Ibrutinib monotherapy for relapse or refractory primary CNS lymphoma and primary vitreoretinal lymphoma: Final analysis of the phase II 'proof-of-concept' iLOC study by the Lymphoma study association (LYSA) and the French oculo-cerebral lymphoma (LOC) network.

BACKGROUND: Primary central nervous system lymphomas (PCNSLs) are mainly diffuse large B-cell lymphomas (DLBCLs) of the non-germinal centre B-cell subtype, with unmet medical needs. This study aimed to evaluate the efficacy and toxicity of ibrutinib in DLBCL-PCNSL PATIENTS AND METHODS: This prospective, multicentre, phase II study involved patients with relapse or refractory(R/R) DLBCL-PCNSL or primary vitreoretinal lymphoma. The treatment consisted of ibrutinib (560 mg/day) until disease progression or unacceptable toxicity occurred. The primary outcome was the disease control (DC) rate after two months of treatment (P0 < 10%; P1 > 30%). RESULTS: Fifty-two patients were recruited. Forty-four patients were evaluable for response. After 2 months of treatment, the DC was 70% in evaluable patients and 62% in the intent-to-treat analysis, including 10 complete responses (19%), 17 partial responses (33%) and 5 stable diseases (10%). With a median follow-up of 25.7 months (range, 0.7-30.5), the median progression-free and overall survivals were 4.8 months (95% confidence interval [CI]; 2.8-12.7) and 19.2 months (95% CI; 7.2-NR), respectively. Thirteen patients received ibrutinib for more than 12 months. Two patients experienced pulmonary aspergillosis with a favourable (n = 1) or fatal outcome (n = 1). Ibrutinib was detectable in the cerebrospinal fluid (CSF). The clinical response to ibrutinib seemed independent of the gene mutations in the BCR pathway. CONCLUSION: Ibrutinib showed clinical activity in the brain, the CSF and the intraocular compartment and was tolerated in R/R PCNSL. The addition of ibrutinib to standard methotrexate-base induction chemotherapy will be further evaluated in the first-line treatment. CLINICAL TRIAL NUMBER: NCT02542514.

Acute polyradiculopathy secondary to idelalisib in Relapsed Classical Hodgkin's lymphoma.

Patients with relapsed or refractory Hodgkin's lymphoma are likely incurable with standard treatment. Idelalisib, a delta-isoform specific Phosphatidyl-inositol-3-kinase (PI3K) inhibitor has shown its efficacy in other hematopoietic B malignancies. We report the case of a 51-years old patient with relapsed and refractory Hodgkin's Lymphoma receiving idelalisib after several regimens of chemotherapy. He achieved a good partial response for several months, unfortunately, idelalisib had to be stopped because of the onset of a severe polyradiculoneuritis attributed to this treatment. We assume here that the polyradiculoneuritis could be caused by T cell mediated autoimmunity to myelin proteins. To our knowledge, this adverse event has never been described so far with idelalisib.

Development and validation of an UHPLC-MS/MS method for simultaneous quantification of ibrutinib and its dihydrodiol-metabolite in human cerebrospinal fluid.

