Pharmacokinetic Variables of Dapagliflozin/Metformin Extended-release Fixed-dose Combination in Healthy Chinese Volunteers and Regional Comparison.

PURPOSE: A fixed-dose combination (FDC) product combining dapagliflozin and metformin may increase medication adherence in patients with type 2 diabetes mellitus (T2DM) by minimizing pill burden associated with co-administration of individual component (IC) formulations and, consequently, improve cost-efficiency and compliance. This study evaluated the bioequivalence of the dapagliflozin/metformin FDC product versus IC administration in healthy volunteers from a Chinese population and assessed the safety profile of the FDC product. In addition, pharmacokinetic (PK) and safety comparisons of dapagliflozin and metformin across different regions were conducted to evaluate regional differences. METHODS: This single-center, open-label, parallel-cohort, randomized, 2-period, crossover study enrolled Chinese adults (aged 18-55 years). Volunteers in cohort 1 received either a single FDC tablet of dapagliflozin/metformin extended release (XR) (5/500 mg) or IC tablets (dapagliflozin [5 mg] and metformin XR [500 mg]). Volunteers in cohort 2 received a higher dosage in a similar manner (dapagliflozin [10 mg] and metformin XR [1000 mg]). Volunteers in each cohort were subsequently crossed over to receive the alternate cohort treatment. Plasma concentrations of dapagliflozin and metformin were determined, and bioequivalence analyses were performed under standard fed conditions. FINDINGS: Eighty healthy Chinese volunteers (89.9% male; mean age, 28.7 years) were randomized into cohort 1 (n = 40) and cohort 2 (n = 39; 1 volunteer withdrew before receiving study treatment). The mean plasma concentration-time profiles of the dapagliflozin and metformin FDC and IC formulations for both doses were found to be nearly superimposable. Dapagliflozin and metformin XR FDC were bioequivalent to the IC tablets, with 90% CIs for each pairwise comparison contained within the 80% to 125% bioequivalence limits. Both the FDC and IC formulations were well tolerated, with no serious adverse events/death. PK parameters for dapagliflozin in the Chinese volunteers were slightly to moderately higher than those from studies conducted in Brazil, Russia, and the United States, and the safety profile of the dapagliflozin/metformin FDC product was consistent with that of other studies. The difference in PK parameters among the 4 regions was not clinically meaningful. IMPLICATIONS: The bioequivalence of the dapagliflozin/metformin FDC and IC formulations in healthy Chinese adults was established without any new safety concerns. Notably, the observed bioequivalence may be extrapolated to patients with T2DM as the PK parameters of dapagliflozin and metformin in healthy adults are similar to those reported in patients with T2DM. CLINICALTRIALS: gov identifier: NCT04856007.

Merkel cell carcinoma: a forty-year experience at the Peter MacCallum Cancer Centre.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine skin malignancy, with Australia having the highest reported incidence in the world. There is currently a lack of consensus regarding optimal management of this disease. METHODS: This was a retrospective audit conducted by reviewing existing medical records of MCC patients presenting to the Peter MacCallum Cancer Centre (PMCC) between 1980 and 2018. The primary endpoint was locoregional recurrence. The secondary endpoints were distant recurrence, disease-free survival (DFS) and overall survival (OS). RESULTS: A total of 533 patients were identified. Locoregional recurrence occurring at one, two and 5 years was 24, 31 and 32%, respectively. The estimated 5-year OS and DFS were 46% (95% Confidence Interval [CI] 41-51%) and 34% (95% CI 30-39%) respectively. Older age at diagnosis (hazard ratio [HR] per year = 1.07, 95% CI 1.06-1.07, p < 0.001), and larger primary tumour diameter (HR =1.16, 95% CI 1.03-1.31, p = 0.019) were associated with worse OS on multivariable analysis. Positive or negative histopathological margin status was not associated with OS or DFS differences in patients treated with post-operative radiotherapy. CONCLUSIONS: In our study, about a third of patients developed locoregional recurrence, distal recurrence or both, and there appears to be no change over the last four decades. If treated with adjuvant radiotherapy, there is no difference in OS or DFS with positive surgical margins. Findings should influence future guidelines.

