Identification of Genomic Variants Associated with the Risk of Acute Lymphoblastic Leukemia in Native Americans from Brazilian Amazonia.

A number of genomic variants related to native American ancestry may be associated with an increased risk of developing Acute Lymphoblastic Leukemia (ALL), which means that Latin American and hispanic populations from the New World may be relatively susceptible to this disease. However, there has not yet been any comprehensive investigation of the variants associated with susceptibility to ALL in traditional Amerindian populations from Brazilian Amazonia. We investigated the exomes of the 18 principal genes associated with susceptibility to ALL in samples of 64 Amerindians from this region, including cancer-free individuals and patients with ALL. We compared the findings with the data on populations representing five continents available in the 1000 Genomes database. The variation in the allele frequencies found between the different groups was evaluated using Fisher's exact test. The analyses of the exomes of the Brazilian Amerindians identified 125 variants, seven of which were new. The comparison of the allele frequencies between the two Amerindian groups analyzed in the present study (ALL patients vs. cancer-free individuals) identified six variants (rs11515, rs2765997, rs1053454, rs8068981, rs3764342, and rs2304465) that may be associated with susceptibility to ALL. These findings contribute to the identification of genetic variants that represent a potential risk for ALL in Amazonian Amerindian populations and might favor precision oncology measures.

Multicentre study of hospitalised patients with sports- and recreational cycling-related traumatic brain injury in Hong Kong.

INTRODUCTION: Cycling is associated with a greater risk of traumatic brain injury (TBI) than other recreational activities. This study aimed to investigate the epidemiology of sports-related TBI in Hong Kong and to examine predictors for recreational cycling-induced intracranial haemorrhage. METHODS: This retrospective multicentre study included patients diagnosed with sports-related TBI in public hospitals in Hong Kong from 2015 to 2019. Computed tomography scans were reviewed by an independent assessor. The primary endpoint was traumatic intracranial haemorrhage. The secondary endpoint was an unfavourable Glasgow Outcome Scale (GOS) score at discharge from hospital. RESULTS: In total, 720 patients were hospitalised with sports-related TBI. The most common sport was cycling (59.2%). The crude incidence of cycling-related TBI was 1.1 per 100 000 population. Cyclists were more likely to exhibit intracranial haemorrhage and an unfavourable GOS score, compared with patients who had TBI because of other sports. Although 47% of cyclists had intracranial haemorrhage, only 15% wore a helmet. In multivariate analysis, significant predictors for intracranial haemorrhage were age ≥60 years, antiplatelet medication, moderate or severe TBI, and skull fracture. Among 426 cyclists, 375 (88%) had mild TBI, and helmet wearing was protective against intracranial haemorrhage, regardless of age, antiplatelet medication intake, and mechanism of injury. Of 426 cyclists, 31 (7.3%) had unfavourable outcomes on discharge from hospital. CONCLUSIONS: The incidence of sports-related TBI is low in Hong Kong. Although cycling-related head injuries carried greater risks of intracranial haemorrhage and unfavourable outcomes compared with other sports, most cyclists experienced good recovery. Helmet wearing among recreational cyclists with mild TBI was protective against intracranial haemorrhage and skull fracture.

Pre-hospital stroke screening and notification of patients with reperfusion-eligible acute ischaemic stroke using modified Face Arm Speech Time test.

OBJECTIVES: To investigate the effects of pre-hospital stroke screening and notification on reperfusion therapy for patients with acute ischaemic stroke. METHODS: Pre-hospital stroke screening criteria were established based on a modified version of the Face Arm Speech Time (FAST) test. Screening was performed during ambulance transport by emergency medical service (EMS) personnel who completed a 2-hour training session on stroke screening. Temporal trends affecting acute ischaemic stroke investigation and intervention were compared before and after implementation of the pre-hospital screening. RESULTS: From July 2018 to October 2019, 298 patients with suspected stroke were screened by EMS personnel during ambulance transport prior to hospital arrival. Of these 298 patients, 213 fulfilled the screening criteria, 166 were diagnosed with acute stroke, and 32 received reperfusion therapy. The onset-to-door time was shortened by more than 1.5 hours (100.6 min vs 197.6 min, P<0.001). The door-to-computed tomography time (25.6 min vs 32.0 min, P=0.021), door-to-needle time (49.2 min vs 70.1 min, P=0.003), and door-to-groin puncture time for intra-arterial mechanical thrombectomy (126.7 min vs 168.6 min, P=0.04) were significantly shortened after implementation of the pre-hospital screening and notification, compared with historical control data of patients admitted from January 2018 to June 2018, before implementation of the screening system. CONCLUSION: Implementation of pre-hospital stroke screening using criteria based on a modified version of the FAST test, together with pre-arrival notification, significantly shortened the door-to-reperfusion therapy time for patients with ischaemic stroke. Pre-hospital stroke screening during ambulance transport by EMS personnel who complete a 2-hour focused training session is effective for identifying reperfusion-eligible patients with stroke.

