Characterization of patients with aHUS and associated triggers or clinical conditions: A Global aHUS Registry analysis.

INTRODUCTION: Atypical haemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) associated with complement dysregulation; aHUS may be associated with other 'triggers' or 'clinical conditions'. This study aimed to characterize this patient population using data from the Global aHUS Registry, the largest collection of real-world data on patients with aHUS. METHODS: Patients enrolled in the Global aHUS Registry between April 2012 and June 2021 and with recorded aHUS-associated triggers or clinical conditions prior/up to aHUS onset were analysed. aHUS was diagnosed by the treating physician. Data were classified by age at onset of aHUS (< or ≥18 years) and additionally by the presence/absence of identified pathogenic complement genetic variant(s) and/or anti-complement factor H (CFH) antibodies. Genetically/immunologically untested patients were excluded. RESULTS: 1947 patients were enrolled in the Global aHUS Registry by June 2021, and 349 (17.9%) met inclusion criteria. 307/349 patients (88.0%) had a single associated trigger or clinical condition and were included in the primary analysis. Malignancy was most common (58/307, 18.9%), followed by pregnancy and acute infections (both 53/307, 17.3%). Patients with an associated trigger or clinical condition were generally more likely to be adults at aHUS onset. CONCLUSION: Our analysis suggests that aHUS-associated triggers or clinical conditions may be organized into clinically relevant categories, and their presence does not exclude the concurrent presence of pathogenic complement genetic variants and/or anti-CFH antibodies. Considering a diagnosis of aHUS with associated triggers or clinical conditions in patients presenting with TMA may allow faster and more appropriate treatment.

Atypical Hemolytic Uremic Syndrome Treated With Ravulizumab or Eculizumab: A Claims-Based Evaluation of Health Care Resource Utilization and Clinical Outcomes in the United States.

Rationale and Objective: Ravulizumab and eculizumab have shown efficacy for the treatment of atypical hemolytic uremic syndrome (aHUS), but real-world evidence for ravulizumab is limited owing to its more recent approval. This real-world database study examined outcomes for adult patients switching to ravulizumab from eculizumab and patients treated with individual treatments. Study Design: A retrospective, observational study using the Clarivate Real World Database. Setting and Population: US health-insurance billing data (January 2012 to March 2021) of patients aged 18 years or older with ≥1 diagnosis relevant to aHUS, ≥1 claim for treatment with eculizumab or ravulizumab, and no evidence of other indicated conditions. Exposures: Treatment-switch (to ravulizumab after eculizumab), ravulizumab-only, and eculizumab-only cohorts were examined. Outcomes: Clinical procedures, facility visits, health care costs, and clinical manifestations. Analytical Approach: Paired-sample statistical testing compared the mean numbers of claims for each group 0-3 months before (preindex period) and 0-3 months and 3-6 months after (postindex period) the index date (point of initiation with a single treatment or treatment switch). Results: In total, 322 patients met the eligibility criteria at 3-6 months postindex in the treatment-switch (n=65), ravulizumab-only (n=9), and eculizumab-only (n=248) cohorts. The proportions of patients with claims for key clinical procedures continued to be small after treatment switch and were small (0%-11%) across all cohorts at 3-6 months postindex. Inpatient visits were reduced in the postindex period across all cohorts. At 3-6 months after treatment switch, patients reported fewer claims for outpatient, private practice, and home visits and lower median health care costs. The proportions of patients with claims for clinical manifestations of aHUS were generally reduced in the postindex period compared with those of the preindex period. Limitations: Low patient numbers receiving ravulizumab only. Conclusions: The health-insurance claims data showed a reduced health care burden for US adult patients after treatment with ravulizumab or eculizumab for treatment of aHUS.

Clinical characteristics and outcomes of a patient population with atypical hemolytic uremic syndrome and malignant hypertension: analysis from the Global aHUS registry.

INTRODUCTION: Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) often caused by alternative complement dysregulation. Patients with aHUS can present with malignant hypertension (MHT), which may also cause TMA. METHODS: This analysis of the Global aHUS Registry (NCT01522183) assessed demographics and clinical characteristics in eculizumab-treated and not-treated patients with aHUS, with (n = 71) and without (n = 1026) malignant hypertension, to further elucidate the potential relationship between aHUS and malignant hypertension. RESULTS: While demographics were similar, patients with aHUS + malignant hypertension had an increased need for renal replacement therapy, including kidney transplantation (47% vs 32%), and more pathogenic variants/anti-complement factor H antibodies (56% vs 37%) than those without malignant hypertension. Not-treated patients with malignant hypertension had the highest incidence of variants/antibodies (65%) and a greater need for kidney transplantation than treated patients with malignant hypertension (65% vs none). In a multivariate analysis, the risk of end-stage kidney disease or death was similar between not-treated patients irrespective of malignant hypertension and was significantly reduced in treated vs not-treated patients with aHUS + malignant hypertension (adjusted HR (95% CI), 0.11 [0.01-0.87], P = 0.036). CONCLUSIONS: These results confirm the high severity and poor prognosis of untreated aHUS and suggest that eculizumab is effective in patients with aHUS ± malignant hypertension. Furthermore, these data highlight the importance of accurate, timely diagnosis and treatment in these populations and support consideration of aHUS in patients with malignant hypertension and TMA. TRIAL REGISTRATION DETAILS: Atypical Hemolytic-Uremic Syndrome (aHUS) Registry. Registry number: NCT01522183 (first listed 31st January, 2012; start date 30th April, 2012).

