Mechanisms of sensitivity and resistance to CDK4/CDK6 inhibitors in hormone receptor-positive breast cancer treatment.

Cell cycle dysregulation is a hallmark of cancer that promotes eccessive cell division. Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) are key molecules in the G1-to-S phase cell cycle transition and are crucial for the onset, survival, and progression of breast cancer (BC). Small-molecule CDK4/CDK6 inhibitors (CDK4/6i) block phosphorylation of tumor suppressor Rb and thus restrain susceptible BC cells in G1 phase. Three CDK4/6i are approved for the first-line treatment of patients with advanced/metastatic hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) BC in combination with endocrine therapy (ET). Though this has improved the clinical outcomes for survival of BC patients, there is no established standard next-line treatment to tackle drug resistance. Recent studies suggest that CDK4/6i can modulate other distinct effects in both BC and breast stromal compartments, which may provide new insights into aspects of their clinical activity. This review describes the biochemistry of the CDK4/6-Rb-E2F pathway in HR+ BC, then discusses how CDK4/6i can trigger other effects in BC/breast stromal compartments, and finally outlines the mechanisms of CDK4/6i resistance that have emerged in recent preclinical studies and clinical cohorts, emphasizing the impact of these findings on novel therapeutic opportunities in BC.

PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.

The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.

Pathophysiological Mechanisms of Gastro-esophageal Reflux After Sleeve Gastrectomy.

OBJECTIVE: To evaluate the mechanisms associated with reflux events after sleeve gastrectomy (SG). SUMMARY BACKGROUND DATA: Gastro-esophageal reflux (GERD) post-SG is a critical issue due to symptom severity, impact on quality of life, requirement for reoperation, and potential for Barrett esophagus. The pathophysiology is incompletely delineated. METHODS: Post-SG patients, stratified into asymptomatic and symptomatic, underwent protocolized nuclear scintigraphy (n = 83), 24-hour esophageal pH monitoring, and stationary manometry (n = 143) to characterize reflux patterns. Ten patients underwent fasting and postprandial concurrent manometry and pH for detailed analysis of reflux events. RESULTS: Baseline demographics between cohorts were similar: Age 47.2 ± 11.6 versus 44.1 ± 11.3 years ( P = 0.121); females 73.2% versus 90.8% ( P = 0.005); excess weight loss 53.8 ± 28.1% versus 57.4 ± 25.5% ( P = 0.422), follow-up duration 12.3 versus 7.4 months ( P = 0.503). Nuclear scintigraphy delineated bolus-induced deglutitive reflux events (29.6% vs 62.5%, P = 0.005) and postprandial reflux events [4 (IQR2) versus 4 (IQR 3) events, P = 0.356]. Total acid exposure was significantly elevated in the symptomatic population (7.7% vs 3.6%, P < 0.001), especially fasting acid exposure (6.0% vs 1.3%, P < 0.001). pH/manometry analysis demonstrated acute elevations of the gastro-esophageal pressure gradient (>10 mm Hg) underpinned most reflux events. Swallow-induced intragastric hyper-pressur-ization was associated with individual reflux events in most patients (90% in fasting state and 40% postprandial). CONCLUSIONS: We found reflux to be strongly associated with SG and identified 3 unique categories. Bolus-induced deglutitive and postprandial reflux occurred in most patients. Elevated fasting esophageal acid exposure mediated symptoms. Frequent, significant elevation in the gastro-esophageal pressure gradient was the mechanism of reflux and seemed to relate to the noncompliant proximal stomach.

Yield of baseline imaging for distant metastases in high-risk primary melanoma.

