Evolution of CD4 T-Cell Count With Age in a Cohort of Young People Growing Up With Perinatally Acquired Human Immunodeficiency Virus.

BACKGROUND: Recent studies have shown a decrease in CD4 count during adolescence in young people with perinatally acquired human immunodeficiency virus (HIV, PHIV). METHODS: Young people with PHIV in the United Kingdom, followed in the Collaborative HIV Paediatric Study who started antiretroviral therapy (ART) from 2000 onward were included. Changes in CD4 count over time from age 10 to 20 years were analyzed using mixed-effects models, and were compared to published CD4 data for the gerneral population. Potential predictors were examined and included demographics, age at ART start, nadir CD4 z score (age-adjusted) in childhood, and time-updated viral load. RESULTS: Of 1258 young people with PHIV included, 669 (53%) were female, median age at ART initiation was 8.3 years, and the median nadir CD4 z score was -4.0. Mean CD4 count was higher in young people with PHIV who started ART before age 10 years and had a nadir CD4 z score ≥-4; these young people with PHIV had a decline in CD4 count after age 10 that was comparable to that of the general population. Mean CD4 count was lower in young people with PHIV who had started ART before age 10 and had a nadir CD4 z score <-4; for this group, the decline in CD4 count after age 10 was steeper over time. CONCLUSIONS: In children, in addition to starting ART at an early age, optimizing ART to maintain a higher CD4 z score during childhood may be important to maximizing immune reconstitution later in life.

Risk factors for stunting in children who are HIV-exposed and uninfected after Option B+ implementation in Malawi.

Evidence suggests children HIV-exposed and uninfected (CHEU) experience poor growth. We analysed child anthropometrics and explored factors associated with stunting among Malawian CHEU. Mothers with HIV and their infants HIV-exposed were enroled in a nationally representative prospective cohort within the National Evaluation of Malawi's Prevention of Mother-to-Child HIV Transmission Programme after Option B+ implementation (2014-2018). Anthropometry was measured at enrolment (age 1-6 months), visit 1 (approximately 12 months), and visit 2 (approximately 24 months). Weight-for-age (WAZ) and length-for-age (LAZ) z-scores were calculated using World Health Organization Growth Standards; underweight and stunting were defined as WAZ and LAZ more than 2 standard deviations below the reference median. Multivariable logistic regression restricted to CHEU aged 24 months (±3 months) was used to identify factors associated with stunting. Among 1211 CHEU, 562/1211 attended visit 2, of which 529 were aged 24 months (±3 months) and were included. At age 24 months, 40.4% of CHEU were stunted and/or underweight, respectively. In multi-variable analysis, adjusting for child age and sex, the odds of stunting were higher among CHEU with infectious disease diagnosis compared to those with no diagnosis (adjusted odds ratio = 3.35 [95% confidence interval: 1.82-6.17]), which was modified by co-trimoxazole prophylaxis (p = 0.028). Infant low birthweight was associated with an increased odds of stunting; optimal feeding and maternal employment were correlated with reduced odds. This is one of the first studies examining CHEU growth since Option B+. Interventions to improve linear growth among CHEU should address their multi-faceted health risks, alongside maternal ART prescription, and follow-up of mother-child pairs.

Long-term kidney function of patients discharged from hospital after an intensive care admission: observational cohort study.

The long-term trajectory of kidney function recovery or decline for survivors of critical illness is incompletely understood. Characterising changes in kidney function after critical illness and associated episodes of acute kidney injury (AKI), could inform strategies to monitor and treat new or progressive chronic kidney disease. We assessed changes in estimated glomerular filtration rate (eGFR) and impact of AKI for 1301 critical care survivors with 5291 eGFR measurements (median 3 [IQR 2, 5] per patient) between hospital discharge (2004-2008) and end of 7 years of follow-up. Linear mixed effects models showed initial decline in eGFR over the first 6 months was greatest in patients without AKI (- 9.5%, 95% CI - 11.5% to - 7.4%) and with mild AKI (- 12.3%, CI - 15.1% to - 9.4%) and least in patients with moderate-severe AKI (- 4.3%, CI - 7.0% to - 1.4%). However, compared to patients without AKI, hospital discharge eGFR was lowest for the moderate-severe AKI group (median 61 [37, 96] vs 101 [78, 120] ml/min/1.73m2) and two thirds (66.5%, CI 59.8-72.6% vs 9.2%, CI 6.8-12.4%) had an eGFR of < 60 ml/min/1.73m2 through to 7 years after discharge. Kidney function trajectory after critical care discharge follows a distinctive pattern of initial drop then sustained decline. Regardless of AKI severity, this evidence suggests follow-up should incorporate monitoring of eGFR in the early months after hospital discharge.