Pregnancy in Women with Atypical Hemolytic Uremic Syndrome.

BACKGROUND: Pregnancy outcomes in patients with atypical hemolytic uremic syndrome (aHUS) are not well-documented. Here, we present characteristics of and outcomes for patients with aHUS who became pregnant while enrolled in the Global aHUS Registry. METHODS: The observational Global aHUS Registry (NCT01522183), initiated in April 2012, collects demographics, disease history, treatment, and outcomes data for patients with aHUS, regardless of treatment approach. This descriptive analysis includes patients from the Registry with evaluable pregnancy data supplemented with pharmacovigilance information; the number of pregnancies, outcomes, and exposure to eculizumab were evaluated. RESULTS: As of April 1, 2019, 44 pregnancies were recorded in 41 patients, with 24 pregnancies exposed to eculizumab. Pathogenic variants were identified in 48.8% of patients. Three patients were on dialysis and 6 patients had a kidney graft at the time of pregnancy. Excluding elective terminations, 85.3% of pregnancies resulted in live births. Elective terminations were recorded in 22.7% of pregnancies, miscarriages occurred in 9.1% of pregnancies, and late fetal death in 2.3% of pregnancies. No malformations or anomalies were reported. CONCLUSIONS: Our results show that in women with aHUS, even on dialysis or with a kidney graft, pregnancy is possible with careful monitoring for aHUS flares and prematurity. Prophylactic or therapeutic eculizumab offers disease control with low-risk of fetal abnormalities.

Pregnancy-triggered atypical hemolytic uremic syndrome (aHUS): a Global aHUS Registry analysis.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare disease in which uncontrolled terminal complement activation leads to systemic thrombotic microangiopathy (TMA). Pregnancy can trigger aHUS and, without complement inhibition, many women with pregnancy-triggered aHUS (p-aHUS) progress to end-stage renal disease (ESRD) with a high risk of morbidity. Owing to relatively small patient numbers, published characterizations of p-aHUS have been limited, thus the Global aHUS Registry (NCT01522183, April 2012) provides a unique opportunity to analyze data from a large single cohort of women with p-aHUS. METHODS: The demographics and clinical characteristics of women with p-aHUS (n = 51) were compared with those of women of childbearing age with aHUS and no identified trigger (non-p-aHUS, n = 397). Outcome evaluations, including renal survival according to time to ESRD, were compared for patients with and without eculizumab treatment (a complement C5 inhibitor) in both aHUS groups. RESULTS: Baseline demographics and clinical characteristics were broadly similar in both groups. The proportion of women with p-aHUS and non-p-aHUS with pathogenic variant(s) in complement genes and/or anti-complement factor H antibodies was similar (45% and 43%, respectively), as was the proportion with a family history of aHUS (12% and 13%, respectively). Eculizumab treatment led to significantly improved renal outcomes in women with aHUS, regardless of whether aHUS was triggered by pregnancy or not: adjusted hazard ratio for time to ESRD was 0.06 (p = 0.006) in the p-aHUS group and 0.20 (p < 0.0001) in the non-p-aHUS group. CONCLUSION: Findings from this study support the characterization of p-aHUS as a complement-mediated TMA.

Evaluating the Effectiveness of Apixaban Additional Risk Minimisation Measures Using Surveys in Europe.

BACKGROUND: Apixaban (ELIQUIS®) is a direct oral anticoagulant authorised for multiple indications in the European Economic Area (EEA). Additional risk minimisation measures (aRMMs) to address the risk of bleeding include educational materials comprising a Prescriber Guide and Patient Alert Card. OBJECTIVES: This study evaluated effectiveness of the apixaban Prescriber Guide and Patient Alert Card in terms of healthcare professional (HCP) and patient knowledge of associated bleeding risk, as well as material distribution, utilisation and behaviour. METHODS: This non-interventional, cross-sectional study included online surveys in ten countries that represented a high proportion of apixaban usage in the EEA. The HCP source population was based on HCP lists used for communications about and distribution of the risk minimisation materials. Patient recruitment took place via HCPs. Study participants included HCPs involved in apixaban treatment and patients treated with apixaban (or their caregivers) for multiple indications. Data collection took place over an 18-month period between August 2015 and February 2017. RESULTS: Survey responses from 385 HCPs and 125 patients/caregivers were analysed. HCP knowledge of bleeding risk included early recognition of symptoms requiring immediate contact with an HCP (96.1%), appropriate dosing (83.6%), contraindications (76.1%) and subpopulations at increased risk of bleeding complications (ranging from 63.5 to 85.9%). Patient knowledge included abnormal bleeding as an important side effect (71.2%), communicating risk factors to HCPs (76.8%) and recognition of potential bleeding symptoms ('high' knowledge levels 22.4%, 'moderate' knowledge levels 49.6%). Of 226 (58.7%) HCPs who recalled receiving/obtaining the Prescriber Guide, 97.8% read at least part of it and 74.8% had used it to assist patient discussions. Of 74 (59.2%) patients who were aware of the Patient Alert Card, 89.2% recalled receiving/obtaining a copy. When received, 90.9% of patients read the card at least once and 93.9% kept it with them at least some of the time. CONCLUSIONS: HCP and patient respondent knowledge of bleeding risk was satisfactory. Although not optimal, reach of the aRMMs was consistent with other studies. No modifications to aRMM content were required. To increase reach, the Prescriber Guide has been provided in an additional format as a web-based platform whilst the Patient Alert Card was included within product packaging.