BACKGROUND: The yield of baseline imaging in patients presenting with higher risk primary tumours, at least American Joint Committee on Cancer 8th edition stage IIC or III melanoma, is unclear. METHODS: This retrospective study included patients referred to the Victorian Melanoma Service from January 2017 to April 2020, diagnosed with at least stage IIC or stage III melanoma. Patients with a T4b tumour and no sentinel lymph node biopsy were included as 'T4bNX'. RESULTS: One hundred and sixty-four patients (median age 65 years) with baseline imaging (T4bNX: 19, IIC: 30, IIIA: 21, IIIB: 43, IIIC: 50, IIID: 1) were included. The majority were male (73%), and those with T4bNX melanoma tended to be older (median age 79 years). Distant metastases were detected in 21% (4/19) of T4bNX, 3% (1/30) of stage IIC, 0% (0/21) of stage IIIA, and 6% (6/94) of stages IIIB-D melanoma patients. All stage III patients with distant metastases had palpable lymphadenopathy a presentation. Two patients had brain metastases, both of whom had T4bNX melanoma and synchronous extra-cranial metastases. CONCLUSIONS: Compared to stage IIC, baseline imaging detects higher rates of extra-cranial distant disease in stages IIIB-D and T4bNX melanoma. Intracranial imaging has greater yield in patients with distant extra-cranial disease.

HIV-1-infection in a man who has sex with men despite self-reported excellent adherence to pre-exposure prophylaxis, the Netherlands, August 2021: be alert to emtricitabine/tenofovir-resistant strain transmission.

In August 2021, a man who has sex with men was diagnosed with HIV-1 infection despite using event-driven pre-exposure prophylaxis for over 2 years with self-reported excellent adherence. Sequencing identified resistance-associated mutations (RAM) M184V and K65R, conferring resistance to emtricitabine and tenofovir, and RAM V108I and E138A. Background RAM prevalence was two of 164 (1.2%) new HIV diagnoses in Amsterdam (2017-19). We reiterate the need for frequent HIV testing among PrEP users and additional testing in case of symptoms.

Demystifying the Functional Role of Nuclear Receptors in Esophageal Cancer.

Esophageal cancer (EC), an aggressive and poorly understood disease, is one of the top causes of cancer-related fatalities. GLOBOCAN 2020 reports that there are 544,076 deaths and 604,100 new cases expected worldwide. Even though there are various advancements in treatment procedures, this cancer has been reported as one of the most difficult cancers to cure, and to increase patient survival; treatment targets still need to be established. Nuclear receptors (NRs) are a type of transcription factor, which has a key role in several biological processes such as reproduction, development, cellular differentiation, stress response, immunity, metabolism, lipids, and drugs, and are essential regulators of several diseases, including cancer. Numerous studies have demonstrated the importance of NRs in tumor immunology and proved the well-known roles of multiple NRs in modulating proliferation, differentiation, and apoptosis. There are surplus of studies conducted on NRs and their implications in EC, but only a few studies have demonstrated the diagnostic and prognostic potential of NRs. Therefore, there is still a paucity of the role of NRs and different ways to target them in EC cells to stop them from spreading malignancy. This review emphasizes the significance of NRs in EC by discussing their diverse agonists as well as antagonists and their response to tumor progression. Additionally, we emphasize NRs' potential to serve as a novel therapeutic target and their capacity to treat and prevent EC.

Systemic doxycycline as an adjunct to scaling and root planing in diabetic patients with periodontitis: a systematic review and meta-analysis.

BACKGROUND: To compare the effectiveness of systemic doxycycline as an adjunct to scaling and root planing (SRP) with SRP alone in improving periodontal clinical attachment level and glycemic control in diabetic patients with periodontitis. METHODS: Two independent reviewers (KY and SJ) screened two electronic databases, PubMed and Scopus, for randomized clinical trials on the use of systemic doxycycline as an adjunct to scaling and root planing in improving periodontal status and glycemic control in diabetic patients with periodontitis using predetermined selection criteria within a 3-month period. The reviewers independently did data screening, data selection, data extraction and risk of bias. Quality of studies involved was analysed using the revised Cochrane Risk of Bias 2.0. Weighted standard mean differences (SMD) and 95% confidence intervals were calculated using a random effects meta-analysis model. Publication bias was evaluated using funnel plot. Quality of evidence was evaluated by Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Electronic searches provided 1358 records and six studies were selected. The meta-analyses indicated that there was no statistically significant difference in the improvement of periodontal status with the use of systemic doxycycline as an adjunct for scaling and root planing (SRP). SMD of clinical attachment levels (- 0.22 [- 0.52, 0.08]) and HbA1c levels (- 0.13 [- 0.41, 0.15]) were calculated. Overall risk of bias is high in 2 out of 6 studies involved. CONCLUSION: Systemic doxycycline when used in addition to scaling and root planing yields no significant improvement of clinical attachment levels for periodontal status and reduction of HbA1c levels in treatment of diabetic patients with periodontitis when comparing the test group to the control group.

