical presentation, risk factors, imaging characteristics, preventive measures, and multimodality treatment options for PES. METHODS: The authors present a comprehensive management algorithm for PES, including treatment by dilation, stenting, spray cryotherapy and dilation, and reconstructive treatment options utilizing different pedicled and free flaps. RESULTS: The authors advocate for a thorough assessment of the extent and degree of pharyngoesophageal involvement of PES to determine the optimal management strategy. CONCLUSIONS: The development of post treatment dysphagia requires appropriate imaging and biopsy, when indicated, to rule out the presence of persistent/recurrent cancer. Multidisciplinary management by a team of physicians well-versed in the range of diagnostic and therapeutic interventions available for PES is critical to its successful management.

Primary Hyperparathyroidism During Pregnancy Treated With Parathyroidectomy: A Systematic Review.

OBJECTIVES/HYPOTHESIS: The primary objective of this study was to assess the safety of parathyroidectomy during pregnancy as treatment for hyperparathyroidism (HPTH) in comparison to nonsurgical management plans. Secondary outcomes involved analyzing the safety of surgery in the third trimester and the benefit of operating on asymptomatic pregnant patients. STUDY DESIGN: Systematic review. METHODS: PRISMA-guided systematic review of all cases of primary hyperparathyroidism during pregnancy published in peer-reviewed English journals on PubMed/MEDLINE, EMBASE, and SCOPUS from 1980 to 2020. RESULTS: A total of 75 manuscripts were included in this review describing 382 cases of gestational hyperparathyroidism. The median maternal age was 31 years. Overall, 108 cases (28.3%) underwent parathyroidectomy during pregnancy while 274 cases (71.7%) were treated nonsurgically. The majority of surgeries took place during the second trimester (67.6%). Complications and/or deaths were less likely to occur after surgery in the second trimester (4.48%) as compared to surgery in the third trimester (21.1%). Nine surgically treated cases resulted in infant complications and/or death; however, none of these nine cases had any surgical complications. Despite these complications, the overall infant complication rate for patients who underwent surgical treatment remained lower than that of patients treated with conservative therapy (9.1% vs. 38.9%). CONCLUSIONS: This review suggests that for all pregnant patients with diagnosed HPTH, parathyroidectomy should be considered regardless of symptomatology. Our data suggest that parathyroidectomy is associated with fewer risks than more conservative treatments and results in better fetal outcomes. Surgery during the third trimester is feasible and surgery should be considered in both symptomatic and asymptomatic patients. Laryngoscope, 131:1915-1921, 2021.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging as Imaging Biomarker for Vascular Normalization Effect of Infigratinib in High-FGFR-Expressing Hepatocellular Carcinoma Xenografts.

PURPOSE: Overexpression of fibroblast growth factor receptor (FGFR) contributes to tumorigenesis, metastasis, and poor prognosis of hepatocellular carcinoma (HCC). Infigratinib-a pan-FGFR inhibitor-potently suppresses the growth of high-FGFR-expressing HCCs in part via alteration of the tumor microenvironment and vessel normalization. In this study, we aim to assess the utility of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) as a non-invasive imaging technique to detect microenvironment changes associated with infigratinib and sorafenib treatment in high-FGFR-expressing HCC xenografts. PROCEDURES: Serial DCE-MRIs were performed on 12 nude mice bearing high-FGFR-expressing patient-derived HCC xenografts to quantify tumor microenvironment pre- (day 0) and post-treatment (days 3, 6, 9, and 15) of vehicle, sorafenib, and infigratinib. DCE-MRI data were analyzed using extended generalized kinetic model and two-compartment distributed parameter model. After treatment, immunohistochemistry stains were performed on the harvested tumors to confirm DCE-MRI findings. RESULTS: By treatment day 15, infigratinib induced tumor regression (70 % volume reduction from baseline) while sorafenib induced relative growth arrest (185 % volume increase from baseline versus 694 % volume increase from baseline of control). DCE-MRI analysis revealed different changes in microcirculatory parameters upon exposure to sorafenib versus infigratinib. While sorafenib induced microenvironment changes similar to those of rapidly growing tumors, such as a decrease in blood flow (F), fractional intravascular volume (vp), and permeability surface area product (PS), infigratinib induced the exact opposite changes as early as day 3 after treatment: increase in F, vp, and PS. CONCLUSIONS: Our study demonstrated that DCE-MRI is a reliable non-invasive imaging technique to monitor tumor microcirculatory response to FGFR inhibition and VEGF inhibition in high-FGFR-expressing HCC xenografts. Furthermore, the microcirculatory changes from FGFR inhibition manifested early upon treatment initiation and were reliably detected by DCE-MRI, creating possibilities of combinatorial therapy for synergistic effect.

Medication safety improvements during care transitions in an Australian intensive care unit following implementation of an electronic medication management system.

