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Background: Noise, an unwanted variability in judgment, is ubiquitous in medicine, including in the prescription of radioactive iodine (RAI). Building upon our recently developed predictive risk model, we created an online clinical support tool to facilitate the translation of our model into clinical practice. The aim of this study is to assess the utility of an online clinical support tool to reduce noise in the treatment for patients with differentiated thyroid cancer (DTC). Methods: The tool was accessible via weblink or a QR code. Activity recommendations were applied to the calculator’s four risk categories: 0 GBq for very low risk, 1 GBq for low risk, 4 GBq for intermediate risk, and 6 GBq for high risk. The tool was applied prospectively to 103 patients who received RAI at Royal North Shore Hospital between 2021 and 2022 and retrospectively to 393 patients treated with RAI between 2017 and 2021. Results: A significant difference was observed in administered activity between the 2021–2022 and 2017–2021 cohorts in patients stratified as intermediate risk (median activity 3.95 GBq, interquartile range 2.03–4.04 vs 4 GBq, 4–4) and high risk (4.07 GBq, 3.95–5.7 vs 6 GBq, 6–6) with P-values of 0.01 and

Pregnancy in the setting of metastatic paraganglioma is challenging, particularly in the context of tyrosine kinase use. We describe a 26-year-old female with a background of metastatic paraganglioma harboring a pathogenic SDHB variant, requiring sunitinib, which was withheld to facilitate the safe conception and delivery of a healthy baby. She required no alpha- or beta-blockade during her pregnancy and exhibited no signs of tumor progression or symptoms throughout this period. Historically, higher rates of fetal and maternal morbidity and mortality have been experienced in the setting of pregnancy. Although limited data exist on the management of metastatic paraganglioma in pregnant patients, this case suggests that careful treatment modifications, such as temporary tyrosine kinase therapy cessation and vigilant monitoring, can result in successful pregnancies without compromising maternal or fetal well-being.

RET mutations are implicated in 60% of medullary thyroid cancer (MTC) cases. The RET-selective tyrosine kinase inhibitor selpercatinib is associated with unprecedented efficacy compared to previous multi-kinase treatments. Langerhans cell histiocytosis (LCH) is a clonal histiocytic neoplasm usually driven by somatic BRAF mutations, resulting in dysregulated MAPK signalling. We describe a 22-year-old woman with metastatic MTC to regional lymph nodes, lung and liver. Tumour tissue harboured a somatic pathogenic RET variant p.(M918T) and selpercatinib was commenced. She experienced sustained clinical, biochemical and radiological responses. Two years later, she developed rapidly progressive apical lung nodules, prompting biopsy. Histopathology demonstrated LCH with a rare BRAF variant p.(V600_K601>D). The lung nodules improved with inhaled corticosteroids. We hypothesize that selective pressure from RET blockade may have activated a downstream somatic BRAF mutation, resulting in pulmonary LCH. We recommend continued vigilance for neoplasms driven by dysregulated downstream MAPK signalling in patients undergoing selective RET inhibition.

High entropy ultra-high temperature ceramics (HE-UHTCs) have garnered intense research interest due to the potential for optimized oxidation and mechanical properties for extreme environment applications. HE-UHTCs are expected to oxidize according to the thermodynamic favorability of their respective oxidation reactions, which varies according to the periodic grouping. Based on this, the oxidation resistance of equimolar (metals-basis) group IV + V (HfZrTiTaNb), group IV + V + VI (HfZrTiTaMo) and group IV + VI (HfZrTiMoW) carbides and borides were evaluated at 1700°C in 1 mol% O2 for 5 min and compared. Group IV elements oxidized preferentially in all three compositions. Group V element-containing carbides exhibited the lowest oxidation resistance, attributed to the formation of intergranular liquid oxides. (HfZrTiMoW)C exhibited the best resistance among the carbides. The diborides exhibited similar material consumption, reinforcing the hypothesis that the oxidation behavior under these conditions is controlled by the presence of boria. These findings provide direction for HE-UHTC composition design for oxidation resistance.

