Multi-institutional Outcomes and Associations After Excision and Primary Anastomosis for Radiotherapy-associated Bulbomembranous Urethral Stenoses Following Prostate Cancer Treatment.

OBJECTIVE: To evaluate the outcomes of excision and primary anastomosis (EPA) for radiation-associated bulbomembranous stenoses using a multi-institutional analysis. The treatment of radiation-associated urethral stenosis is typically complex owing to the adverse impact of radiation on adjacent tissue. METHODS: An IRB-approved multi-institutional retrospective review was performed on patients who underwent EPA for bulbomembranous urethral stenosis following prostate radiotherapy. Preoperative patient demographics, operative technique, and postoperative outcomes were abstracted from 1/2007-6/2018. Success was defined as voiding per urethra without the need for endoscopic treatment and a minimum follow-up of 12 months. RESULTS: One hundred and thirty-seven patients from 10 centers met study criteria with a mean age of 69.3 years (50-86), stenosis length of 2.3 cm (1-5) and an 86.9% (119/137) success rate at a mean follow-up 32.3 months (12-118). Univariate Cox regression analysis identified increasing patient age (P = .02), stricture length (P <.0001) and combined modality radiotherapy (P = .004) as factors associated with stricture recurrence while body mass index (P = .79), diabetes (P = .93), smoking (P = .62), failed endoscopic treatment (P = .08) and gracilis muscle use (P = .25) were not. On multivariate analysis, increasing patient age (H.R.1.09, 95%CI 1.01-1.16; P = .02) and stenosis length (H.R.2.62, 95%CI 1.49-4.60; P = .001) remained associated with recurrence. Subsequent artificial urinary sphincter was performed in 30 men (21.9%), of which 25 required a transcorporal cuff and 5 developed cuff erosion. CONCLUSIONS: EPA for radiation-associated urethral stenosis effectively provides unobstructed instrumentation-free voiding. However, increasing stenosis length and age are independently associated with surgical failure. Patients should be counseled that further surgery for incontinence may be necessary.

EBV-associated primary CNS lymphoma occurring after immunosuppression is a distinct immunobiological entity.

Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression (eg, posttransplant lymphoproliferative disorders or HIV [AIDS-related PCNSL]). These cases are poorly characterized, have dismal outcome, and are typically Epstein-Barr virus (EBV)-associated (ie, tissue-positive). We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. Forty-seven were EBV tissue-negative: 45 EBV- HIV- PCNSL and 2 EBV- HIV+ PCNSL; and 44 were EBV tissue-positive: 23 EBV+ HIV+ PCNSL and 21 EBV+ HIV- PCNSL. As with prior studies, EBV- HIV- PCNSL had frequent MYD88, CD79B, and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin subtype. In contrast, these mutations were absent in all EBV tissue-positive cases and ABC frequency was low. Furthermore, copy number loss in HLA class I/II and antigen-presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV+ HIV- PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-associated PCNSL in the immunosuppressed is immunobiologically distinct from EBV- HIV- PCNSL, and, despite expressing an immunogenic virus, retains the ability to present EBV antigens. Results provide a framework for targeted treatment.

Goats singly heterozygous for PRNP S146 or K222 orally inoculated with classical scrapie at birth show no disease at ages well beyond 6 years.

Scrapie is a transmissible spongiform encephalopathy of sheep and goats, and scrapie eradication programs in many parts of the world rely on strong genetic resistance to classical scrapie in sheep. However, the utility of putative resistance alleles in goats has been a focus of research because goats can transmit scrapie to sheep and may serve as a scrapie reservoir. Prior work showed that disease-free survival time was significantly extended in orally inoculated goats singly heterozygous for prion amino acid substitutions S146 or K222, but average durations were only around 3 years post-inoculation. The aim of this study was to investigate whether extended survival would exceed 6 years, which represents the productive lifetimes of most commercial goats. While all control homozygotes were clinically affected by an average of <2 years, none of the NS146 or QK222 goats developed clinical scrapie or had PrPSc-positive rectal biopsies. Several NS146 and QK222 goats developed other conditions unrelated to scrapie, but tissue accumulation of PrPSc was not detected in any of these animals. The NS146 heterozygotes have remained disease-free for an average of 2734days (approximately 7.5 years), the longest duration of any classical scrapie challenge experiment with any genotype to date. The QK222 heterozygotes have remained disease-free for an average of 2450days (approximately 6.7 years), the longest reported average duration for QK222 goats challenged with classical scrapie. This research is ongoing, but the current results demonstrate S146 and K222 confer strong resistance to classical scrapie in goats.

