Brain-stem serotonin transporter availability in maternal uniparental disomy and deletion Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a rare condition because of the deletion of paternal chromosomal material (del PWS), or a maternal uniparental disomy (mUPD PWS), at 15q11-13. Affective psychosis is more prevalent in mUPD PWS. We investigated the relationship between the two PWS genetic variants and brain-stem serotonin transporter (5-HTT) availability in adult humans. Mean brain-stem 5-HTT availability determined by [123I]-beta-CIT single photon emission tomography was lower in eight adults with mUPD PWS compared with nine adults with del PWS (mean difference -0.93, t = -2.85, P = 0.014). Our findings confirm an association between PWS genotype and brain-stem 5-HTT availability, implicating a maternally expressed/paternally imprinted gene, that is likely to account for the difference in psychiatric phenotypes between the PWS variants. Declaration of interest None.

Circulating tumour necrosis factor is highly correlated with brainstem serotonin transporter availability in humans.

Preclinical studies demonstrate that pro-inflammatory cytokines increase serotonin transporter availability and function, leading to depressive symptoms in rodent models. Herein we investigate associations between circulating inflammatory markers and brainstem serotonin transporter (5-HTT) availability in humans. We hypothesised that higher circulating inflammatory cytokine concentrations, particularly of tumour necrosis factor (TNF-α), would be associated with greater 5-HTT availability, and that TNF-α inhibition with etanercept (sTNFR:Fc) would in turn reduce 5-HTT availability. In 13 neurologically healthy adult women, plasma TNF-α correlated significantly with 5-HTT availability (rho=0.6; p=0.03) determined by [(123)I]-beta-CIT SPECT scanning. This association was replicated in an independent sample of 12 patients with psoriasis/psoriatic arthritis (rho=0.76; p=0.003). Indirect effects analysis, showed that there was a significant overlap in the variance explained by 5-HTT availability and TNF-α concentrations on BDI scores. Treatment with etanercept for 6-8weeks was associated with a significant reduction in 5-HTT availability (Z=2.09; p=0.03; r=0.6) consistent with a functional link. Our findings confirm an association between TNF-α and 5-HTT in both the basal physiological and pathological condition. Modulation of both TNF-α and 5-HTT by etanercept indicate the presence of a mechanistic pathway whereby circulating inflammatory cytokines are related to central nervous system substrates underlying major depression.

Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer.

BACKGROUND: It is not known whether low-dose radioiodine (1.1 GBq [30 mCi]) is as effective as high-dose radioiodine (3.7 GBq [100 mCi]) for treating patients with differentiated thyroid cancer or whether the effects of radioiodine (especially at a low dose) are influenced by using either recombinant human thyrotropin (thyrotropin alfa) or thyroid hormone withdrawal. METHODS: At 29 centers in the United Kingdom, we conducted a randomized noninferiority trial comparing low-dose and high-dose radioiodine, each in combination with either thyrotropin alfa or thyroid hormone withdrawal before ablation. Patients (age range, 16 to 80 years) had tumor stage T1 to T3, with possible spread to nearby lymph nodes but without metastasis. End points were the rate of success of ablation at 6 to 9 months, adverse events, quality of life, and length of hospital stay. RESULTS: A total of 438 patients underwent randomization; data could be analyzed for 421. Ablation success rates were 85.0% in the group receiving low-dose radioiodine versus 88.9% in the group receiving the high dose and 87.1% in the thyrotropin alfa group versus 86.7% in the group undergoing thyroid hormone withdrawal. All 95% confidence intervals for the differences were within ±10 percentage points, indicating noninferiority. Similar results were found for low-dose radioiodine plus thyrotropin alfa (84.3%) versus high-dose radioiodine plus thyroid hormone withdrawal (87.6%) or high-dose radioiodine plus thyrotropin alfa (90.2%). More patients in the high-dose group than in the low-dose group were hospitalized for at least 3 days (36.3% vs. 13.0%, P<0.001). The proportions of patients with adverse events were 21% in the low-dose group versus 33% in the high-dose group (P=0.007) and 23% in the thyrotropin alfa group versus 30% in the group undergoing thyroid hormone withdrawal (P=0.11). CONCLUSIONS: Low-dose radioiodine plus thyrotropin alfa was as effective as high-dose radioiodine, with a lower rate of adverse events. (Funded by Cancer Research UK; ClinicalTrials.gov number, NCT00415233.).