BACKGROUND: For patients requiring admission to the Intensive Care Unit (ICU), transfers of care (TOC) during admission to and discharge from the ICU are particularly high-risk periods for medication errors. In the Australian setting, commonly general wards and the ICU do not share an integrated Electronic Medical ecord (EMR) and specifically an Electronic Medication Management System (EMMS) as part of the EMR. PURPOSE: To evaluate the effect of a hospital wide integrated EMMS on medication error rates during ICU admission and at TOC. METHOD: A 6-month historical control study was performed before and after implementation of the EMMS in the ICU of a tertiary hospital. Prescribing errors detected by pharmacists in the study period were divided into phase 1, (pre-EMMS, 6months), phase 2 (3 months post implementation after shakedown stage) and phase 3 (next 3 months of post implementation). They were categorized as prescribing error types under system or clinical intervention. Chi square statistics and interrupted time series analysis were used to determine if there was significant change in the proportion of patients who had an error at TOC during each phase. Logistics regression was used to determine the relationship between the dependent (error type) and the independent variable (study phase) for errors that occurred during TOC. RESULTS: Errors occurred during TOC in 42 %, 64 % and 19 % of patients in phase 1, 2 and 3 respectively. There was a significant decline in the proportion of patients with an error between phase 1 and 3 (p < 0.01). During a patient's ICU admission, at least one medication error occurred in 28.3 %, 62.6 % and 25.1 % in phase 1, 2 and 3 respectively. Besides procedural errors, the likelihood of an error occurring was greatest in phase 1, compared to phase 2 and 3 across system-related error categories. CONCLUSION: Medication errors during TOC reduced following implementation of the integrated ICU EMMS. EMMS safety features facilitated reduced system related prescribing errors as well as the severity of errors made.

Bevacizumab Augments the Antitumor Efficacy of Infigratinib in Hepatocellular Carcinoma.

The fibroblast growth factor (FGF) signaling cascade is one of the key signaling pathways in hepatocellular carcinoma (HCC). FGF has been shown to augment vascular endothelial growth factor (VEGF)-mediated HCC development and angiogenesis, as well as to potentially lead to resistance to VEGF/VEGF receptor (VEGFR)-targeted agents. Thus, novel agents targeting FGF/FGF receptor (FGFR) signaling may enhance and/or overcome de novo or acquired resistance to VEGF-targeted agents in HCC. Mice bearing high- and low-FGFR tumors were treated with Infigratinib (i.e., a pan-FGFR kinase inhibitor) and/or Bevacizumab (i.e., an angiogenesis inhibitor). The antitumor activity of both agents was assessed individually or in combination. Tumor vasculature, intratumoral hypoxia, and downstream targets of FGFR signaling pathways were also investigated. Infigratinib, when combined with Bevacizumab, exerted a synergistic inhibitory effect on tumor growth, invasion, and lung metastasis, and it significantly improved the overall survival of mice bearing FGFR-dependent HCC. Infigratinib/Bevacizumab promoted apoptosis, inhibited cell proliferation concomitant with upregulation of p27, and reduction in the expression of FGFR2-4, p-FRS-2, p-ERK1/2, p-p70S6K/4EBP1, Cdc25C, survivin, p-Cdc2, and p-Rb. Combining Infigratinib/Bevacizumab may provide therapeutic benefits for a subpopulation of HCC patients with FGFR-dependent tumors. A high level of FGFR-2/3 may serve as a potential biomarker for patient selection to Infigratinib/Bevacizumab.

HM30181A, a potent P-glycoprotein inhibitor, potentiates the absorption and in vivo antitumor efficacy of paclitaxel in an orthotopic brain tumor model.

Objective: Delivery of chemotherapeutic drugs to the brain has remained a major obstacle in the treatment of glioma, owing to the presence of the blood-brain barrier and the activity of P-gp, which pumps its substrate back into the systemic circulation. The aim of the present study was to develop an intravenous formulation of HM30181A (HM) to inhibit P-gp in the brain to effectively deliver paclitaxel (PTX) for the treatment of malignant glioma. Methods: Two formulations of solubilized HM were designed on the basis of different solid dispersion strategies: i) spray-drying [polyvinlypyrrolidone (PVP)-HM] and ii) solvent evaporation [HP-ß-cyclodextrin (cyclodextrin)-HM]. The P-gp inhibition of these 2 formulations was assessed on the basis of rhodamine 123 uptake in cancer cells. Blood and brain pharmacokinetic parameters were also determined, and the antitumor effect of cyclodextrin-HM with PTX was evaluated in an orthotopic glioma xenograft mouse model. Results: Although both PVP-HM and cyclodextrin-HM formulations showed promising P-gp inhibition activity in vitro, cyclodextrin-HM had a higher maximum tolerated dose in mice than did PVP-HM. Pharmacokinetic study of cyclodextrin-HM revealed a plasma concentration plateau at 20 mg/kg, and the mice began to lose weight at doses above this level. Cyclodextrin-HM (10 mg/kg) administered with PTX at 10 mg/kg showed optimal antitumor activity in a mouse model, according to both tumor volume measurement and survival time (P < 0.05). Conclusions: In a mouse orthotopic brain tumor model, the intravenous co-administration of cyclodextrin-HM with PTX showed potent antitumor effects and therefore may have potential for glioma therapy in humans.

