Patient-reported outcomes after oesophagectomy in the multicentre LASER study.

BACKGROUND: Data on the long-term symptom burden in patients surviving oesophageal cancer surgery are scarce. The aim of this study was to identify the most prevalent symptoms and their interactions with health-related quality of life. METHODS: This was a cross-sectional cohort study of patients who underwent oesophageal cancer surgery in 20 European centres between 2010 and 2016. Patients had to be disease-free for at least 1 year. They were asked to complete a 28-symptom questionnaire at a single time point, at least 1 year after surgery. Principal component analysis was used to assess for clustering and association of symptoms. Risk factors associated with the development of severe symptoms were identified by multivariable logistic regression models. RESULTS: Of 1081 invited patients, 876 (81.0 per cent) responded. Symptoms in the preceding 6 months associated with previous surgery were experienced by 586 patients (66.9 per cent). The most common severe symptoms included reduced energy or activity tolerance (30.7 per cent), feeling of early fullness after eating (30.0 per cent), tiredness (28.7 per cent), and heartburn/acid or bile regurgitation (19.6 per cent). Clustering analysis showed that symptoms clustered into six domains: lethargy, musculoskeletal pain, dumping, lower gastrointestinal symptoms, regurgitation/reflux, and swallowing/conduit problems; the latter two were the most closely associated. Surgical approach, neoadjuvant therapy, patient age, and sex were factors associated with severe symptoms. CONCLUSION: A long-term symptom burden is common after oesophageal cancer surgery.

Cisplatin- and cyclophosphamide-induced primordial follicle depletion is caused by direct damage to oocytes.

It is well established that DNA-damaging chemotherapies can cause infertility and ovarian endocrine failure by depleting the ovarian reserve of primordial follicles. Currently, no effective pharmacological therapies exist for the preservation of long-term fertility and ovarian function in female cancer patients, due to a limited understanding of the mechanisms of chemotherapy-induced follicle depletion. This study investigated the cellular targets, molecular mechanisms, and temporal course of ovarian reserve depletion following treatment with commonly used chemotherapeutic drugs. Adult female C57BL/6 mice were injected i.p. with saline, cisplatin (5mg/kg), or cyclophosphamide (300mg/kg); ovaries were harvested after 8 or 24 hours. Follicle counts showed depletion of all follicular stages 24 hours after administration of cisplatin or cyclophosphamide. Eight hours post-treatment, H2A histone family member X (γH2AX) immunofluorescence showed DNA double-stranded breaks at all follicular stages, including within primordial follicle oocytes. This staining was resolving by 24 hours, indicating that primordial follicle oocytes begin to undergo either apoptosis or repair in this timeframe. γH2AX-positive follicles were further examined to identify the specific cell types damaged. In primordial, transitional, and primary follicles, only oocytes sustained DNA damage, whereas in secondary and antral follicles, only somatic cells were affected. TUNEL staining confirmed that apoptosis occurs in these targeted cell types. Whilst multi-drug and multi-dose regimens were not examined, this study conclusively shows that cyclophosphamide and cisplatin cause direct damage to primordial follicle oocytes, which then undergo apoptosis. Therefore, future pharmacological strategies to prevent chemotherapy-induced infertility in females must specifically prevent primordial follicle oocyte death.

FBXW7 regulates DISC1 stability via the ubiquitin-proteosome system.

Disrupted in schizophrenia 1 (DISC1) is a multi-functional scaffolding protein that has been associated with neuropsychiatric disease. The role of DISC1 is to assemble protein complexes that promote neural development and signaling, hence tight control of the concentration of cellular DISC1 in neurons is vital to brain function. Using structural and biochemical techniques, we show for we believe the first time that not only is DISC1 turnover elicited by the ubiquitin proteasome system (UPS) but that it is orchestrated by the F-Box protein, FBXW7. We present the structure of FBXW7 bound to the DISC1 phosphodegron motif and exploit this information to prove that disruption of the FBXW7-DISC1 complex results in a stabilization of DISC1. This action can counteract DISC1 deficiencies observed in neural progenitor cells derived from induced pluripotent stem cells from schizophrenia patients with a DISC1 frameshift mutation. Thus manipulation of DISC1 levels via the UPS may provide a novel method to explore DISC1 function.

Recent Trends in Neurosurgery Career Outcomes in Canada.