Incisional hernias following robotic-assisted laparoscopic prostatectomy: does the extraction site matter?

The incidence of incisional hernia (IH) following robotic-assisted laparoscopic prostatectomy (RALP) varies widely within the literature (0.4-9.7%). Whilst small hernias may go unnoticed, the potential exists for bowel strangulation and subsequent emergency surgery. We suggest that the extraction site may influence the rate of IH. A retrospective chart review of a single surgeon RALP series was undertaken. One hundred charts were sampled, of which 69 had sufficient data to be analysed. Prior to July 2017, specimen extraction had been via the supra-umbilical port site. After this time, specimens were extracted via a Pfannenstiel incision. Of the 69 patients, 24 underwent RALP prior to July 2017. Three patients developed IH at the supra-umbilical port extended for extraction site in the pre-2017 group and three patients developed IH at the supra-umbilical port (not extraction) site in the post-2017 group. The rate of IH was almost double in the pre-July 2017 group (12.5% vs. 6.7%). No patient developed an incisional hernia at the Pfannenstiel site in the post-2017 group. In our series, no patient developed a hernia at the Pfannenstiel site. This is in keeping with the reported < 1% IH rate following Pfannenstiel specimen extraction. Given that incisional hernias are a known complication of robotic surgery, thought should be given to changing the site of specimen extraction site to lower the rate of incisional hernias and the morbidity associated with such.

TGF-ß signalling limits effector function capacity of NK cell anti-tumour immunity in human bladder cancer.

BACKGROUND: Natural killer (NK) cells are important innate immunity players and have unique abilities to recognize and eliminate cancer cells, particularly in settings of antibody-opsonization and antibody-dependant cellular cytotoxicity (ADCC). However, NK cell-based responses in bladder cancers to therapeutic antibodies are typically immunosuppressed, and these immunosuppressive mechanisms are largely unknown. METHODS: Single cell RNA sequencing (scRNA-seq) and high-dimensional flow cytometry were used to investigate the phenotype of tumour-infiltrating NK cells in patients with bladder cancer. Further, in vitro, and in vivo models of this disease were used to validate these findings. FINDINGS: NK cells within bladder tumours displayed reduced expression of FcγRIIIa/CD16, the critical Fc receptor involved in ADCC-mediated cytotoxicity, on both transcriptional and protein levels. Transcriptional signatures of transforming growth factor (TGF)-ß-signalling, a pleiotropic cytokine known for its immunosuppressive and tissue residency-inducing effects, were upregulated in tumour-infiltrating NK cells. TGF-ß mediated CD16 downregulation on NK cells, was further validated in vitro, which was accompanied by a transition into a tissue residency phenotype. This CD16 downregulation was also abrogated by TGF-ßR signalling inhibition, which could also restore the ADCC ability of NK cells subject to TGF-ß effects. In a humanized mouse model of bladder cancer, mice treated with a TGF-ß inhibitor exhibited increased ADCC activity compared to mice treated only with antibodies. INTERPRETATION: This study highlights how TGF-ß-rich bladder cancers inhibit NK cell-mediated ADCC by downregulating CD16. TGF-ß inhibition represents new avenues to reverse immunosuppression and enhance the tumoricidal capacity of NK cells in bladder cancer. FUNDING: The Guimaraes Laboratory is funded by a US Department of Defense-Breast Cancer Research Program-Breakthrough Award Level 1 (#BC200025), a grant (#2019485) awarded through the Medical Research Future Fund (MRFF, with the support of the Queensland Children's Hospital Foundation, Microba Life Sciences, Richie's Rainbow Foundation, Translational Research Institute (TRI) and UQ), and a grant (#RSS_2023_085) funded by a Metro South Health Research Support Scheme. J.K.M.W. is funded by a UQ Research Training Program PhD Scholarship and N.O. is funded by a NHMRC Postgraduate Scholarship (#2021932).

