Treatment and Long-Term Safety Outcomes of Peptide Receptor Radionuclide Therapy for Metastatic Neuroendocrine Tumours: An Asian Experience.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) is a targeted molecular therapy used to treat neuroendocrine tumours (NETs). It has been shown to be effective and well tolerated in patients with metastatic NETs in several centres in the USA, Europe, and Australia. Tolerability and efficacy data emerging from Asian centres remain few. Epidemiological evidence suggests that there are differences in neuroendocrine neoplasms between the population groups. We aim to describe the treatment and safety outcomes of PRRT in the Asian population. METHODS: One hundred and seven (107) patients with metastatic NETs who had undergone PRRT treatment from January 2012 to March 2019 were included in this retrospective study. The response rates using RECIST 1.1 and qualitative analysis were examined. The overall and progression-free survival curves were also evaluated. RESULTS: The median progression-free survival was 49 months. Response assessment after completion of treatment showed that 33 (37.9%) of 87 patients had partial or complete response. Subgroup analysis comparing high- and low-grade NET showed that there was a significant difference in the time to progression curves. Comparison of the number of cycles and progression-free and overall survival also showed a significant difference. Ten patients (9%) had grade 3 or more haematological toxicities. Four patients (4%) had grade 3/4 hepatobiliary toxicities, although the presence of extensive liver metastases was a confounding factor. None of the patients had grade 3/4 acute kidney injury. CONCLUSION: Our results show that PRRT is safe and effective in the treatment of metastatic NET in the Asian population. There was a significant difference in the progression-free survival curves between low-grade and high-grade NET and in the progression-free and overall survival comparing the number of cycles received.

International recommendations for personalised selective internal radiation therapy of primary and metastatic liver diseases with yttrium-90 resin microspheres.

PURPOSE: A multidisciplinary expert panel convened to formulate state-of-the-art recommendations for optimisation of selective internal radiation therapy (SIRT) with yttrium-90 (90Y)-resin microspheres. METHODS: A steering committee of 23 international experts representing all participating specialties formulated recommendations for SIRT with 90Y-resin microspheres activity prescription and post-treatment dosimetry, based on literature searches and the responses to a 61-question survey that was completed by 43 leading experts (including the steering committee members). The survey was validated by the steering committee and completed anonymously. In a face-to-face meeting, the results of the survey were presented and discussed. Recommendations were derived and level of agreement defined (strong agreement ≥ 80%, moderate agreement 50%-79%, no agreement ≤ 49%). RESULTS: Forty-seven recommendations were established, including guidance such as a multidisciplinary team should define treatment strategy and therapeutic intent (strong agreement); 3D imaging with CT and an angiography with cone-beam-CT, if available, and 99mTc-MAA SPECT/CT are recommended for extrahepatic/intrahepatic deposition assessment, treatment field definition and calculation of the 90Y-resin microspheres activity needed (moderate/strong agreement). A personalised approach, using dosimetry (partition model and/or voxel-based) is recommended for activity prescription, when either whole liver or selective, non-ablative or ablative SIRT is planned (strong agreement). A mean absorbed dose to non-tumoural liver of 40 Gy or less is considered safe (strong agreement). A minimum mean target-absorbed dose to tumour of 100-120 Gy is recommended for hepatocellular carcinoma, liver metastatic colorectal cancer and cholangiocarcinoma (moderate/strong agreement). Post-SIRT imaging for treatment verification with 90Y-PET/CT is recommended (strong agreement). Post-SIRT dosimetry is also recommended (strong agreement). CONCLUSION: Practitioners are encouraged to work towards adoption of these recommendations.

Acute and Delayed Deaths after West Nile Virus Infection, Texas, USA, 2002-2012.