Combined aspiration thrombectomy and continuous intrasinus thrombolysis for cerebral venous sinus thrombosis: technical note and case series.

Cerebral venous sinus thrombosis is an uncommon cause of stroke with high morbidity and mortality rates from venous infarction, intracranial hemorrhage, and extensive cerebral edema. Endovascular treatment with various devices has been proposed as a salvage treatment when standard medical treatment with systemic anticoagulation is ineffective, especially in long segment dural sinus thrombosis. We describe our technique of transvenous endovascular aspiration thrombectomy with large bore thrombectomy catheters, followed by placement of microcatheter for local thrombolytic infusion at the site of thrombosis. We report a retrospective study of angiographic and clinical outcome of six consecutive patients treated with this approach. Endovascular aspiration thrombectomy with large bore catheters followed by continuous local thrombolytic infusion appeared to be a safe and effective salvage treatment for selected patients with cerebral dural venous sinus thrombosis refractory to medical treatment.

Emergency thrombectomy for acute ischaemic stroke: current evidence, international guidelines, and local clinical practice.

Acute ischaemic stroke due to large vessel occlusion leads to grave neurological morbidity and mortality. Conventional intravenous thrombolysis is ineffective in achieving timely reperfusion in this group of patients. The publication of five positive randomised controlled trials of emergency thrombectomy for acute ischaemic stroke in 2015 provided strong evidence to support endovascular reperfusion therapy and represented a paradigm shift in acute stroke management. In this article, we review the current evidence and international guidelines, and report on the findings of a survey study of the clinical practice and opinions of local neurologists, neurosurgeons, and interventional radiologists in emergency thrombectomy. We also discuss the controversies around thrombectomy treatment, local experience, and suggestions to incorporate thrombectomy in acute stroke treatment.

Primary ventriculoperitoneal shunting outcomes: a multicentre clinical audit for shunt infection and its risk factors.

OBJECTIVES: To determine the frequency of primary ventriculoperitoneal shunt infection among patients treated at neurosurgical centres of the Hospital Authority and to identify underlying risk factors. METHODS: This multicentre historical cohort study included consecutive patients who underwent primary ventriculoperitoneal shunting at a Hospital Authority neurosurgery centre from 1 January 2009 to 31 December 2011. The primary endpoint was shunt infection, defined as: (1) the presence of cerebrospinal fluid or shunt hardware culture that yielded the pathogenic micro-organism with associated compatible symptoms and signs of central nervous system infection or shunt malfunction; or (2) surgical incision site infection requiring shunt reinsertion (even in the absence of positive culture); or (3) intraperitoneal pseudocyst formation (even in the absence of positive culture). Secondary endpoints were shunt malfunction, defined as unsatisfactory cerebrospinal fluid drainage that required shunt reinsertion, and 30-day mortality. RESULTS: A primary ventriculoperitoneal shunt was inserted in 538 patients during the study period. The mean age of patients was 48 years (range, 13-88 years) with a male-to-female ratio of 1:1. Aneurysmal subarachnoid haemorrhage was the most common aetiology (n=169, 31%) followed by intracranial tumour (n=164, 30%), central nervous system infection (n=42, 8%), and traumatic brain injury (n=27, 5%). The mean operating time was 75 (standard deviation, 29) minutes. Shunt reinsertion and infection rates were 16% (n=87) and 7% (n=36), respectively. The most common cause for shunt reinsertion was malfunction followed by shunt infection. Independent predictors for shunt infection were: traumatic brain injury (adjusted odds ratio=6.2; 95% confidence interval, 2.3-16.8), emergency shunting (2.3; 1.0-5.1), and prophylactic vancomycin as the sole antibiotic (3.4; 1.1-11.0). The 30-day all-cause mortality was 6% and none were directly procedure-related. CONCLUSIONS: This is the first Hong Kong territory-wide review of infection in primary ventriculoperitoneal shunts. Although the ventriculoperitoneal shunt infection rate met international standards, there are areas of improvement such as vancomycin administration and the avoidance of scheduling the procedure as an emergency.

