Effect of SARS and COVID-19 outbreaks on urology practice and training.

INTRODUCTION: The objective was to investigate the changes in urology practice during coronavirus disease 2019 (COVID-19) pandemic with a perspective from our experience with severe acute respiratory syndrome (SARS) in 2003. METHODS: Institutional data from all urology centres in the Hong Kong public sector during the COVID-19 pandemic (1 Feb 2020-31 Mar 2020) and a non-COVID-19 control period (1 Feb 2019-31 Mar 2019) were acquired. An online anonymous questionnaire was used to gauge the impact of COVID-19 on resident training. The clinical output of tertiary centres was compared with data from the SARS period. RESULTS: The numbers of operating sessions, clinic attendance, cystoscopy sessions, prostate biopsy, and shockwave lithotripsy sessions were reduced by 40.5%, 28.5%, 49.6%, 44.8%, and 38.5%, respectively, across all the centres reviewed. The mean numbers of operating sessions before and during the COVID-19 pandemic were 85.1±30.3 and 50.6±25.7, respectively (P=0.005). All centres gave priority to cancer-related surgeries. Benign prostatic hyperplasia-related surgery (39.1%) and ureteric stone surgery (25.5%) were the most commonly delayed surgeries. The degree of reduction in urology services was less than that during SARS (47.2%, 55.3%, and 70.5% for operating sessions, cystoscopy, and biopsy, respectively). The mean numbers of operations performed by residents before and during the COVID-19 pandemic were 75.4±48.0 and 34.9±17.2, respectively (P=0.002). CONCLUSION: A comprehensive review of urology practice during the COVID-19 pandemic revealed changes in every aspect of practice.

Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry.

BACKGROUND: Anti-PD1/PD-L1 directed immune checkpoint inhibitors (ICI) are widely used to treat patients with advanced non-small-cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction. PATIENTS AND METHODS: We conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS), and overall survival (OS) from ICI initiation. The primary end point was PFS under ICI. Secondary end points were best response (RECIST 1.1) and OS from ICI initiation. RESULTS: We studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n = 271), EGFR (n = 125), BRAF (n = 43), MET (n = 36), HER2 (n = 29), ALK (n = 23), RET (n = 16), ROS1 (n = 7), and multiple drivers (n = 1). Median age was 60 years, gender ratio was 1 : 1, never/former/current smokers were 28%/51%/21%, respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS = 26%, BRAF = 24%, ROS1 = 17%, MET = 16%, EGFR = 12%, HER2 = 7%, RET = 6%, and ALK = 0%. In the entire cohort, median PFS was 2.8 months, OS 13.3 months, and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2). CONCLUSIONS: : ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared with the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy as a single agent.

HER2 exon 20 insertions in non-small-cell lung cancer are sensitive to the irreversible pan-HER receptor tyrosine kinase inhibitor pyrotinib.

BACKGROUND: Effective targeted therapy for non-small-cell lung cancer (NSCLC) patients with human epidermal growth factor receptor 2 (HER2) mutations remains an unmet need. This study investigated the antitumor effect of an irreversible pan-HER receptor tyrosine kinase inhibitor, pyrotinib. PATIENTS AND METHODS: Using patient-derived organoids and xenografts established from an HER2-A775_G776YVMA-inserted advanced lung adenocarcinoma patient sample, we investigated the antitumor activity of pyrotinib. Preliminary safety and efficacy of pyrotinib in 15 HER2-mutant NSCLC patients in a phase II clinical trial are also presented. RESULTS: Pyrotinib showed significant growth inhibition of organoids relative to afatinib in vitro (P = 0.0038). In the PDX model, pyrotinib showed a superior antitumor effect than afatinib (P = 0.0471) and T-DM1 (P = 0.0138). Mice treated with pyrotinib displayed significant tumor burden reduction (mean tumor volume, -52.2%). In contrast, afatinib (25.4%) and T-DM1 (10.9%) showed no obvious reduction. Moreover, pyrotinib showed a robust ability to inhibit pHER2, pERK and pAkt. In the phase II cohort of 15 patients with HER2-mutant NSCLC, pyrotinib 400 mg resulted in a objective response rate of 53.3% and a median progression-free survival of 6.4 months. CONCLUSION: Pyrotinib showed activity against NSCLC with HER2 exon 20 mutations in both patient-derived organoids and a PDX model. In the clinical trial, pyrotinib showed promising efficacy. CLINICAL TRIAL REGISTRATION: NCT02535507.