Ibrutinib is an orally administered first-in-class irreversible Bruton's tyrosine kinase (BTK) covalent inhibitor for the treatment of patients with B-cell malignancies. Several isolated clinical observations reported its efficacy in central nervous system dissemination. Herein, we described the development and validation of an ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) procedure for the quantification of ibrutinib and its active metabolite PCI-45227 in cerebrospinal fluid (CSF). This is the first complete validated method for quantification of ibrutinib and PCI-45227 in CSF. The compounds were eluted on a Waters BEH C18 column (50.0 × 2.1 mm; 1.7 µm) using a gradient elution with a mobile phase composed of ammonium formate buffer 5 mM pH 3.2 and acetonitrile +0.1% formic acid with a flow rate of 400 µL·min-1. Two deuterated internal standards were used to obtain the most accurate quantification. The CSF samples were prepared by a simple and rapid dilution. The method was validated by testing the selectivity, response function, intra-day and inter-day precisions, trueness, limits of detection (LOD) and lower limits of quantification (LLOQ). The validation results proved that the methods were suitable to quantify ibrutinib and PCI-45227 in real biological CSF samples from 0.50 (ibrutinib) or 1.00 (PCI-45227) to 30.00 ng·mL-1. Furthermore, the developed method was adapted to allow the quantification of both compounds in plasma and the results were compared to those reported in literature. The plasmatic samples were treated by protein precipitation and the method was validated to quantify ibrutinib and PCI-45227 in real biological plasmatic samples from 5.00 to 491 ng·mL-1. Lastly, for both matrices, accuracy profiles were plotted from the trueness and precision results using a 20% α-risk (ß = 80%) and the tolerance intervals were comprised within the acceptance limits fixed at ±25% for the LLOQ and ±15% for the other concentrations. Finally, these methods were successfully applied to quantify ibrutinib and PCI-45227 in real human CSF and plasma samples.

Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients.

Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10-7), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10-14) and 1.68 (P=2.18 × 10-14), respectively. Patients with 'double-hit' defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10-27) for all patients and 3.19 (P=1.23 × 10-18) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10-15), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment.

Expressed fusion gene landscape and its impact in multiple myeloma.

Multiple myeloma is a plasma cell malignancy characterized by recurrent IgH translocations and well described genomic heterogeneity. Although transcriptome profiles in multiple myeloma has been described, landscape of expressed fusion genes and their clinical impact remains unknown. To provide a comprehensive and detailed fusion gene cartography and suggest new mechanisms of tumorigenesis in multiple myeloma, we performed RNA sequencing in a cohort of 255 newly diagnosed and homogeneously treated multiple myeloma patients with long follow-up. Here, we report that patients have on average 5.5 expressed fusion genes. Kappa and lambda light chains and IgH genes are main partners in a third of all fusion genes. We also identify recurrent fusion genes that significantly impact both progression-free and overall survival and may act as drivers of the disease. Lastly, we find a correlation between the number of fusions, the age of patients and the clinical outcome, strongly suggesting that genomic instability drives prognosis of the disease.

Treating Clostridium difficile infection in patients presenting with hematological malignancies: Are current guidelines applicable?

OBJECTIVES: Adults with hematological malignancies are at high-risk of Clostridium difficile infection (CDI), but no guidelines for CDI treatment are available in this population. Our primary objective was to evaluate the clinical outcomes in CDI patients with hematological malignancies. Our secondary objectives were to describe CDI severity using the main clinical guidelines and to evaluate the compliance of treatment choice with published guidelines. PATIENTS AND METHODS: Single-center, retrospective, observational case series including every consecutive adult patient with a confirmed diagnosis of CDI admitted in the hematology unit of our teaching hospital. Each CDI episode was classified as moderate, severe, or complicated according to the main clinical guidelines (IDSA 2010, AJG 2013, ESCMID 2014). RESULTS: Twenty-three episodes of CDI in 19 patients admitted to the hematology unit occurred between June 2012 and October 2013. Clinical cure was achieved for 20 episodes (87%). Ten weeks after diagnosis, global cure was reached for 14 episodes (61%) whereas recurrence occurred in two episodes (10%). The mortality rate reached 37% (7/19) but the attributable mortality rate was 5% (1/19). ESCMID criteria more frequently classified patients in the severe category compared with the two other classifications. Prescription compliance with clinical guidelines was observed in 61% of episodes with IDSA criteria, 43% with AJG, and 9% with ESCMID. CONCLUSIONS: IDSA and AJG assessment may underestimate the potential risk of unfavorable clinical outcome. Further prospective studies on a larger cohort are needed to develop adequate treatment guidelines for CDI in hematology settings.

Endovascular versus open repair of ruptured abdominal aortic aneurysm.