Purpose This study investigated the functional outcomes and complication rates of cuff downsizing for the treatment of recurrent or persistent stress urinary incontinence (SUI) in men after the implantation of an artificial urinary sphincter (AUS). Methods Data from our institutional AUS database spanning the period from 2009 to 2020 were retrospectively analyzed. The number of pads per day was determined, a standardized quality of life (QoL) questionnaire and the International Consultation on Incontinence Questionnaire (ICIQ) were administered, and postoperative complications according to the Clavien-Dindo classification were analyzed. Results Out of 477 patients who received AUS implantation during the study period, 25 (5.2%) underwent cuff downsizing (median age, 77 years; interquartile range [IQR], 74–81 years; median follow-up, 4.4 years; IQR, 3–6.9 years). Before downsizing, SUI was very severe (ICIQ score 19–21) or severe (ICQ score 13–18) in 80% of patients, moderate (ICIQ score 6–12) in 12%, and slight (ICIQ score 1–5) in 8%. After downsizing, 52% showed an improvement of >5 out of 21 points. However, 28% still had very severe or severe SUI, 48% had moderate SUI, and 20% had slight SUI. One patient no longer had SUI. In 52% of patients, the use of pads per day was reduced by ≥50%. QoL improved by >2 out of 6 points in 56% of patients. Complications (infections/urethral erosions) requiring device explantation occurred in 36% of patients, with a median time to event of 14.5 months. Conclusions Although cuff downsizing carries a risk of AUS explantation, it can be a valuable treatment option for selected patients with persistent or recurrent SUI after AUS implantation. Over half of patients experienced improvements in symptoms, satisfaction, ICIQ scores, and pad use. It is important to inform patients about the potential risks and benefits of AUS to manage their expectations and assess individual risks.

Background: The 2015 American Thyroid Association (ATA) Guidelines permit thyroid lobectomy (TL) or total thyroidectomy in the management of low-risk papillary thyroid cancer (PTC). As definitive risk-stratification is only possible post-operatively, some patients may require completion thyroidectomy (CT) after final histopathological analysis. Methods: A retrospective cohort study of patients undergoing surgery for low-risk PTC in a tertiary referral centre was undertaken. Consecutive adult patients treated from January 2013 to March 2021 were divided into two groups (pre- and post-publication of ATA Guidelines on 01/01/2016). Only those eligible for lobectomy under rule 35(B) of the ATA Guidelines were included: Bethesda V/VI cytology, 1–4 cm post-operative size and without pre-operative evidence of extrathyroidal extension or nodal metastases. We examined rates of TL, CT, local recurrence and surgical complications. Results: There were 1488 primary surgical procedures performed for PTC on consecutive adult patients during the study period, of which 461 were eligible for TL. Mean tumour size (P = 0.20) and mean age (P = 0.78) were similar between time periods. The TL rate increased significantly from 4.5 to 18% in the post-publication period (P < 0.001). The proportion of TL patients requiring CT (43 vs 38%) was similar between groups (P = 1.0). There was no significant change in complications (P = 0.55) or local recurrence rates (P = 0.24). Conclusion: The introduction of the 2015 ATA Guidelines resulted in a modest but significant increase in the rate of lobectomy for eligible PTC patients. In the post-publication period, 38% of patients who underwent TL ultimately required CT after complete pathological analysis.