Inhibition of prolyl 4-hydroxylase, beta polypeptide (P4HB) attenuates temozolomide resistance in malignant glioma via the endoplasmic reticulum stress response (ERSR) pathways.

BACKGROUND: Glioblastoma multiforme (GBM), the most aggressive malignant primary brain tumor of the central nervous system, is characterized by a relentless disease recurrence despite continued advancement in surgery, radiotherapy, and chemotherapy. Resistance to temozolomide (TMZ), a standard chemotherapeutic agent for GBM, remains a major challenge. Understanding the mechanisms behind TMZ resistance can direct the development of novel strategies for the prevention, monitoring, and treatment of tumor relapse. METHODS AND RESULTS: Our research platform, based on the establishment of 2 pairs of TMZ-sensitive/resistant GBM cells (D54-S and D54-R; U87-S and U87-R), has successfully identified prolyl 4-hydroxylase, beta polypeptide (P4HB) over-expression to be associated with an increased IC50 of TMZ. Elevated P4HB expression was verified using in vivo xenografts developed from U87-R cells. Clinically, we found that P4HB was relatively up-regulated in the recurrent GBM specimens that were initially responsive to TMZ but later developed acquired resistance, when compared with treatment-naive tumors. Functionally, P4HB inhibition by RNAi knockdown and bacitracin inhibition could sensitize D54-R and U87-R cells to TMZ in vitro and in vivo, whereas over-expression of P4HB in vitro conferred resistance to TMZ in both D54-S and U87-S cells. Moreover, targeting P4HB blocked its protective function and sensitized glioma cells to TMZ through the PERK arm of the endoplasmic reticulum stress response. CONCLUSIONS: Our study identified a novel target together with its functional pathway in the development of TMZ resistance. P4HB inhibition may be used alone or in combination with TMZ for the treatment of TMZ-resistant GBM.

Angioplasty and stenting for intracranial atherosclerotic stenosis: position statement of the Hong Kong Society of Interventional and Therapeutic Neuroradiology.

As a means of preventing secondary ischaemic stroke, angioplasty and stenting are considered potentially beneficial for patients with severe intracranial atherosclerotic stenosis. However, the role of stenting has been challenged since the publication of the first randomised controlled trial on Stenting versus Aggressive Medical Management for Preventing Recurrent stroke in Intracranial arterial Stenosis (SAMMPRIS). This indicated that aggressive medical management was superior to stenting using Wingspan to prevent recurrent stroke, because stenting has a high peri-procedural stroke and death rate. In this paper, we review the management of intracranial atherosclerosis, revisit the skepticism on stenting, and state our position on the topic in the form of recommendations. These are based on the prevalence of the disease in Hong Kong, the high risk of recurrent stroke despite medical therapy in the presence of haemodynamic intracranial stenosis without sufficient collaterals, an analysis of the weak points of SAMMPRIS, and results of clinical studies in Hong Kong.

Pipeline embolization device for intracranial aneurysm: a systematic review.