Male sexual dysfunction: Clinical diagnosis and management strategies for common sexual problems.

BACKGROUND: Male sexual dysfunction (MSD) can affect males of all ages. The most common problems associated with sexual dysfunction include low sexual desire, erectile dysfunction, Peyronie's disease and disorders of ejaculation and orgasm. Each of these male sexual problems can be difficult to treat, and some males may have more than one form of sexual dysfunction. OBJECTIVE: This review article provides an overview of the clinical assessment and evidence-based management strategies for MSD problems. Emphasis is placed on a practical set of recommendations relevant to general practice. DISCUSSION: Comprehensive clinical history-taking, tailored physical examination and relevant laboratory testing can provide relevant clues for MSD diagnosis. Modifying lifestyle behaviours, managing reversible risk factors and optimising existing medical conditions are important first-line management options. Medical therapy can be initiated by general practitioners (GPs) with subsequent referrals to a relevant non-GP specialist(s) if patients do not respond and/or require surgical interventions.

Outcomes of the overweight and obese major trauma patient in the rural setting.

PURPOSE: Overweight and obese patients are more prevalent in rural and remote areas and are of major public health concern in Australia. We aimed to evaluate the mortality and morbidity of overweight and obese trauma patients in the rural Australian context. METHOD: This was a retrospective cohort study on 207 major trauma patients (injury severity score [ISS] > 12) treated at the Mackay Base Hospital between 2018 and 2021. Data was extracted from the Mackay Base Hospital trauma database and hospital records. Outcomes were compared between body mass index (BMI) groups. RESULTS: There were 164 males (79%) and 43 females (21%). The average BMI was 27.09 (standard deviation 5.46). 7 patients (3%) were in the underweight category (BMI < 18.5 kg/m2), 70 (34%) were of normal weight (BMI 18.5-24.9 kg/m2), 79 (38%) were overweight (BMI 25-29.9 kg/m2), and 51 (25%) were obese (BMI > 30 kg/m2). The majority of trauma was blunt (n = 203, 98%). Compared to patients with normal BMI, obese patients were significantly more likely to require intubation, intensive care unit (ICU) admission, and have a longer ICU stay. There were no significant differences in requirement for surgery, duration of surgery, hospital length of stay, ventilator time, or mortality (P > 0.05). However, subgroup analysis of the obese patient group showed an increased rate of complications (sepsis, acute kidney injury, fluid overload and pneumonia), longer ventilation times, hospital and ICU length of stay with increasing BMI in these patients. CONCLUSION: The majority of trauma presentations in our regional community are in overweight or obese patients. Overweight and obese patients are more likely to require intubation and have a longer intensive care unit admission than normal weight counterparts. Amongst obese patients, those with BMI > 40 (obesity class 3) are at significantly increased risk of complications.

Biodistribution and dosimetry of ¹²³I-mZIENT: a novel ligand for imaging serotonin transporters.