BACKGROUND: As with other specialties, Royal College of Physicians and Surgeons of Canada (RCPSC) trainees in Neurosurgery have anecdotally had challenges securing full-time employment. This study presents the employment status, research pursuits, and fellowship choices of neurosurgery trainees in Canadian programs. METHODS: RCPSC neurosurgery trainees (n = 143) who began their residency training between 1998 and 2008 were included in this study. Associations between year of residency completion, research pursuits, and fellowship choice with career outcomes were determined by Fisher's exact test (p < 0.05, statistical significance). RESULTS: In 2015, 60% and 26% of neurosurgery trainees had permanent positions in Canada and the USA, respectively. Underemployment, defined as locum and clinical associate positions, pursuit of multiple unrelated fellowships, unemployment, and career change to non-surgical career, was 12% in 2015. The proportion of neurosurgery trainees who had been underemployed at some point within 5 years since residency completion was 20%. Pursuit of in-folded research (MSc, PhD, or non-degree research greater than 1 year) was significantly associated with obtaining full employment (94% vs. 73%, p = 0.011). However, fellowship training was not significantly associated with obtaining full employment (78% vs. 75%, p = 1.000). CONCLUSIONS: Underemployment in neurosurgery has become a significant issue in Canada for various reasons. Pursuit of in-folded research, but not fellowship training, was associated with obtaining full employment.

Tendances récentes au Canada en ce qui regarde les possibilités d'emploi en neurochirurgie.Contexte: À l'instar d'autres stagiaires de la médecine spécialisée, des stagiaires en neurochirurgie membres du Collège royal des médecins et des chirurgiens du Canada (CRMCC) ont dit éprouver, selon des données empiriques, des difficultés à obtenir un emploi à plein temps. Cette étude entend présenter la situation professionnelle des stagiaires inscrits dans des programmes canadiens en neurochirurgie ainsi que leurs activités de recherche et leurs choix en matière de bourses de recherche postdoctorale. Méthodes : Des stagiaires membres du CRMCC ayant entrepris leur résidence entre 1998 et 2008 (n = 143) ont été inclus dans cette étude. Les liens pouvant exister entre l'année de résidence complétée, les activités de recherche, les choix en matière de bourses de recherche postdoctorale et les possibilités d'emploi ont été déterminés au moyen du test exact de Fisher (p < 0,05 ; signification statistique). Résultats : En 2015, 60 % des stagiaires en neurochirurgie du Canada disaient compter sur un poste permanent alors qu'ils étaient 26 % à affirmer la même chose aux États-Unis. Le sous-emploi, défini comme par des postes de suppléant (locum) et de clinicien adjoint, par l'obtention de plusieurs bourses de recherche postdoctorale sans liens apparents, par le chômage et par un changement d'orientation excluant la chirurgie, atteignait 12 % la même année. La proportion de stagiaires disant avoir été sous-employés à un moment ou un autre au cours des 5 années de leur résidence était par ailleurs de 20 %. Le fait de mener un projet de recherche dans le cadre de sa résidence (M.Sc., Ph.D. ou en dehors des cycles supérieurs pendant au moins 12 mois) était clairement associé à l'obtention d'un emploi à temps plein (94 % contre 73 % ; p = 0,011). Cela dit, une formation offerte à la suite de l'obtention d'une bourse de recherche postdoctorale n'a pas été associée de manière notable à l'obtention d'un emploi à temps plein (78 % contre 75 % ; p = 1,000). Conclusions : Le sous-emploi en neurochirurgie est désormais un enjeu important au Canada, et ce, pour toutes sortes de raisons. Contrairement aux formations liées à l'obtention d'une bourse de recherche postdoctorale, le fait de mener un projet de recherche régulier a été associé à l'obtention d'un emploi à temps plein.

A comparison of the left thoracoabdominal and Ivor-Lewis esophagectomy.