BackgroundActive surveillance (AS) is an alternative to surgery in select patients with very low risk papillary thyroid cancer (PTC). Many clinicians feel ill-equipped in selecting appropriate patients. We aimed to 1) Develop an evidence-based web delivered decision support tool to assist clinicians in identifying patients appropriate for AS; and 2) Evaluate the prevalence of patients suitable for AS in a tertiary high volume thyroid cancer centre.MethodA REDCap web based clinical support tool was developed utilising evidence-based characteristics for AS suitability available to clinicals during initial assessment. A retrospective database was interrogated for patients who underwent hemithyroidectomy between 2012 – 2021 with final histopathology demonstrating PTC. Patients with PTCs>2cm, missing data, benign disease on surgical histopathology or incidental PTC were excluded.ResultsBetween 2012 - 2021, 763 patients underwent hemithyroidectomy with final histopathology confirming PTC. Of these, 316 patients were excluded (missing data, incidental PTC, concomitant hyperparathyroidism were most common reasons for exclusion) and 114/447 remaining patients had a pre-operative fine needle aspirate (FNA) of Bethesda V or VI (high likelihood of malignancy). Using the tool, 59/114 (52%) met criteria for AS. The majority of patients were female (85% vs 15% male); median age 36 years (range 19 – 78). Following initial surgery, 10/59 patients had a completion thyroidectomy, with 4/10 demonstrating malignancy in contralateral lobe and eight of those patients undergoing I131 ablation. During a median follow up of over 3 years, 49/59 (83%) did not require further surgery or intervention with no patients developing recurrence. A subgroup analysis with second radiology assessment excluded 4/59 patients as meeting criteria for AS based on presence of ETE on preoperative ultrasound. None of these 4 patients had completion thyroidectomy.ConclusionOur clinical support tool identifies patients with PTC potentially suitable for AS which could be utilised during initial patient assessment. In a retrospective cohort of patients who had hemithyroidectomy for PTC with a pre-operative FNA diagnosis of Bethesda V or VI, 55/114 (48%) patients may have been suitable for AS. Prospective validation studies are required for implementation of the tool in clinical practice.

Abstract Thyroid cancer is the most common endocrine cancer, with papillary thyroid carcinoma (PTC) accounting for the majority of these cases. Cerebellar metastasis is rarely the presenting feature and confers poor prognosis. Genetic mutations in this setting are most commonly TERTp, in contrast to BRAFV600E in the majority of PTC. We report the case of an 82 year‐old male who presented with a symptomatic right cerebellar lesion and underwent surgical resection to demonstrate metastatic PTC. Extensive workup with computed tomography, neck ultrasound and FDG‐PET was suggestive of a left thyroid primary lesion, with FNA confirming PTC. However, total thyroidectomy demonstrated incidental microMTC (medullary thyroid microcarcinoma, defined as tumour

Abstract The aim of the present study was to analyze copy number variations (CNV) of multiple oncogenes and tumor suppressor genes in genomic DNA from primary tumor tissue, lymph node metastasis and cell-free DNA (cfDNA) from serum of 72 urothelial carcinoma of bladder (UCB) patients treated with radical cystectomy (RC), using multiplex ligation-dependent probe amplification (MLPA). We hypothesized that primary tumor and lymph node metastasis show similar CNV profiles, and CNV are more present in lymph node metastasis compared to primary tumor tissue. Samples from 43 (59.7%) patients could be analyzed. In total, 35 (83%), 26 (68%) and 8 (42%) patients had CNV in primary tumor, serum and lymph node metastasis, respectively. MYC, CCND1, ERBB2 and CCNE1 displayed the most frequent amplifications. In particular, CNV in ERBB2 was associated with aggressive tumor characteristics. CNV in both ERBB2 and TOP2A were risk factors for disease recurrence. The current findings show that CNV are present in various oncogenes and tumor suppressor genes in genomic DNA from primary tumor, lymph node metastasis and cfDNA from serum. CNV were more present in genomic DNA from primary tumor tissue compared to cfDNA from serum and genomic DNA from lymph node metastasis. Patients with CNV in ERBB2 and TOP2A are at increased risk for disease recurrence following RC. Further studies are necessary to validate, whether these genes may represent promising candidates for targeted-therapy.