Novel antibody associations in immune-mediated necrotising myopathy without inflammation.

INTRODUCTION: The patient presenting with proximal muscle weakness, elevated serum creatinine kinase and myopathic electromyography and biopsy findings has a wide differential diagnosis that includes toxic, autoimmune, paraneoplastic and congenital myopathies. Autoimmune myopathies are important to identify because they may respond to immunosuppressive therapies. METHODS: We describe two cases of immune-mediated necrotizing myopathy each associated with a novel antibody. RESULTS: Case 1 describes a progressive myopathy in a statin user. Antibodies to 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase were identified and the patient responded to steroid therapy. Case 2 describes an aggressive myopathy associated with antibodies to signal recognition particle. There was no response to steroids. Clinical improvement followed treatment with rituximab and cyclophosphamide. CONCLUSION: The identification of myositis-specific antibodies is important because they are associated with distinct clinical phenotypes and may guide the physician in terms of treatment strategies.

A multicentre retrospective comparison of central nervous system prophylaxis strategies among patients with high-risk diffuse large B-cell lymphoma.

BACKGROUND: Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is a devastating complication; the optimal prophylactic strategy remains unclear. METHODS: We performed a multicentre, retrospective analysis of patients with DLBCL with high risk for CNS relapse as defined by two or more of: multiple extranodal sites, elevated serum LDH and B symptoms or involvement of specific high-risk anatomical sites. We compared three different strategies of CNS-directed therapy: intrathecal (IT) methotrexate (MTX) with (R)-CHOP 'group 1'; R-CHOP with IT MTX and two cycles of high-dose intravenous (IV) MTX 'group 2'; dose-intensive systemic antimetabolite-containing chemotherapy (Hyper-CVAD or CODOXM/IVAC) with IT/IV MTX 'group 3'. RESULTS: Overall, 217 patients were identified (49, 125 and 43 in groups 1-3, respectively). With median follow-up of 3.4 (range 0.2-18.6) years, 23 CNS relapses occurred (12, 10 and 1 in groups 1-3 respectively). The 3-year actuarial rates (95% CI) of CNS relapse were 18.4% (9.5-33.1%), 6.9% (3.5-13.4%) and 2.3% (0.4-15.4%) in groups 1-3, respectively (P=0.009). CONCLUSIONS: The addition of high-dose IV MTX and/or cytarabine was associated with lower incidence of CNS relapse compared with IT chemotherapy alone. However, these data are limited by their retrospective nature and warrant confirmation in prospective randomised studies.

Lower limb injuries caused by improvised explosive devices: proposed 'Bastion classification' and prospective validation.

BACKGROUND: Complex lower limb injury caused by improvised explosive devices (IEDs) has become the signature wounding pattern of the conflict in Afghanistan. Current classifications neither describe this injury pattern well, nor correlate with management. There is need for a new classification, to aid communication between clinicians, and help evaluate interventions and outcomes. We propose such a classification, and present the results of an initial prospective evaluation. PATIENTS AND METHODS: The classification was developed by a panel of military surgeons whilst deployed to Camp Bastion, Afghanistan. Injuries were divided into five classes, by anatomic level. Segmental injuries were recognised as a distinct entity. Associated injuries to the intraperitoneal abdomen, genitalia and perineum, pelvic ring, and upper limbs, which impact on clinical management and resources, were also accounted for. RESULTS: Between 1 November 2010 and 20 February 2011, 179 IED-related lower limb injuries in 103 consecutive casualties were classified, and their subsequent vascular and musculoskeletal treatment recorded. 69% of the injuries were traumatic amputations, and the remainder segmental injuries. 49% of casualties suffered bilateral lower limb amputation. The most common injury was class 3 (involving proximal lower leg or thigh, permitting effective above-knee tourniquet application, 49%), but more proximal patterns (class 4 or 5, preventing effective tourniquet application) accounted for 18% of injuries. Eleven casualties had associated intraperitoneal abdominal injuries, 41 suffered genital or perineal injuries, 9 had pelvic ring fractures, and 66 had upper limb injuries. The classification was easy to apply and correlated with management. CONCLUSIONS: The 'Bastion classification' is a pragmatic yet clinically relevant injury categorisation, which describes current injury patterns well, and should facilitate communication between clinicians, and the evaluation of interventions and outcomes. The validation cohort confirms that the injury burden from IEDs in the Helmand Province of Afghanistan remains high, with most casualties sustaining amputation through or above the knee. The rates of associated injury to the abdomen, perineum, pelvis and upper limbs are high. These findings have important implications for the training of military surgeons, staffing and resourcing of medical treatment facilities, to ensure an adequate skill mix to manage these complex and challenging injuries.