Correction to: Pioglitazone reduces cold-induced brown fat glucose uptake despite induction of browning in cultured human adipocytes: a randomised, controlled trial in humans.

The baseline insulin data given in Table 1 for the placebo group were incorrectly reported as 51 ± 10 pmol/l instead of 48 ± 10 pmol/l. This mistake also impacts on data reported in Table 4.

Pioglitazone reduces cold-induced brown fat glucose uptake despite induction of browning in cultured human adipocytes: a randomised, controlled trial in humans.

AIMS/HYPOTHESIS: Increasing brown adipose tissue (BAT) activity is a possible therapeutic strategy to increase energy expenditure and glucose and lipid clearance to ameliorate obesity and associated comorbidities. The thiazolidinedione (TZD) class of glucose-lowering drugs increase BAT browning in preclinical experimental models but whether these actions extend to humans in vivo is unknown. The aim of this study was to determine the effect of pioglitazone treatment on adipocyte browning and adaptive thermogenesis in humans. METHODS: We first examined whether pioglitazone treatment of cultured human primary subacromioclavicular-derived adipocytes induced browning. Then, in a blinded, placebo-controlled, parallel trial, conducted within the Baker Institute clinical research laboratories, 14 lean male participants who were free of cardiometabolic disease were randomised to receive either placebo (lactose; n = 7, age 22 ± 1 years) or pioglitazone (45 mg/day, n = 7, age 21 ± 1 years) for 28 days. Participants were allocated to treatments by Alfred Hospital staff independent from the study via electronic generation of a random number sequence. Researchers conducting trials and analysing data were blind to treatment allocation. The change in cold-stimulated BAT activity, assessed before and after the intervention by [18F]fluorodeoxyglucose uptake via positron emission tomography/computed tomography in upper thoracic and cervical adipose tissue, was the primary outcome measure. Energy expenditure, cardiovascular responses, core temperature, blood metabolites and hormones were measured in response to acute cold exposure along with body composition before and after the intervention. RESULTS: Pioglitazone significantly increased in vitro browning and adipogenesis of adipocytes. In the clinical trial, cold-induced BAT maximum standardised uptake value was significantly reduced after pioglitazone compared with placebo (-57 ± 6% vs -12 ± 18%, respectively; p < 0.05). BAT total glucose uptake followed a similar but non-significant trend (-50 ± 10% vs -6 ± 24%, respectively; p = 0.097). Pioglitazone increased total and lean body mass compared with placebo (p < 0.05). No other changes between groups were detected. CONCLUSIONS/INTERPRETATION: The disparity in the actions of pioglitazone on BAT between preclinical experimental models and our in vivo human trial highlight the imperative to conduct human proof-of-concept studies as early as possible in BAT research programmes aimed at therapeutic development. Our clinical trial findings suggest that reduced BAT activity may contribute to weight gain associated with pioglitazone and other TZDs. TRIAL REGISTRATION: ClinicalTrials.gov NCT02236962 FUNDING: This work was supported by the Diabetes Australia Research Program and OIS scheme from the Victorian State Government.

Morbidity and mortality after minor bile duct injury following laparoscopic cholecystectomy.