INTRODUCTION: The pipeline embolization device (PED) is a new endovascular stent designed for the treatment of challenging intracranial aneurysms (IAs). Its use has been extended to nonruptured and ruptured IAs of a variety of configurations and etiologies in both the anterior and posterior circulations. METHODS: We conducted a systematic review of ten eligible reports on its clinical efficacy and safety. RESULTS: There were 414 patients with 448 IAs. The majority of the IAs were large (40.2 %), saccular or blister-like (78.3 %), and were located mostly in the anterior circulation (83.5 %). The regimens of antiplatelet therapy varied greatly between and within studies. The mean number of the PED used was 2.0 per IA. Deployment was successful in around 95 % of procedures. Aneurysm obliteration was achieved in 82.9 % of IAs at 6-month. The overall incidences of periprocedural intracranial vascular complication rate and mortality rate were 6.3 and 1.5 %, respectively. CONCLUSION: The PED is a safe and effective treatment for nonruptured IAs. Its use in the context of acute subarachnoid hemorrhage (SAH) should be cautioned. Its main limitations include the need for prolonged antiplatelet therapy, as well as the potential risks of IA rupture and non-IA-related intracerebral hemorrhages (ICH). Future studies should aim at identifying factors that predispose to incomplete obliteration, delayed rupture, and thromboembolic complications.

Functional survival after acute care for severe head injury at a designated trauma center in Hong Kong.

BACKGROUND: Severe head injury is known to be a major cause of early mortalities and morbidities. Patients' long-term outcome after acute care, however, has not been widely studied. We aim to review the outcome of severely head-injured patients after discharge from acute care at a designated trauma center in Hong Kong. MATERIALS AND METHODS: This is a retrospective study of prospectively collected data of patients admitted with severe head injuries between 2004 and 2008. Patients' functional status post-discharge was assessed using the Extended Glasgow Outcome Score (GOSE). RESULTS: Of a total of 1565 trauma patients, 116 had severe head injuries and 41 of them survived acute hospital care. Upon the last follow-up, 23 (56.1%) of the acute-care survivors had improvements in their GOSE, six (11.8%) experienced deteriorations, and 12 (23.5%) did not exhibit any change. The greatest improvement was observed in patients with GOSE of 5 and 6 upon discharge, but two of the 16 patients with GOSE 2 or 3 also had a good recovery. On logistic regression analysis, old age and prolonged acute hospital stay were found to be independent predictors of poor functional outcome after a mean follow-up duration of 42 months. CONCLUSION: Multidisciplinary neurorehabilitation service is an important component of comprehensive trauma care. Despite significant early mortalities, a proportion of severely head-injured patients who survive acute care may achieve good long-term functional recovery.

Hyperoxia resensitizes chemoresistant human glioblastoma cells to temozolomide.

Temozolomide (TMZ) is standard chemotherapy for glioblastoma multiforme (GBM). Intratumoral hypoxia is common in GBM and may be associated with the development of TMZ resistance. Oxygen therapy has previously been reported to potentiate the effect of chemotherapy in cancer. In this study, we investigated whether hyperoxia can enhance the TMZ-induced cytotoxicity of human GBM cells, and whether and how it would resensitize TMZ-resistant GBM cells to TMZ. TMZ-sensitive human GBM cells (D54-S and U87-S) were treated with TMZ to develop isogenic subclones of TMZ-resistant cells (D54-R and U87-R). All cell lines were then exposed to different oxygen levels (1, 21, 40, or 80 %), with or without concomitant TMZ treatment, before assessment of cell cytotoxicity and morphology. Cell death and survival pathways elicited by TMZ and/or hyperoxia were elucidated by western blotting. Our results showed that TMZ sensitivity of both chemo-sensitive and resistant cells was enhanced significantly under hyperoxia. At the cell line-specific optimum oxygen concentration (D54-R, 80 %; U87-R, 40 %), resistant cells had the same response to TMZ as the parent chemosensitive cells under normoxia via the caspase-dependent pathway. Both TMZ and hyperoxia were associated with increased phosphorylation of ERK p44/42 MAPK (Erk1/2), but to a lesser extent in D54-R cells, suggesting that Erk1/2 activity may be involved in regulation of hyperoxia and TMZ-mediated cell death. Overall, hyperoxia enhanced TMZ toxicity in GBM cells by induction of apoptosis, possibly via MAPK-related pathways. Induced hyperoxia is a potentially promising approach for treatment of TMZ-resistant GBM.

Protein alterations associated with temozolomide resistance in subclones of human glioblastoma cell lines.