Seven equimolar, five-component, metal diborides were fabricated via high-energy ball milling and spark plasma sintering. Six of them, including (Hf0.2Zr0.2Ta0.2Nb0.2Ti0.2)B2, (Hf0.2Zr0.2Ta0.2Mo0.2Ti0.2)B2, (Hf0.2Zr0.2Mo0.2Nb0.2Ti0.2)B2, (Hf0.2Mo0.2Ta0.2Nb0.2Ti0.2)B2, (Mo0.2Zr0.2Ta0.2Nb0.2Ti0.2)B2, and (Hf0.2Zr0.2Ta0.2Cr0.2Ti0.2)B2, possess virtually one solid-solution boride phase of the hexagonal AlB2 structure. Revised Hume-Rothery size-difference factors are used to rationalize the formation of high-entropy solid solutions in these metal diborides. Greater than 92% of the theoretical densities have been generally achieved with largely uniform compositions from nanoscale to microscale. Aberration-corrected scanning transmission electron microscopy (AC STEM), with high-angle annular dark-field and annular bright-field (HAADF and ABF) imaging and nanoscale compositional mapping, has been conducted to confirm the formation of 2-D high-entropy metal layers, separated by rigid 2-D boron nets, without any detectable layered segregation along the c-axis. These materials represent a new type of ultra-high temperature ceramics (UHTCs) as well as a new class of high-entropy materials, which not only exemplify the first high-entropy non-oxide ceramics (borides) fabricated but also possess a unique non-cubic (hexagonal) and layered (quasi-2D) high-entropy crystal structure that markedly differs from all those reported in prior studies. Initial property assessments show that both the hardness and the oxidation resistance of these high-entropy metal diborides are generally higher/better than the average performances of five individual metal diborides made by identical fabrication processing.

Lymphocytic hypophysitis is a rare neuroendocrine disease characterised by an autoimmune inflammatory disorder of the pituitary gland. We report a 50-year-old woman who presented with headaches and bilateral sixth cranial nerve palsies. MRI of the pituitary revealed extensive fibrosis involving the sellar and extending into both cavernous sinuses causing bilateral occlusion of the internal carotid arteries (ICA). Transphenoidal biopsy confirmed the diagnosis of infiltrative fibrotic lymphocytic hypophysitis. Symptoms resolved with high dose of oral steroids but relapsed on tapering, requiring several treatments of i.v. pulse steroids over 8 months. Rituximab combined with mycophenolate mofetil was required to achieve long-term symptom relief. Serial MRI pituitary imaging showed stabilisation of her disease without reduction in sellar mass or regression of ICA occlusion. The patient’s brain remained perfused solely by her posterior circulation. This case demonstrates an unusual presentation of a rare disease and highlights a successful steroid-sparing regimen in a refractory setting.

Struma ovarii is a rare, usually benign ovarian tumour with malignancy occurring in 3000 μg/L following recombinant TSH administration prior to her first dose of I131. At 25 months following radioiodine treatment, she is in remission with an undetectable thyroglobulin and clear I131 surveillance scans. This case demonstrates an unusual presentation of malignant struma ovarii together with challenges of predicting metastatic disease, and demonstrates a successful radioiodine regimen inducing remission.

ObjectivesNumbers of PIV are rising. The aim of this study is to analyze the surgical learning-curve (LC) on the grounds of perioperative complications.Patients and Methods108 PIVs, performed by a single surgeon between 2015 and 2018 have been analyzed. Learning-curve analysis was based on three factors: operating time, vaginal depth and complications.ResultsThe median FU was 6.3 months. Median age at surgery was 36 years, median time of hormone treatment was 36 months. The median CI was 0.3 and the median BMI was 25 kg/cm3. Median CCI® was 8.08. 40.7% of the patients developed short-term complications, more than half of which were Clavien I. Overall only 1.9% had Clavien IIIb complications. There were no Clavien IV or V complications. 17.6% of patients had wound infections, 13% wound dehiscence, 9.3% introitus strictures, 13.9% suffered from atrophy of the neovagina, i.e. loss of depth or width, and 8.3% from meatus urethrae strictures. Duration of hormonal therapy, BMI and CI had no impact on surgical outcome. Age had a significant impact on CCI®, as younger patients had a higher risk for complications. Use of scrotal skin and surgeries performed had a significant influence. LC analysis via CUSUM analysis showed that after 32 surgeries, the PIV is performed safely.ConclusionThe PIV is a safe GAS-technique, associated with minor complications leading to low rates of revision surgery. Younger age, the use of scrotal skin and surgeon's experience has significant impact on complications. Duration of hormonal therapy, circumcision and BMI has no impact on complications.