The purpose of this study was to assess the oncological outcomes of a large multicenter series of left thoracoabdominal esophagectomies, and compare these to the more widely utilized Ivor-Lewis esophagectomy. With ethics approval and an established study protocol, anonymized data from five centers were merged into a structured database. The study exposure was operative approach (ILE or LTE). The primary outcome measure was time to death. Secondary outcome measures included time to tumor recurrence, positive surgical resection margins, lymph node yield, postoperative death, and hospital length of stay. Cox proportional hazards models provided hazard ratios (HR) with 95% confidence intervals (CI) adjusting for age, pathological tumor stage, tumor grade, lymphovascular invasion, and neoadjuvant treatment. Among 1228 patients (598 ILE; 630 LTE), most (86%) had adenocarcinoma (AC) and were male (81%). Comparing ILE and LTE for AC patients, no difference was seen in terms of time to death (HR 0.904 95%CI 0.749-1.1090) or time to recurrence (HR 0.973 95%CI 0.768-1.232). The risk of a positive resection margin was also similar (OR 1.022 95%CI 0.731-1.429). Median lymph node yield did not differ between approaches (LTE 21; ILE 21; P = 0.426). In-hospital mortality was 2.4%, significantly lower in the LTE group (LTE 1.3%; ILE 3.6%; P = 0.004). Median hospital stay was 11 days in the LTE group and 14 days in the ILE group (P < 0.0001). In conclusion, this is the largest series of left thoracoabdominal esophagectomies to be submitted for publication and the only one to compare two different transthoracic esophagectomy strategies. It demonstrates oncological equivalence between operative approaches but possible short- term advantages to the left thoracoabdominal esophagectomy.

Prophylactic mesh reinforcement of stomas: a cost-effectiveness meta-analysis of randomised controlled trials.

BACKGROUND: Previous meta-analyses of randomised controlled trials (RCTs) have suggested a reduction in parastomal hernias (PSH) with prophylactic mesh. However, concerns persist regarding variably supportive evidence and cost. We performed an updated systematic review and meta-analysis to inform a novel cost-effectiveness analysis. METHODS: The PubMed, EMBASE and Cochrane Centre Register of Controlled Trials databases were searched (February 2018). We included RCTs assessing mesh reinforcement during stoma formation. We assessed PSH rates, subsequent repair, complications and operative time. Odds ratios (OR) and numbers needed to treat (NNT) were generated on intention to treat (ITT) and per protocol (PP) bases. These then informed cost analysis using 2017 UK/USA reimbursement rates and stoma care costs. RESULTS: Eleven RCTs were included. Four hundred fifty-three patients were randomised to mesh (PP 412), with 454 controls (PP 413). Six studies used synthetic meshes, three composite and two biological (91.7% colostomies; 3.64% ileostomies, 4.63% not specified). Reductions were seen in the number of hernias detected clinically and on computed tomography scan. For the former, ITT OR was 0.23 (95% confidence interval 0.11-0.51; p = 0.0003; n = 11); NNT 4.17 (2.56-10.0), with fewer subsequent repairs: OR 0.29 (0.13-0.64; p = 0.002; n = 7; NNT16.7 (10.0-33.3). Reductions persisted for synthetic and composite meshes. Operative time was similar, with zero incidence of mesh infection/fistulation, and fewer peristomal complications. Synthetic mesh demonstrated a favourable cost profile, with composite approximately cost neutral, and biological incurring net costs. CONCLUSIONS: Reinforcing elective stomas with mesh (primarily synthetic) reduces subsequent PSH rates, complications, repairs and saves money. We recommend that future RCTs compare mesh subtypes, techniques, and applicability to emergency stomas.

Nurse-led primary health care for homeless men: a multimethods descriptive study.

AIM: To explore the primary healthcare needs and health service use of homeless men in inner Sydney. BACKGROUND: People experiencing homelessness have greater health needs than the general population and place high demands on tertiary care, which is expensive and may not be the optimum service for their needs. Accessible, approachable and affordable primary healthcare services could improve the health of homeless persons and potentially decrease costs to the healthcare system. METHODS: A multimethod design using a cross-sectional survey (n = 40) and administrative data (n = 2 707 daily summaries) collected from a nurse-led primary healthcare clinic for homeless men in Sydney. FINDINGS: Survey respondents were aged 27-76 years. Health problems reflected multimorbidity, with mental health issues present in almost all respondents. The majority had attended the clinic more than 20 times in the past year and said the services, treatments and referrals helped them avoid the emergency department. Administrative data indicated that medication administration was the most frequent service provided. Referrals to other health services doubled over the 7-year period. DISCUSSION: Multiple morbidities, particularly mental health issues, are associated with homelessness. A proactive approach by nurses including preventative services appeared to overcome barriers to health service use. CONCLUSION: This nurse-led primary healthcare clinic highlights the importance of providing services to homeless men with multiple comorbidities. Respect and trust in addition to easy access to health services appear to be important facilitators of health service use. IMPLICATIONS FOR NURSING, AND IMPLICATIONS FOR HEALTH POLICY: A greater number of primary health services that collaborate with specialist services, including nurse-led clinics, may facilitate health care for persons who are homeless, reducing the burden on acute services.

Multimodality treatment for esophageal adenocarcinoma: multi-center propensity-score matched study.