PURPOSE: 123I-labelled mZIENT (2ß-carbomethoxy-3ß-(3'-((Z)-2-iodoethenyl)phenyl)nortropane) has been developed as a radioligand for the serotonin transporter. The aim of this preliminary study was to assess its whole-body biodistribution in humans and estimate dosimetry. METHODS: Three healthy controls and three patients receiving selective serotonin reuptake inhibitor (SSRI) therapy for depression were included (two men, four women, age range 41-56 years). Whole-body imaging, brain SPECT imaging and blood and urine sampling were performed. Whole-body images were analysed using regions of interest (ROIs), time-activity curves were derived using compartmental analysis and dosimetry estimated using OLINDA software. Brain ROI analysis was performed to obtain specific-to-nonspecific binding ratios in the midbrain, thalamus and striatum. RESULTS: Initial high uptake in the lungs decreased in later images. Lower uptake was seen in the brain, liver and intestines. Excretion was primarily through the urinary system. The effective dose was estimated to be of the order of 0.03 mSv/MBq. The organ receiving the highest absorbed dose was the lower large intestine wall. Uptake in the brain was consistent with the known SERT distribution with higher specific-to-nonspecific binding in the midbrain, thalamus and striatum in healthy controls compared with patients receiving SSRI therapy. CONCLUSION: ¹²³I-mZIENT may be a promising radioligand for imaging the serotonin transporters in humans with acceptable dosimetry.

Sentinel lymph node biopsy for early oral cancer - accuracy and considerations in patient selection.

Sentinel lymph node biopsy (SLNB) for staging oral squamous cell carcinoma (OSCC) patients presenting with early (T1 and T2 N0) disease in preference to elective neck dissection (END) remains controversial worldwide. A retrospective analysis of 145 patients who underwent sentinel lymph node biopsy for a previously untreated early oral cancer between 2010 and 2020 was performed. The primary outcome measures were predictors of occult metastases, accuracy of SLNB and disease specific plus overall survival. The negative predictive value, the false negative rate, and sensitivity for SLNB were 97%, 7.8%, and 92%, respectively. Depth of invasion (DOI) was a significant predictor of N status, overall survival, and disease specific survival. There was a significant difference in the incidence of the neck node metastasis in patients with DOI <5mm compared to those with DOI >5mm. For tumours >5mm there was a moderate to good correlation between radiological depth on contrast enhanced computed tomography (CECT) and histopathological DOI. Preoperative estimation of DOI may be a useful tool in the counselling of patients in the selection of either SLNB or END for N staging purposes in early OSCC.

Characterisation of 99mTc EDDA/HYNIC-TOC (Tektrotyd) physiological and neuroendocrine tumour uptake using SPECT/CT standardised uptake values: initial experience.

99mTc Ethylene diamine N,N'-diacetic acid hydrazinonicotinamide-conjugated Tyr3-octreotide (99mTc EDDA/HYNIC-TOC) single photon emission tomography/computed tomography (SPECT/CT) imaging of somatostatin receptors is used in the assessment of neuroendocrine tumours (NETs). The objective of this study was to characterise quantitative standardised uptake value (SUV) SPECT/CT of normal physiological uptake and NET disease. Forty-four patients (22 female and 22 male) referred for 99mTc EDDA/HYNIC-TOC SPECT/CT imaging for diagnosis/primary staging (n = 28) or the assessment of residual/recurrent disease (n = 16) were included. SPECT/CT SUVmax values were determined for normal physiological uptake (spleen, kidney, liver and bone) and NET disease (liver metastases, metastatic lymph nodes, bone metastases and intrapulmonary lesions). Statistical testing was performed to compare normal uptake and NET disease uptake in liver and bone (Student's t-test). The highest normal physiological uptake was observed in the spleen (mean SUVmax 29.8, SD 13.7), with lower uptake in the kidneys (16.7, 3.2) and liver (7.3, 2.1). Increased SUVmax values were observed in primary tumour and metastatic disease, greatest in liver metastases (21.8, 13.3), with lower, similar values obtained for metastatic lymph nodes (16.3, 7.5) and intrapulmonary lesions (17.5, 16.8). SUVmax in bone metastases averaged 12.9 (7.0). Significant differences were observed between normal and metastatic SUVmax in the liver and bone (P < 0.01). SPECT/CT SUV quantification is feasible in a manner similar to PET/CT. 99mTc EDDA/HYNIC-TOC SPECT/CT SUVmax has been characterised in NET disease, demonstrating high target to non-target ratios for primary tumours and metastatic lesions.

Anatomical pelvic loading of a monoblock polyethylene acetabular component.