Low incidence of neurological recurrent side-effects following COVID-19 reimmunization.

BACKGROUND: Individuals who suffered a neurological adverse event after the Coronavirus disease (COVID-19) vaccine could hesitate and defer reimmunization. AIM: We examine the risk of recurrence following reimmunization among patients who developed a neurological event after the first dose of the COVID-19 mRNA vaccine. DESIGN: Observational study. METHODS: Individuals who developed an adjudicated neurological adverse event (based on Brighton Collaboration criteria) within 6 weeks of the first dose of the COVID-19 vaccine requiring hospitalization were enrolled into a multicenter national registry in Singapore. Neurological recurrence, defined by the development of another neurological event within 6 weeks of the second vaccine dose, was reviewed. Clinical characteristics were compared between patients who chose to proceed or withhold further vaccination, and between those who received timely (3-6 weeks) or delayed (>6 weeks) reimmunization. RESULTS: From 235 patients (median age, 67 years; 63% men) who developed an adjudicated neurological event after their first dose of mRNA vaccine between 30 December 2020 and 20 April 2021, 181 (77%) chose to undergo reimmunization. Those who decided against reimmunization were older (median age, 74 vs. 66 years) and had greater physical disability following their primary neurological event (46% vs. 20%, P < 0.001). Patients who suffered greater physical disability were three times more likely to delay their reimmunization (odds ratio 3.36, 95% confidence interval: 1.76-6.40). Neurological recurrence was observed in only four individuals (three with seizures and one with myasthenia gravis exacerbation). CONCLUSIONS: A prior neurological event should not necessarily preclude reimmunization and the decision to proceed with reimmunization should consider the overwhelming benefits conferred by vaccination toward ending this pandemic.

Incidence of Cerebral Venous Thrombosis Following SARS-CoV-2 Infection vs mRNA SARS-CoV-2 Vaccination in Singapore.

Importance: Reports of cerebral venous thrombosis (CVT) after messenger RNA (mRNA)-based SARS-CoV-2 vaccination has caused safety concerns, but CVT is also known to occur after SARS-CoV-2 infection. Comparing the relative incidence of CVT after infection vs vaccination may provide a better perspective of this complication. Objective: To compare the incidence rates and clinical characteristics of CVT following either SARS-CoV-2 infection or mRNA-based SARS-CoV-2 vaccines. Design, Setting, and Participants: Between January 23, 2020, and August 3, 2021, this observational cohort study was conducted at all public acute hospitals in Singapore, where patients hospitalized with CVT within 6 weeks of SARS-CoV-2 infection or after mRNA-based SARS-CoV-2 vaccination (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) were identified. Diagnosis of SARS-CoV-2 infection was based on quantitative reverse transcription-polymerase chain reaction or positive serology. National SARS-CoV-2 infection data were obtained from the National Centre for Infectious Disease, Singapore, and vaccination data were obtained from the National Immunisation Registry, Singapore. Exposures: SARS-CoV-2 infection or mRNA-based SARS-CoV-2 vaccines. Main Outcomes and Measures: Clinical characteristics, crude incidence rate (IR), and incidence rate ratio (IRR) of CVT after SARS-CoV-2 infection and after mRNA SARS-CoV-2 vaccination. Results: Among 62 447 individuals diagnosed with SARS-CoV-2 infections included in this study, 58 989 (94.5%) were male; the median (range) age was 34 (0-102) years; 6 CVT cases were identified (all were male; median [range] age was 33.5 [27-40] years). Among 3 006 662 individuals who received at least 1 dose of mRNA-based SARS-CoV-2 vaccine, 1 626 623 (54.1%) were male; the median (range) age was 50 (12-121) years; 9 CVT cases were identified (7 male individuals [77.8%]; median [range] age: 60 [46-76] years). The crude IR of CVT after SARS-CoV-2 infections was 83.3 per 100 000 person-years (95% CI, 30.6-181.2 per 100 000 person-years) and 2.59 per 100 000 person-years (95% CI, 1.19-4.92 per 100 000 person-years) after mRNA-based SARS-CoV-2 vaccination. Six (66.7%) received BNT162b2 (Pfizer-BioNTech) vaccine and 3 (33.3%) received mRNA-1273 (Moderna) vaccine. The crude IRR of CVT hospitalizations with SARS-CoV-2 infection compared with those who received mRNA SARS-CoV-2 vaccination was 32.1 (95% CI, 9.40-101; P < .001). Conclusions and Relevance: The incidence rate of CVT after SARS-CoV-2 infection was significantly higher compared with after mRNA-based SARS-CoV-2 vaccination. CVT remained rare after mRNA-based SARS-CoV-2 vaccines, reinforcing its safety.