Infection with West Nile virus (WNV) has a well-characterized acute disease process. However, long-term consequences are less understood. We searched death records for 4,142 residents of Texas, USA, infected with WNV during 2002-2012 and identified 557 (13%) deaths. We analyzed all-cause and cause-specific deaths after WNV infection by calculating standardized mortality ratios and using statewide mortality data. Acute-phase deaths (<90 days after symptom onset) occurred in 289 (7%) of case-patients; of those deaths, 289 (92%) were cases of West Nile neuroinvasive disease (WNND). Convalescent-phase deaths (>90 days after symptom onset) occurred in 268 (7%) of the remaining 3,853 case-patients; 210 (78%) of these deaths occurred in patients with WNND. Convalescent-phase WNND case-patients showed excess deaths from infectious and renal causes; case-patients <60 years of age had increased risk for all-cause death, specifically from renal, infectious, digestive, and circulatory causes. We provide population-level evidence of increased risk for death after WNV infection resulting in WNND.

Strontium enhances proliferation and osteogenic behavior of periodontal ligament cells in vitro.

BACKGROUND AND OBJECTIVE: Strontium (Sr) enhances osteogenic differentiation of certain multipotent cells. Periodontal ligament cells (PDLCs) are known to be multipotent, and Sr might be useful in periodontal bone tissue engineering. This study investigates the effect of high concentration of Sr on the proliferation and osteogenic behavior of PDLCs in vitro. MATERIAL AND METHODS: Primary human PDLCs were cultured in MEM + 10% FBS without (Ctrl) or with Sr in four diverse concentrations: Sr1, 11.3 × 10-3  mg/L, human serum physiological level; Sr2, 13 mg/L, typical human serum level after strontium ranelate treatment; Sr3, 130 mg/L, and Sr4, 360 mg/L. The spreading area (2, 4, 6, 24 hours), proliferation rate (1, 3, 7 days), osteogenic behavior (alkaline phosphatase - ALP activity, 7 and 14 days; expression of osteogenic genes, ALP, Runt-related transcription factor 2 - RUNX2, osteopontin - OPN, osteocalcin - OCN, and osteoprotegerin -OPG, 1, 3, 7, 14, 21 days), and formation of mineralized nodules (14 and 21 days) of the PDLCs were assessed. Data were compared group- and period-wise using ANOVA tests. RESULTS: Periodontal ligament cells cultured with Sr4 showed increased spreading area (after 4 hours), proliferation rate (from 3 days), and OCN and OPN (from 7 days) gene expression as compared to Ctrl, Sr1, Sr2, and Sr3. Sr4 also led to lower ALP activity (from 7 days), ALP (from 3 days), and RUNX2 (at 7 and 14 days) gene expression, together with more evident formation of mineralized nodules, compared to Ctrl, Sr1, Sr2, and Sr3. CONCLUSION: Periodontal ligament cells responded to Sr4 with increased cellular proliferation and osteogenic behavior in vitro.

Clinical and demographic pattern of chronic granulomatous disease (CGD) from a multicenter perspective: Malaysia's experience over 26 years.

BACKGROUND: A retrospective review of clinical manifestations and demographic pattern of patients diagnosed as chronic granulomatous disease (CGD) from 7 hospitals in Malaysia. An analysis of the available database would establish clinical characteristics, diagnoses and outcome including microbiologic pattern. Studying the demography allows us to document the occurrence of CGD amongst multiethnic groups and its geographical distribution for Malaysia. METHODS: Data from the Malaysia Primary Immunodeficiency Network (MyPIN) with cases of CGD diagnosed from 1991 until 2016 were collated and analysed. RESULTS: Twenty patients were diagnosed as CGD. Males (N = 13, 65%) outnumber females (N = 7, 35%). CGD is commonest amongst the Malays (65%) followed by the Chinese (15.0%), Indians (10.0%) and natives of Borneo (10.0%), reflecting the ethnic composition of the country. The mean age of diagnosis was 3.7 years. There was a positive family history in 40% of the cases. Abscess was the main presenting feature in 16 patients (80%) with one involving the brain. Pneumonia occurred in 10 (50%) and one with complicated bronchiectasis. Catalase-positive bacteria were the most commonly isolated pathogen with Chromobacterium violaceum predominating (N = 5, 25%) with consequent high mortality (N = 4, 80%). All CGD patients with C. violaceum infection displayed CD4 + (T helper cells) lymphopenia. CONCLUSION: This study has shown CGD occurs in the major ethnic groups of Malaysia. To the best of our knowledge, this is the first and the largest series of chronic granulomatous disease in South East Asia which may be reflective of similar clinical pattern in the region. C. violaceum infection is associated with a higher mortality in CGD patients in Malaysia. All the CGD patients with C. violaceum infection in this patient series displayed CD4 + (T helper) lymphopenia. We recorded rare clinical manifestation of CGD viz. brain abscess and bronchiectasis.