Anti-NMDA receptor encephalitis with associated catatonia during pregnancy.

Anti-NMDA-R encephalitis has been described as a cause of acute psychosis in young females. It is rare during pregnancy. We describe a primigravida 32-year-old woman with acute onset psychosis during the first trimester. Eight weeks after becoming pregnant, the patient became psychotic with associated catatonia and autonomic disturbance. Serum anti-NMDA-R antibodies were found. She responded to plasma exchange. At caesarean section, a healthy baby boy was born and a benign mature cystic teratoma was removed from the left ovary. Catatonia associated with psychosis may occur in pregnancy secondary to anti-NMDA-R encephalitis. Prompt and aggressive treatment can lead to a good outcome for both baby and mother.

Disease-associated prion protein in neural and lymphoid tissues of mink (Mustela vison) inoculated with transmissible mink encephalopathy.

Transmissible spongiform encephalopathies (TSEs) are diagnosed by immunodetection of disease-associated prion protein (PrP(d)). The distribution of PrP(d) within the body varies with the time-course of infection and between species, during interspecies transmission, as well as with prion strain. Mink are susceptible to a form of TSE known as transmissible mink encephalopathy (TME), presumed to arise due to consumption of feed contaminated with a single prion strain of ruminant origin. After extended passage of TME isolates in hamsters, two strains emerge, HY and DY, each of which is associated with unique structural isoforms of PrP(TME) and of which only the HY strain is associated with accumulation of PrP(TME) in lymphoid tissues. Information on the structural nature and lymphoid accumulation of PrP(TME) in mink is limited. In this study, 13 mink were challenged by intracerebral inoculation using late passage TME inoculum, after which brain and lymphoid tissues were collected at preclinical and clinical time points. The distribution and molecular nature of PrP(TME) was investigated by techniques including blotting of paraffin wax-embedded tissue and epitope mapping by western blotting. PrP(TME) was detected readily in the brain and retropharyngeal lymph node during preclinical infection, with delayed progression of accumulation within other lymphoid tissues. For comparison, three mink were inoculated by the oral route and examined during clinical disease. Accumulation of PrP(TME) in these mink was greater and more widespread, including follicles of rectoanal mucosa-associated lymphoid tissue. Western blot analyses revealed that PrP(TME) accumulating in the brain of mink is structurally most similar to that accumulating in the brain of hamsters infected with the DY strain. Collectively, the results of extended passage in mink are consistent with the presence of only a single strain of TME, the DY strain, capable of inducing accumulation of PrP(TME) in the lymphoid tissues of mink but not in hamsters. Thus, mink are a relevant animal model for further study of this unique strain, which ultimately may have been introduced through consumption of a TSE of ruminant origin.

The role of a movement disorders clinic.

Ireland's ageing population will result in a substantial increase in neurodegenerative disease with a projected increase in prevalence of Idiopathic Parkinson's disease (IPD) to 9,000 by 2021. There are few published audits of neurology services to assist care planning. As a first step towards evaluating future service needs for this group of patients, we audited a single tertiary referral IPD and Other Movement Disorders clinic for 2006. A total of 497 patients from all counties in Ireland were seen; 225 (59%) of patients had IPD, 32 (8.2%) had atypical parkinsonism, and 22 (5.8%) dystonia. In a subset of 275 patients, 151 (55%) were referred by GPs, 74 (27%) by other consultants, and 49 (18%) by other consultant neurologists. Diagnosis was changed in 22 (38%) and medication was adjusted in 203 (74%). A telephone survey of 50 patients demonstrated 100% satisfaction with the improved access to the clinical nurse specialist, telephone support and improved continuity of care. The IPD and Other Movement Disorders clinic provides an important local, regional, and national diagnostic and therapeutic service for complex movement disorders. It is proposed that a national registry of IPD and audit of the delivery of care to patients with movement disorders is needed.

'Sink or swim': an evaluation of the clinical characteristics of individuals with high bone mass.

