Genetics of epilepsy: The testimony of twins in the molecular era.

OBJECTIVE: Analysis of twins with epilepsy to explore the genetic architecture of specific epilepsies, to evaluate the applicability of the 2010 International League Against Epilepsy (ILAE) organization of epilepsy syndromes, and to integrate molecular genetics with phenotypic analyses. METHODS: A total of 558 twin pairs suspected to have epilepsy were ascertained from twin registries (69%) or referral (31%). Casewise concordance estimates were calculated for epilepsy syndromes. Epilepsies were then grouped according to the 2010 ILAE organizational scheme. Molecular genetic information was utilized where applicable. RESULTS: Of 558 twin pairs, 418 had confirmed seizures. A total of 534 twin individuals were affected. There were higher twin concordance estimates for monozygotic (MZ) than for dizygotic (DZ) twins for idiopathic generalized epilepsies (MZ = 0.77; DZ = 0.35), genetic epilepsy with febrile seizures plus (MZ = 0.85; DZ = 0.25), and focal epilepsies (MZ = 0.40; DZ = 0.03). Utilizing the 2010 ILAE scheme, the twin data clearly demonstrated genetic influences in the syndromes designated as genetic. Of the 384 tested twin individuals, 10.9% had mutations of large effect in known epilepsy genes or carried validated susceptibility alleles. CONCLUSIONS: Twin studies confirm clear genetic influences for specific epilepsies. Analysis of the twin sample using the 2010 ILAE scheme strongly supported the validity of grouping the "genetic" syndromes together and shows this organizational scheme to be a more flexible and biologically meaningful system than previous classifications. Successful selected molecular testing applied to this cohort is the prelude to future large-scale next-generation sequencing of epilepsy research cohorts. Insights into genetic architecture provided by twin studies provide essential data for optimizing such approaches.

Lung cancer in Victoria: are we making progress?

OBJECTIVES: To identify areas to improve patient management in lung cancer, which remains the greatest cause of death from cancer in Australia. DESIGN AND SETTING: Retrospective survey of all cases of lung cancer reported to the Victorian Cancer Registry from 1 January to 30 June 2003 and followed up for 5 years. MAIN OUTCOME MEASURES: Patient and disease characteristics, investigations, staging, treatment, cause of death, survival. RESULTS: 841 patients were included. Smoking data were available for 799, of whom 63 (7.9%) had never smoked. Of 655 non-small cell lung cancer (NSCLC) cases, 198 (30.2%) were treated with curative intent, 125 (19.1%) by surgery and 73 (11.1%) by radiotherapy with or without chemotherapy. Only 7 (6.9%) of surgical patients with complete R0 resection had adjuvant chemotherapy. Of 101 small cell lung cancer (SCLC) cases, a third had limited stage disease which was mostly treated with curative intent by chemotherapy with or without radiotherapy. Patients whose cases were discussed at a multidisciplinary meeting (MDM) were significantly more likely to receive anticancer treatment and had longer survival; on multivariate analysis, MDM discussion was an independent prognostic factor. Compared with a similar survey 10 years earlier, the median age of patients diagnosed with lung cancer had increased by almost 3 years, the proportion of affected men decreased and adenocarcinoma was more frequent, while 10% of patients continued to have no pathologically confirmed diagnosis and 26% continued to receive no anticancer treatment. The number of patients with NSCLC who went on to a definitive surgical procedure fell with no detriment to survival, which likely reflected better staging with the introduction of positron emission tomography scanning. CONCLUSIONS: Opportunities to improve patient management included increasing the proportion with a pathologically confirmed diagnosis and greater use of postsurgical adjuvant chemotherapy. A high proportion of patients received no treatment, with underuse of chemotherapy and radiotherapy. Critically, the low rate of case discussions at MDMs needs to increase. However, effective strategies are required to identify cases early, as over two-thirds currently present with incurable disease.

Evaluation of the Simplified Comorbidity Score (Colinet) as a prognostic indicator for patients with lung cancer: a cancer registry study.