Background: The primary aim of this study was to compare survival from neoadjuvant chemoradiotherapy plus surgery (NCRS) versus neoadjuvant chemotherapy plus surgery (NCS) for the treatment of esophageal or junctional adenocarcinoma. The secondary aims were to compare pathological effects, short-term mortality and morbidity, and to evaluate the effect of lymph node harvest upon survival in both treatment groups. Methods: Data were collected from 10 European centers from 2001 to 2012. Six hundred and eight patients with stage II or III oesophageal or oesophago-gastric junctional adenocarcinoma were included; 301 in the NCRS group and 307 in the NCS group. Propensity score matching and Cox regression analyses were used to compensate for differences in baseline characteristics. Results: NCRS resulted in significant pathological benefits with more ypT0 (26.7% versus 5%; P < 0.001), more ypN0 (63.3% versus 32.1%; P < 0.001), and reduced R1/2 resection margins (7.7% versus 21.8%; P < 0.001). Analysis of short-term outcomes showed no statistically significant differences in 30-day or 90-day mortality, but increased incidence of anastomotic leak (23.1% versus 6.8%; P < 0.001) in NCRS patients. There were no statistically significant differences between the groups in 3-year overall survival (57.9% versus 53.4%; Hazard Ratio (HR)= 0.89, 95%C.I. 0.67-1.17, P = 0.391) nor disease-free survival (52.9% versus 48.9%; HR = 0.90, 95%C.I. 0.69-1.18, P = 0.443). The pattern of recurrence was also similar (P = 0.660). There was a higher lymph node harvest in the NCS group (27 versus 14; P < 0.001), which was significantly associated with a lower recurrence rate and improved disease free survival within the NCS group. Conclusion: The survival differences between NCRS and NCS maybe modest, if present at all, for the treatment of locally advanced esophageal or junctional adenocarcinoma. Future large-scale randomized trials must control and monitor indicators of the quality of surgery, as the extent of lymphadenectomy appears to influence prognosis in patients treated with NCS, from this large multi-center European study.

Major role of pKpQIL-like plasmids in the early dissemination of KPC-type carbapenemases in the UK.

Objectives: Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae were first seen in the UK in 2003 and have been increasingly reported since 2010, largely owing to an ongoing outbreak in North-West England. We examined the role of clonal spread and plasmid transmission in their emergence. Methods: Isolates comprised KPC-positive K. pneumoniae ( n = 33), Escherichia coli ( n = 7) and Enterobacter spp. ( n = 4) referred to the national reference laboratory between 2008 and 2010 from 17 UK centres, including three in North-West England. Isolates were typed by MLST. Plasmids were transferred by electroporation and characterized by PCR or sequencing. PCR screening assays were developed to distinguish plasmid pKpQIL variants. Results: The K. pneumoniae isolates included 10 STs, of which three belonged to clonal group (CG) 258. CG258 ( n = 19) isolates were detected in 13 centres but accounted for only 7/19 (36.8%) of those from North-West England. Most KPC-producers (37/44, 84.1%), including 16/19 CG258 K. pneumoniae , carried bla KPC on IncFII K2 plasmids. Sequencing of a subset of these plasmids ( n = 11) revealed similarities with published pKpQIL. One variant, pKpQIL-UK [identified in K. pneumoniae CG258 ( n = 5) and ST468 ( n = 1) isolates from distinct centres] had only a few nucleotide changes from classical pKpQIL, whereas pKpQIL-D1 ( n = 1) and pKpQIL-D2 ( n = 4), from isolates of various species in the North-West, harboured large variations, reflecting replacement of the partitioning and replication functions and potentially thereby facilitating spread. PCR revealed that 36/37 (97.3%) IncFII K2 -type plasmids in KPC-positive isolates had pKpQIL markers. Conclusions: pKpQIL-like plasmids played a major role in the early dissemination of KPC enzymes in the UK.

Metabolic nodal response as a prognostic marker after neoadjuvant therapy for oesophageal cancer.