BACKGROUND AND STUDY AIMS: Cystic duct and Luschka duct leakage after laparoscopic cholecystectomy are often classified as minor injuries because the outcome of endoscopic stenting and percutaneous drainage is generally reported to be good. However, the potential associated early mortality and risk factors for mortality are scarcely reported. The aim of this study was to describe the outcome, mortality, and risk factors for poor survival of patients with type A bile duct injury (BDI) referred to a tertiary center. PATIENTS AND METHODS: Between January 1990 and January 2012, 800 patients were referred for BDI treatment and included in a prospective database. RESULTS: Type A BDI, according to the Amsterdam and Strasberg classifications, was diagnosed in 216 patients. Treatment after referral was mainly endoscopic (n = 192 [88.9 %]) and radiologic (n = 14 [6.5 %]). Complications related to endoscopic retrograde cholangiopancreatography (ERCP) occurred in 14 patients (6.5 %). Other complications were sepsis (n = 34 [15.7 %]), cardiopulmonary (n = 22 [10.2 %]), and abscess formation (n = 15 [6.9 %]). BDI-related mortality was 4.2 % (9/216). Multivariate analysis showed age (hazard ratio [HR] = 1.04, 95 % confidence interval [CI] 1.00 - 1.07) and American Society of Anesthesiologists class 3 or 4 (HR = 5.64, 95 %CI 2.31 - 13.77) to be independent factors significantly associated with mortality. CONCLUSIONS: Type A "minor" BDI after laparoscopic cholecystectomy is associated with considerable short-term mortality related to the patient's condition at referral. Older patients and patients with ASA 3 or 4 have a significantly higher risk of mortality.

The prevalence of thyroglossal tract thyroid tissue on SPECT/CT following (131) I ablation therapy after total thyroidectomy for thyroid cancer.

OBJECTIVE: To determine the prevalence of thyroglossal tract thyroid tissue on SPECT/CT and to assess the contribution of this tissue to total neck radioactive iodine (RAI) activity in patients given (131) I ablation therapy after total thyroidectomy for thyroid cancer. PATIENTS AND METHODS: Eighty-three consecutive patients with thyroid cancer treated with total thyroidectomy underwent whole-body planar and SPECT/CT imaging of the neck following initial RAI ablation. On SPECT/CT, thyroglossal tract thyroid tissue was defined as RAI in the anterior neck, superior to the thyroid bed in close proximity to the midline without evidence of localization to lymph nodes. Quantification was performed using region of interest analysis on planar imaging following localization on SPECT/CT. SPECT/CT, and planar images were classified by two reviewers as positive, negative or equivocal with interobserver agreement quantified using a Kappa score. Disagreement was resolved using a third reviewer. RESULTS: Thyroglossal tract thyroid tissue was present in 39/83 (47%; 95%CI: 36-58%) patients on SPECT/CT. In these 39 patients, this tissue contributed to a significant amount of total neck activity (median = 50%; IQR 19-74%). Interobserver agreement for the presence of thyroglossal tract thyroid tissue was substantial on SPECT/CT (Kappa = 0.73) and fair on planar imaging (Kappa = 0.31). CONCLUSION: Thyroglossal tract thyroid tissue was present in one half of our study population and contributed to a significant amount of total neck RAI activity. Given the high prevalence of this tissue, our results suggest that total neck RAI activity on planar imaging may not be suitable to assess the completeness of thyroid bed surgery.

Imaging in osteoarticular infection in adults.

BACKGROUND: Osteoarticular infections are uncommon and required a multimodal approach for diagnosis. Imaging forms an important component of this multimodal approach. OBJECTIVES: In this narrative review, we describe the different imaging modalities, features of osteoarticular infections present on these imaging approaches and recommendations for which imaging modality should be considered in different types of osteoarticular infections. SOURCES: This narrative review was based on literature review from PubMed and was limited to bacterial infections in adult patients. CONTENT: Imaging modalities include modalities that provide information on the anatomy or radionuclide imaging that provides information about the metabolic activity of the area of interest. Anatomical imaging includes plain radiographs (X-ray), computed tomography, and magnetic resonance imaging. Radionuclide approaches include three-phase bone scintigraphy, gallium scans, white blood cell scintigraphy, and 18F-fluorodeoxy-glucose positron emission tomography. The optimal radiological modality for diagnosis is influenced by multiple factors, including infection location, presence of metalware, timing of infection from any preceding surgery or fracture, antibiotic use, and patient comorbidities. Local availability of scanning modality, tracer supply, technical expertise, and patient access also influences choice. IMPLICATIONS: A collaborative approach with imaging, pathology and clinical input in a multidisciplinary setting is paramount for the diagnosis of osteoarticular infections. Increasing research and improvements in technology will further improve the utility and accuracy of imaging approaches for imaging in osteoarticular infections.

A survey of gamma camera and SPECT/CT quality control programs across a sample of public hospitals in Australia.