Clearance of inflammatory cytokines in patients with septic acute kidney injury during renal replacement therapy using the EMiC2 filter (Clic-AKI study).

BACKGROUND: The EMiC2 membrane is a medium cut-off haemofilter (45 kiloDalton). Little is known regarding its efficacy in eliminating medium-sized cytokines in sepsis. This study aimed to explore the effects of continuous veno-venous haemodialysis (CVVHD) using the EMiC2 filter on cytokine clearance. METHODS: This was a prospective observational study conducted in critically ill patients with sepsis and acute kidney injury requiring kidney replacement therapy. We measured concentrations of 12 cytokines [Interleukin (IL) IL-1ß, IL-1α, IL-2, IL-4, IL-6, IL-8, IL-10, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, vascular endothelial growth factor, monocyte chemoattractant protein (MCP)-1, epidermal growth factor (EGF)] in plasma at baseline (T0) and pre- and post-dialyzer at 1, 6, 24, and 48 h after CVVHD initiation and in the effluent fluid at corresponding time points. Outcomes were the effluent and adsorptive clearance rates, mass balances, and changes in serial serum concentrations. RESULTS: Twelve patients were included in the final analysis. All cytokines except EGF concentrations declined over 48 h (p < 0.001). The effluent clearance rates were variable and ranged from negligible values for IL-2, IFN-γ, IL-1α, IL-1ß, and EGF, to 19.0 ml/min for TNF-α. Negative or minimal adsorption was observed. The effluent and adsorptive clearance rates remained steady over time. The percentage of cytokine removal was low for most cytokines throughout the 48-h period. CONCLUSION: EMiC2-CVVHD achieved modest removal of most cytokines and demonstrated small to no adsorptive capacity despite a decline in plasma cytokine concentrations. This suggests that changes in plasma cytokine concentrations may not be solely influenced by extracorporeal removal. TRIAL REGISTRATION: NCT03231748, registered on 27th July 2017.

Acute kidney injury in critically ill cancer patients is associated with mortality: A retrospective analysis.

BACKGROUND: In critically ill patients, acute kidney injury (AKI) is common and associated with short- and long-term complications. Our objectives were to describe the epidemiology and impact of AKI in cancer patients admitted to the Intensive Care Unit (ICU). METHODS: We identified all patients with a haematological malignancy (HM) or solid tumour (ST) who had an emergency admission to the ICU in a tertiary care centre between January 2004 and July 2012. AKI was defined according to the KDIGO criteria. RESULTS: 429 patients were included of whom 259 (60%) had AKI. Among HM patients, 73 (78%) had AKI (70% AKI on admission to ICU; 7% during ICU stay); among ST patients, 186 (56%) had AKI (45% on admission to ICU, 11% during ICU stay). ICU and 28-day mortality rates were 33% and 48%, respectively in HM patients, and 22% and 31%, respectively in ST patients. Multivariable analysis showed that AKI was an independent risk factor for both ICU and 28-day mortality. New AKI after 24 hours in ICU was associated with higher mortality than AKI on admission. CONCLUSIONS: AKI is common in critically ill cancer patients and independently associated with ICU and 28-day mortality.

Advanced liver disease in Russian children and adolescents with chronic hepatitis C.