BACKGROUND: The ability to predict recurrence and survival after neoadjuvant chemotherapy (NAC) and surgery for oesophageal cancer remains elusive. This study evaluated the role of [18 F]fluorodeoxyglucose (FDG) PET-CT in assessing tumour and nodal response as a prognostic marker. METHODS: This was a single-centre UK cohort study. From 2006 to 2014, patients with oesophageal cancer staged with PET-CT before NAC, and restaged by CT or PET-CT before resection, were included. Pathological tumour response was evaluated using Mandard regression grades. Metabolic tumour and nodal responses (mTR and mNR respectively) were quantified using absolute and threshold reductions. RESULTS: Among 294 included patients, mTR and mNR independently predicted prognosis before surgery. After surgery, mNR (but not mTR), pathological tumour response, resection margin status and pathological node category predicted prognosis. Patients with FDG-avid nodal disease after NAC were at high risk of recurrence/death at 1 and 2 years (43 and 71 per cent respectively; P = 0·030 and P = 0·025 versus patients without avid nodes), and had a worse prognosis than patients with non-avid nodal metastases: hazard ratio 4·19 (95 per cent c.i. 1·87 to 9·40) and 2·11 (1·12 to 3·97) respectively versus patients without nodal metastases. Considering mTR and mNR response separately improved prognostication. CONCLUSION: mNR is a novel prognostic factor, independent of conventional N status. Primary and nodal tumours may respond discordantly and patients with FDG-avid nodes after NAC have a poor prognosis.

Surgical clipping or endovascular coiling for unruptured intracranial aneurysms: a pragmatic randomised trial.

BACKGROUND: Unruptured intracranial aneurysms (UIAs) are increasingly diagnosed and are commonly treated using endovascular treatment or microsurgical clipping. The safety and efficacy of treatments have not been compared in a randomised trial. How to treat patients with UIAs suitable for both options remains unknown. METHODS: We randomly allocated clipping or coiling to patients with one or more 3-25 mm UIAs judged treatable both ways. The primary outcome was treatment failure, defined as: initial failure of aneurysm treatment, intracranial haemorrhage or residual aneurysm on 1-year imaging. Secondary outcomes included neurological deficits following treatment, hospitalisation >5 days, overall morbidity and mortality and angiographic results at 1 year. RESULTS: The trial was designed to include 260 patients. An analysis was performed for slow accrual: 136 patients were enrolled from 2010 through 2016 and 134 patients were treated. The 1-year primary outcome, available for 104 patients, was reached in 5/48 (10.4% (4.5%-22.2%)) patients allocated surgical clipping, and 10/56 (17.9% (10.0%-29.8%)) patients allocated endovascular coiling (OR: 0.54 (0.13-1.90), p=0.40). Morbidity and mortality (modified Rankin Scale>2) at 1 year occurred in 2/48 (4.2% (1.2%-14.0%)) and 2/56 (3.6% (1.0%-12.1%)) patients allocated clipping and coiling, respectively. New neurological deficits (15/65 vs 6/69; OR: 3.12 (1.05-10.57), p=0.031), and hospitalisations beyond 5 days (30/65 vs 6/69; OR: 8.85 (3.22-28.59), p=0.0001) were more frequent after clipping. CONCLUSION: Surgical clipping or endovascular coiling of UIAs did not show differences in morbidity at 1 year. Trial continuation and additional randomised evidence will be necessary to establish the supposed superior efficacy of clipping.

Combined Stump Pressure and Oximetry for Shunt Use During Carotid Endarterectomy.

BACKGROUND: Cross-clamp ischemia during carotid endarterectomy can be prevented with carotid bypass shunts in vulnerable patients identified by cerebral monitoring for ischemia. We compared transcranial cerebral oximetry (TCO) with carotid stump pressure measurements for selective shunt use. METHODS: We prospectively collected data on 300 consecutive patients operated on under general anesthesia between 2009 and 2016. Shunts were inserted for a 10% or greater drop in cerebral saturations and/or a mean stump pressure less than 40 mmHg. RESULTS: Seventy-five patients, 25% of the study population, were shunted. The indication was a combined desaturation and stump pressure in 38 (50% of the shunted group), desaturation alone in 11 patients (15%), and a low stump pressure alone in 26 patients (35%). There were no significant differences in baseline characteristics between those patients who were or were not shunted, except angiographic collateral blood supply, which was more commonly identified in patients who were not shunted. A watershed infarct occurred in just one patient with borderline TCO and stump pressure measurements in whom a shunt was not used. CONCLUSIONS: There was poor concordance between TCO and stump pressures, but using both in determining the need for shunt use almost eliminated cross-clamp ischemia in this series of 300 carotid endarterectomy patients.

A two-centre experience of transanal total mesorectal excision.