INTRODUCTION: Endovascular aneurysm repair (EVAR) is a comparatively less invasive technique than open repair (OR). Debate remains with regard to the benefit of EVAR for patients with ruptured abdominal aortic aneurysm (RAAA). We sought to evaluate and report outcomes of EVAR for RAAA in an Irish tertiary vascular referral centre. METHODS: Patients undergoing emergency surgery for ruptured or symptomatic AAA were identified from theatre logbooks and HIPE database. Retrospective chart review was undertaken. Data were exported to IBM SPSS version 21 for statistical analysis with p < 0.05 considered significant. RESULTS: A total of 41 patients underwent surgery for RAAA. The mean age was 74 years old with a range from 55 to 89 years. The majority (n = 25, 61%) were baseline American Society of Anaesthesiology (ASA) grade 3-4. Of these 56% underwent EVAR with the remaining 44% repaired open. Mortality rate in those undergoing emergency EVAR was 34.8%, compared with 38.9% in those undergoing open surgery. This difference was not statistically significant. The mean overall length of stay was 13 days. With regard to prognostic indicators of patient outcome, increasing patient age was noted to be significantly associated with increased mortality (p = 0.013), as was increased ASA score at time of surgery (p = 0.029). CONCLUSIONS: Mortality rates in those undergoing EVAR for RAAA are comparable with those undergoing open repair. Increasing age and ASA score are significant predictors of mortality in patients with RAAA undergoing intervention.

A MultiCenter Pilot Randomized Controlled Trial of Remote Ischemic Preconditioning in Major Vascular Surgery.

A pilot randomized controlled trial that evaluated the effect of remote ischemic preconditioning (RIPC) on clinical outcomes following major vascular surgery was performed. Eligible patients were those scheduled to undergo open abdominal aortic aneurysm repair, endovascular aortic aneurysm repair, carotid endarterectomy, and lower limb revascularization procedures. Patients were randomized to RIPC or to control groups. The primary outcome was a composite clinical end point comprising any of cardiovascular death, myocardial infarction, new-onset arrhythmia, cardiac arrest, congestive cardiac failure, cerebrovascular accident, renal failure requiring renal replacement therapy, mesenteric ischemia, and urgent cardiac revascularization. Secondary outcomes were components of the primary outcome and myocardial injury as assessed by serum troponin values. The primary outcome occurred in 19 (19.2%) of 99 controls and 14 (14.1%) of 99 RIPC group patients (P = .446). There were no significant differences in secondary outcomes. Our trial generated data that will guide future trials. Further trials are urgently needed.

Using Social Media to Increase Accessibility to Online Teaching Resources.

The key learning points of Surgical Grand Rounds (SGR) are often not accessible at times of exam revision for students. We sought to use Twitter as an online teaching repository. A SGR Twitter profile was created. 23 SGR presentations were made accessible on Twitter over a 3 month period. 93 students were invited to complete a questionnaire assessing usage of the repository. 84 (90%) in total responded, of these, 25 (80.6%) felt that the online provision of SGR through twitter was "useful". The majority (71%) felt that the online content was easily accessible. The novel use of social media is a useful adjunctive educational tool in accessing an online repository of SGR presentations.

Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity.

BACKGROUND: Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterised by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances and a distinctive mid-hindbrain malformation. JS demonstrates substantial phenotypic variability and genetic heterogeneity. This study provides a comprehensive view of the current genetic basis, phenotypic range and gene-phenotype associations in JS. METHODS: We sequenced 27 JS-associated genes in 440 affected individuals (375 families) from a cohort of 532 individuals (440 families) with JS, using molecular inversion probe-based targeted capture and next-generation sequencing. Variant pathogenicity was defined using the Combined Annotation Dependent Depletion algorithm with an optimised score cut-off. RESULTS: We identified presumed causal variants in 62% of pedigrees, including the first B9D2 mutations associated with JS. 253 different mutations in 23 genes highlight the extreme genetic heterogeneity of JS. Phenotypic analysis revealed that only 34% of individuals have a 'pure JS' phenotype. Retinal disease is present in 30% of individuals, renal disease in 25%, coloboma in 17%, polydactyly in 15%, liver fibrosis in 14% and encephalocele in 8%. Loss of CEP290 function is associated with retinal dystrophy, while loss of TMEM67 function is associated with liver fibrosis and coloboma, but we observe no clear-cut distinction between JS subtypes. CONCLUSIONS: This work illustrates how combining advanced sequencing techniques with phenotypic data addresses extreme genetic heterogeneity to provide diagnostic and carrier testing, guide medical monitoring for progressive complications, facilitate interpretation of genome-wide sequencing results in individuals with a variety of phenotypes and enable gene-specific treatments in the future.