Performance testing of gamma cameras and single photon computed tomography/computed tomography (SPECT/CT) systems is not subject to regulatory requirements across states and territories in Australia. Internationally recognised testing standards from organisations such as the National Electrical Manufacturers Association (NEMA) describe methodologies for recommended tests. However, variations exist in suggested quality control (QC) schedules from professional bodies such as the Australia and New Zealand Society of Nuclear Medicine (ANZSNM). In this study, a survey was conducted to benchmark current QC programs across a selected sample of eight standalone and networked Australian public hospitals. Vendor-specific flood-field uniformity (intrinsic or extrinsic/system) verification without photomultiplier (PMT) tuning and CT QC were performed at all sites. Weekly and monthly PMT tuning followed by intrinsic flood-field verifications were performed at most sites. At least half of the sites performed monthly centre of rotation (COR) offset verifications. SPECT/CT alignment calibrations and verifications were undertaken by service engineers at all sites, and periodic verifications were performed by local staff at varying frequencies. Variations were observed for other periodic QC tests such as spatial resolution and planar sensitivity. Similarly, variations were observed for tests specific to whole-body systems and SPECT systems. Most sites checked daily and periodic QC results against pass/fail criteria set by vendors. Additional analyses of the QC results, including trend analysis and periodic reviews, were not common practice. The lack of regulatory requirements is likely to have led to variations in QC tests that are generally either harder to perform or are more labour intensive.

The Evaluation of Gastric Emptying Using Nuclear Scintigraphy Compared to Three-Dimensional Multi-detector Computed Tomography (3D-MDCT) Gastric Volumetry in the Assessment of Poor Weight Loss Following Sleeve Gastrectomy.

BACKGROUND: Poor weight loss and weight regain are principal challenges following laparoscopic sleeve gastrectomy (LSG). There is a lack of standardised assessments and diagnostic tests to stratify the status post-LSG and determine whether anatomical or physiological problem exists. We aimed to compare nuclear scintigraphy gastric emptying with CT volumetric analysis of sleeve anatomy and determine the impact of anatomy on physiological function and its correlation with weight loss. MATERIALS AND METHODS: Patients greater than 12 months post-LSG were categorised into optimal weight loss (OWL) (n = 29) and poor weight loss groups (PWL) (n = 50). All patients underwent a protocolised nuclear scintigraphy and three-dimensional multi-detector computed tomography (3D-MDCT) gastric volumetry imaging. RESULTS: Post-operative % total weight loss in OWL was 26.2 ± 10.5% vs. 14.2 ± 10.7% in the PWL group (p value < 0.0001). The PWL group had significantly more delayed gastric emptying half-time than OWL (34.1 ± 18.8 vs. 19.5 ± 4.7, p value < 0.0001). Gastric emptying half-time showed statistically significant correlations with weight loss parameters (BMI; r = 0.215, p value 0.048, %EWL; r = - 0.336, p value 0.002 and %TWL; r = - 0.379, p value < 0.001). The median gastric volume on 3D-MDCT did not differ between the OWL (246 (IQR 50) ml) and PWL group (262 (IQR 129.5) ml), p value 0.515. Nuclear scintigraphy gastric emptying half-time was the most highly discriminant measure. A threshold of 21.2 min distinguished OWL from PWL patients with 86.4% sensitivity and 68.4% specificity. CONCLUSION: Nuclear scintigraphy is a potentially highly accurate tool in the functional assessment of sleeve gastrectomy physiology. It appears to perform better as a diagnostic test than volumetric assessment. Gastric volume did not correlate with weight loss outcomes. We have established diagnostic criteria of greater than 21 min to assess sleeve failure, which is linked to suboptimal weight loss outcomes.

Modified One Anastomosis Gastric Bypass Following Sleeve Gastrectomy for Severe Reflux and Delayed Gastric Emptying: A Prospective Trial with Clinical and Physiological Outcome Measures.