Mechanosensitivity of dental pulp stem cells is related to their osteogenic maturity.

For engineering bone tissue, mechanosensitive cells are needed for bone (re)modelling. Local bone mass and architecture are affected by mechanical loading, which provokes a cellular response via loading-induced interstitial fluid flow. We studied whether human dental pulp-derived mesenchymal stem cells (PDSCs) portraying mature (PDSC-mature) or immature (PDSC-immature) bone cell characteristics are responsive to pulsating fluid flow (PFF) in vitro. We also assessed bone formation by PDSCs on hydroxyapatite-tricalcium phosphate granules after subcutaneous implantation in mice. Cultured PDSC-mature exhibited higher osteocalcin and alkaline phosphatase gene expression and activity than PDSC-immature. Pulsating fluid flow (PFF) stimulated nitric oxide production within 5 min by PDSC-mature but not by PDSC-immature. In PDSC-mature, PFF induced prostaglandin E(2) production, and cyclooxygenase 2 gene expression was higher than in PDSC-immature. Implantation of PDSC-mature resulted in more osteoid deposition and lamellar bone formation than PDSC-immature. We conclude that PDSCs with a mature osteogenic phenotype are more responsive to pulsating fluid shear stress than osteogenically immature PDSCs and produce more bone in vivo. These data suggest that PDSCs with a mature osteogenic phenotype might be preferable for bone tissue engineering to restore, for example, maxillofacial defects, because they might be able to perform mature bone cell-specific functions during bone adaptation to mechanical loading in vivo.

Divide and Conquer: Strategies in Singapore to Manage a Nuclear Medicine Department During COVID-19.

The COVID-19 outbreak was declared a public health emergency of international concern by the World Health Organization on January 30, 2020. Since then, the virus has spread to affect more countries worldwide. During this period, our nuclear medicine department at Singapore General Hospital segregated our staff and patients by time, by space, or both, to minimize contact and prevent spread of the virus. Necessary changes to our clinical practices and stricter infection control measures were also enforced. We share our personal experience in managing a nuclear medicine department during this epidemic.

COVID-19: Four Paediatric Cases in Malaysia.

OBJECTIVE: This is a brief report of 4 paediatric cases of COVID-19 infection in Malaysia BACKGROUND: COVID-19, a coronavirus, first detected in Wuhan, China has now spread rapidly to over 60 countries and territories around the world, infecting more than 85000 individuals. As the case count amongst children is low, there is need to report COVID-19 in children to better understand the virus and the disease. CASES: In Malaysia, until end of February 2020, there were four COVID-19 paediatric cases with ages ranging from 20 months to 11 years. All four cases were likely to have contracted the virus in China. The children had no symptoms or mild flu-like illness. The cases were managed symptomatically. None required antiviral therapy. DISCUSSION: There were 2 major issues regarding the care of infected children. Firstly, the quarantine of an infected child with a parent who tested negative was an ethical dilemma. Secondly, oropharyngeal and nasal swabs in children were at risk of false negative results. These issues have implications for infection control. Consequently, there is a need for clearer guidelines for child quarantine and testing methods in the management of COVID-19 in children.

SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma.