AIM: Transanal total mesorectal excision (TaTME) offers a promising alternative to the standard surgical abdominopelvic approach for rectal cancer. The aim of this study was to report a two-centre experience of this technique, focusing on the short-term and oncological outcome. METHOD: From May 2013 to May 2015, 40 selected patients with histologically proven rectal adenocarcinoma underwent TaTME in two institutions and were prospectively entered on an online international registry. RESULTS: Forty patients (80% men, mean body mass index 27.4 kg/m2 ) requiring TME underwent TaTME. Procedures included low anterior resection (n = 31), abdominoperineal excision (n = 7) and proctocolectomy (n = 2). A minimally invasive approach was attempted in all cases, with three conversions. The mean operation time was 368 min and 16 patients (40%) had a synchronous abdominal and transanal approach. There was no mortality and 16 postoperative complications occurred, of which 68.8% were minor. The median length of stay was 7.5 (3-92) days. A complete or near-complete TME specimen was delivered in 39 (97.5%) cases with a mean number of 20 lymph nodes harvested. R0 resection was achieved in 38 (95%) patients. After a median follow-up of 10.7 months, there were no local recurrences and six (15%) patients had developed distant metastases. CONCLUSION: TaTME appears to be feasible, safe and reproducible, without compromising the oncological principles of rectal cancer surgery. It is an attractive option for patients for whom laparoscopy is likely to be particularly difficult. These encouraging results should encourage larger studies with assessment of long-term function and the oncological outcome.

Cerebral Vasospasm: A Review.

Cerebral vasospasm is a prolonged but reversible narrowing of cerebral arteries beginning days after subarachnoid hemorrhage. Progression to cerebral ischemia is tied mostly to vasospasm severity, and its pathogenesis lies in artery encasement by blood clot, although the complex interactions between hematoma and surrounding structures are not fully understood. The delayed onset of vasospasm provides a potential opportunity for its prevention. It is disappointing that recent randomized, controlled trials did not demonstrate that the endothelin antagonist clazosentan, the cholesterol-lowering agent simvastatin, and the vasodilator magnesium sulfate improve patient outcome. Minimizing ischemia by avoiding inadequate blood volume and pressure, administering the calcium antagonist nimodipine, and intervention with balloon angioplasty, when necessary, constitutes current best management. Over the past two decades, our ability to manage vasospasm has led to a significant decline in patient morbidity and mortality from vasospasm, yet it still remains an important determinant of outcome after aneurysm rupture.

A systematic review and meta-analysis of somatic and germline DNA sequence biomarkers of esophageal cancer survival, therapy response and stage.

INTRODUCTION: There is an urgent need for biomarkers to help predict prognosis and guide management of esophageal cancer. This review identifies, evaluates and meta-analyses the evidence for reported somatic and germline DNA sequence biomarkers of outcome and stage. METHODS: A systematic review was carried out of the PubMed, EMBASE and Cochrane databases (20 August 2014), in conjunction with the ASCO Level of Evidence scale for biomarker research. Meta-analyses were carried out for all reported markers associated with outcome measures by more than one study. RESULTS: Four thousand and four articles were identified, 762 retrieved and 182 studies included. There were 65 reported markers of survival or recurrence 12 (18.5%) were excluded due to multiple comparisons. Following meta-analysis, significant associations were seen for six tumor variants (mutant TP53 and PIK3CA, copy number gain of ERBB2/HER2, CCND1 and FGF3, and chromosomal instability/ploidy) and seven germline polymorphisms: ERCC1 rs3212986, ERCC2 rs1799793, TP53 rs1042522, MDM2 rs2279744, TYMS rs34743033, ABCB1 rs1045642 and MTHFR rs1801133. Twelve germline markers of treatment complications were reported; 10 were excluded. Two tumor and 15 germline markers (11 excluded) of chemo (radio)therapy response were reported. Following meta-analysis, associations were demonstrated for mutant TP53, ERCC1 rs11615 and XRCC1 rs25487. There were 41 tumor/germline reported markers of stage; 27 (65.9%) were excluded. CONCLUSIONS: Numerous DNA markers of outcome and stage have been reported, yet few are backed by high-quality evidence. Despite this, a small number of variants appear reliable. These merit evaluation in prospective trials, within the context of high-throughput sequencing and gene expression.

Pragmatic staging of oesophageal cancer using decision theory involving selective endoscopic ultrasonography, PET and laparoscopy.