AIMS: Uncemented metal acetabular components show good osseointegration, but material stiffness causes stress shielding and retroacetabular bone loss. Cemented monoblock polyethylene components load more physiologically; however, the cement bone interface can suffer fibrous encapsulation and loosening. It was hypothesized that an uncemented titanium-sintered monoblock polyethylene component may offer the optimum combination of osseointegration and anatomical loading. METHODS: A total of 38 patients were prospectively enrolled and received an uncemented monoblock polyethylene acetabular (pressfit) component. This single cohort was then retrospectively compared with previously reported randomized cohorts of cemented monoblock (cemented) and trabecular metal (trabecular) acetabular implants. The primary outcome measure was periprosthetic bone density using dual-energy x-ray absorptiometry over two years. Secondary outcomes included radiological and clinical analysis. RESULTS: Although there were differences in the number of males and females in each group, no significant sex bias was noted (p = 0.080). Furthermore, there was no significant difference in age (p = 0.910) or baseline lumbar bone mineral density (BMD) (p = 0.998) found between any of the groups (pressfit, cemented, or trabecular). The pressfit implant initially behaved like the trabecular component with an immediate fall in BMD in the inferior and medial regions, with preserved BMD laterally, suggesting lateral rim loading. However, the pressfit component subsequently showed a reversal in BMD medially with recovery back towards baseline, and a continued rise in lateral BMD. This would suggest that the pressfit component begins to reload the medial bone over time, more akin to the cemented component. Analysis of postoperative radiographs revealed no pressfit component subsidence or movement up to two years postoperatively (100% interobserver reliability). Medial defects seen immediately postoperatively in five cases had completely resolved by two years in four patients. CONCLUSION: Initially, the uncemented monoblock component behaved similarly to the rigid trabecular metal component with lateral rim loading; however, over two years this changed to more closely resemble the loading pattern of a cemented polyethylene component with increasing medial pelvic loading. This indicates that the uncemented monoblock acetabular component may result in optimized fixation and preservation of retroacetabular bone stock. Cite this article: Bone Joint J 2021;103-B(5):872-880.

Development and validation of a full model of a four-headed neuroimaging single-photon emission computed tomography scanner.

OBJECTIVE: The Nucline X-Ring 4R is a four-headed gamma camera dedicated to neuroimaging. In this paper, we describe and validate a GATE (Geant4 Application for Tomographic Emission) model of the Nucline X-Ring 4R. MATERIALS AND METHODS: Images produced during model simulations were compared with those acquired experimentally to confirm the model was an accurate representation of the scanner. The most commonly reported measurements used to validate a GATE model include energy resolution, spatial resolution and sensitivity. In addition to the commonly reported static imaging measures, single-photon emission computed tomography (SPECT) spatial resolution was investigated to confirm that the model produces similar SPECT images to the experimental output. RESULTS: The experimental full-width at half-maximum was calculated to be 12.3 keV, which corresponds to an energy resolution of 8.8%. The simulated full-width at half-maximum was measured to be 12 keV, giving an energy resolution of 8.6%. The average spatial resolutions were found to be well matched (5.69 mm - simulated and 5.64 mm - experimental). However, the sensitivity was overestimated using the GATE model (47.8 and 54.3 cps/MBq) compared with the values obtained experimentally (42.7 and 44.3 cps/MBq). Finally, the simulated SPECT spatial resolution images were found to produce qualitatively comparable results. CONCLUSION: The model developed has been shown to produce similar results and images to those obtained experimentally. This model has the potential to simulate patient scans with the aim of improving patient care by optimizing scanner protocols.

Optimization of the CT component of SPECT-CT and establishment of local CT diagnostic reference levels for clinical practice.