Functional Assessment of Fatigue and Other Patient-Reported Outcomes in Patients Enrolled in the Global aHUS Registry.

INTRODUCTION: Atypical hemolytic uremic syndrome (aHUS) is a progressive and potentially life-threatening disease characterized by complement-mediated thrombotic microangiopathy. Patients with aHUS may experience fatigue, which can negatively impact their lives, but there is a knowledge gap regarding disease burden in these patients. METHODS: In this longitudinal study, patients with aHUS from the Global aHUS Registry who completed patient-reported outcome assessments (Functional Assessment of Chronic Illness Therapy-Fatigue scale [FACIT-Fatigue], general health status, and work status) at ≥2 time points were assessed relative to treatment status: (i) never treated with eculizumab; (ii) on eculizumab at registry enrollment and continued therapy; and (iii) started eculizumab after registry enrollment. RESULTS: Patients who started eculizumab after the baseline visit (n = 23) exhibited improvements in fatigue (nearly 75% achieved clinically meaningful improvement), improved general health status (55%), and 25% to 30% rate reduction in symptoms of fatigue, weakness, irritability, nausea/vomiting, and swelling at last follow-up. Among patients already on eculizumab at registry enrollment (n = 295) and those never treated (n = 233), these parameters changed minimally relative to the baseline. Emergency room visits and hospital admissions were similar between groups. The number of health care provider visits and work days missed were higher in patients who started eculizumab after registry enrollment. CONCLUSION: These real-world findings confirm the detrimental effects of aHUS on patients' daily lives, including high levels of fatigue and impairments in general health status. The results suggest clinically meaningful improvement in fatigue, other patient-reported outcomes, and symptoms with eculizumab initiation after enrollment into the aHUS registry.

Clinical Characteristics and Outcome of Canadian Patients Diagnosed With Atypical Hemolytic Uremic Syndrome.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is an extremely rare, heterogeneous disease of uncontrolled activation of the alternative complement pathway that is difficult to diagnose. We have evaluated the Canadian patients enrolled in the Global aHUS Registry to provide a Canadian perspective regarding the diagnosis and management of aHUS and the specific challenges faced. OBJECTIVE: To evaluate Canadian patients enrolled in the Global aHUS Registry to provide a Canadian perspective regarding the diagnosis and management of aHUS and the specific challenges faced. METHODS: The Global aHUS Registry is an observational, noninterventional, multicenter study that has prospectively and retrospectively collected data from patients of all ages with an investigator-made clinical diagnosis of aHUS, irrespective of treatment. Patients of all ages with a clinical diagnosis of aHUS were eligible and invited for enrollment, and those with evidence of Shiga toxin-producing Escherichia coli infection, or with ADAMTS13 activity ≤10%, or a subsequent diagnosis of thrombotic thrombocytopenic purpura were excluded. Data were collected at enrollment and every 6 months thereafter and were analyzed descriptively for categorical and continuous variables. End-stage renal disease (ESRD)-free survival was evaluated using Kaplan-Meier estimates, and ESRD-associated risk factors of interest were assessed using Cox proportional hazards regression models. Patients were censored at start of eculizumab for any outcome measures. RESULTS: A total of 37 Canadian patients were enrolled (15 pediatric and 22 adult patients) between February 2014 and May 2017; the median age at initial aHUS presentation was 25.9 (interquartile range = 6.7-51.7) years; 62.2% were female and 94.6% had no family history of aHUS. Over three-quarters of patients (78.4%) had no conclusive genetic or anti-complement factor H (CFH) antibody information available, and most patients (94%) had no reported precipitating factors prior to aHUS diagnosis. Nine patients (8 adults and 1 child) experienced ESRD prior to the study. After initial presentation, there appears to be a trend that children are less likely to experience ESRD than adults, with 5-year ESRD-free survival of 93 and 56% (P = .05) in children and adults, respectively. Enrolling physicians reported renal manifestations in all patients at initial presentation, and 68.4% of patients during the chronic phase (study entry ≥6 months after initial presentation). Likewise, extrarenal manifestations also occurred in more patients during the initial presenting phase than the chronic phase, particularly for gastrointestinal (61.1% vs 15.8%) and central nervous system sites (38.9% vs 5.3%). Fewer children than adults experienced gastrointestinal manifestations (50.0% vs 70.0%), but more children than adults experienced pulmonary manifestations (37.5% vs 10.0%). CONCLUSIONS: This evaluation provides insight into the diagnosis and management of aHUS in Canadian patients and the challenges faced. More genetic or anti-CFH antibody testing is needed to improve the diagnosis of aHUS, and the management of children and adults needs to consider several factors such as the risk of progression to ESRD is based on age (more likely in adults), and that the location of extrarenal manifestations differs in children and adults.