BACKGROUND: Following CT, guidelines for staging oesophageal and gastro-oesophageal junction (GOJ) cancer recommend endoscopic ultrasonography (EUS), PET-CT and laparoscopy for T3-T4 GOJ tumours. These recommendations are based on generic utilities, but it is unclear whether the test risk outweighs the potential benefit for some patients. This study sought to quantify investigation risks, benefits and utilities, in order to develop pragmatic, personalized staging recommendations. METHODS: All patients with a histological diagnosis of oesophageal or GOJ cancer staged between May 2006 and July 2013 comprised a development set; those staged from July 2013 to July 2014 formed the prospective validation set. Probability thresholds of altering management were calculated and predictive factors identified. Algorithms and models (decision tree analysis, logistic regression, artificial neural networks) were validated internally and independently. RESULTS: Some 953 patients were staged following CT, by [(18) F]fluorodeoxyglucose PET-CT (918), EUS (798) and laparoscopy (458). Of these patients, 829 comprised the development set (800 PET-CT, 698 EUS, 397 laparoscopy) and 124 the validation set (118 PET-CT, 100 EUS, 61 laparoscopy). EUS utility in the 71.8 per cent of patients with T2-T4a disease on CT was minimal (0.4 per cent), its risk exceeding benefit. EUS was moderately accurate for pT1 N0 disease. A number of factors predicted metastases on PET-CT and laparoscopy, although none could inform an algorithm. PET-CT altered management in 23.0 per cent, and laparoscopy in 7.1 per cent, including those with T2 and distal oesophageal tumours. CONCLUSION: Although EUS provided additional information on T and N category, its risk outweighed potential benefit in patients with T2-T4a disease on CT. Laparoscopy seemed justified for distal oesophageal tumours of T2 or greater.

Predicting recurrence after chronic subdural haematoma drainage.

BACKGROUND: Recurrence of chronic subdural haematomas (CSDHs) after surgical drainage is a significant problem with rates up to 20%. This study focuses on determining factors predictive of haematoma recurrence and presents a scoring system stratifying recurrence risk for individual patients. METHODS: Between the years 2005 and 2009, 331 consecutive patients with CSDHs treated with surgery were included in this study. Univariate and multivariate analyses were performed searching for risk factors of increased post-operative haematoma volume and haematoma recurrence requiring repeat drainage. RESULTS: We found a 12% reoperation rate. CSDH septation (seen on computed tomogram scan) was found to be an independent risk factor for recurrence requiring reoperation (p=0.04). Larger post-operative subdural haematoma volume was also significantly associated with requiring a second drainage procedure (p<0.001). Independent risk factors of larger post-operative haematoma volume included septations within a CSDH (p<0.01), increased pre-operative haematoma volume (p<0.01), and a greater amount of parenchymal atrophy (p=0.04). A simple scoring system for quantifying recurrence risk was created and validated based on patient age (< or ≥ 80 years), haematoma volume (< or ≥ 160 cc), and presence of septations within the subdural collection (yes or no). CONCLUSION: Septations within CSDHs are associated with larger post-operative residual haematoma collections requiring repeat drainage. When septations are clearly visible within a CSDH, craniotomy might be more suitable as a primary procedure as it allows greater access to a septated subdural collection. Our proposed scoring system combining haematoma volume, age, and presence of septations might be useful in identifying patients at higher risk for recurrence.

Attempted validation of the NUn score and inflammatory markers as predictors of esophageal anastomotic leak and major complications.

The ability to predict complications following esophagectomy/extended total gastrectomy would be of great clinical value. A recent study demonstrated significant correlations between anastomotic leak (AL) and numerical values of C-reactive protein (CRP), white cell count (WCC) and albumin measured on postoperative day (POD) 4. A predictive model comprising all three (NUn score >10) was found to be highly sensitive and discriminant in predicting AL and complications. We attempted a retrospective validation in our center. Data were collected on all resections performed during a 5-year period (April 2008-2013) using prospectively maintained databases. Our biochemistry laboratory uses a maximum CRP value (156 mg/L), unlike that of the original study; otherwise all variables and outcome measures were comparable. Analysis was performed for all patients with complete blood results on POD4. Three hundred twenty-six patients underwent resection, of which 248 had POD4 bloods. There were 21 AL overall (6.44%); 16 among those with complete POD4 blood results (6.45%). There were 8 (2.45%) in-hospital deaths; 7 (2.82%) in those with POD4 results. No parameters were associated with AL or complication severity on univariate analysis. WCC was associated with AL in multivariate binary logistic regression with albumin and CRP (OR 1.23 [95% CI 1.03-1.47]; P = 0.021). When a binary variable of CRP ≥ 156 mg/L was used rather than an absolute value, no factors were significant. Mean NUn was 8.30 for AL, compared with 8.40 for non-AL (P = 0.710 independent t-test). NUn > 10 predicted 0 of 16 leaks (sensitivity 0.00%, specificity 94.4%, receiver operator curve [ROC] area under the curve [AUC] 0.485; P = 0.843). NUn > 7.65 was 93% sensitive and 21.6% specific. ROC for WCC alone was comparable with NUn (AUC 0.641 [0.504-0.779]; P = 0.059; WCC > 6.89 93.8% sensitive, 20.7% specific; WCC > 15 6.3% sensitive and 97% specific). There were no associations between any parameters and other complications. In a comparable cohort with the original study, we demonstrated a similar multivariate association between WCC alone on POD4 and subsequent demonstration of AL, but not albumin or CRP (measured up to 156 mg/L). The NUn score overall (calculated with this caveat) and a threshold of 10 was not found to have clinical utility in predicting AL or complications.