Vinorelbine Augments Radiotherapy in Hepatocellular Carcinoma.

There is a need to improve the effectiveness of radiotherapy (RT) in hepatocellular carcinoma (HCC). Therefore, the purpose of this study was to explore the efficacy and toxicity of the anti-microtubule agent Vinorelbine as a radiosensitizer in HCC. The radio sensitivity of 16 HCC patient-derived xenograft (PDX) models was determined by quantifying the survival fraction following irradiation in vitro, and Vinorelbine radio sensitization was determined by clonogenic assay. Ectopic HCC xenografts were treated with a single dose of 8 Gy irradiation and twice-weekly 3 mg/kg Vinorelbine. Tumor growth and changes in the proteins involved in DNA repair, angiogenesis, tumor cell proliferation, and survival were assessed, and the 3/16 (18.75%), 7/16 (43.75%), and 6/16 (37.5%) HCC lines were classified as sensitive, moderately sensitive, and resistant, respectively. The combination of RT and Vinorelbine significantly inhibited tumor growth, DNA repair proteins, angiogenesis, and cell proliferation, and promoted more apoptosis compared with RT or Vinorelbine treatment alone. Vinorelbine improved HCC tumor response to standard irradiation with no increase in toxicity. HCC is prevalent in less developed parts of the world and is mostly unresectable on presentation. Vinorelbine and conventional radiotherapy are cost-effective, well-established modalities of cancer treatment that are readily available. Therefore, this strategy can potentially address an unmet clinical need, warranting further investigation in early-phase clinical trials.

The role of molecular testing in the diagnosis of medullary thyroid cancer: A case report of oncocytic medullary thyroid carcinoma and review of the literature.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a somewhat rare, particularly aggressive form of thyroid cancer. The authors present what we believe to be the first case of MTC diagnosed solely on the basis of molecular testing, as well as a review of the literature concerning this topic and oncocytic variants of MTC. CASE DESCRIPTION: A 30-year-old female patient with a 1.1 cm thyroid nodule underwent a fine-needle aspiration biopsy showing a Bethesda IV Hurthle cell neoplasm. Molecular testing of the specimen identified a RET M918 T mutation. The patient underwent a total thyroidectomy and bilateral central neck dissection. Initial pathologic analysis yielded a diagnosis of Hurthle cell adenoma. Based on the patient's known RET mutation, immunohistochemistry for calcitonin was performed and yielded a positive result. The final diagnosis was amended to an oncocytic variant of medullary thyroid carcinoma. DISCUSSION: Had this patient undergone fine-needle aspiration (FNA) biopsy without molecular testing or serum calcitonin measurement, the patient's disease would have been diagnosed as a Hurthle cell adenoma. Despite the lack of characteristic features of malignancy and the rarity of oncocytic MTC, the diagnostic pitfall in this oncocytic lesion was avoided due to molecular testing at the time of FNA biopsy. CONCLUSION: This case draws attention to the unique clinical value of molecular testing in the diagnosis of MTC. The authors believe this case supports the consideration for molecular testing to prevent missed diagnoses in cases of rare benign-appearing disease.

Modern microprocessor built from complementary carbon nanotube transistors.

Electronics is approaching a major paradigm shift because silicon transistor scaling no longer yields historical energy-efficiency benefits, spurring research towards beyond-silicon nanotechnologies. In particular, carbon nanotube field-effect transistor (CNFET)-based digital circuits promise substantial energy-efficiency benefits, but the inability to perfectly control intrinsic nanoscale defects and variability in carbon nanotubes has precluded the realization of very-large-scale integrated systems. Here we overcome these challenges to demonstrate a beyond-silicon microprocessor built entirely from CNFETs. This 16-bit microprocessor is based on the RISC-V instruction set, runs standard 32-bit instructions on 16-bit data and addresses, comprises more than 14,000 complementary metal-oxide-semiconductor CNFETs and is designed and fabricated using industry-standard design flows and processes. We propose a manufacturing methodology for carbon nanotubes, a set of combined processing and design techniques for overcoming nanoscale imperfections at macroscopic scales across full wafer substrates. This work experimentally validates a promising path towards practical beyond-silicon electronic systems.

A novel approach to neurologic function sparing surgical management of vagal schwannomas: Continuous intraoperative nerve monitoring of the laryngeal adductor reflex.

