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Background: Encephalitis, brain inflammation and swelling, most often caused by an infection or the body’s immune defences, can have devastating consequences, especially if diagnosed late. We looked for clinical predictors of different types of encephalitis to help clinicians consider earlier treatment. Methods: We conducted a multicentre prospective observational cohort study (ENCEPH-UK) of adults (> 16 years) with suspected encephalitis at 31 UK hospitals. We evaluated clinical features and investigated for infectious and autoimmune causes. Findings: 341 patients were enrolled between December 2012 and December 2015 and followed up for 12 months. 233 had encephalitis, of whom 65 (28%) had herpes simplex virus (HSV), 38 (16%) had confirmed or probable autoimmune encephalitis, and 87 (37%) had no cause found. The median time from admission to 1st dose of aciclovir for those with HSV was 14 hours (IQR 5-50); time to 1st dose of immunosuppressant for the autoimmune group was 125 hours (IQR 45-250). Compared to non-HSV encephalitis, patients with HSV more often had fever, lower serum sodium and lacked a rash. Those with probable or confirmed autoimmune encephalitis were more likely to be female, have abnormal movements, normal serum sodium levels and a cerebrospinal fluid white cell count < 20 cells x106/L, but they were less likely to have a febrile illness. Interpretation: Initiation of treatment for autoimmune encephalitis is delayed considerably compared with HSV encephalitis. Clinical features can help identify patients with autoimmune disease and could be used to initiate earlier presumptive therapy. Clinical Trial Registration Details: Funding Information: National Institute for Health Research, UK. Declaration of Interests: None to declare. Ethics Approval Statement: The study protocols were approved by participating sites and the National Research Ethics Service (now part of the Health Research Authority) East Midlands Nottingham 1 committee (reference 11/EM/0442). Written consent for entry into the study was obtained from patients or an accompanying relative.

OBJECTIVE: Today most patients with Lynch syndrome (LS) survive their first cancer. There is limited information on the incidences and outcome of subsequent cancers. The present study addresses three questions: (i) what is the cumulative incidence of a subsequent cancer; (ii) in which organs do subsequent cancers occur; and (iii) what is the survival following these cancers?DESIGN: Information was collated on prospectively organised surveillance and prospectively observed outcomes in patients with LS who had cancer prior to inclusion and analysed by age, gender and genetic variants.RESULTS: 1273 patients with LS from 10 countries were followed up for 7753 observation years. 318 patients (25.7%) developed 341 first subsequent cancers, including colorectal (n=147, 43%), upper GI, pancreas or bile duct (n=37, 11%) and urinary tract (n=32, 10%). The cumulative incidences for any subsequent cancer from age 40 to age 70 years were 73% for pathogenic MLH1 (path_MLH1), 76% for path_MSH2 carriers and 52% for path_MSH6 carriers, and for colorectal cancer (CRC) the cumulative incidences were 46%, 48% and 23%, respectively. Crude survival after any subsequent cancer was 82% (95% CI 76% to 87%) and 10-year crude survival after CRC was 91% (95% CI 83% to 95%).CONCLUSIONS: Relative incidence of subsequent cancer compared with incidence of first cancer was slightly but insignificantly higher than cancer incidence in patients with LS without previous cancer (range 0.94-1.49). The favourable survival after subsequent cancers validated continued follow-up to prevent death from cancer. The interactive website http://lscarisk.org was expanded to calculate the risks by gender, genetic variant and age for subsequent cancer for any patient with LS with previous cancer.

BackgroundMost patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival.Objective and designThis observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age.Results3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer.ConclusionCarriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient’s age, gender and path_MMR variant. We have updated our open-access website www.lscarisk.org to facilitate this.