ePTFE/FEP stents for malignant biliary obstruction.

BACKGROUND: Biliary obstruction due to malignant disease causes debilitating symptoms and palliation of the disease involves placement of biliary stents. Covered self-expanding metal biliary stents may provide a longer patency and a lower risk of complications and dysfunction compared to uncovered stents, making them better for patients' quality of life and cost effectiveness. This study aims to evaluate the indications and outcomes for a group of cases where expanded polytetrafluoroethylene/fluorinated ethylene propylene (ePTFE/FEP) covered metal stents were used to palliate malignant biliary obstruction. METHODS: All cases of ePTFE/FEP-covered Viabil stent implantation in a 4-year period in a single hospital were identified and details of indications and outcomes for stent placement were recorded. Kaplan-Meier estimator analysis was used to create plots for stent patency and survival time. RESULTS: The median stent patency was 173 days (standard error of the mean, SE = 54) and the median survival time was 247 days (SE = 88). No complications of stent implantation were recorded and in seven cases no dysfunction was noted. In one case, tumour ingrowth was observed, and in one other case the stent was no longer found in situ on subsequent imaging. CONCLUSION: The use of the ePTFE/FEP-covered Viabil stent in the palliation of malignant obstruction where indicated is promising, providing a low rate of stent dysfunction and complications. More data need to be collected to conclusively ascertain whether covered stents have a longer patency and lower complication rate compared to uncovered stents.

Hospital-based observational study of neurological disorders in patients recently vaccinated with COVID-19 mRNA vaccines.

PURPOSE: We describe the spectrum of acute neurological disorders among hospitalized patients who recently had COVID-19 mRNA vaccination. METHOD: We performed a prospective study at 7 acute hospitals in Singapore. Hospitalized patients who were referred for neurological complaints and had COVID-19 mRNA vaccines, BNT162b2 and mRNA-1273, in the last 6 weeks were classified into central nervous system (CNS) syndromes, cerebrovascular disorders, peripheral nervous system (PNS) disorders, autonomic nervous system (ANS) disorders and immunization stress-related responses (ISRR). RESULTS: From 30 December 2020 to 20 April 2021, 1,398,074 persons (median age 59 years, 54.5% males) received COVID-19 mRNA vaccine (86.7% BNT162b2, 13.3% mRNA-1273); 915,344(65.5%) completed 2 doses. Four hundred and fifty-seven(0.03%) patients were referred for neurological complaints [median age 67(20-97) years, 281(61.5%) males; 95.8% received BNT162b2 and 4.2% mRNA-1273], classified into 73(16.0%) CNS syndromes, 286(62.6%) cerebrovascular disorders, 59(12.9%) PNS disorders, 0 ANS disorders and 39(8.5%) ISRRs. Eleven of 27 patients with cranial mononeuropathy had Bell's palsy. Of 33 patients with seizures, only 4 were unprovoked and occurred within 2 weeks of vaccination. All strokes occurred among individuals with pre-existing cardiovascular risk factors. We recorded 2 cases of cerebral venous thrombosis; none were vaccine-induced thrombotic thrombocytopenia. Five had mild flares of immune-mediated diseases. CONCLUSION: Our observational study does not establish causality of the described disorders to vaccines. Though limited by the lack of baseline incidence data of several conditions, we observed no obvious signal of serious neurological morbidity associated with mRNA vaccination. The benefits of COVID-19 vaccination outweigh concerns over neurological adverse events.