BACKGROUND: Gastro-esophageal reflux (GORD) following sleeve gastrectomy (SG) is a central challenge, and precise indications for revisional surgery or the physiology have not been precisely defined. We aimed to determine whether OAGB performed for reflux post-SG (1) accelerates gastric emptying half-time, (2) reduces the frequency and severity of reflux events, and (3) improves reflux symptoms. METHODS: We undertook a prospective trial (ACTRN12616001089426). There were 22 participants who underwent measurement before and after revisional surgery with 29 optimal SG (patients with optimal outcome from their primary surgery) as controls. All participants underwent a protocolized nuclear scintigraphy, 24-h pH monitoring, and gastroscopy and completed objective questionnaires. RESULTS: Trial patients were 90.9% female, age 44.4 years. Conversion from SG to OAGB was at a median of 45.2 ± 19.6 months. Scintigraphy showed an increased rate of gastric emptying post-OAGB 34 (IQR 14) vs 24 (IQR 10.3) min, p-value 0.008, with decreased number of reflux events post-prandially (39 (IQR 13) vs 26 (IQR 7), p-value 0.001). This data correlated with the pH analysis; total acid events substantially reduced post-OAGB 58.5 (IQR 88) vs 12 (IQR 9.4) events, p-value 0.017. Endoscopic findings indicated a reduction in incidence of bile stasis 72.7% vs 40.9% post-OAGB, p-value < 0.00010. Post-OAGB, patients experienced less frequent regurgitation (12 ± 4.1 vs. 5.5 ± 3, p-value 0.012) and reflux (37.1 ± 15.7 vs. 16.8 ± 12.6, p-value 0.003). CONCLUSIONS: We found OAGB is an effective treatment for reflux associated with delayed gastric emptying post-SG. The likely mechanisms is by, an increase in the rate of gastric clearance and reduced reflux events and overall esophageal acid exposure. This suggests that some forms of post-SG reflux are driven by slower emptying of the residual stomach and are amenable to treatment with drainage above the incisura.

Comparison of contemporaneous left ventricular ejection fraction (LVEF) obtained from planar gated cardiac blood pool scans (GCBPS) and Tl-201 gated myocardial perfusion scans (MPS) using a novel solid state dedicated cardiac camera.

BACKGROUND: There is limited data on the concordance of left ventricular ejection fraction (LVEF) obtained via solid state dedicated cardiac cameras (SSD) and gated cardiac blood pool scans (GCBPS). This study aimed to examine the agreement of LVEF measured during GCBPS and Tl-201 myocardial perfusion scans (MPS) using SSD. METHODS: Seventy six patients were enrolled. Following stress MPS with 0.8 Mbq/kg (0.022 mCi/kg) Tl-201 and 8-frame gated rest studies after additional 15 Mbq (0.41 mCi) Tl-201, LVEFs were obtained using ECToolbox (ECT) and quantitative gated SPECT (QGS) software. Same day 16-frame planar GCBPS were performed. Interobserver variability was compared and LVEF results were compared using paired t tests, Pearson's correlation and the differences of the LVEF were plotted against GCBPS values. RESULTS: For GCBPS, ECT and QGS, the mean (±SD) LVEF was 52% ± 14%, 61% ± 18% and 48% ± 19%, respectively. When compared to GCBPS, ECT and QGS, LVEFs had similar R values of 0.85 and 0.83, respectively, and mean differences [95% limits of agreement (LA)] of -8.6% (-27.4% to +10.2%, P < .001) and 4.2% (-17.2% to +25.6%, P = .001), respectively. CONCLUSION: While the LVEF obtained by ECT or QGS demonstrates a statistically significant correlation with GCBPS, they are significantly different and the wide 95% LA suggest that Tl-201 MPS LVEFs derived from either software package are not interchangeable with GCBPS results.

Changes in Oesophageal Transit, Macro-Reflux Events, and Gastric Emptying Correlate with Improvements in Gastro-Intestinal Symptoms and Food Tolerance Early Post Sleeve Gastrectomy.