INTRODUCTION: A Simplified Comorbidity Score (SCS) provided additional prognostic information to the established factors in patients with non-small cell lung cancer lung cancer. We undertook this analysis to test the prognostic value of the SCS in a population-based study. PATIENTS AND METHODS: Retrospective survey of all Victorians diagnosed with lung cancer in January-June 2003, identified from the Victorian Cancer Registry. RESULTS: There were 921 patients, with data available for 841 (91.3%). Median age was 72 years (range 30-94) and 63.1% were male. A tissue diagnosis was made for 89.9%, of which 86.6% were non-small cell (NSCLC), and 13.4% small cell carcinoma (SCLC). Comorbidities on which the SCS is based were distributed: cardiovascular 54.6%; respiratory 38.9%; neoplastic 19.9%; renal 4.6%; diabetes 11.7%; alcoholism 5.5%; and tobacco 83.1%. In patients with NSCLC, higher SCS score (>9) was associated with increasing stage, ECOG performance status, male sex, increasing age, tobacco consumption and not receiving treatment. Using Cox regression, survival was analysed by SCS score after adjusting for the effect of age, sex, cell type (NSCLC, SCLC, no histology), ECOG performance status and stage for all patients and then restricted to NSCLC. As a continuous or dichotomous (≤ or >9) variable, SCS was not a significant prognostic factor for all patients or when restricted to NSCLC. CONCLUSION: In this retrospective analysis of population based registry patients, SCS did not provide additional prognostic information in patients with lung cancer. ECOG performance status may be a substitute for the effect of comorbidity.

Pancreatic cancer: surgical management and outcomes after 6 years of follow-up.

OBJECTIVE: To describe the management and outcomes of a population-based cohort of patients with pancreatic cancer in Victoria, Australia. DESIGN, SETTING AND PATIENTS: Retrospective study based on questionnaires completed from medical histories of patients diagnosed with pancreatic cancer during 2002-2003 in Victoria who were identified from the Victorian Cancer Registry and followed up for 6 years. MAIN OUTCOME MEASURES: Proportion of patients receiving each form of treatment, 30-day mortality, median survival, and 5-year and 6-year survival. RESULTS: Of 1044 patients with pancreatic cancer identified, 927 were eligible for the study, and questionnaires were completed for 830 (response rate, 89.5%); 67 patients with ampulla of Vater and neuroendocrine tumours were excluded. Of the 763 remaining patients (median age, 72 years), notification of death was available for 747 (97.9%). Most patients (n = 548) had tumours in the head and neck of the pancreas. Resection was performed in a total of 87 patients (11.4%). Patients managed with Whipple resection (n = 75) had a 30-day mortality rate of 5.3% and median survival of 16.3 months. A relatively large number of surgeons (n = 31) each performed a modest number of Whipple resections during the study period. Jaundice was palliated with biliary stents (n = 240) and bypass surgery (n = 99). Survival was shortest in those treated with best supportive care (median, 2.3 months for those with head and neck of pancreas tumours, and 3.4 months for body and tail of pancreas tumours). Of the 20 patients who survived to 5 years, 10 did not have histological confirmation of carcinoma and were presumably false-positive diagnoses, and three of the 10 patients who did have positive histological results had experienced recurrent disease by 6-year follow-up. CONCLUSIONS: Most outcomes in Victoria compared favourably with other studies. Prognosis for patients with carcinoma of the pancreas is grim, with few long-term survivors. Six-year survival appears to be a better proxy for cure than 5-year survival.

Use of chemotherapy and radiotherapy in patients with pancreatic cancer in Victoria (2002-2003): a retrospective cohort study.