Perforated closed-loop obstruction secondary to gallstone ileus of the transverse colon: a rare entity.

Introduction. Gallstone ileus (GSI) of the colon is an extremely rare entity with potentially serious complications including perforation. Case Presentation. An 88-year-old man presented to the emergency department with abdominal pain and distension. Clinical exam revealed signs of peritonism. Computed tomography (CT) revealed GSI of the transverse colon with a closed-loop large bowel obstruction (LBO) and caecal perforation. The patient underwent emergency laparotomy. A right hemicolectomy was performed, the gallstone was removed, and a primary bowel anastomosis was undertaken. A Foley catheter was sutured into the residual gallbladder bed to create a controlled biliary fistula. The patient recovered well postoperatively with no complications. He was discharged home with the Foley catheter in situ. Discussion. Gallstone ileus is a difficult diagnosis both clinically and radiologically with only 50% of cases being diagnosed preoperatively. Most commonly it is associated with impaction at the ileocaecal valve and small bowel obstruction. Gallstone ileus should also be considered as a rare but potential cause of LBO. This is the first reported case of caecal perforation secondary to gallstone ileus of the transverse colon. Successful operative management consisted of a one-stage procedure with right hemicolectomy and formation of a controlled biliary fistula.

Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients.

Secondary MYC translocations in myeloma have been shown to be important in the pathogenesis and progression of disease. Here, we have used a DNA capture and massively parallel sequencing approach to identify the partner chromosomes in 104 presentation myeloma samples. 8q24 breakpoints were identified in 21 (20%) samples with partner loci including IGH, IGK and IGL, which juxtapose the immunoglobulin (Ig) enhancers next to MYC in 8/23 samples. The remaining samples had partner loci including XBP1, FAM46C, CCND1 and KRAS, which are important in B-cell maturation or myeloma pathogenesis. Analysis of the region surrounding the breakpoints indicated the presence of superenhancers on the partner chromosomes and gene expression analysis showed increased expression of MYC in these samples. Patients with MYC translocations had a decreased progression-free and overall survival. We postulate that translocation breakpoints near MYC result in colocalization of the gene with superenhancers from loci, which are important in the development of the cell type in which they occur. In the case of myeloma these are the Ig loci and those important for plasma cell development and myeloma pathogenesis, resulting in increased expression of MYC and an aggressive disease phenotype.

Contrast-enhanced magnetic resonance angiography in diabetic patients with infra-genicular peripheral arterial disease: systematic review.

OBJECTIVE: Diabetes is a leading risk factor for the development of peripheral arterial disease (PAD). The optimal imaging modality for patients with diabetes and PAD is uncertain. We sought to analyse the literature to determine the accuracy of contrast enhanced magnetic resonance angiography (CE-MRA) in differentiating extent of disease in patients with infragenicular PAD and diabetes, using digital subtraction angiography (DSA) as the gold standard. METHODS: Online databases were searched for relevant keywords (January 1998-June 2012). Eligible studies prospectively compared CE-MRA and DSA of infragenicular vessels and provided data to construct contingency tables in at least 10 patients with diabetes and PAD symptoms. Pooled sensitivity and specificity values were calculated using random effects modelling. RESULTS: Only three studies (83 patients) provided data regarding the infragenicular vessels. The pooled sensitivity of MRA was 86% while the pooled specificity of MRA was 93%. CONCLUSIONS: The assumptions regarding CE-MRA's efficacy for infragenicular disease in diabetics are based upon low patient numbers. Inadequate diagnostic imaging in this high-risk group risks adoption of incorrect revascularisation strategies. Further studies are required.