Acute Ischemic Stroke During the Convalescent Phase of Asymptomatic COVID-2019 Infection in Men.

Importance: Acute ischemic stroke (AIS) is a known neurological complication in patients with respiratory symptoms of COVID-19 infection. However, AIS has not been described as a late sequelae in patients without respiratory symptoms of COVID-19. Objective: To assess AIS experienced by adults 50 years or younger in the convalescent phase of asymptomatic COVID-19 infection. Design, Setting, and Participants: This case series prospectively identified consecutive male patients who received care for AIS from public health hospitals in Singapore between May 21, 2020, and October 14, 2020. All of these patients had laboratory-confirmed asymptomatic COVID-19 infection based on a positive SARS-CoV-2 serological (antibodies) test result. These patients were individuals from South Asian countries (India and Bangladesh) who were working in Singapore and living in dormitories. The total number of COVID-19 cases (54 485) in the worker dormitory population was the population at risk. Patients with ongoing respiratory symptoms or positive SARS-CoV-2 serological test results confirmed through reverse transcriptase-polymerase chain reaction nasopharyngeal swabs were excluded. Main Outcomes and Measures: Clinical course, imaging, and laboratory findings were retrieved from the electronic medical records of each participating hospital. The incidence rate of AIS in the case series was compared with that of a historical age-, sex-, and ethnicity-matched national cohort. Results: A total of 18 male patients, with a median (range) age of 41 (35-50) years and South Asian ethnicity, were included. The median (range) time from a positive serological test result to AIS was 54.5 (0-130) days. The median (range) National Institutes of Health Stroke Scale score was 5 (1-25). Ten patients (56%) presented with a large vessel occlusion, of whom 6 patients underwent intravenous thrombolysis and/or endovascular therapy. Only 3 patients (17%) had a possible cardiac source of embolus. The estimated annual incidence rate of AIS was 82.6 cases per 100 000 people in this study compared with 38.2 cases per 100 000 people in the historical age-, sex-, and ethnicity-matched cohort (rate ratio, 2.16; 95% CI, 1.36-3.48; P < .001). Conclusions and Relevance: This case series suggests that the risk for AIS is higher in adults 50 years or younger during the convalescent period of a COVID-19 infection without respiratory symptoms. Acute ischemic stroke could be part of the next wave of complications of COVID-19, and stroke units should be on alert and use serological testing, especially in younger patients or in the absence of traditional risk factors.

Reproductive outcomes in women and men using complementary and alternative medicine treatment and not receiving artificial reproductive technology: a systematic review.

PURPOSE: Infertility is a global problem, but only a minority of couples access assisted reproductive technologies due to financial and sociocultural barriers. Complementary and alternative medicine are seen as another option. We aimed to determine the impact of complementary and alternative medicine on conception, miscarriage and live birth rates in couples not receiving assisted reproductive technology treatments. METHODS: The electronic databases EMBASE, PubMed, Web of Science and the Allied and Complementary Medicine Database were systematically searched before March 24th 2020. Reference lists of eligible studies were searched for relevant studies. Eligible studies included trials and observational studies that assessed a complementary or alternative medicine and conception, miscarriage or live births in men or women not undergoing fertility treatment. Data were extracted by two independent reviewers using a pre-designed data collection form. The study protocol was published in the PROSPERO database (CRD42018086980). RESULTS: Twenty randomized controlled trials were identified, including 2748 individuals. Most studies did not demonstrate any effect of a complementary or alternative medicine on pregnancy, live birth or miscarriage rates. Limited evidence was found for a positive effect of herbal therapies taken by women on conception rates. There was substantial diversity in quality across the studies. CONCLUSION: There is limited evidence of the effectiveness of complementary and alternative medicine on improving the chances of conception and live births, or increasing miscarriage risk. Owing to the generally sub-optimal quality and heterogeneous nature of the evidence, rigorous studies are needed to determine the impact of complementary and alternative medicine on fertility.