Purpose Selective internal radiation therapy or radioembolization (RE) shows efficacy in unresectable hepatocellular carcinoma (HCC) limited to the liver. This study compared the safety and efficacy of RE and sorafenib in patients with locally advanced HCC. Patients and Methods SIRveNIB (selective internal radiation therapy v sorafenib), an open-label, investigator-initiated, phase III trial, compared yttrium-90 (90Y) resin microspheres RE with sorafenib 800 mg/d in patients with locally advanced HCC in a two-tailed study designed for superiority/detriment. Patients were randomly assigned 1:1 and stratified by center and presence of portal vein thrombosis. Primary end point was overall survival (OS). Efficacy analyses were performed in the intention-to-treat population and safety analyses in the treated population. Results A total of 360 patients were randomly assigned (RE, 182; sorafenib, 178) from 11 countries in the Asia-Pacific region. In the RE and sorafenib groups, 28.6% and 9.0%, respectively, failed to receive assigned therapy without significant cross-over to either group. Median OS was 8.8 and 10.0 months with RE and sorafenib, respectively (hazard ratio, 1.1; 95% CI, 0.9 to 1.4; P = .36). A total of 1,468 treatment-emergent adverse events (AEs) were reported (RE, 437; sorafenib, 1,031). Significantly fewer patients in the RE than sorafenib group had grade ≥ 3 AEs (36 of 130 [27.7%]) v 82 of 162 [50.6%]; P < .001). The most common grade ≥ 3 AEs were ascites (five of 130 [3.8%] v four of 162 [2.5%] patients), abdominal pain (three [2.3%] v two [1.2%] patients), anemia (zero v four [2.5%] patients), and radiation hepatitis (two [1.5%] v zero [0%] patients). Fewer patients in the RE group (27 of 130 [20.8%]) than in the sorafenib group (57 of 162 [35.2%]) had serious AEs. Conclusion In patients with locally advanced HCC, OS did not differ significantly between RE and sorafenib. The improved toxicity profile of RE may inform treatment choice in selected patients.

Positron emission tomography with 2-deoxy-2-[18f] fluoro-D-glucose in the detection of malignancy in intraductal papillary mucinous neoplasms of the pancreas.

A 79-year-old Indian male was admitted with upper abdominal discomfort of 1-year duration which was associated with loss of weight and appetite. Serum tumor markers, including carcinoembryonic antigen and carbohydrate antigen 19-9, were within normal limits. A computed tomographic scan demonstrated a cystically dilated and tortuous pancreatic duct measuring 1.9 cm, suggestive of an intraductal papillary mucinous neoplasm. Fusion positron emission tomography/computed tomography with 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography (FDG-PET/CT) which was subsequently performed confirmed a metabolically active focus within the pancreatic head mass with a standard uptake value (SUVmax) of 3.5 compatible with carcinoma. A total pancreatectomy was performed and the final histology demonstrated a main-duct type intraductal papillary mucinous neoplasm with a focus of high-grade dysplasia compatible with carcinoma-in-situ. These images illustrate the emerging utility of FDG-PET/CT in the preoperative detection of malignancy in intraductal papillary mucinous neoplasm.

Paradoxical orthodeoxia in a patient with a large thoracic aortic aneurysm.

INTRODUCTION: Orthodeoxia is a rare clinical syndrome characterised by dyspnoea and arterial deoxygenation that accompanies a change from a supine to erect position. CLINICAL PICTURE: We describe an unusual case of "paradoxical orthodeoxia" in a 70-year-old man with a thoracic aortic aneurysm: arterial desaturation when supine that improved when erect. TREATMENT AND OUTCOME: Non-invasive imaging revealed compression of the left pulmonary artery by the aneurysm (thoracic computed tomography) and patent foramen ovale (transesophageal echocardiography). Nuclear studies show decreased relative left lung perfusion attributable to the former, and right-to-left atrial shunt attributable to the latter. The degree of right-to-left shunt increases in the supine position: nuclear pulmonary shunt study shows shunt extent of 21% when supine versus 10% erect. CONCLUSION: A physioanatomical explanation is proposed.

Yttrium-90 hepatic radioembolization: clinical review and current techniques in interventional radiology and personalized dosimetry.