PURPOSE: There are significant alterations in gastro-intestinal function, food tolerance, and symptoms following sleeve gastrectomy (SG). These substantially change over the first year, but it is unclear what the underlying physiological basis for these changes is. We examined changes in oesophageal transit and gastric emptying and how these correlate with changes in gastro-intestinal symptoms and food tolerance. MATERIAL AND METHODS: Post-SG patients undertook protocolised nuclear scintigraphy imaging along with a clinical questionnaire at 6 weeks, 6 months, and 12 months. RESULTS: Thirteen patients were studied: mean age (44.8 ± 8.5 years), 76.9% females, pre-operative BMI (46.9 ± 6.7 kg/m2). Post-operative %TWL was 11.9 ± 5.1% (6 weeks) and 32.2 ± 10.1% (12 months), p-value < 0.0001. There was a substantial increase of meal within the proximal stomach; 22.3% (IQR 12%) (6 weeks) vs. 34.2% (IQR 19.7%) (12 months), p = 0.038. Hyper-accelerated transit into the small bowel decreased from 6 weeks 49.6% (IQR 10.8%) to 42.7% (IQR 20.5%) 12 months, p = 0.022. Gastric emptying half-time increased from 6 weeks 19 (IQR 8.5) to 12 months 27 (IQR 11.5) min, p = 0.027. The incidence of deglutitive reflux of semi-solids decreased over time; 46.2% (6 weeks) vs. 18.2% (12 months), p-value < 0.0001. Reflux score of 10.6 ± 7.6 at 6 weeks vs. 3.5 ± 4.4 at 12 months, (p = 0.049) and regurgitation score of 9.9 ± 3.3 at 6 weeks vs. 6.5 ± 1.7, p = 0.021 significantly reduced. CONCLUSIONS: These data demonstrate that there is an increase in the capacity of the proximal gastric sleeve to accommodate substrate over the first year. Gastric emptying remains rapid but reduce over time, correlating with improved food tolerance and reduced reflux symptoms. This is likely the physiological basis for the changes in symptoms and food tolerance observed early post-SG.

The role of surveillance imaging for resected high-risk melanoma.

BACKGROUND: Recommendations for surveillance imaging for resected melanoma vary considerably. This study examined the utility of imaging in patients with a high-risk primary melanoma undergoing a protocolized imaging schedule. METHODS: This retrospective study involved data collection regarding imaging, recurrence, and outcome characteristics for patients referred to the Victorian Melanoma Service from January 2016-April 2020 and managed for resected stage IIC or III melanoma. Patients with a T4b tumor who did not undergo a sentinel lymph node biopsy were included (T4bNX). Recurrences were "clinically detected" if they were primarily detected by patient symptoms or physical examination, or 'imaging-detected' if the patient was asymptomatic. Cox regression models including time-varying co-variates were used to assess the impact of imaging-detected versus clinically-detected recurrence on overall survival. RESULTS: Over a median follow-up time of 2.7 years, 199 patients underwent surveillance imaging (T4bNX:22, IIC:33, IIIA:22, IIIB:60, IIIC:61, IIID:1), and 44% (n = 88) experienced disease recurrence. Imaging detected over half (53%) of all recurrences. In adjusted analyses, mortality risk was reduced after an imaging-detected compared to clinically-detected recurrence at any given time from the start of surveillance (hazard ratio 0.25, 95% confidence interval 0.10-0.66, p = .005). CONCLUSION: Our study indicates that routine imaging in the early follow-up period of resected T4bNX, stage IIC and III melanoma plays an important role in the detection of asymptomatic recurrences. Imaging-detected recurrence may be associated with a survival benefit and studies with more prolonged follow-up are required to confirm these findings.

Online-Mediated HIV Pre-exposure Prophylaxis Care and Reduced Monitoring Frequency for Men Who Have Sex With Men: Protocol for a Randomized Controlled Noninferiority Trial (EZI-PrEP Study).