Russia has one of the highest prevalences of paediatric chronic hepatitis C infection (CHC). Our aim was to provide a detailed characterization of children and adolescents with CHC including treatment outcomes. Thus, an observational study of children with CHC aged <18 years was conducted in three hepatology centres from November 2014 to May 2017. Of 301 children (52% male), 196 (65%) acquired HCV vertically, 70 (23%) had a history of blood transfusion or invasive procedures, 1 injecting drug use and 34 (11%) had no known risk factors. Median age at HCV diagnosis was 3.1 [interquartile range, IQR 1.1, 8.2] and 10.8 [7.4, 14.7] at last follow-up. The most common genotype was 1b (51%), followed by 3 (37%). Over a quarter of patients (84, 28%) had raised liver transaminases. Of 92 with liver biopsy, 38 (41%) had bridging fibrosis (median age 10.4 [7.1, 14.1]). Of 223 evaluated by transient elastography, 67 (30%) had liver stiffness ≥5.0 kPa. For each year, increase in age mean stiffness increased by 0.09 kPa (95% CI 0.05, 0.13, P < 0.001). There was significant correlation between liver stiffness and biopsy results (Tau-b = 0.29, P = 0.042). Of 205 treated with IFN-based regimens, 100 (49%) had SVR24. Most children (191, 93%) experienced adverse reactions, leading to treatment discontinuation in 6 (3%). In conclusion, a third of children acquired HCV via nonvertical routes and a substantial proportion of those with liver biopsy had advanced liver disease. Only half of children achieved SVR24 with IFN-based regimens highlighting the need for more effective and better-tolerated treatments with direct-acting antivirals. Further studies are warranted in Russia on causes and prevention of nonvertical transmission of HCV in children.

Editor's Choice - Long-term Survival and Risk Analysis in 136 Consecutive Patients With Type B Aortic Dissection Presenting to a Single Centre Over an 11 Year Period.

OBJECTIVES: To evaluate, in patients with acute type B aortic dissection, the results of medical and endovascular treatment in a large single centre experience and to investigate the clinical and imaging features on presentation that relate to poor outcome. METHODS: This was a retrospective analysis of prospectively collected clinical and CT imaging data. Consecutive patients (136) with acute type B aortic dissection were included in the study over an 11 year period. The characteristics of patients receiving endovascular (complicated) or medical treatment (uncomplicated) were compared. Kaplan-Meier estimators were used to estimate cumulative overall survival and survival free of aortic events. Factors associated with overall and aortic event free survival were also explored using Cox proportional hazards models. RESULTS: The mean follow up was 51 months (1-132), during which time 33 deaths and 48 aortic events occurred. At one and five years, overall survival was 94.0% and 74.8%, respectively, and freedom from aortic events was 75.6% and 58.7%. There was no difference in all cause survival and aortic event free survival at one and five years between the patients treated endovascularly and those receiving medical treatment alone. Risk analysis for aortic events demonstrated the maximum size of the proximal entry tear, the maximum thoracic aortic diameter, and the thoracic aortic false lumen maximum diameter to have a significant effect on the incidence of aortic events. CONCLUSIONS: Active management of patients with type B aortic dissection results in good long-term survival even in the presence of features traditionally associated with adverse outcomes. All patients require close lifetime surveillance as aortic events continue to occur during follow up even after endografting.

Patients electing to have PET rather than surgery for operable breast cancer are a high risk of treatment failure.

BACKGROUND: Primary endocrine therapy (PET) is a treatment option for elderly patients with ER-positive breast cancer enabling frail patients to avoid surgery. As a long-term treatment option, it has been shown to be inferior to surgery in controlling local disease. Decision-making in these patients is crucial in avoiding treatment failure. We examined the influence of decision-making on outcomes of PET failure as a secondary analysis as part of a large observational study. METHODS: Consecutive patients treated with PET between 2005 and 2015 for operable breast cancers were included in a retrospective observational study in 3 breast centres in the North-East. Treatment decision processes were examined by case note review and outcomes of treatment success or failure recorded. RESULTS: 488 patients were included with mean follow-up of 31 months. Overall 63 (12%) experienced treatment failure. 227 (46.6%) were given a choice between surgery and PET at diagnosis. Logistic regression identified older age [OR 0.94 (0.91-0.96) p < 0.001] and reduced mobility [OR 0.6 (0.37-0.97) p 0.036] to be less likely offered surgery. Those offered surgery were more likely to experience treatment failure with PET [SHR 1.78 (1.05-3.02) p 0.033]. CONCLUSIONS: Despite a low failure rate in our series (literature failure rates vary between 12 and 85%), these results suggest that those actively offered a choice between surgery and PET are at greater risk of failure when choosing PET.