Background We have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path_MLH1) despite follow-up with colonoscopy including polypectomy. Methods The cohort included Finnish carriers enrolled in 3-yearly colonoscopy (n = 505; 4625 observation years) and carriers from other countries enrolled in colonoscopy 2-yearly or more frequently (n = 439; 3299 observation years). We examined whether the longer interval between colonoscopies in Finland could explain the high incidence of CRC and whether disease expression correlated with differences in population CRC incidence. Results Cumulative CRC incidences in carriers of path_MLH1 at 70-years of age were 41% for males and 36% for females in the Finnish series and 58% and 55% in the non-Finnish series, respectively (p > 0.05). Mean time from last colonoscopy to CRC was 32.7 months in the Finnish compared to 31.0 months in the non-Finnish (p > 0.05) and was therefore unaffected by the recommended colonoscopy interval. Differences in population incidence of CRC could not explain the lower point estimates for CRC in the Finnish series. Ten-year overall survival after CRC was similar for the Finnish and non-Finnish series (88% and 91%, respectively; p > 0.05). Conclusions The hypothesis that the high incidence of CRC in path_MLH1 carriers was caused by a higher incidence in the Finnish series was not valid. We discuss whether the results were influenced by methodological shortcomings in our study or whether the assumption that a shorter interval between colonoscopies leads to a lower CRC incidence may be wrong. This second possibility is intriguing, because it suggests the dogma that CRC in path_MLH1 carriers develops from polyps that can be detected at colonoscopy and removed to prevent CRC may be erroneous. In view of the excellent 10-year overall survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with LS pending studies that will inform new recommendations on the best surveillance interval., published version, peerReviewed

ObjectiveEstimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates in patients undergoing prospective cancer surveillance.DesignWe undertook a multicentre study of patients carrying Lynch syndrome-associated mutations affectingMLH1,MSH2,MSH6orPMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle relational database and analysed by age, sex and mutated gene.Results1942 mutation carriers without previous cancer had follow-up including colonoscopic surveillance for 13 782 observation years. 314 patients developed cancer, mostly colorectal (n=151), endometrial (n=72) and ovarian (n=19). Cancers were detected from 25 years onwards inMLH1andMSH2mutation carriers, and from about 40 years inMSH6andPMS2carriers. Among first cancer detected in each patient the colorectal cancer cumulative incidences at 70 years by gene were 46%, 35%, 20% and 10% forMLH1, MSH2, MSH6andPMS2mutation carriers, respectively. The equivalent cumulative incidences for endometrial cancer were 34%, 51%, 49% and 24%; and for ovarian cancer 11%, 15%, 0% and 0%. Ten-year crude survival was 87% after any cancer, 91% if the first cancer was colorectal, 98% if endometrial and 89% if ovarian.ConclusionsThe four Lynch syndrome-associated genes had different penetrance and expression. Colorectal cancer occurred frequently despite colonoscopic surveillance but resulted in few deaths. Using our data, a website has been established athttp://LScarisk.orgenabling calculation of cumulative cancer risks as an aid to genetic counselling in Lynch syndrome.