CONTEXTE: Le syndrome hémolytique et urémique atypique (SHUa) se caractérise par l'activation incontrôlée de la voie alternative du complément. Il s'agit d'une maladie rare, hétérogène et très difficile à diagnostiquer. Nous avons évalué les patients Canadiens inscrits au registre international du SHUa afin d'offrir une perspective canadienne sur le diagnostic et la prise en charge du SHUa, de même que sur les défis posés par la maladie. OBJECTIF: Évaluer les patients Canadiens inscrits au registre international du SHUa afin d'offrir une perspective canadienne sur le diagnostic et la prise en charge du SHUa, de même que sur les défis posés par la maladie. MÉTHODOLOGIE: Le registre international du SHUa est une étude observationnelle, non interventionnelle et multicentrique ayant recueilli, de façon rétrospective et prospective, des données auprès de patients de tous âges ayant reçu un diagnostic clinique de SHUa, quel que soit le traitement. Tous ces patients étaient admissibles et ont été invités à participer à l'étude. Les patients présentant une infection diagnostiquée à Escherichia coli producteur de shigatoxine, une activité de l'ADAMTS13 inférieure ou égale à 10 % ou un diagnostic subséquent de purpura thrombocytopénique thrombotique ont été exclus. Les données colligées à l'inclusion et à tous les six mois par la suite ont fait l'objet d'une analyze descriptive des variables catégorielles et continues. Des estimations de Kaplan-Meier ont été employées pour évaluer la survie sans insuffisance rénale terminale (IRT) et des modèles de régression à risques proportionnels de Cox ont servi à évaluer les facteurs de risques associés à l'IRT. Les patients ont été censurés au début du traitement par l'eculizumab pour la mesure des résultats. RÉSULTATS: Au total, 37 patients canadiens ont été inscrits (15 enfants et 22 adultes) entre février 2014 et mai 2017. L'âge médian lors de l'épisode initial était de 25,9 ans (intervalle interquartile: 6,7­51,7); 62,2 % des sujets étaient de sexe féminin et 94,6 % n'avaient pas d'antécédents familiaux de SHUa. Plus des trois quarts des patients (78,4 %) ne disposaient d'aucune information génétique ou relative aux anticorps anti-complément du facteur H concluante, et aucun facteur précipitant n'avait été rapporté avant le diagnostic pour la majorité des patients (94 %). Neuf patients (8 adultes et 1 enfant) avaient souffert d'IRT avant l'étude. Une tendance semble indiquer qu'après l'épisode initial, les enfants seraient moins susceptibles que les adultes de progresser vers l'IRT (survie sans IRT après 5 ans: 93 % et 56 % respectivement; P = 0,05). Les médecins-recruteurs ont observé des manifestations rénales chez tous les patients lors de l'épisode initial de SHUa et chez 68,4 % des patients au cours de la phase chronique (inscription à l'étude au moins 6 mois après l'épisode initial). Parallèlement, les manifestations extra-rénales sont également survenues chez davantage de patients lors de l'épisode initial que lors de la phase chronique, particulièrement pour les manifestations gastro-intestinales (61,1 % contre 15,8 %) et du système nerveux central (38,9 % contre 5,3 %). Les enfants ont été moins nombreux que les adultes à subir des manifestations gastro-intestinales (50,0 % contre 70,0 %), mais ont subi davantage de manifestations pulmonaires (37,5 % contre 10,0 %). CONCLUSION: Cette étude offre un éclairage sur le diagnostic et la prise en charge du SHUa chez les patients canadiens, de même que sur les défis posés par la maladie. Davantage de dépistage génétique et de dépistage des anticorps anti-CFH sont requis pour améliorer le diagnostic du SHUa. La prise en charge de la maladie doit tenir compte de plusieurs facteurs, notamment du risque de progression vers l'IRT qui varie selon l'âge (plus probable chez l'adulte) et du fait que le site des manifestations extrarénales diffère chez l'enfant et l'adulte.

Eculizumab Safety: Five-Year Experience From the Global Atypical Hemolytic Uremic Syndrome Registry.