Effect of dexamethasone exposure on the neonatal unit on the school age lung function of children born very prematurely.

The objective of this study was to determine the impact of postnatal dexamethasone treatment on the neonatal unit on the school age lung function of very prematurely born children. Children born prior to 29 weeks of gestational age had been entered into a randomised trial of two methods of neonatal ventilation (United Kingdom Oscillation Study). They had comprehensive lung function measurements at 11 to 14 years of age. One hundred and seventy-nine children born at a mean gestational age of 26.9 (range 23-28) weeks were assessed at 11 to 14 years; 50 had received postnatal dexamethasone. Forced expiratory flow at 75% (FEF75), 50%, 25% and 25-75% of the expired vital capacity, forced expiratory volume in one second, peak expiratory flow and forced vital capacity and lung volumes including total lung capacity and residual volume were assessed. Lung function outcomes were compared between children who had and had not been exposed to dexamethasone after adjustment for neonatal factors using linear mixed effects regression. After adjustment for confounders all the mean spirometry results were between 0.38 and 0.87 standard deviations lower in those exposed to dexamethasone compared to the unexposed. For example, the mean FEF75 z-score was 0.53 lower (95% CI 0.21 to 0.85). The mean lung function was lower as the number of courses of dexamethasone increased. In conclusion, postnatal dexamethasone exposure was associated with lower mean lung function at school age in children born extremely prematurely. Our results suggest the larger the cumulative dose the greater the adverse effect on lung function at follow-up.

An observational study investigating failure of primary endocrine therapy for operable breast cancer in the elderly.

BACKGROUND: Elderly patients are more likely to have oestrogen receptor positive cancers that can be treated without surgery with primary endocrine therapy (PET). Few studies have sought to identify predictors of failure of PET and so the aim of this study was to evaluate treatment failures in elderly breast cancer patients treated with PET and to determine predictors of failure. METHODS: A retrospective observational study was performed on consecutive patients with ER-positive early stage breast cancer treated with PET between 2005 and 2015 in the three breast units in the North East of England. The primary outcome measure was treatment failure and secondary outcome measure was disease progression. RESULTS: 488 patients were included with mean follow-up 31 months (SD 23). Overall, 206 patients were still alive with their disease controlled at the end of follow-up, 219 had died with their disease controlled and 63 (12%) experienced treatment failure. Younger age [SHR 0.96 (95% CI 0.94-0.99) p 0.013], larger tumours [SHR 1.03 (1.01-1.06) p 0.015], grade 3 cancers [SHR 3.58 (1.93-6.63) p < 0.001] and axillary lymph node metastases [SHR 1.93 (1.06-3.52) p 0.030] were all independent predictors of treatment failure. Disease progression was reported in 86 (17.6%) of patients. CONCLUSIONS: This is the largest retrospective series evaluating PET treatment failure. Clear predictors of failure have been identified, which can be used to facilitate treatment decision making. These results support previous analyses, further validating our results.

Short-term and medium-term survival of critically ill patients with solid tumours admitted to the intensive care unit: a retrospective analysis.