OBJECTIVE: The aim of this study was to perform a process of optimization and establish local diagnostic reference levels (DRLs) for the computed tomography (CT) component of single-photon emission computed tomography (SPECT)-CT imaging, for use in clinical practice. METHODS: A multidisciplinary group defined categories for the clinical purpose of the CT component of local SPECT-CT examinations. Each of the examinations were assigned a category, and optimization of acquisition and reconstruction parameters was performed to achieve the required image quality. Dose data were collated for 754 SPECT-CT scans performed on three systems over 10 months. The third quartile values for volume CT dose index and dose length product were calculated and established as local DRLs. RESULTS: Four categories of CT examinations were defined: attenuation correction; localization and attenuation correction; localization, characterization and attenuation correction; and diagnostic and attenuation correction. Local DRLs were established for 11 examinations. Reference was made to the proposed national DRLs set by a recent UK survey. CONCLUSION: This work describes a process of optimization and the creation of practical and effective local DRLs. These can be used in local audit of practice. In future, improved descriptors and standardization of SPECT-CT use would allow more practicable UK national DRLs to be created.

Assessment of 123I-FIAU imaging of herpes simplex viral gene expression in the treatment of glioma.

BACKGROUND: Herpes simplex virus 1716 (HSV1716), a selectively replication competent mutant of HSV1, is under investigation as an oncolytic viral therapy in human malignant glioma. As with similar therapies, a technique for measurement of viral replication and distribution over time following virus administration is required. Imaging expression of the HSV-thymidine kinase (HSV-tk) gene offers an opportunity for non-invasive assessment of viral distribution in living subjects. This is the first study to explore the use of HSV-tk as a reporter gene and radiolabelled thymidine analogue 5-[(123)I]iodo-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil ((123)I-FIAU) as a marker substrate to non-invasively monitor HSV1716 replication in humans during treatment of high-grade glioma. METHODS: I-FIAU brain SPECT imaging was undertaken in eight patients receiving intra-tumoural injection of HSV1716, before and after administration of the virus. Baseline images were acquired 3 days prior to virus administration and between 1 and 5 days following virus administration. Region of interest analysis was used to investigate whether there was an increase in (123)I-FIAU concentration following virus administration due to HSV-tk expression. RESULT: Increased (123)I-FIAU accumulation due to HSV-tk expression was not detected in this study. The possible explanations for this finding are explored and design options for future studies are discussed.

Venlafaxine alters microvascular perfusion, [¹²³I]-beta-CIT binding and BDI scores in flushing postmenopausal women.

BACKGROUND: Although 70% of postmenopausal women suffer from hot flashes the pathophysiology is poorly understood. The serotonin and noradrenaline reuptake inhibitor (SNRI) venlafaxine provides relief of flushing although the mechanism is unknown and could involve a central effect and/or a peripheral effect. Using single photon emission computed tomography (SPECT) we studied the central serotonin transporter (SERT) in vivo using [(123)I]-beta-carbomethoxy-3-ß-(4-iodophenyl)tropane (beta-CIT) and, as previous studies have shown that reactivity of the skin blood vessels is enhanced in those who flush, we examined cutaneous microvascular perfusion. METHODS: Cutaneous microvascular perfusion was assessed in 31 postmenopausal women, with flushing, using laser Doppler imaging with iontophoresis (LDI+ION), before and after 8 weeks of treatment with venlafaxine. A sub-group of 14 of these women also had SPECT imaging at both time points to evaluate the availability of SERT in the brain. Flush frequency and score was recorded, and Beck Depression Inventory (BDI) II scores were assessed before and after treatment. RESULTS: Following treatment with venlafaxine, there was a significant reduction in the [(123)I]-beta-CIT binding ratio, BDI scores, flushing and endothelial dependent perfusion response. [(123)I]-Beta-CIT reduction was associated with BDI reduction (r(2)=0.54; F=8.8; p=0.004), but not flushing reduction or perfusion reduction. CONCLUSIONS: Venlafaxine resulted in a decrease in BDI II scores with an associated reduction in [(123)I]-beta-CIT binding in a group of non-depressed women. It also improved flush frequency and severity which may be as a result of decreases seen in enhanced cutaneous microvascular perfusion.