Initial results of selective renal parenchymal clamping with an adjustable kidney clamp in nephron-sparing surgery: an easy way to minimise renal ischaemia.

INTRODUCTION: A renal parenchymal clamp has been used at our centre since March 2012. It is used in position over the kidney to achieve optimal vascular control of a tumour while minimising parenchymal ischaemia. This study aimed to report the feasibility, surgical outcome, and oncological control of a kidney clamp in partial nephrectomy. METHODS: This study was conducted at a teaching hospital in Hong Kong. Partial nephrectomies performed from January 2009 to March 2015 were reviewed. The tumour characteristics and surgical outcomes of kidney clamp were studied and compared with traditional hilar clamping. RESULTS: A total of 92 patients were identified during the study period. Kidney clamps were used in 20 patients and hilar clamping in 72, with a mean follow-up of 27 and 37 months, respectively. For patients in whom a kidney clamp was applied, all tumours were exophytic to a different extent and the majority (90%) were located at the polar region. The PADUA (preoperative aspects and dimensions used for an anatomical) classification nephrometry score was also lower than those in whom hilar clamping was used (7.07 vs 8.34; P=0.002). The clamp was used in open, laparoscopic, and robot-assisted surgery. Operating time was shorter (207 ± 72 mins vs 306 ± 80 mins; P<0.001) and estimated blood loss was lower (205 ± 191 mL vs 331 ± 275 mL; P=0.045) with kidney clamp. No acute kidney injury occurred. Postoperative renal function was comparable between the two groups. CONCLUSIONS: Partial nephrectomy using parenchymal clamping is safe and feasible in selected cases. The postoperative renal function and oncological control were satisfactory.

PEComa of the terminal ileum mesentery as a secondary tumour in an adult survivor of embryonal rhabdomyosarcoma.

Perivascular epithelioid cell tumours (pecomas) are rare mesenchymal tumours that are characterized by perivascular epithelioid cell differentiation and immunoreactivity to myogenic and melanocytic markers. These tumours can be classified as benign, uncertain malignant potential, or malignant. Because of the rarity of pecomas, their cause and clinical prognosis remain unclear. To the best of our knowledge, no reports in the literature describe a pecoma of the terminal ileum mesentery as a secondary tumour in an adult survivor of childhood embryonal rhabdomyosarcoma, let alone any childhood cancer. Here, we present the case of a 27-year-old man with a pecoma involving the mesentery of the terminal ileum. At the age of 5, he had been treated with a combination of chemotherapy and high-dose pelvic radiation therapy for embryonal rhabdomyosarcoma, most likely arising from the posterior bladder wall. During routine follow-up 22 years after this patient's initial treatment, computed tomography imaging revealed a mass within the terminal ileum mesentery. The tumour was successfully treated with surgical resection, and pathology examination determined the mass to be a pecoma with uncertain malignant potential. This first case of a pecoma of the terminal ileum mesentery arising within a high-dose radiation therapy field as a secondary tumour in an adult survivor of childhood cancer highlights the importance of screening and surveillance in high-risk childhood cancer survivors treated with high-dose radiation therapy. Further research to build a better understanding of this remarkably rare tumour is warranted.

The AMPK stress response pathway mediates anoikis resistance through inhibition of mTOR and suppression of protein synthesis.