Career choices of today's medical students: where does surgery rank?

INTRODUCTION: The national junior doctor recruitment crisis prompts an appraisal of medical student attitudes to different career pathways. The purpose of this study was to perform a national review of surgical career intentions of Irish final year medical students. METHODS: Ethical and institutional approval was obtained at each study location. A questionnaire was designed and distributed to final year students. Domains assessed included demographics, career plans and reasons associated. Anonymised responses were collated and evaluated. Categorical data were compared with Fisher's exact test. RESULTS: Responses were obtained from 342 students in four medical schools of whom 78.6% were undergraduates. Over half (53%) were Irish, with Malaysia, Canada and the USA the next most common countries of origin. Only 18% of students intended to pursue surgery, with 60% stating they did not plan to, and 22% undecided. Of those who plan not to pursue surgery, 28% were unsure about a speciality but the most common choices were medicine (39%), general practice (16%) and paediatrics (8%). Reasons for not picking a career in surgery included long hours and the unstructured career path. Suggestions to improve uptake included earlier and more practical exposure to surgery, improved teaching/training and reduction in working hours. CONCLUSIONS: In this study 18% of final year medical students identified surgery as their chosen career pathway. Although lifestyle factors are significant in many students' decision, perceived quality and duration of surgical training were also relevant and are modifiable factors which, if improved could increase interest in surgery as a career.

Patient satisfaction following emergency admission via a surgical assessment unit and an emergency department.

AIM: Acute surgical patients are admitted to our regional hospital through the emergency department (ED) and through a new surgical assessment unit (SAU). The aim of this study was to compare the efficiency of the two units in seeing and assessing acute surgical patients, as well as patients' satisfaction with their experiences in both units. METHODS: A patient satisfaction scoring questionnaire was distributed to 115 consecutive surgical patients attending the SAU and ED over an 8-week period. Patients' impressions of waiting times, pain management and interactions with staff were detailed. The actual times taken for assessment, admission and discharge were recorded and compared with those perceived by the patients. RESULTS: Patients' perceptions of care were very high within both the ED and the SAU, with 95 % of SAU patients reporting their care as excellent or very good compared with 86 % of ED patients (p = 0.014). Patients were assessed considerably faster in the SAU compared with the ED, with an average wait from registration to admission or discharge totalling 5 h in the SAU compared with 12 h in the ED. CONCLUSION: The SAU provides an effective and efficient mode of assessment of acute surgical patients. While patients were discharged faster from the SAU than the ED, patients rated both units highly in terms of satisfaction with the service provided.

Improving patient care--the first year in a dedicated surgical assessment unit.

A surgical assessment unit (SAU) was established in October 2009 at the Mid-Western Regional Hospital. We assessed this servic in its initial year and compared it to Emergency Department (ED) services. We audited SAU and ED databases and theatre logbooks from November 2009 to October 2010. 1949 patients were referred to the SAU and 857 patients were admitted (44%). Only 44 SAU patients (6%) waited more than 6 hours for a bed compared to 828 patients (68%) admitted through the ED. SAU patients who required emergency surgery had a shorter waiting time before theatre (37 (18.6%) vs 9(6%) waited less than 6 hours, p < 0.05). To summarise, we found that almost 2,000 patients who would otherwise have presented to the ED were referred to the SAU. Waiting times for admission and theatre were significantly shorter. Further resource allocation could expand the service and improve it further, by diverting more patients from the ED.

The delivery of general paediatric surgery in Ireland: a survey of higher surgical trainees.