Temozolomide (TMZ) is the standard chemotherapeutic agent for human malignant glioma, but intrinsic or acquired chemoresistance represents a major obstacle to successful treatment of this highly lethal group of tumours. Obtaining better understanding of the molecular mechanisms underlying TMZ resistance in malignant glioma is important for the development of better treatment strategies. We have successfully established a passage control line (D54-C10) and resistant variants (D54-P5 and D54-P10) from the parental TMZ-sensitive malignant glioma cell line D54-C0. The resistant sub-cell lines showed alterations in cell morphology, enhanced cell adhesion, increased migration capacities, and cell cycle arrests. Proteomic analysis identified a set of proteins that showed gradual changes in expression according to their 50% inhibitory concentration (IC(50)). Successful validation was provided by transcript profiling in another malignant glioma cell line U87-MG and its resistant counterparts. Moreover, three of the identified proteins (vimentin, cathepsin D and prolyl 4-hydroxylase, beta polypeptide) were confirmed to be upregulated in high-grade glioma. Our data suggest that acquired TMZ resistance in human malignant glioma is associated with promotion of malignant phenotypes, and our reported molecular candidates may serve not only as markers of chemoresistance but also as potential therapeutic targets in the treatment of TMZ-resistant human malignant glioma, providing a platform for future investigations.

Surgical recanalisation of thrombosed M2 trunk after coil embolisation of a ruptured middle cerebral artery aneurysm.

Thromboembolic events are known complications of endovascular coiling of intracerebral aneurysms. We report a case of a 50-year-old patient whose ruptured middle cerebral artery aneurysm was treated with endovascular coiling, which was complicated by occlusion of the inferior M2 trunk during the procedure. An emergency craniotomy was performed to enable coil retrieval, evacuation of the thrombus and clipping of the aneurysm. All the middle cerebral artery branches were recanalised and the patient recovered with no neurological deficits. Our experience suggests that an emergency salvage operation for thrombosis after endovascular coiling is a treatment option offering a good clinical outcome.

Size, location, and multiplicity of ruptured intracranial aneurysms in the Hong Kong Chinese population with subarachnoid haemorrhage.

OBJECTIVE: To review the pattern of ruptured intracranial aneurysms in terms of size, location, and the prevalence of multiple aneurysms in the Hong Kong Chinese population with subarachnoid haemorrhage. DESIGN: Retrospective study. SETTING: Three public hospitals in Hong Kong. PATIENTS: A total of 267 Chinese patients with subarachnoid haemorrhage from ruptured intracranial aneurysms between July 1998 and June 2002 were reviewed retrospectively. RESULTS: The patients had a mean age of 59 (range, 13-96) years, with a female-to-male ratio of 2:1. Concerning the age at presentation, males presented with ruptured intracranial aneurysms at a younger age (P=0.001) than females. Ruptured aneurysms were more commonly located in the anterior than posterior circulation (84% vs 16%). The posterior communicating artery (26%) and anterior communicating artery (22%) were the most common sites of rupture. As a whole, 64% of the aneurysms had a size of 5 mm or less. The anterior communicating artery had a higher proportion with a size of 5 mm or less compared to other locations (P<0.05). In this cohort, the prevalence of multiple aneurysms was 17%. There was no significant difference in the prevalence of multiple aneurysms between men and women (P=0.30). In patients with multiple aneurysms, the sizes of ruptured aneurysms were greater than those of the largest unruptured aneurysms (P<0.001). When compared with the group with single aneurysms, patients with multiple aneurysms had a smaller proportion of small aneurysms, sized 5 mm or less (P<0.05). CONCLUSIONS: The pattern of ruptured intracranial aneurysms in the Hong Kong Chinese population was different from western and Japanese populations. Although the distribution of locations for ruptured aneurysms was similar, Hong Kong Chinese had a larger proportion of small aneurysms sized 5 mm or less. The prevalence of multiple aneurysms in Hong Kong is comparable to that in the Japanese population, but lower than that in the western populations.

Meta-analysis using individual patient data from randomised trials to assess the effectiveness of laparoscopic uterosacral nerve ablation in the treatment of chronic pelvic pain: a proposed protocol.