Exploring the utility of RDoC in differentiating effectiveness amongst antidepressants: A systematic review using proposed psychometrics as the unit of analysis for the Negative Valence Systems domain.

BACKGROUND: RDoC conceptualises psychopathology as neurobiologically-rooted behavioural psychological "constructs" that span dimensionally from normality to pathology, but its clinical utility remains controversial. AIM: To explore RDoC's potential clinical utility by examining antidepressant effectiveness through Negative Valence Systems (NVS) domain constructs. METHOD: A systematic review was conducted on Web of Science, MEDLINE, EMBASE and PsycINFO for antidepressant trials that included psychometric instruments assessed by Watson, Stanton & Clark (2017) to represent NVS constructs of Acute Threat, Potential Threat and Loss. RESULTS: 221 citations were identified; 13 were included in qualitative synthesis, none for quantitative analysis. All suffered from significant bias risks. 9 antidepressants were investigated, most within 1 construct, and most were found to be effective. Paroxetine, citalopram and fluvoxamine were found to be effective for Acute Threat, fluoxetine, desvenlafaxine and sertraline for Potential Threat, and sertraline, fluvoxamine, fluoxetine and desvenlafaxine effective for Loss. Nefazodone was found to be ineffective for acute fear. CONCLUSION: Preliminary evidence supports RDoC NVS constructs' clinical utility in assessing antidepressant effectiveness, but lack of discriminant validity between Potential Threat and Loss supports their recombination into a single Distress construct. Finding of effectiveness within "normal" construct levels support the utility of a dimensional approach. Testable hypotheses were generated that can further test RDoC's clinical utility.

Cerebral Venous Thrombosis in Patients with COVID-19 Infection: a Case Series and Systematic Review.

BACKGROUND: There has been increasing reports associating the coronavirus disease 2019 (COVID-19) with thromboembolic phenomenon including ischemic strokes and venous thromboembolism. Cerebral venous thrombosis (CVT) is a rare neurovascular emergency that has been observed in some COVID-19 patients, yet much remains to be learnt of its underlying pathophysiology. OBJECTIVE: We present a case series of local patients with concomitant COVID-19 infection and CVT; and aim to perform a systematic review of known cases in the current literature. METHODS: We describe two patients with concomitant COVID-19 infection and CVT from a nationwide registry in Singapore. We then conducted a literature search in PubMed and Embase using a suitable keyword search strategy from 1st December 2019 to 11th June 2020. All studies reporting CVT in COVID-19 patients were included. RESULTS: Nine studies and 14 COVID-19 patients with CVT were studied. The median age was 43 years (IQR=36-58) and majority had no significant past medical conditions (60.0%). The time taken from onset of COVID-19 symptoms to CVT diagnosis was a median of 7 days (IQR=6-14). CVT was commonly seen in the transverse (75.0%) and sigmoid sinus (50.0%); 33.3% had involvement of the deep venous sinus system. A significant proportion of patients had raised D-dimer (75.0%) and CRP levels (50.0%). Two patients reported presence of antiphospholipid antibodies. Most patients received anticoagulation (91.7%) while overall mortality rate was 45.5%. CONCLUSIONS: The high mortality rate of CVT in COVID-19 infection warrants a high index of suspicion from physicians, and early treatment with anticoagulation should be initiated.

Neurology of COVID-19 in Singapore.