OBJECTIVE: To describe the management and outcomes of a population-based cohort of patients with pancreatic cancer treated with chemotherapy or radiotherapy in Victoria, Australia. DESIGN, SETTING AND PATIENTS: Questionnaire-based study of patients diagnosed with pancreatic cancer during 2002-2003 in Victoria who were retrospectively identified from the Victorian Cancer Registry and followed up for a minimum of 5 years. MAIN OUTCOME MEASURES: Reported treatment, referral patterns and survival rates. RESULTS: 1044 patients with pancreatic cancer were identified, of whom 927 were eligible for the study. Completed questionnaires were obtained for 831 eligible patients (response rate, 89.6%) and data for 66 patients with tumours of the ampulla of Vater and neuroendocrine tumours were excluded. Of the remaining 765 patients, 6.5% were managed in multimodality clinics. Chemotherapy was considered for 413 patients and radiotherapy was considered for 162. One-third of the cohort (275 patients) received chemotherapy, most commonly as palliative treatment (185). Single-agent gemcitabine was the most common palliative treatment (154), and was associated with a median overall survival of 6.6 months. Radiotherapy was used in 119 patients (15.6% of the cohort) - it was used alone or with chemotherapy, as postoperative adjuvant treatment, as potentially curative radical treatment, or as palliative treatment. For 45 patients with locally advanced disease who were treated with chemoradiation as radical treatment, median overall survival was 13.1 months. CONCLUSIONS: There appears to be under-referral of patients to medical and radiation oncologists. Median survival of patients treated with radical chemoradiation or palliative chemotherapy is consistent with clinical trial data, but outcomes for patients in our cohort were generally poor. Development and implementation of treatment guidelines may result in improved outcomes.

Obstetric events as a risk factor for febrile seizures: a community-based twin study.

Adverse events during the perinatal period have traditionally been thought to contribute to the risk of febrile seizures although an association has not been found in large epidemiological studies. Disease-discordant twins provide a means to assess the role of non-shared environmental factors while matching for confounding factors and avoiding difficulties of epidemiological studies in singletons. This study aimed to examine the association of obstetric events and febrile seizures in a community-based twin study. Twenty-one twin pairs discordant for febrile seizures were ascertained from a community-based twin register. Obstetric events were scored using the McNeil-Sjöström Scale for Obstetric Complications and expressed as a summary score (OC score). The frequency of individual obstetric events in affected and unaffected twins, the within-pair differences in OC scores and other markers of perinatal risk including birthweight, birth order and Apgar scores were examined. No significant difference was found in the frequency of individual obstetric events, nor in OC scores between affected and unaffected twins. No differences in birth weight, birth order, 1- or 5-minute Apgar scores were observed. Our results confirm previous findings that obstetric events are not associated with the risk of febrile seizures.

A twin study of genetic influences on epilepsy outcome.

The identification of genetic factors that confer susceptibility to the epilepsies has to date been the focus of genetic efforts in this field. Few studies have assessed the genetic contribution to disease course in epilepsy, yet an understanding of the genetic influences on epilepsy outcome is key to developing new therapeutic strategies. The aim of this study was to assess the genetic contributions to epilepsy outcome in twin pairs concordant for epilepsy. We studied 37 epilepsy concordant twin pairs (27 monozygotic, 10 dizygotic) in whom there were no recognized environmental contributions (e.g., acquired brain injury) to epilepsy, and in whom the most likely cause for epilepsy was a shared genetic susceptibility. Clinical outcome was determined using the binary measure of Seizure Status (seizure remission or recurrence) and on a six-category ordinal Outcome Scale. Epilepsy outcome was independent of age of seizure onset, age at assessment and major epilepsy syndrome diagnosis. The proportion of twin pairs concordant for Seizure Status was 0.81 (22/27) for monozygous and 1.0 (10/10) for dizygous pairs, p = 0.3. Within-pair correlation in outcome (Outcome Scale) was 0.60 (95% CI: 0.32, 0.78) in monozygous and 0.78 (0.48, 0.92) in dizygous pairs. These data provide no evidence for genetic influences on epilepsy outcome independent of those that contribute to disease susceptibility. The observed high correlations for outcome suggest that, for epilepsy, susceptibility genes also have a major influence on outcome.