BACKGROUND: Currently, there are a number of clinical trials, but no international collaboration for collating research on effectiveness of laparoscopic uterosacral nerve ablation (LUNA) for alleviating chronic pelvic pain. OBJECTIVE: Meta-analysis was used by collecting individual patient data (IPD) from the existing trials, to provide a comprehensive assessment of the effectiveness of LUNA that will be generalisable in various clinical contexts. METHODS: IPD will be sought and collected from all relevant (both already finished and continuing) randomised trials identified through previous systematic reviews. After obtaining raw data and cleaning the database, analysis will be of all patients ever randomised based on the intention-to-treat principle using endpoints measured at 12 months following randomisation. PROPOSAL: We will update searches, contact all authors, obtain data in whatever form it can be provided, build a single database, produce results for individual studies, have them verified by original authors, explore of any heterogeneity and reasons behind it and finally pool all raw data in to a meta-analysis using appropriate statistical methods. The project will test the effectiveness of LUNA for women with chronic pelvic pain. It will also motivate collaborating primary investigators to undertake new primary studies to corroborate or improve upon the conclusions derived from the retrospective analysis.

Preliminary results of radiation dose escalation for locally advanced nasopharyngeal carcinoma.

PURPOSE: To study the safety and efficacy of dose escalation in tumor for locally advanced nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: From September 2000 to June 2004, 50 patients with T3-T4 NPC were treated with intensity-modulated radiotherapy (IMRT). Fourteen patients had Stage III and 36 patients had Stage IVA-IVB disease. The prescribed dose was 76 Gy to gross tumor volume (GTV), 70 Gy to planning target volume (PTV), and 72 Gy to enlarged neck nodes (GTVn). All doses were given in 35 fractions over 7 weeks. Thirty-four patients also had concurrent cisplatin and induction or adjuvant PF (cisplatin and 5-fluorouracil). RESULTS: The average mean dose achieved in GTV, GTVn, and PTV were 79.5 Gy, 75.3 Gy, and 74.6 Gy, respectively. The median follow-up was 25 months, with 4 recurrences: 2 locoregional and 2 distant failures. All patients with recurrence had IMRT alone without chemotherapy. The 2-year locoregional control rate, distant metastases-free and disease-free survivals were 95.7%, 94.2%, and 93.1%, respectively. One treatment-related death caused by adjuvant chemotherapy occurred. The 2-year overall survival was 92.1%. CONCLUSIONS: Dose escalation to 76 Gy in tumor is feasible with T3-T4 NPC and can be combined with chemotherapy. Initial results showed good local control and survival.

Endonasal endoscopic removal of growth-hormone-secreting pituitary adenomas.

Trans-sphenoidal removal of pituitary tumours using the endonasal endoscopic technique, a novel application, is herein reported in five consecutive patients with growth-hormone-secreting pituitary adenomas seen at a teaching hospital in Hong Kong. All five patients demonstrated complete tumour removal on postoperative imaging and hormonal assessment following the procedure. Surgical morbidity and symptoms were minimal; postoperative obstructive nasal packing was not required with this technique, which greatly improved patient comfort. Preliminary experience suggests that the endonasal endoscopic approach is a safe and effective alternative to the conventional trans-septal microscopic method for the treatment of pituitary tumour. A randomised controlled trial comparing these two approaches is currently underway at this institution.

Retrograde suction decompression of paraclinoid aneurysm--a revised technique.

BACKGROUND: Aneurysms of the ophthalmic segment of the carotid artery are difficult lesions to handle. Batjer and Samson described the technique of suction decompression of the aneurysm by inserting a needle and aspirating blood from the internal carotid artery in the neck. However, this method carries a risk of arterial dissection and distal embolization. METHOD: We describe a revised technique for suction decompression of paraclinoid aneurysms. The method makes use of the anatomical advantage of the carotid bifurcation. Instead of direct clamping of the internal carotid artery, we isolated the common and external carotid arteries and decompressed the aneurysm via the external carotid artery. We also saved the aspirated blood for autotransfusion. RESULTS: We have used this technique in two elderly patients with good results. CONCLUSION: This technique avoids dissection of the internal carotid artery and minimizes the risk of embolization.