PURPOSE: To describe the spectrum of COVID-19 neurology in Singapore. METHOD: We prospectively studied all microbiologically-confirmed COVID-19 patients in Singapore, who were referred for any neurological complaint within three months of COVID-19 onset. Neurological diagnoses and relationship to COVID-19 was made by consensus guided by contemporaneous literature, refined using recent case definitions. RESULTS: 47,572 patients (median age 34 years, 98% males) were diagnosed with COVID-19 in Singapore between 19 March to 19 July 2020. We identified 90 patients (median age 38, 98.9% males) with neurological disorders; 39 with varying certainty of relationship to COVID-19 categorised as: i) Central nervous system syndromes-4 acute disseminated encephalomyelitis (ADEM) and encephalitis, ii) Cerebrovascular disorders-19 acute ischaemic stroke and transient ischaemic attack (AIS/TIA), 4 cerebral venous thrombosis (CVT), 2 intracerebral haemorrhage, iii) Peripheral nervous system-7 mono/polyneuropathies, and a novel group, iv) Autonomic nervous system-4 limited dysautonomic syndromes. Fifty-one other patients had pre/co-existent neurological conditions unrelated to COVID-19. Encephalitis/ADEM is delayed, occurring in critical COVID-19, while CVT and dysautonomia occurred relatively early, and largely in mild infections. AIS/TIA was variable in onset, occurring in patients with differing COVID-19 severity; remarkably 63.2% were asymptomatic. CVT was more frequent than expected and occurred in mild/asymptomatic patients. There were no neurological complications in all 81 paediatric COVID-19 cases. CONCLUSION: COVID-19 neurology has a wide spectrum of dysimmune-thrombotic disorders. We encountered relatively few neurological complications, probably because our outbreak involved largely young men with mild/asymptomatic COVID-19. It is also widely perceived that the pandemic did not unduly affect the Singapore healthcare system.

Regulation of nerve growth and patterning by cell surface protein disulphide isomerase.

Contact repulsion of growing axons is an essential mechanism for spinal nerve patterning. In birds and mammals the embryonic somites generate a linear series of impenetrable barriers, forcing axon growth cones to traverse one half of each somite as they extend towards their body targets. This study shows that protein disulphide isomerase provides a key component of these barriers, mediating contact repulsion at the cell surface in chick half-somites. Repulsion is reduced both in vivo and in vitro by a range of methods that inhibit enzyme activity. The activity is critical in initiating a nitric oxide/S-nitrosylation-dependent signal transduction pathway that regulates the growth cone cytoskeleton. Rat forebrain grey matter extracts contain a similar activity, and the enzyme is expressed at the surface of cultured human astrocytic cells and rat cortical astrocytes. We suggest this system is co-opted in the brain to counteract and regulate aberrant nerve terminal growth.

The Thenar Crease Skin Graft: A Novel Addition to "Camouflage" Grafts of the Hand.

Palmar skin defects of the hand are common. When wound conditions are favorable, glabrous skin grafting provides ideal resurfacing-simple, predictable, and excellent esthetic outcome. Glabrous skin grafts are however confined to small sizes from limited donor sites. We present a novel technique of harvesting full-thickness skin grafts from the thenar crease and report the outcome of our cases. We provide further insights to adapt the technique to a variety of clinical scenarios-degloving injuries and shaving injuries of the finger including subcomplete pulp skin loss. Graft size is up to 75 mm by 10 mm, with tension-free donor site closure. We further report the operative experience, functional and esthetic outcome. The technique is fast, versatile, and provides large surface areas of good quality glabrous skin in a single-stage procedure. It will sit well in the armamentarium of the hand surgeon.

Herpes simplex virus (HSV) encephalitis in a young man: an unusual course.

We present a case of cerebral venous sinus thrombosis (CVST) as a rare complication of herpes simplex virus (HSV) encephalitis. A young man with no pertinent medical history was diagnosed with HSV encephalitis. After initial treatment, he showed improvement in symptomatology until day 6 when he acutely developed new neurological deficits. An urgent MRI brain showed changes in left temporal lobe consistent with HSV encephalitis and lack of flow void in superior sagittal sinus. Subsequent magnetic resonance venography confirmed the diagnosis of superior sagittal sinus thrombosis along with thrombosis of bilateral frontoparietal cortical draining veins. Anticoagulation was immediately initiated and oral anticoagulation was continued for 1 year. He made complete recovery subsequently. Our case serves as a reminder for the treating clinicians to consider CVST in patients with HSV encephalitis who develop an unexpected new neurological deficits during early phase of appropriate treatment.