In recent years, yttrium-90 ((90)Y) microsphere radioembolization has been establishing itself as a safe and efficacious treatment for both primary and metastatic liver cancers. This extends to both first-line therapies as well as in the salvage setting. In addition, radioembolization appears efficacious for patients with portal vein thrombosis, which is currently a contraindication for surgery, transplantation and transarterial chemoembolization. This article reviews the efficacy and expanding use of (90)Y microsphere radioembolization with an added emphasis on recent advances in personalized dosimetry and interventional radiology techniques. Directions for future research into combination therapies with radioembolization and expansion into sites other than the liver are also explored.

Combinatorial Biomolecular Nanopatterning for High-Throughput Screening of Stem-Cell Behavior.

A novel combinatorial biomolecular nanopatterning method is reported, in which multiple biomolecular ligands can be patterned in multiple nanoscale dimensions on a single surface. The applicability of the combinatorial platform toward cell-biology applications is demonstrated by screening the adhesion behavior of a population of human dental pulp stem cell (hDPSC) on 64 combinations of nanopatterned extracellular matrix (ECM) proteins in parallel.

National Cancer Centre Singapore Consensus Guidelines for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the 6th most common cancer in the world, but the second most common cause of cancer death. There is no universally accepted consensus practice guidelines for HCC owing to rapid developments in new treatment modalities, the heterogeneous epidemiology and clinical presentation of HCC worldwide. However, a number of regional and national guidelines currently exist which reflect practice relevant to the epidemiology and collective experience of the consensus group. In 2014, clinicians at the multidisciplinary Comprehensive Liver Cancer Clinic (CLCC) at the National Cancer Centre Singapore (NCCS) reviewed the latest published scientific data and existing international and regional practice guidelines, such as those of the National Comprehensive Cancer Network, American Association for the Study of Liver Diseases and the Asian Pacific Association for the Study of the Liver, and modified them to reflect local practice. These would serve as a template by which treatment outcomes can be collated and benchmarked against international data. The NCCS Consensus Guidelines for HCC have been successfully implemented in the CLCC since their publication online on 26(th) September 2014, and the guidelines allow outcomes of treatment to be compared to international data. These guidelines will be reviewed periodically to incorporate new data.

Gender, Race, and Age at Diagnosis as Risk Factors for Metastasis or Recurrence among 1,657 Thyroid Cancer Patients Treated with Radioiodine across 40 Years in Singapore.

BACKGROUND: To obtain descriptive data on Singaporean thyroid cancer patients treated with radioiodine and to assess gender, race, and age at diagnosis as risk factors for metastasis or recurrence. METHODS: This is a retrospective study of all thyroid cancer patients treated with radioiodine of any prescribed activity at our institution. Data collected included: age at diagnosis, gender, race, histopathological type, duration of follow-up, and metastasis at diagnosis (locoregional or distant) or recurrence at any time. Gender, race, and age at diagnosis were analyzed for possible associations with metastasis or recurrence. RESULTS: A total of 1,657 thyroid cancer patients were treated with radioiodine across a 40-year period; mean follow-up 6.4 ± 6.9 years (median 4.2 years). 656 (39.6%) patients had metastasis or recurrence over the duration of their follow-up. Male gender (odds ratio (OR) 1.38; p = 0.006), Malay race (OR 1.71; p < 0.0001), and age at diagnosis of > 46 years (OR 1.31; p = 0.007) were significantly associated with metastasis or recurrence. CONCLUSION: Male gender, Malay race, and age at diagnosis of > 46 years were significant risk factors for metastasis or recurrence in Singaporean thyroid cancer patients treated with radioiodine.

Palatal myoclonus secondary to vertebral artery compression of the inferior olive.

A 47-year-old male with a 5-year history of palatal myoclonus was found on magnetic resonance imaging (MRI) examination to have an ectatic dominant left vertebral artery that compressed the left inferior olive. Microvascular decompression effectively eliminated his symptoms. This case and a similar case presented here with an ectatic vertebral-basilar system illustrate the value of standard MRI in conjunction with magnetic resonance angiography (MRA) in evaluating palatal myoclonus, and they suggest a potential role for decompressive surgery when persistent, highly symptomatic inferior olivary ischemia or compression occurs.