SUMMARY: High bone mineral density on routine dual energy X-ray absorptiometry (DXA) may indicate an underlying skeletal dysplasia. Two hundred fifty-eight individuals with unexplained high bone mass (HBM), 236 relatives (41% with HBM) and 58 spouses were studied. Cases could not float, had mandible enlargement, extra bone, broad frames, larger shoe sizes and increased body mass index (BMI). HBM cases may harbour an underlying genetic disorder. INTRODUCTION: High bone mineral density is a sporadic incidental finding on routine DXA scanning of apparently asymptomatic individuals. Such individuals may have an underlying skeletal dysplasia, as seen in LRP5 mutations. We aimed to characterize unexplained HBM and determine the potential for an underlying skeletal dysplasia. METHODS: Two hundred fifty-eight individuals with unexplained HBM (defined as L1 Z-score ≥ +3.2 plus total hip Z-score ≥ +1.2, or total hip Z-score ≥ +3.2) were recruited from 15 UK centres, by screening 335,115 DXA scans. Unexplained HBM affected 0.181% of DXA scans. Next 236 relatives were recruited of whom 94 (41%) had HBM (defined as L1 Z-score + total hip Z-score ≥ +3.2). Fifty-eight spouses were also recruited together with the unaffected relatives as controls. Phenotypes of cases and controls, obtained from clinical assessment, were compared using random-effects linear and logistic regression models, clustered by family, adjusted for confounders, including age and sex. RESULTS: Individuals with unexplained HBM had an excess of sinking when swimming (7.11 [3.65, 13.84], p < 0.001; adjusted odds ratio with 95% confidence interval shown), mandible enlargement (4.16 [2.34, 7.39], p < 0.001), extra bone at tendon/ligament insertions (2.07 [1.13, 3.78], p = 0.018) and broad frame (3.55 [2.12, 5.95], p < 0.001). HBM cases also had a larger shoe size (mean difference 0.4 [0.1, 0.7] UK sizes, p = 0.009) and increased BMI (mean difference 2.2 [1.3, 3.1] kg/m(2), p < 0.001). CONCLUSION: Individuals with unexplained HBM have an excess of clinical characteristics associated with skeletal dysplasia and their relatives are commonly affected, suggesting many may harbour an underlying genetic disorder affecting bone mass.

Malignancy in scleroderma patients from south west England: a population-based cohort study.

The pathophysiological relationship between scleroderma and malignancy remains poorly understood. Although some previous studies have demonstrated an increased malignancy risk in patients with scleroderma, others have been inconclusive. We aimed to determine if patients with scleroderma had an increased risk of malignancy compared to an age- and sex-matched local South West England population, and if there were any important differences between scleroderma patients with and without malignancy. Methods of this study are as follows. Notes were obtained on all local scleroderma patients (n = 68) locally, and those diagnosed with malignancy verified by contacting each patient's general practitioner. Expected malignancy figures were obtained from age- and sex-stratified regional prevalence data provided by the South West Cancer Intelligence Service registry. Among the patients, 22.1% with scleroderma were identified with concurrent malignancy. Affected sites were of the breast (n = 5), haematological system (n = 5), skin (n = 4), and unknown primary (n = 1). Overall, malignancy risk was found to be increased in scleroderma (RR = 3.15, 95% CI 1.77-5.20, p = 0.01). In particular, this risk was the highest for haematological malignancies (RR = 18.5, 95% CI 6-43, p = 0.03), especially for non-Hodgkin's lymphoma (RR = 25.8, 95% CI 5-75, p = 0.10). The majority of patients (86.7%) developed malignancy after the onset of scleroderma (mean = 6.9 years). Age of >70 and patients with limited scleroderma were significant risk factors for a patient with scleroderma to have a concurrent malignancy; however, no increased risk was found in patients with any particular pattern of organ involvement, cytotoxic usage or serology. To conclude, in this small patient cohort, we have found that scleroderma is associated with an increased risk of malignancy. This risk is statistically significant in patients with limited scleroderma. Patients who are elderly and those with limited disease should be closely scrutinized at follow-up appointments.

Anti-glycolipid GM2-positive Guillain-Barre syndrome due to hepatitis E infection.

BACKGROUND: Hepatitis E infection is most prevalent in developing countries with poor sanitation, but can also occur apparently sporadically in more developed areas. CASE: We here report a second European case of Guillain-Barre syndrome due to hepatitis E infection in association with anti-glycolipid GM2 antibody. INTERPRETATION: This is likely to be a specific association involving molecular mimicry, and further European cases can therefore be expected.