OBJECTIVES: Patients with cancer frequently require unplanned admission to the intensive care unit (ICU). Our objectives were to assess hospital and 180-day mortality in patients with a non-haematological malignancy and unplanned ICU admission and to identify which factors present on admission were the best predictors of mortality. DESIGN: Retrospective review of all patients with a diagnosis of solid tumours following unplanned admission to the ICU between 1 August 2008 and 31 July 2012. SETTING: Single centre tertiary care hospital in London (UK). PARTICIPANTS: 300 adult patients with non-haematological solid tumours requiring unplanned admission to the ICU. INTERVENTIONS: None. PRIMARY AND SECONDARY OUTCOMES: Hospital and 180-day survival. RESULTS: 300 patients were admitted to the ICU (median age 66.5 years; 61.7% men). Survival to hospital discharge and 180 days were 69% and 47.8%, respectively. Greater number of failed organ systems on admission was associated with significantly worse hospital survival (p<0.001) but not with 180-day survival (p=0.24). In multivariate analysis, predictors of hospital mortality were the presence of metastases (OR 1.97, 95% CI 1.08 to 3.59), Acute Physiology and Chronic Health Evaluation II (APACHE II) Score (OR 1.07, 95% CI 1.01 to 1.13) and a Glasgow Coma Scale Score <7 on admission to ICU (OR 5.21, 95% CI 1.65 to 16.43). Predictors of worse 180-day survival were the presence of metastases (OR 2.82, 95% CI 1.57 to 5.06), APACHE II Score (OR 1.07, 95% CI 1.01 to 1.13) and sepsis (OR 1.92, 95% CI 1.09 to 3.38). CONCLUSIONS: Short-term and medium-term survival in patients with solid tumours admitted to ICU is better than previously reported, suggesting that the presence of cancer alone should not be a barrier to ICU admission.

The effects of socioeconomic status on stroke risk and outcomes.

The latest evidence on socioeconomic status and stroke shows that stroke not only disproportionately affects low-income and middle-income countries, but also socioeconomically deprived populations within high-income countries. These disparities are reflected not only in risk of stroke but also in short-term and long-term outcomes after stroke. Increased average levels of conventional risk factors (eg, hypertension, hyperlipidaemia, excessive alcohol intake, smoking, obesity, and sedentary lifestyle) in populations with low socioeconomic status account for about half of these effects. In many countries, evidence shows that people with lower socioeconomic status are less likely to receive good-quality acute hospital and rehabilitation care than people with higher socioeconomic status. For clinical practice, better implementation of well established treatments, effective management of risk factors, and equity of access to high-quality acute stroke care and rehabilitation will probably reduce inequality substantially. Overcoming barriers and adapting evidence-based interventions to different countries and health-care settings remains a research priority.

Explanatory factors for the association between depression and long-term physical disability after stroke.

OBJECTIVES: To identify explanatory factors for the association between depression at 3 months after stroke and physical disability at 3 years. METHODS: Data from the South London Stroke Register (1998-2013) were used. Patients (n = 3,612) were assessed at stroke onset. Follow-up at 3 months included assessment for depression with the Hospital Anxiety and Depression scale (scores ≥ 7 = depression), physical disability (Barthel index) cognitive function, smoking habit, selective serotonin reuptake inhibitors (SSRIs) use, perception of recovery and social support. Physical disability was reassessed at 3 years. The associations between depression at 3 months and physical disability at 3 years were estimated with multinomial regression adjusting for age, gender, ethnicity, stroke severity and possible explanatory factors for the association (introduced in the models first individually and then sequentially): pre-stroke medical history and physical disability, cognitive function, smoking, SSRIs, perception of recovery and social support at 3 months. RESULTS: One thousand three hundred and seven survivors were assessed at 3 months, of which 418 (32.0%) had depression. Survivors with depression had a higher physical disability rate at 3 years. These associations remained significant after adjustment for individual explanatory factors but were not significant after adjustment for combined explanatory factors. Physical disability at 3 months was a relevant explanatory factor for this association. SSRIs were associated with severe, relative risk: 6.62 (2.92-15.02) P < 0.001, and moderate physical disability, relative risk: 3.45 (1.58-7.52) P = 0.002, at 3 years. CONCLUSION: The association between depression and physical disability appears to be multifactorial. The use of SSRIs after stroke requires further research.

Low Systemic Oxygen Delivery and BP and Risk of Progression of Early AKI.