BACKGROUND: The delivery of general paediatric surgery is changing in Ireland. Fewer paediatric surgical procedures are being performed by newly appointed consultant general surgeons, resulting in increased referrals to the specialist paediatric surgeons of uncomplicated general paediatric surgical problems. We surveyed current higher surgical trainees about their views on provision of paediatric surgical services. METHODS: A questionnaire regarding provision of paediatric surgery was developed by incorporating dichotomous and qualitative questions. This was emailed to all higher surgical trainees in Ireland. Responses were analysed anonymously. RESULTS: There was a response rate of 54%. Most questions drew divided responses. More than half of the responders were opposed to mandatory paediatric surgical training on their scheme and would not be willing to provide paediatric surgery as a consultant. The most common reasons were limited training time and the unlikelihood of becoming competent in paediatric surgery with brief exposure. Sixty-four percent of responders felt that general paediatric surgery should be provided by paediatric surgeons in the future. CONCLUSIONS: The opinions expressed here suggest that the current system of local provision of general paediatric surgery is unsustainable. Alternative training arrangements or regionalisation of paediatric surgery may be necessary to avoid overwhelming specialist paediatric centres.

Towards continuous improvement of endoscopy standards: validation of a colonoscopy assessment form.

AIM: The assessment of procedural colonoscopy skills is important and topical. The aim of this study was to develop and validate a competency-based colonoscopy assessment form that would be easy to use, suitable for the assessment of junior and senior endoscopists and potentially a useful instrument to detect differences in performance standards following different training interventions. METHOD: A standardized assessment form was developed incorporating a checklist with dichotomous yes/no responses and a global assessment section incorporating several different elements. This form was used prospectively to evaluate colonoscopy cases during the period of the study in several university teaching hospitals. Results were analysed using ANOVA with Bonferroni corrections for post hoc analysis. RESULTS: Eighty-one procedures were assessed, performed by eight consultant and 19 trainee endoscopists. There were no serious errors. When divided into three groups based on previous experience (novice, intermediate and expert) the assessment form demonstrated statistically significant differences between all three groups (P<0.05). When separate elements were taken into account, the global assessment section was a better discriminator of skill level than the checklist. CONCLUSION: This form is a valid, easy-to-use assessment method. We intend to use it to assess the value of simulator training in trainee endoscopists. It also has the potential to be a useful training tool when feedback is given to the trainee.

Video gaming enhances psychomotor skills but not visuospatial and perceptual abilities in surgical trainees.

INTRODUCTION: There is considerable interest in the identification and assessment of underlying aptitudes or innate abilities that could potentially predict excellence in the technical aspects of operating. However, before the assessment of innate abilities is introduced for high-stakes assessment (such as competitive selection into surgical training programs), it is essential to determine that these abilities are stable and unchanging and are not influenced by other factors, such as the use of video games. The aim of this study was to investigate whether experience playing video games will predict psychomotor performance on a laparoscopic simulator or scores on tests of visuospatial and perceptual abilities, and to examine the correlation, if any, between these innate abilities. METHODS: Institutional ethical approval was obtained. Thirty-eight undergraduate medical students with no previous surgical experience were recruited. All participants completed a self-reported questionnaire that asked them to detail their video game experience. They then underwent assessment of their psychomotor, visuospatial, and perceptual abilities using previously validated tests. The results were analyzed using independent samples t tests to compare means and linear regression curves for subsequent analysis. RESULTS: Students who played video games for at least 7 hours per week demonstrated significantly better psychomotor skills than students who did not play video games regularly. However, there was no difference on measures of visuospatial and perceptual abilities. There was no correlation between psychomotor tests and visuospatial or perceptual tests. CONCLUSIONS: Regular video gaming correlates positively with psychomotor ability, but it does not seem to influence visuospatial or perceptual ability. This study suggests that video game experience might be beneficial to a future career in surgery. It also suggests that relevant surgical skills may be gained usefully outside the operating room in activities that are not related to surgery.