INTRODUCTION: Eculizumab has transformed outcomes for patients with atypical hemolytic uremic syndrome (aHUS). Its efficacy and safety profile was well characterized in the clinical trial program. The long-term safety profile was not previously assessed or compared against nontreated patients in an observational registry setting. METHODS: The Global aHUS Registry recruits patients with clinical diagnoses of aHUS. This analysis includes baseline characteristics and targeted safety events from adult and pediatric patients who were "ever treated" versus "never treated" with eculizumab in the first 5 years of the registry, through January 26, 2017. RESULTS: Overall, 1321 patients (adult, n = 842; pediatric, n = 479; ever treated, n = 865; never treated, n = 456) were enrolled. A higher proportion of ever-treated versus never-treated adult and pediatric patients had renal, cardiovascular, pulmonary, central nervous system, gastrointestinal symptoms, and hepatic impairment. No differences in safety event rates between ever-treated and never-treated patients were observed, except serious infections in pediatric patients (5.15 versus 1.12 events/100 patient-years for ever- and never-treated patients, respectively). Deaths were more frequent in adult (4.7% and 9.9% of ever- and never-treated patients) compared with pediatric patients (1.8% of ever-treated patients; no deaths in never-treated patients).Three meningococcal infections were reported in ever-treated patients; 1 infection led to a fatal outcome. CONCLUSION: In this large observational dataset covering 5 years of registry enrollment, no new safety concerns were identified for adult or pediatric eculizumab-treated patients with aHUS, confirming a positive benefit-risk profile in a real-world setting.

Effectiveness Evaluation of Additional Risk Minimization Measures for Adolescent Use of Aripiprazole in the European Union: Results from a Post-Authorization Safety Study.

INTRODUCTION: Two risk minimization (RM) tools-a healthcare professional frequently asked questions (HCP-FAQs) brochure and a patient/caregiver information brochure (PCIB)-were developed for HCPs and for adolescents (aged ≥ 13 years) receiving aripiprazole for bipolar I mania and their caregivers. OBJECTIVES: This study evaluated the effectiveness of these RM tools in improving the awareness and education of HCPs and patients/caregivers. METHOD: The RM tools were distributed to HCPs (identified in agreement with the marketing authorization holder [MAH] and local regulatory authorities), who in turn distributed the PCIBs to patients/caregivers. A web-based survey was then conducted targeting HCPs and patients/caregivers. RESULTS: The response rate was low: 118 of 23,282 invited HCPs and 16 patients/caregivers completed the survey. Overall, 42% (49/118) of HCP respondents were aware of aripiprazole RM tools; of these, 59% (29/49) of HCPs read them at least once and 66% (19/29) of these used the RM tools while discussing the benefit-risk profile of aripiprazole with patients/caregivers. In total, 30 of the 118 HCPs (25%) were aware of the PCIB, and 26 distributed it to their patients/caregivers, whereas seven HCPs advised them to read the brochure. Overall, 15 of the 16 patients/caregivers were aware of the PCIB, and 13 read/referred to it. Of these, 12 found the PCIB useful, and five monitored their weight while receiving aripiprazole and reported potential risks immediately to their HCP. CONCLUSION: The response rate to the survey was low, and the tools displayed limited utility and effectiveness in improving awareness and education in a small number of responders. Therefore, the aripiprazole risk management plan was amended, and the tools were discontinued.

Which Metrics Are Appropriate to Describe the Value of New Cancer Therapies?

Patients with certain cancers are treated with curative intent, but for others the results are less favorable and different therapeutic approaches are needed. Early data suggest that new therapies, which modulate immune responses to cancers, may have potential for long-term survival in a proportion of cases. Therefore, it is timely to consider whether metrics generally used to describe the medical value of therapies for patients with common solid tumors remain appropriate for therapies with curative potential. Literature reviews were conducted to define how various stakeholders describe cure in oncology and to identify the endpoints used in clinical trials for selected solid tumors. The results showed that "cure" is described using various terms that can be divided broadly into lack of disease progression, eradication of cancerous cells, and survival. The review of trial endpoints showed frequent use of median overall survival (OS) and progression- and response-related endpoints. Because these endpoints were mainly described in the context of chemotherapies that are not generally curative, they may not adequately capture outcomes of new therapeutic modalities with potential for long-term survival. More appropriate endpoints may include mean OS, cure fraction, and OS rate at landmark time points.

The impact of specific HIV treatment-related adverse events on adherence to antiretroviral therapy: a systematic review and meta-analysis.