Suppression of anoikis after detachment of cancer cells from the extracellular matrix is a key step during metastasis. Here we show that, after detachment, mouse embryonic fibroblasts (MEFs) transformed by K-Ras(V12) or ETV6-NTRK3 (EN) activate a transcriptional response overrepresented by genes related to bioenergetic stress and the AMP-activated protein kinase (AMPK) energy-sensing pathway. Accordingly, AMPK is activated in both transformed and non-transformed cells after detachment, and AMPK deficiency restores anoikis to transformed MEFs. However, AMPK activation represses the mTOR complex-1 (mTORC1) pathway only in transformed cells, suggesting a key role for AMPK-mediated mTORC1 inhibition in the suppression of anoikis. Consistent with this, AMPK-/- MEFs transformed by EN or K-Ras show sustained mTORC1 activation after detachment and fail to suppress anoikis. Transformed TSC1-/- MEFs, which are incapable of suppressing mTORC1, also undergo anoikis after detachment, which is reversed by mTORC1 inhibitors. Furthermore, transformed AMPK-/- and TSC1-/- MEFs both have higher total protein synthesis rates than wild-type controls, and translation inhibition using cycloheximide partially restores their anoikis resistance, indicating a mechanism whereby mTORC1 inhibition suppresses anoikis. Finally, breast carcinoma cell lines show similar detachment-induced AMPK/mTORC1 activation and restoration of anoikis by AMPK inhibition. Our data implicate AMPK-mediated mTORC1 inhibition and suppression of protein synthesis as a means for bioenergetic conservation during detachment, thus promoting anoikis resistance.

Immunoglobulin G4-related sclerosing disease: experience with this novel entity in a local hospital.

OBJECTIVE: To review the site of involvement, clinical presentation, and treatment outcome of patients having immunoglobulin G4-related sclerosing disease in a local regional hospital. DESIGN: Retrospective case series. SETTING: Pamela Youde Nethersole Eastern Hospital, Hong Kong. PATIENTS: All patients with a diagnosis of immunoglobulin G4-related sclerosing disease in the hospital diagnosed in the period from April 2008 to March 2010. RESULTS: A total of 12 patients with involvement of various organs were identified. There was a male predominance (male-to-female ratio=5:1). The mean age at diagnosis was 65 years. The salivary glands, biliary tract, pancreas, and cervical lymph nodes were the commonest involved sites. The immunoglobulin G4 level was elevated in 83% of the patients. Patients usually appeared to respond well to steroid treatment. CONCLUSION: Immunoglobulin G4-related sclerosing disease is a systemic disease and can involve various systems.

Oyster-associated outbreaks of Norovirus gastroenteritis in Singapore.

Outbreaks of gastroenteritis associated with the consumption of raw imported half-shelled frozen oysters occurred in Singapore between 16 Dec 2003 and 04 Jan 2004. A total of 305 cases were reported with clinical symptoms of diarrhoea (94%), abdominal cramps (72%), vomiting (69%) and fever (54%). The median incubation period was 30.8h and the duration of illness was 2-3 days. The overall relative risk of oyster consumption was 14.1 (95% CI: 8.3-24.0, P<0.001). Stool and oyster samples tested negative for common bacterial pathogens, including Vibrio parahaemolyticus. However, stool samples were positive for the presence of Norovirus group II RNA via RT PCR while oyster samples indicated the presence of Norovirus particles by electron microscopy. The clinical and epidemiological features were suggestive of Norovirus gastroenteritis and were subsequently confirmed by laboratory tests of stools and implicated oysters. Steps have been taken to ensure that food outlets do not thaw frozen oysters and serve them raw.

Clinical drug evaluation: the regulatory perspectives.

INTRODUCTION: This paper presents the regulatory perspectives of the clinical drug evaluation process and the role of the newly established Centre for Drug Evaluation in Singapore in this process. It describes the major drug evaluation systems in the developed countries and their similarities and differences. METHODS: The issues related to the benefits and risks assessments of new drugs are discussed, with examples, against the backdrop of the various drug evaluation systems and medical practices. RESULTS: The implications of Singapore's Medicines (Clinical Trial) (Amendment) Regulations 1998 and the Singapore Good Clinical Practice Guidelines published by the Ministry of Health in 1998 were discussed. The future development of international harmonisation in the context of the International Conference on Harmonisation was explored. CONCLUSIONS: Building the capability for the evaluation of new drugs is essential as part of the regulatory infrastructure for a knowledge-based economy in Singapore. To conduct better clinical trials, investigators should develop a good understanding of the clinical drug evaluation process and an appreciation of the regulatory angle.

A 10-year review of drug seizures in Singapore.

The trend of illicit drug seizures and analysis in Singapore over a 10-year period from 1986 to 1995 was examined and reviewed. The main drugs were heroin, opium, cannabis, and illicit tablets containing benzodiazepines and amphetamines. The emergence of amphetamines in early 1996 was a major departure from the traditional drug abuse pattern in Singapore. Changes in the legal definitions of opium and cannabis were also reviewed.