BACKGROUND: Vagal schwannomas are rare, benign tumors of the head and neck. Nerve damage during surgical resection is associated with significant morbidity. A new technique of continuous intraoperative nerve monitoring (IONM) that allows for real-time intraoperative feedback has recently been used for thyroid and cervical spine surgeries but has not previously been used in vagal schwannoma surgery. METHODS: Case series of three patients who underwent vagal schwannoma excision utilizing this novel IONM technique. The recurrent laryngeal and vagus nerves were monitored via the laryngeal adductor reflex (LAR) using an electromyographic endotracheal tube. RESULTS: Three patients with suspected vagal schwannomas were treated surgically using the intracapsular enucleation approach with a combination of intermittent IONM and continuous IONM of the LAR. CONCLUSION: This combination of continuous and intermittent IONM can be used to preserve vagal laryngeal innervation and function and may represent the future standard of care for vagal schwannoma excision.

Vagal schwannomas of the head and neck: A comprehensive review and a novel approach to preserving vocal cord innervation and function.

BACKGROUND: Schwannomas, benign tumors arising from neurolemmocytes, are the most common type of peripheral nerve tumors. Extracranial schwannomas are most often found in the parapharyngeal space, commonly involving the vagus nerve to cervical sympathetic trunk. Vagal schwannomas present several unique clinical and therapeutic challenges. METHODS: A comprehensive literature review was conducted on 197 articles reporting 235 cases of cervical vagal schwannomas. Presenting symptoms, treatment approach, and postoperative outcomes were recorded and analyzed. RESULTS: Vagal schwannomas commonly present as asymptomatic neck masses. When they become symptomatic, surgical resection is the standard of care. Gross total resection is associated with higher postoperative morbidity compared to subtotal resection. Initial reports using intraoperative nerve monitoring have shown improved nerve preservation. Recurrence rates are low. CONCLUSION: The combination of intermittent nerve mapping with novel continuous vagal nerve monitoring techniques may reduce postoperative morbidity and could represent the future standard of care for vagal schwannoma treatment.

A rare invasion route for differentiated thyroid carcinoma: The tracheoesophageal common party wall.

Thyroid carcinoma can infiltrate the aerodigestive tract. Invasion via the common party wall of the tracheoesophageal groove (TEG) is rare. A review of patients with thyroid cancer invading the aerodigestive tract was performed. We describe three cases of invasive thyroid cancer presenting 4 to 6 years after the initial thyroidectomy. Original pathology showed positive margins near the recurrent laryngeal nerve and TEG. A partial tracheal resection with a stair-step reconstruction was performed in one case; the other cases required total laryngopharyngectomy. Surgeons should be prepared to perform oncologically complete resections at the primary surgery to avoid potentially significant clinical consequences requiring aggressive surgery. Laryngoscope, 129:E455-E459, 2019.

Enhanced anti-tumor efficacy and mechanisms associated with docetaxel-piperine combination- in vitro and in vivo investigation using a taxane-resistant prostate cancer model.

Docetaxel (DTX) is widely used for metastatic castrated resistant prostate cancer, but its efficacy is often compromised by drug resistance associated with low intracellular concentrations. Piperine (PIP) could enhance the bioavailability of other drugs via the inhibition of CYPs and P-gp activities. Thus, we hypothesize a positive effect with the DTX-PIP combination on the anti-tumor efficacy and intra-tumor DTX concentrations in taxane-resistant prostate cancer. ICR-NOD/SCID mice implanted with taxane-resistant human prostate cancer cells were administrated with saline as well as PIP and DTX separately or in combination. The tumor growth was monitored together with intra-tumor concentrations of DTX. The inhibitory effects on CYPs and P-gp were further assessed in mouse liver microsome and MDCK-MDR1 cells. Compared with DTX alone, DTX-PIP combination significantly inhibited the tumor growth (114% vs. 217%, p = 0.002) with corresponding significantly higher intra-tumor DTX concentrations (5.854 ± 5.510 ng/ml vs. 1.312 ± 0.754 ng/mg, p = 0.037). The percentage of DTX metabolism was significantly decreased from 28.94 ± 1.06% to 18.14 ± 2.22% in mouse liver microsome after administration of PIP for two weeks. DTX accumulation in MDCK-MDR1 cell was significantly enhanced in the presence of PIP. Further microarray analysis revealed that PIP inhibited P-gp as well as CYP1B1 gene expression and induced a significant gene expression change relating to inflammatory response, angiogenesis, cell proliferation, or cell migration. In conclusion, DTX-PIP combination significantly induces activity against taxane-resistant prostate tumor. Such effect appeared to be attributed to the inhibitory effect of PIP on CYPs and P-gp activity as well as gene expression changes relating to tumorigenesis and cellular responses.