Poor adherence to antiretroviral therapies (ARTs) in human immunodeficiency virus (HIV)-infected patients increases the risk of incomplete viral suppression, development of viral resistance, progression to acquired immune deficiency syndrome and death. This study assesses the impact of specific treatment-related adverse events (AEs) on adherence to ART in the adult HIV patient population. A systematic review of studies involving adult HIV-infected patients aged ≥ 16 years that reported an odds ratio (OR) for factors affecting adherence to ART was conducted through a search of the EMBASE(®) and Medline(®) databases. Database searches were complemented with a search of titles in the bibliographies of review papers. Studies conducted in populations limited to a particular demographic characteristic or behavioural risk were excluded. To qualify for inclusion into a meta-analysis, treatment-related AEs had to be defined similarly across studies. Also, multiple ORs from the same study were included where study sub-groups were distinct. Random effects models were used to pool ORs. In total, 19 studies and 18 ART-related AEs were included in meta-analyses. Adherence to ART was significantly lower in patients with non-specific AEs than in patients who did not experience AEs [OR = 0.623; 95% confidence interval (CI): 0.465-0.834]. Patients with specific AEs such as fatigue (OR = 0.631; 95% CI: 0.433-0.918), confusion (OR = 0.349; 95% CI: 0.184-0.661), taste disturbances (OR = 0.485; 95% CI: 0.303-0.775) and nausea (OR = 0.574; 95% CI: 0.427-0.772) were significantly less likely to adhere to ART compared to patients without these AEs. Knowledge of specific treatment-related AEs may allow for targeted management of these events and a careful consideration of well-tolerated treatment regimens to improve ART adherence and clinical outcomes.

Socio-economic status and upper aerodigestive tract cancer.

DESIGN: A multicentre case-control study. CASE/CONTROL SELECTION: Cases were defined as those diagnosed with primary squamous cell tumours of the UADT between 2002 and 2005. Diagnoses included malignant cancers of the oral cavity, oropharynx, hypo-pharynx, larynx or oesophagus. Incident cases were ascertained through weekly monitoring of head and neck cancer clinics in hospital departments and confirmed by pathology department records. Controls were frequency-matched to cases by sex and age (five-year groups). In the UK centres, population controls were randomly selected from the same community medical practice list as the corresponding cases. Specifically, for each case, a total of 10 controls were selected, matched by age and sex. Potential controls were approached in a random order one at a time until one agreed to participate. In all other centres, hospital controls were used. Only controls with a recently diagnosed disease were accepted, and admission diagnoses related to alcohol, tobacco or diet were excluded. Eligible diagnoses included endocrine and metabolic; genito-urinary; skin, subcutaneous tissue and musculoskeletal; gastro-intestinal; circulatory; ear, eye and mastoid; nervous system diseases; trauma and plastic surgery. The proportion of controls within a specific diagnostic group could not exceed 33% of the total in any particular centre. DATA ANALYSIS: Personal interviews collected information on demographics, lifetime occupation, history, smoking, alcohol consumption and diet. Socioeconomic status was measured by education, occupational social class and unemployment. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using unconditional logistic regression. RESULTS: When controlling for age, sex and centre, significantly increased risks for UADT cancer were observed for those with low versus high educational attainment OR = 1.98 (95% CI 1.67, 2.36). Similarly, for occupational socioeconomic indicators--comparing the lowest versus highest International Socio-Economic Index (ISEI) quartile for the longest occupation gave OR = 1.60 (1.28, 2.00); and for unemployment OR = 1.64 (1.24, 2.17). Statistical significance remained for low education when adjusting for smoking, alcohol and diet behaviours OR = 1.29 (1.06, 1.57) in the multivariate analysis. Inequalities were observed only among men but not among women and were greater among those in the British Isles and Eastern European countries than in Southern and Central/Northern European countries. Associations were broadly consistent for subsite and source of controls (hospital and community) CONCLUSIONS: Socioeconomic inequalities for UADT cancers are only observed among men and are not totally explained by smoking, alcohol drinking and diet.

The association between cancer treatments and oral diseases.

DATA SOURCES: MEDLINE/PubMed and EMBASE. STUDY SELECTION: The review included papers published between January 1, 1990 and December 31, 2008. The primary outcome was to retrieve all literature containing original data on dental caries, periodontal disease and pre-cancer dental clearance protocols in cancer patients undergoing head and neck radiotherapy, chemotherapy or combined treatment modalities. Excluded studies included systematic and non-systematic reviews, microbiology studies, growth and development studies, organ transplant studies, studies eliciting dental complications through questionnaires, studies reporting data from previous publications, phase I and II trials, opinion papers, case reports, articles published before 1990, and publications from the 1990 National Cancer Institute Monographs, which were based on the 1989 National Institutes of Health Development Consensus Conference on the Oral Complications of Cancer Therapies. DATA EXTRACTION AND SYNTHESIS: Each article was independently evaluated by two reviewers with pilot-tested collection forms customised for reviewing dental disease data. Dental caries was assessed by the presence (Y/N), DMFT/dmft (decayed, missing, and filled teeth: DMFT for permanent adult teeth and dmft signifying deciduous teeth), and DMFS/dmfs indexes (decayed, missing, and filled surfaces: DMFS for permanent adult teeth and dmfs signifying deciduous teeth), if available. In addition, periodontal health was assessed using the plaque and gingival indexes. Further data collected for each article such as type of study, blinding, presence of control group, scale validity, and sample size were used to determine quality outcomes utilised to determine the weighted prevalence of caries and dental infection. RESULTS: Sixty-four published papers between 1990 and 2008 were reviewed. The weighted overall prevalence of dental caries was 28.1%. The overall DMFT for patients who were post-antineoplastic therapy was 9.19 (n=457). The overall plaque index for patients who were post-antineoplastic therapy was 1.38 (n=189). The gingival index for patients who were post-chemotherapy was 1.02 (n=162). The weighted prevalence of dental infection/abscess during chemotherapy was reported in three studies and was 5.8%. CONCLUSIONS: Patients who were post-radiotherapy had the highest DMFT. The use of fluoride products and chlorhexidine rinses is beneficial in patients who are post-radiotherapy. There continues to be a lack of clinical studies on the extent and severity of dental disease that are associated with infectious complications during cancer therapy.