Significant progress has been achieved in the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, results in patients with aggressive variant prostate cancer (AVPC) have been disappointing. Here, we report retrospectively collected data from intensively pretreated AVPC patients (n = 17; 88.2% visceral metastases; 82% elevation of neuroendocrine markers) treated with salvage chemotherapy consisting of cisplatin, ifosfamide, and paclitaxel (TIP). At the interim analysis, 60% of patients showed radiographic response or stable disease (PFS = 2.5 months; OS = 6 months). In men who responded to chemotherapy, an OS > 15 months was observed. Preclinical analyses confirmed the high activity of the TIP regimen, especially in docetaxel-resistant prostate cancer cells. This effect was primarily mediated by increased cisplatin sensitivity in the emergence of taxane resistance. Proteomic and functional analyses identified a lower DNA repair capacity and cell cycle machinery deficiency to be causative. In contrast, paclitaxel showed inconsistent effects, partially antagonizing cisplatin and ifosfamide in some AVPC models. Consequently, paclitaxel has been excluded from the TIP combination for future patients. In summary, we report for the first time the promising efficacy of TIP as salvage therapy in AVPC. Our preclinical data indicate a pivotal role for cisplatin in overcoming docetaxel resistance.

A high-entropy metal disilicide, (Mo0.2Nb0.2Ta0.2Ti0.2W0.2)Si2, has been successfully synthesized. X-ray diffraction (XRD), energy dispersive X-ray spectroscopy (EDX), and electron backscatter diffraction (EBSD) collectively show the formation of a single high-entropy silicide phase. This high-entropy (Mo0.2Nb0.2Ta0.2Ti0.2W0.2)Si2 possesses a hexagonal C40 crystal structure with ABC stacking sequence and a space group of P6222. This discovery expands the known families of high-entropy materials from metals, oxides, borides, carbides, and nitrides to a silicide, for the first time to our knowledge, as well as demonstrating that a new, non-cubic, crystal structure (with lower symmetry) can be made into high-entropy phase. This (Mo0.2Nb0.2Ta0.2Ti0.2W0.2)Si2 exhibits high nanohardness of 16.7 ± 1.9 GPa and Vickers hardness of 11.6 ± 0.5 GPa. Moreover, it has a low thermal conductivity of 6.9 ± 1.1 W m−1 K−1, which is approximately one order of magnitude lower than that of the widely-used tetragonal MoSi2 and ∼1/3 of those reported values for the hexagonal NbSi2 and TaSi2 with the same crystal structure. Keywords: High-entropy ceramics, High-entropy silicide, Thermal conductivity, Hardness, C40 crystal structure