Prospective single-arm study of intraoperative radiotherapy for locally advanced or recurrent rectal cancer.

INTRODUCTION: This study aims to evaluate the feasibility and outcomes of intraoperative radiotherapy (IORT) using high-dose-rate (HDR) brachytherapy for locally advanced or recurrent rectal cancers. Despite preoperative chemoradiation, patients with locally advanced or recurrent rectal cancers undergoing surgery remain at high risk of local recurrence. Intensification of radiation with IORT may improve local control. METHODS: This is a prospective non-randomised study. Eligible patients were those with T4 rectal cancer or pelvic recurrence, deemed suitable for radical surgery but at high risk of positive resection margins, without evidence of metastasis. Chemoradiation was followed by radical surgery. Ten gray (Gy) was delivered to tumour bed via an IORT applicator at time of surgery. RESULTS: There were 15% primary and 85% recurrent cancers. The 71% received preoperative chemoradiation. R0, R1 and R2 resections were 70%, 22% and 7%, respectively. IORT was successfully delivered in 27 of 30 registered patients (90% (95% confidence interval (CI) = 73-98) ) at a median reported time of 12 weeks (interquartile range (IQR) = 10-16) after chemoradiation. Mean IORT procedure and delivery times were 63 minutes (range 22-105 minutes). Ten patients (37% (95% CI = 19-58) ) experienced grade 3 or 4 toxicities (three wound, four abscesses, three soft tissue, three bowel obstructions, three ureteric obstructions and two sensory neuropathies). Local recurrence-free, failure-free and overall survival rates at 2.5 years were 68% (95% CI = 52-89), 37% (95% CI = 23-61) and 82% (95% CI = 68-98), respectively. CONCLUSION: The addition of IORT to radical surgery for T4 or recurrent rectal cancer is feasible. It can be delivered safely with low morbidity and good tumour outcomes.

Cerebral venous thrombosis secondary to ovarian hyperstimulation syndrome.

We report a case of a woman who underwent in-vitro fertilisation embryo transfer treatment for infertility and developed an acute stroke (left hemiparesis and headache). The stroke was caused by cerebral venous thrombosis due to ovarian hyperstimulation syndrome. We review the current background about this uncommon disorder.

Merkel cell carcinoma: 27-year experience at the Peter MacCallum Cancer Centre.

PURPOSE: To retrospectively evaluate the treatment outcome of patients with Merkel cell carcinoma after local and/or regional treatment. METHODS AND MATERIALS: Patients presenting to our center between January 1980 and July 2006 with Merkel cell carcinoma and without distant metastases were reviewed. The primary endpoint was locoregional control. Secondary endpoints were distant recurrence, survival and treatment toxicity. RESULTS: A total of 176 patients were identified. The median age was 79 years. The median follow-up was 2.2 years for all patients and 3.9 years for those alive at the last follow-up visit. The most common primary site was the head and neck (56%), and 62 patients(35%) had regional disease at presentation. The initial surgery to the primary tumor involved (wide) local excision in 140 patients and biopsy only in 28 patients (8 patients had no identifiable primary tumor); 33 patients underwent nodal surgery. Of the 176 patients, 165 (94%) underwent radiotherapy (RT) and 29 of them also underwent concurrent chemotherapy. The median radiation dose was 50 Gy (range, 18-60). Locoregional recurrence developed in 33 patients(19%), with a median interval to recurrence of 8 months. Distant metastases developed in 43 patients(24%). Age, primary tumor size, and RT (no RT vs. < 45 Gy vs. ≥ 45 Gy) were predictive of locoregional control on univariate analysis. However, only RT remained significant on multivariate analysis. The estimated 5-year actuarial rate for locoregional control, progression-free survival, and overall survival was 76%, 60%, and 45%, respectively. CONCLUSION: The locoregional control rate for Merkel cell carcinoma in our study was comparable to those from other series using combined modality treatment with RT an integral part of treatment.