Tea, coffee and oral cancer risk.

DATA SOURCES: Pooled individual-level data from nine case-control studies of head and neck cancers, including 5,139 cases and 9,028 controls. STUDY SELECTION: Nine case-control studies were selected from the International Head and Neck Cancer Epidemiology (INHANCE) consortium pool of 33 studies, which included information on coffee (caffeinated and decaffeinated) and tea drinking and cancer of the oral cavity and pharynx. Seven studies also included information on laryngeal cancer. DATA EXTRACTION AND SYNTHESIS: Data from individual studies were checked for inconsistencies and pooled in a standardised way into a common database, including a range of sociodemographic, behavioural, lifestyle and health information. Data on consumption across studies were then converted into cups of de/caffeinated tea or coffee per day. The association between head and neck cancers and caffeinated coffee, decaffeinated coffee or tea intake was assessed by estimating the odds ratios (OR) and the corresponding 95% confidence intervals (95% CI) using a two-stage random-effects logistic regression model with the maximum likelihood estimator. Pooled ORs were also estimated with a fixed-effects logistic regression model. In addition, a test for heterogeneity among studies was conducted. RESULTS: Caffeinated coffee intake was inversely associated with the risk of cancer of the oral cavity and pharynx: the ORs were 0.96 (95% CI, 0.94-0.98) for an increment of one cup per day and 0.61 (95% CI, 0.47-0.80) in drinkers of >4 cups per day versus non-drinkers. This latter estimate was consistent for different anatomic sites (OR, 0.46; 95% CI, 0.30-0.71 for oral cavity; OR, 0.58; 95% CI, 0.41-0.82 for oropharynx/hypopharynx; and OR, 0.61; 95% CI, 0.37-1.01 for oral cavity/pharynx not otherwise specified) and across strata of selected covariates. No association of caffeinated coffee drinking was found with laryngeal cancer (OR, 0.96; 95% CI, 0.64-1.45 in drinkers of >4 cups per day versus non-drinkers). Data on decaffeinated coffee were too sparse for detailed analysis, but indicated no increased risk. Tea intake was not associated with head and neck cancer risk (OR, 0.99; 95% CI, 0.89-1.11 for drinkers versus non-drinkers). CONCLUSIONS: This pooled analysis of case-control studies supports the hypothesis of an inverse association between caffeinated coffee drinking and risk of cancer of the oral cavity and pharynx.

Public awareness of oral cancer and associated risk factors is low.

STUDY DESIGN: A survey was carried out over a three-year period (2004-2007) in Maggie's Cancer Caring Centres or in patients' homes in Glasgow and Edinburgh, Scotland. Participants included young patients diagnosed with oral cancer. DATA COLLECTION AND ANALYSIS: Data were collected by interview using a semi-structured interview schedule. The interview transcripts were analysed using a thematic framework and with the aid of NVivo qualitative analysis software (Version 8). RESULTS: The majority of the cohort knew that smoking and alcohol could cause oral cancer. None thought it would happen to them, however. Descriptions of symptoms varied widely and several participants used self-treatment modalities provided from a pharmacy. There were various causes of patient delay, and self-treatment was not the only cause. Reinterpretation of symptoms without seeking professional help was not uncommon. None of the patients suspected that they had oral cancer until it was confirmed by their general practitioner (GP) or general dental practitioner (GDP). CONCLUSIONS: The study confirms gaps in understanding and awareness of oral cancer. Most survey participants had heard of oral cancer. However, they did not think their symptoms were indicative of cancer and they self-managed the problem. The culture of not bothering the GP/GDP unless the condition was perceived as serious is a barrier to early diagnosis and treatment. Findings support that further public awareness of oral cancer and its symptoms is required to alert the public that if their symptoms persist beyond three weeks, they need a professional opinion.

Oral dysplasia and risk of progression to cancer.