Gareth Evans et al. in a recent article in the journal [http://www.ncbi.nlm.nih.gov/pubmed/24687378] concluded that survival from breast cancer in very high risk women is better in screened versus unscreened women with or without a demonstrated genetic cause, and that BRCA2 mutation carriers may benefit from MRI screening in addition to mammography (Mx). However, this may not be the case for BRCA1 mutation carriers. Their dataset included no more than 27 and 24 BRCA1 breast cancer cases detected through Mx or MRI, respectively. We recently reported survival in BRCA1 mutation carriers diagnosed with breast cancer through annual Mx and MRI [http://www.ncbi.nlm.nih.gov/pubmed/23615785]. The main finding was that despite detecting tumours at an early stage, survival was inferior to what might have been expected according to Kurian et al. [http://www.ncbi.nlm.nih.gov/pubmed/22231042]. Referring to our results, Evans et al. state in their discussion that ‘.. formal evidence for a survival advantage (for MRI versus mammography alone) has not so far been published’. In order to make our data for patients followed at the outpatient clinic at Oslo University Hospital available to all, we here present updated survival analysis in the MRI series previously reported (MRI series), and compare that series to survival in BRCA1 breast cancer cases detected through annual screening with mammography without MRI (Mx series). Our selection, methods and ethics were described in our recent publication mentioned above. The Mx series were the prospectively detected breast cancer cases before MRI was added to the protocol for BRCA1 mutation carriers in 2001, and those subjected to annual Mx alone based on family history before their BRCA1 mutations were detected subsequently. In contrast to our previous report, only patients not having had any cancer before or at first planned examination were included in the present analysis. We diagnosed 6 carcinoma in situ in the Mx series and 3 in the MRI series. Kaplan–Meier survival analyses were performed in the 47 invasive cancer cases detected in the Mx series among whom 12 had died, and in the 45 invasive cancer cases in the MRI series among whom 8 had died. None of the deceased had any other cancers. 5- and 10-years survival was 0.81 (95 % CI 0.63–0.88) and 0.72 (95 % CI 0.60–0.86), respectively, in the Mx series, compared to 0.82 (95 % CI 0.63–0.92) and 0.73 (95 % CI 0.52–0.86) in the MRI series (Fig. 1). Fig. 1 Survival in the MRI and Mx series with 95 % CIs Age (grouped as = 50 years), tumour size ( 20 mm), nodal spread (yes/no), ER, PR and grade were compared with survival through Cox proportional hazard models in the combined series. None gave significant results for univariate analyses (p ≥ 0.18 for any), nor for multivariate analyses (p ≥ 0.24). The findings in this larger series than the one reported by Gareth Evans et al. support their notion that there may be no additional survival benefit from early diagnosis through MRI compared to Mx for BRCA1 mutation carriers: As previously reported, tumours did appear to be downstaged in the MRI series compared to the Mx series—but the expected improved survival was not observed, and there was no association with survival and stage at diagnosis, which would have been expected if the earlier stage at diagnosis in the MRI series were to be associated with better prognosis. Prevalence of carcinoma in situ was low in both series. Time-trends in treatment are potential confounders to survival studies recruiting patients over many years: The MRI cases were treated in more recent years than the Mx cases and would have been expected to have improved survival because of that, nonetheless this was not found. We had expected a right-shift in the survival curve for the MRI series reflecting the earlier diagnosis even in the absence of a ‘true’ improved survival; however, this was not found. Our population has specific founder BRCA1 mutations, and the female carriers may be subjected to different environment factors compared to carriers in other populations. We had no control group without screening, and our results are not in conflict with the conclusion by Gareth Evans et al. that early diagnosis and treatment may be associated with improved survival. Our results address the putative benefit of adding MRI to annual Mx, for which none was apparent. We look forward to reports from other groups on the observed survival related to early diagnosis with MRI in BRCA1 mutation carriers, because despite our series being the largest reported so far, we are still short of patients included to be sure that results are not caused by chance variation based on limited numbers.

Women from breast cancer families without a demonstrable BRCA1/2 mutation were subjected to annual mammography from age 30 years onwards. One-hundred and ninety-eight patients were diagnosed prospectively with invasive breast cancer and followed for a total of 1513 years. Overall 10-year survival was 88 %. Together with our previous report that women in such kindreds had about twice the population risk of breast cancer, the combined conclusion was that the overall chances of developing breast cancer causing death within 10 years before 50 years of age was 1 % or less when subjected to annual mammography and current treatment. These are empirical prospective observations which may be used for genetic counselling. The majority (160/194 = 84 %) of patients had ER+ and/or low grade tumours with 92 % 10-year survival. One minor group of the patients had ER- tumours, another small group had high grade tumours with nodal spread, both groups were associated with worse prognosis, but the two groups were not mutually associated.

Background The addition of annual MRI screening to mammography has heightened optimism that intensive screening along with improved treatments may substantially improve life expectancy of women at high risk of breast cancer. However, survival data from BRCA2 mutation carriers undergoing intensive combined breast screening are scarce. Methods We have collated the results of screening with either annual mammography or mammography with MRI in female BRCA2 mutation carriers in Manchester and Oslo and use a Manchester control group of BRCA2 mutation carriers who had their first breast cancer diagnosed without intensive screening. Results Eighty-seven BRCA2 mutation carriers had undergone combined (n = 34) or mammography (n = 53) screening compared to 274 without such intensive screening. Ten year breast cancer specific survival was 100 % in the combined group (95 % CI 82.5–100 %) and 85.5 % (95 % CI 72.6–98.4 %) in the mammography group compared to 74.6 % (95 % CI 66.6–82.6 %) in the control group. Better survival was driven by lymph node status (negative in 67 % of screened vs 39 % of unscreened women; p