Forensic applications of DNA profiling.

Deoxyribonucleic acid (DNA) profiling is a powerful forensic tool to identify and individualise biological evidence recovered at crime scenes. Its discriminating power and evidential value are exemplified by many actual forensic cases. Development of new DNA typing techniques, such as the amplification of fluorescently tagged short tandem repeats, would further enhance this capability in forensic investigation.

The development of DNA profiling database in an HAE III based RFLP system for Chinese, Malays, and Indians in Singapore.

Deoxyribonucleic acid (DNA) restriction fragment length polymorphism (RFLP) profiles were obtained for blood specimens from the three population groups--Chinese, Malays and Indians--in Singapore. The population databases were collected from Hae III digested high molecular weight DNA hybridized with four variable number of tandem repeats (VNTR) loci--D2S44, D10S28, D4S139 and D1S7. The data were analyzed statistically using the fixed bin system. Comparison of ratio of bin frequencies of these population data with published data on whites, blacks, and hispanics shows that the alleleic distribution at these loci is not seriously different among the six groups. This has important implications to the statistical significance of forensic DNA applications.

Dope testing in sports: scientific and medico-legal issues.

The paper reviews current issues related to dope testing in sports from the scientific as well as the medico-legal perspectives. The various types of doping, their modes of use and the dangerous consequences of misuse are discussed. It was pointed out that national doping control programmes are essential for the prevention of drug abuse in sports and that proper procedures for sampling and analysis in accredited laboratories are necessary to ensure that justice is done for the competitors and for all others concerned. There was a need for continuous vigilance against drug abuse in sports. Continuous improvement of the dope testing methods, better understanding of the pharmacology of the drugs involved and regular reviews of the banned drugs list are essential to advance the cause of dope control in sports.

Haemophilus influenzae septicaemia in the neonate: report of two cases and review of the English literature.

Two neonates with early onset respiratory illness were found to have Haemophilus influenzae septicaemia. One of them died. A review of the English literature showed that Haemophilus influenzae septicaemia is increasing in incidence. Almost all cases presented with respiratory distress in the first 2 days. Other associated features included meningitis, arthritis, conjunctivitis and cellulitis. The mortality, which averaged 52%, was high, especially in premature babies. The septicaemia was caused by ascending infection from the colonized maternal birth canal, and most cases were caused by nontypable strains of Haemophilus influenzae. Because of the occurrence of ampicillin or chloramphenicol resistance, a third generation cephalosporin is the treatment of choice for known cases of serious infection.

The computerisation of scientific services.

A full computerised laboratory information management system has been developed in the Department of Scientific Services. The system manages the acquisition and flow of laboratory data. A novel automated reporting procedure has been developed to generate customised laboratory reports. Based on the workload values of laboratory tests, the system integrates the laboratory data with management information to provide rapid and reliable productivity measurement and cost and pricing computations.

Spectrophotometric determination of hydralazine hydrochloride tablets using ninhydrin.

A method is described for the assay of hydralazine HCl in tablets, based on the colored product formed by the reaction between hydralazine and ninhydrin. The reaction is conducted at room temperature in a pH 3 buffer solution and the colored product is measured spectrophotometrically at the absorption maximum at 442 nm. Under the stipulated conditions, this reaction is highly specific for hydralazine and is not affected by other drugs which may be used in combination with hydralazine. Results of infrared and mass spectrometric studies suggested that the colored product is a hydrazone. Ultraviolet spectrophotometry also showed that dilute solutions of hydralazine degrade rapidly in the presence of alcohols.

A gas chromatographic/mass spectrometric study of the trimethylsilylation of ethambutol and a tablets assay method based on the trimethylsilyl derivative.

The trimethylsilylation of ethambutol base and ethambutol hydrochloride was studied by means of GC/MS. The derivatisation is shown to proceed in two distinct steps, and the second derivative is identified, by both chemical ionisation and electron impact Ms, and the di-trimethylsilyl ethambutol. Most of the major mass fragments observed are assigned. A tablets assay method, based on the direct trimethylsilylation of ethambutol hydrochloride in tablets, is also described. It is simple, rapid, and unaffected by the presence of the common excipients in the tablets.