DATA SOURCES: Medline, EMbase and Cochrane databases. STUDY SELECTION: Studies were included if they reported data on patients with a histologically-confirmed diagnosis of oral dysplasia. They also had to study at least one outcome measure and one intervention method or clinical risk factor. Outcome measures included malignant transformation rate (MTR) and time to malignant transformation (TMT). In studies on oral lesions, which contained a defined subset of patients with oral dysplasia, this subset but not all patients with oral lesions were included in the meta-analysis. Observational studies were included in the review due to the scarcity of randomised controlled trials with adequate follow-up period. DATA EXTRACTION AND SYNTHESIS: Quality assessment was undertaken independently by two reviewers. When there was disagreement, a third reviewer was consulted. Quality criteria were agreed upon a priori, and the authors used a combination of quality assessment methods. Eligibility of studies was determined independently from the abstracts by two reviewers blinded to each other's selections. Outcome data were abstracted independently by a researcher and a statistician and checked by a third reviewer. Heterogeneity was assessed graphically in a forest plot and a meta-analysis was conducted. Subgroup analysis was performed by histologic grade, clinical risk factors and treatment modality. RESULTS: Fourteen non-randomised studies, reporting on 992 patients, were included. There was considerable heterogeneity between studies. The mean overall MTR was 12.1% (95% CI: 8.1%, 17.9%) and the mean TMT was 4.3 years. Histologic grade significantly affected mean MTR (p < 0.008). Furthermore, lesions that were not excised demonstrated considerably higher MTR than those that were excised (p = 0.003). CONCLUSIONS: Oral dysplasia showed a significant rate of transformation to cancer, which was related to grade, and was decreased significantly but not eliminated by excision. Findings suggest the need for surgical excision and continued surveillance, particularly in high-grade lesions.

Socioeconomic status and head and neck cancer.

DESIGN: This was a population-based case-control study. CASE-CONTROL SELECTION: Eligible patients were aged between 18 and 80 years and had a primary histopathological diagnosis made between April 2002 and December 2004. Diagnosis included malignant cancers of the oral cavity, oropharynx, hypopharynx or larynx. Incident cases were identified through weekly monitoring of head and neck cancer clinics in hospital departments and were confirmed by pathology department records. Controls matched by age (5-year age band) and sex were randomly selected from the lists of general practitioners. DATA ANALYSIS: Information about occupation, education, smoking and alcohol consumption was collected at personal interview. Socioeconomic circumstances were measured at an individual level (education, occupational social class, unemployment), and by area-based measures of deprivation. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were computed by unconditional logistic regression and were adjusted for age and sex. This model was repeated to assess for potential independent effects of the range of socioeconomic components after adjusting for smoking and alcohol consumption. Interactions between smoking and consumption of alcohol, and between individual and area-based measures for socioeconomic factors were tested by the likelihood ratio test. In addition, the most important behavioural risk factors and socioeconomic variables were entered into a stepwise multivariate logistic regression model. All statistical analyses were carried out using Statistical Analysis System (SAS; Cary, North Carolina, USA) software. RESULTS: The study population included 103 cancer patients (38 women and 65 men), and 91 controls (39 women and 52 men). Individuals living in the most deprived areas (OR, 4.66; 95% CI, 1.79- 12.18) and those who were unemployed (OR, 2.27; 95% CI, 1.21- 4.26) had a significantly higher risk of cancer than people who had high levels of educational attainment (OR, 0.17; 95% CI, 0.05-0.58). Significance was lost for all measures of social class when adjustments were made for smoking and consumption of alcohol. When the most important behavioural and socioeconomic factors were combined in a fully adjusted multivariate analysis, smoking was the only significant risk factor (OR, 15.53; 95% CI, 5.36-44.99) found to be independently associated with head and neck cancers. CONCLUSIONS: A high risk of head and neck cancer was consistently associated with poor socioeconomic circumstances. There were strong links for specific components but smoking dominated the overall profile of risk. More detailed research into the nature of such associations is needed in the future.

Diagnostic delay broadly associated with more advanced stage oral cancer.

DATA SOURCES: Medline, Embase, ISI Proceedings and the reference lists of relevant articles were used to find relevant studies. STUDY SELECTION: Studies were included if: they presented original data from observational studies; included patients with a confirmed pathological diagnosis of oral or oropharyngeal squamous cell carcinoma; the outcome of interest was clearly defined as disease stage (TNM classification); the exposure of interest was total diagnostic delay, defined as the period between the patient noticing either the first sign or symptom and definitive diagnosis (data were collected from interviews using a standardised questionnaire and medical records); provided relative risks (RR) and 95% confidence intervals (CI) or provided enough data to allow calculation of these figures. DATA EXTRACTION AND SYNTHESIS: Quality assessment was undertaken independently by two reviewers and followed the recommendations of the Meta-analysis of Observational Studies in Epidemiology (MOOSE). Meta-analysis was conducted using fixed and random-effects models. RESULTS: Nine studies carried out in nine different countries met the inclusion criteria and were included in the analysis. The fixed-effects pooled relative risk (RR) of advanced stages of oropharyngeal cancer when diagnostic delay is present was 1.32 (95% CI, 1.07-1.62). This association was stronger when the analysis was restricted to oral cancer (pooled RR, 1.47; 95% CI, 1.09-1.99) and when the delay was longer than 1 month (pooled RR, 1.69; 95% CI, 1.26-2.77). CONCLUSIONS: The probability for people with delayed diagnosis to present with an advanced-stage tumour at diagnosis was significantly higher than that of individuals with no delay in diagnosis. New prospective studies with strict methodology are needed, however, to shed more light on this association.