BACKGROUND AND OBJECTIVES: The optimal hemodynamic management of patients with early AKI is unknown. This study aimed to investigate the association between hemodynamic parameters in early AKI and progression to severe AKI and hospital mortality. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study retrospectively analyzed the data of all patients admitted to the adult intensive care unit in a tertiary care center between July 2007 and June 2009 and identified those with stage 1 AKI (AKI I) per the AKI Network classification. In patients in whom hemodynamic monitoring was performed within 12 hours of AKI I, hemodynamic parameters in the first 12 hours of AKI I and on the day of AKI III (if AKI III developed) or 72 hours after AKI I (if AKI III did not develop) were recorded. Risk factors for AKI III and mortality were identified using univariate and multivariate logistic regression analyses. RESULTS: Among 790 patients with AKI I, 210 (median age 70 years; 138 men) had hemodynamic monitoring within 12 hours of AKI I; 85 patients (41.5%) progressed to AKI III and 91 (43%) died in the hospital. AKI progressors had a significantly higher Sequential Organ Failure Assessment score (8.0 versus 9.6; P<0.001), lower indexed systemic oxygen delivery (DO2I) (median 325 versus 405 ml/min per m(2); P<0.001), higher central venous pressure (16 versus 13; P=0.02), and lower mean arterial blood pressure (MAP) (median 71 versus 74 mmHg; P=0.01) in the first 12 hours of AKI I compared with nonprogressors. Multivariate analysis confirmed that raised lactate, central venous pressure, and Sequential Organ Failure Assessment score as well as mechanical ventilation were independently associated with progression to AKI III; higher DO2I and MAP were independently associated with a lower risk of AKI III but not survival. The associations were independent of sepsis, heart disease, recent cardiac surgery, or chronic hypertension. CONCLUSIONS: Higher DO2I and MAP in early AKI were independently associated with a lower risk of progression.

Explanatory factors for the increased mortality of stroke patients with depression.

OBJECTIVE: To identify explanatory factors for the association between depression and increased mortality up to 5 years after stroke. METHODS: In this cohort study, data from the South London Stroke Register (1998-2013) were used. Patients (n = 3,722) were assessed at stroke onset. Baseline data included sociodemographics and stroke severity. Follow-up at 3 months included assessment for depression with the Hospital Anxiety and Depression Scale (scores ≥7 = depression). Associations between depression at 3 months and mortality within 5 years of stroke were estimated with Cox regression models adjusted for age, sex, ethnicity, and stroke severity, and subsequently adjusted for possible explanatory factors for the association. These factors, introduced into the model individually, included comorbidities at baseline, smoking and alcohol use, compliance with medication, treatment with selective serotonin reuptake inhibitors (SSRIs), social support, and activities of daily living at 3 months. RESULTS: A total of 1,354 survivors were assessed at 3 months: 435 (32.1%) had depression and 331 (24.4%) died within 5 years. Survivors with depression had a greater risk of mortality (hazard ratio [HR] 1.41 [95% confidence interval (CI) 1.13-1.77]; p = 0.002). The association between depression and mortality was strongest in patients younger than 65 years. Adjustment for comorbidities, smoking and alcohol use, SSRI use, social support, and compliance with medication did not change these associations. SSRIs started after stroke were associated with higher mortality, independently of depression at 3 months (HR 1.72 [95% CI 1.34-2.20]; p < 0.001). CONCLUSION: Depression after stroke is associated with higher mortality, particularly among younger patients. Stroke survivors taking SSRIs have an increased mortality. The association between depression and mortality is not explained by other individual medical factors.

Natural history, predictors and associated outcomes of anxiety up to 10 years after stroke: the South London Stroke Register.

BACKGROUND: evidence on the long-term natural history, predictors and outcomes of anxiety after stroke is insufficient to inform effective interventions. This study estimates within 10 years of stroke: (i) the incidence, cumulative incidence, prevalence, and time of onset of anxiety. (ii) Predictors of anxiety and its association with depression. (iii) The association between anxiety 3 months after stroke and mortality, stroke recurrence, disability, cognitive impairment and quality of life (QoL) at follow-up. METHODS: data from the South London Stroke Register (1995-2010). Patients were assessed at the time of the stroke, at 3 months, 1 year and then annually for up to 10 years. Baseline data included socio-demographics and stroke severity. Follow-up data included assessments for anxiety and depression (hospital anxiety and depression scale), disability, cognition and QoL. Multivariate regression was used to investigate predictors and associated outcomes of anxiety. RESULTS: incidence of anxiety up to 10 years ranged from 17 to 24%. Cumulative incidence: 57%. Prevalence range: 32-38%. Amongst patients with anxiety, 58% were anxious at 3 months. 57-73% of patients with anxiety had co-morbid depression. Predictors of anxiety included age under 65, female gender, inability to work, depression treatment, smoking and stroke severity. Anxiety at 3 months was associated with lower QoL at follow-up. CONCLUSIONS: anxiety is a frequent problem affecting stroke survivors in the long term. Clinicians should pay attention to patients at risk of anxiety since it is associated with lower QoL and depression.