Objective: To investigate the value of standard [digital rectal examination (DRE), PSA] and advanced (mpMRI, prostate biopsy) clinical evaluation for prostate cancer (PCa) detection in contemporary patients with clinical bladder outlet obstruction (BOO) scheduled for Holmium laser enucleation of the prostate (HoLEP).Material and Methods: We retrospectively analyzed 397 patients, who were referred to our tertiary care laser center for HoLEP due to BOO between 11/2017 and 07/2020. Of those, 83 (20.7%) underwent further advanced clinical PCa evaluation with mpMRI and/or prostate biopsy due to elevated PSA and/or lowered PSA ratio and/or suspicious DRE. Logistic regression and binary regression tree models were applied to identify PCa in BOO patients.Results: An mpMRI was conducted in 56 (66%) of 83 patients and revealed PIRADS 4/5 lesions in 14 (25%) patients. Subsequently, a combined systematic randomized and MRI-fusion biopsy was performed in 19 (23%) patients and revealed in PCa detection in four patients (5%). A randomized prostate biopsy was performed in 31 (37%) patients and revealed in PCa detection in three patients (4%). All seven patients (9%) with PCa detection underwent radical prostatectomy with 29% exhibiting non-organ confined disease. Incidental PCa after HoLEP (n = 76) was found in nine patients (12%) with advanced clinical PCa evaluation preoperatively. In univariable logistic regression analyses, PSA, fPSA ratio, and PSA density failed to identify patients with PCa detection. Conversely, patients with a lower International Prostate Symptom Score (IPSS) and PIRADs 4/5 lesion in mpMRI were at higher risk for PCa detection. In multivariable adjusted analyses, PIRADS 4/5 lesions were confirmed as an independent risk factor (OR 9.91, p = 0.04), while IPSS did not reach significance (p = 0.052).Conclusion: In advanced clinical PCa evaluation mpMRI should be considered in patients with elevated total PSA or low fPSA ratio scheduled for BOO treatment with HoLEP. Patients with low IPSS or PIRADS 4/5 lesions in mpMRI are at highest risk for PCa detection. In patients with a history of two or more sets of negative prostate biopsies, advanced clinical PCa evaluation might be omitted.

The zebrafish is a promising model species in biomedical research, including neurotoxicology and neuroactive drug screening. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) evokes degeneration of dopaminergic neurons and is commonly used to model Parkinson’s disease (PD) in laboratory animals, including zebrafish. However, cognitive phenotypes in MPTP-evoked experimental PD models remain poorly understood. Here, we established an LD50 (292 mg/kg) for intraperitoneal MPTP administration in adult zebrafish, and report impaired spatial working memory (poorer spontaneous alternation in the Y-maze) in a PD model utilizing fish treated with 200 µg of this agent. In addition to conventional behavioral analyses, we also employed artificial intelligence (AI)-based approaches to independently and without bias characterize MPTP effects on zebrafish behavior during the Y-maze test. These analyses yielded a distinct cluster for 200-μg MPTP (vs. other) groups, suggesting that high-dose MPTP produced distinct, computationally detectable patterns of zebrafish swimming. Collectively, these findings support MPTP treatment in adult zebrafish as a late-stage experimental PD model with overt cognitive phenotypes.

Iatrogenic ureteral injuries and strictures are relatively common complication of pelvic surgery and radiation treatment. Left untreated they are associated with severe short- and long-term complications such as urinoma, septic state, renal failure, and loss of a renal unit. Treatment depends on timing of diagnosis, as well as extent of injury, and ranges from simple endoscopic management to complex surgical reconstruction under usage of pedicled grafts. While recent advances in ureteral tissue engineering are promising the topic is still underreported. Historically a domain of open surgery, laparoscopic and robotic-assisted approaches have proven their feasibility in small case series, and are increasingly being utilized as means of reconstructive surgery. This review aims to give an outline of incidence and treatment of ureteral injuries and strictures in light of the latest advances. Keywords: Iatrogenic, Outcomes, Reconstructive surgical procedures, Surgical technique, Surgical management, Trauma, Ureter, Ureteral strictures

Inhibitors of the bacterial enzyme dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE; EC 3.5.1.18) hold promise as antibiotics with a new mechanism of action. Herein we describe the discovery of a new series of indoline sulfonamide DapE inhibitors from a high-throughput screen and the synthesis of a series of analogs. Inhibitory potency was measured by a ninhydrin-based DapE assay recently developed by our group. Molecular docking experiments suggest active site binding with the sulfonamide acting as a zinc-binding group (ZBG).