BACKGROUND: Daily and event-driven HIV pre-exposure prophylaxis (PrEP) with oral tenofovir-emtricitabine is highly effective to prevent HIV in men who have sex with men (MSM). PrEP care generally consists of in-clinic monitoring every 3 months that includes PrEP dispensing, counseling, and screening for HIV and sexually transmitted infections (STIs). However, the optimal frequency for monitoring remains undetermined. Attending a clinic every 3 months for monitoring may be a barrier for PrEP. Online-mediated PrEP care and reduced frequency of monitoring may lower this barrier. OBJECTIVE: The primary objective of this study is to establish the noninferiority of online PrEP care (vs in-clinic care) and monitoring every 6 months (vs every 3 months). The secondary objectives are to (1) examine differences between PrEP care modalities regarding incidences of STIs, HIV infection, and hepatitis C virus infection; retention in PrEP care; intracellular tenofovir-diphosphate concentration; and satisfaction, usability, and acceptability of PrEP care modalities; and (2) evaluate associations of these study outcomes with sociodemographic, behavioral, and psychological characteristics. METHODS: This study is a 2×2 factorial, 4-arm, open-label, multi-center, randomized, controlled, noninferiority trial. The 4 arms are (1) in-clinic monitoring every 3 months, (2) in-clinic monitoring every 6 months, (3) online monitoring every 3 months, and (4) online monitoring every 6 months. The primary outcome is a condomless anal sex act with a casual partner not covered or insufficiently covered by PrEP (ie, "unprotected act") as a proxy for HIV infection risk. Eligible individuals are MSM, and transgender and gender diverse people aged ≥18 years who are eligible for PrEP care at 1 of 4 participating sexual health centers in the Netherlands. The required sample size is 442 participants, and the planned observation time is 24 months. All study participants will receive access to a smartphone app, which contains a diary. Participants are requested to complete the diary on a daily basis during the first 18 months of participation. Participants will complete questionnaires at baseline and 6, 12, 18, and 24 months. Dried blood spots will be collected at 6 and 12 months for assessment of intracellular tenofovir-diphosphate concentration. Incidence rates of unprotected acts will be compared between the online and in-clinic arms, and between the 6-month and 3-month arms. Noninferiority will be concluded if the upper limit of the 2-sided 97.5% CI of the incidence rate ratio is <1.8. RESULTS: The results of the main analysis are expected in 2024. CONCLUSIONS: This trial will demonstrate whether online PrEP care and monitoring every 6 months is noninferior to standard PrEP care in terms of PrEP adherence. If noninferiority is established, these modalities may lower barriers for initiating and continuing PrEP use and potentially reduce the systemic burden for PrEP providers. TRIAL REGISTRATION: ClinicalTrials.gov NCT05093036; https://tinyurl.com/28b8ndvj. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51023.

Optimal reproducibility of gated sestamibi and thallium myocardial perfusion study left ventricular ejection fractions obtained on a solid-state CZT cardiac camera requires operator input.

AIM: To evaluate the reproducibility of serial re-acquisitions of gated Tl-201 and Tc-99m sestamibi left ventricular ejection fraction (LVEF) measurements obtained on a new generation solid-state cardiac camera system during myocardial perfusion imaging and the importance of manual operator optimization of left ventricular wall tracking. METHODS: Resting blinded automated (auto) and manual operator optimized (opt) LVEF measurements were measured using ECT toolbox (ECT) and Cedars-Sinai QGS software in two separate cohorts of 55 Tc-99m sestamibi (MIBI) and 50 thallium (Tl-201) myocardial perfusion studies (MPS) acquired in both supine and prone positions on a cadmium zinc telluride (CZT) solid-state camera system. Resting supine and prone automated LVEF measurements were similarly obtained in a further separate cohort of 52 gated cardiac blood pool scans (GCBPS) for validation of methodology and comparison. Appropriate use of Bland-Altman, chi-squared and Levene's equality of variance tests was used to analyse the resultant data comparisons. RESULTS: For all radiotracer and software combinations, manual checking and optimization of valve planes (+/- centre radius with ECT software) resulted in significant improvement in MPS LVEF reproducibility that approached that of planar GCBPS. No difference was demonstrated between optimized MIBI/Tl-201 QGS and planar GCBPS LVEF reproducibility (P = .17 and P = .48, respectively). ECT required significantly more manual optimization compared to QGS software in both supine and prone positions independent of radiotracer used (P < .02). CONCLUSIONS: Reproducibility of gated sestamibi and Tl-201 LVEF measurements obtained during myocardial perfusion imaging with ECT toolbox or QGS software packages using a new generation solid-state cardiac camera with improved image quality approaches that of planar GCBPS however requires visual quality control and operator optimization of left ventricular wall tracking for best results. Using this superior cardiac technology, Tl-201 reproducibility also appears at least equivalent to sestamibi for measuring LVEF.