Can we predict which patients are likely to develop severe complications following reconstruction for osteoradionecrosis?

High morbidity has been reported for free vascularised reconstruction for osteoradionecrosis (ORN) and there are no apparent risk factors. A single nucleotide polymorphism in the transforming growth factor beta 1 gene (TGF-ß1) has been implicated in the cause of ORN and may also predict these complications. We studied a series of 30 consecutive patients who had had reconstruction for severe ORN with free tissue transfer in relation to their outcomes and complications for a number of risk factors including TFG-ß1 genotype, age, sex, comorbidities, site and stage of tumour, type of initial operation, and dose of radiotherapy or chemoradiotherapy. Two patients died and 2 flaps failed. Using the Clavien-Dindo classification, 16 patients developed grade III complications and 6 grade II. Median (IQR) duration of inpatient stay was 19.5 (12-25) days and the median (IQR) duration of outpatient treatment was 6 (4-11) weeks. No specific risk factors for postoperative complications were identified. In view of the severity and unpredictability of the complications, careful preoperative counselling of patients is essential.

Trismus following radiotherapy to the head and neck is likely to have distinct genotype dependent cause.

OBJECTIVES: Trismus frequently occurs as a consequence of radiotherapy or chemo-radiotherapy to the head and neck, with a loss of function that can reduce the overall quality of life. Radiation can trigger an intense fibrosis within the masticatory muscles and transforming growth factor beta 1 (TGF ß1) is involved in this process. As in other tissues the degree of fibrosis may be related to a single nucleotide polymorphism; C-T at position -509 in the TGF ß1 gene. MATERIALS AND METHODS: Trismus was measured in 62 patients before and after radiotherapy or chemoradiotherapy, blood was taken for DNA extraction, and genotype analysis of the TGF ß1 gene. Trismus was analysed against, patient age, sex, tumour site and stage, radiotherapy, and chemotherapy. RESULTS AND CONCLUSIONS: After radiotherapy or chemo-radiotherapy the reduction in mouth opening was shown to be significantly related to the presence of the T allele (p<0.001), with patients homozygous the most likely to be severely affected. No other patient, tumour or treatment factors were significant. Hence the TGF ß1 genotype is likely to be an important predictor of the degree of post radiotherapy or chemo-radiotherapy trismus.

Osteoradionecrosis in head-and-neck cancer has a distinct genotype-dependent cause.

PURPOSE: We performed a case-control study to establish whether the development of osteoradionecrosis (ORN) was related to a variant allele substituting T for C at -509 of the transforming growth factor-ß1 gene (TGF-ß1). PATIENTS AND METHODS: A total of 140 patients, 39 with and 101 without ORN, who underwent radiotherapy for head-and-neck cancer with a minimum of 2 years follow-up, were studied. None of the patients had clinical evidence of recurrence at this time. DNA extracted from blood was genotyped for the -509 C-T variant allele of the TGF-ß1 gene. RESULTS: There were no significant differences in patient, cancer treatment, or tumor characteristics between the two groups. Of the 39 patients who developed ORN, 9 were homozygous for the common CC allele, 19 were heterozygous, and 11 were homozygous for the rare TT genotype. Of the 101 patients without ORN, the distribution was 56 (CC), 33 (CT), and 12 (TT). The difference in distribution was significant, giving an increased risk of ORN of 5.7 (95% CI, 1.7-19.2) for homozygote TT patients (p = 0.001) and 3.6 (95% CI, 1.3-10.0) for heterozygotes (p = 0.004) when compared with patients with the CC genotype. Postradiotherapy dentoalveolar surgery preceding the development of ORN was associated with the CC genotype (p = 0.02). CONCLUSIONS: Our findings support the postulate that the development of ORN is related to the presence of the T variant allele at -509 within the TGF-ß1 gene.