The effect of formalizing enhanced recovery after esophagectomy with a protocol.

Enhanced recovery after surgery (ERAS) pathways aim to accelerate functional return and discharge from hospital. They have proven effective in many forms of surgery, most notably colorectal. However, experience in esophagectomy has been limited. A recent study reported significant reductions in pulmonary complications, mortality, and length of stay following the introduction of an ERAS protocol alone, without the introduction of any clinical changes. We instituted a similar change 16 months ago, introducing a protocol to provide a formal framework, for our existing postoperative care. This retrospective analysis compared outcome following esophagectomy for the 16 months before and 20 months after this change. Data were collected from prospectively maintained secure web-based multidisciplinary databases. Complication severity was classified using the Clavien-Dindo scale. Operative mortality was defined as death within 30 days of surgery, or at any point during the same hospital admission. Lower respiratory tract infection was defined as clinical evidence of infection, with or without radiological signs. Respiratory complications included lower respiratory tract infection, pleural effusion (irrespective of drainage), pulmonary collapse, and pneumothorax. Statistical analysis was performed using SPSS v21. One hundred thirty-two patients underwent esophagectomy (55 protocol group; 77 before). All were performed open. There were no differences between the two groups in terms of age, gender, operation, use of neoadjuvant therapy, cell type, stage, tumor site, or American Society of Anesthesiologists grade. Median length of stay was 14.0 days (protocol) compared with 12.0 before (interquartile range 9-19 and 9.5-15.5, respectively; P = 0.073, Mann-Whitney U-test). Readmission within 30 days of discharge occurred in five (9.26%) and six (8.19%; P = 1.000, Fisher's exact test). There were four in-hospital deaths (3.03%): one (1.82%) and three (3.90%), respectively (P = 0.641). There were no differences in the severity of complications (P = non-significant; Pearson's chi-squared). There were no differences in the type of complications occurring in either group. The protocol was completed successfully by 26 (47.3%). No baseline factors were predictive of this. In contrast to previous studies, we did not demonstrate any improvement in outcome by formalizing our existing pathway using a written protocol. Consequently, improvements in short-term outcome from esophagectomy within ERAS would seem to be primarily due to improvements in components of perioperative care. Consequently, we would recommend that centers introducing new (or reviewing existing) ERAS pathways for esophagectomy focus on optimizing clinical aspects of such standardized pathways.

The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial.

BACKGROUND AND PURPOSE: Acute blood pressure (BP) reduction aimed at attenuation of intracerebral hemorrhage (ICH) expansion might also compromise cerebral blood flow (CBF). We tested the hypothesis that CBF in acute ICH patients is unaffected by BP reduction. METHODS: Patients with spontaneous ICH <24 hours after onset and systolic BP > 150 mm Hg were randomly assigned to an intravenous antihypertensive treatment protocol targeting a systolic BP of <150 mm Hg (n=39) or <180 mm Hg (n=36). Patients underwent computed tomography perfusion imaging 2 hours postrandomization. The primary end point was perihematoma relative (relative CBF). RESULTS: Treatment groups were balanced with respect to baseline systolic BP: 182±20 mm Hg (<150 mm Hg target group) versus 184±25 mm Hg (<180 mm Hg target group; P=0.60), and for hematoma volume: 25.6±30.8 versus 26.9±25.2 mL (P=0.66). Mean systolic BP 2 hours after randomization was significantly lower in the <150 mm Hg target group (140±19 vs 162±12 mm Hg; P<0.001). Perihematoma CBF (38.7±11.9 mL/100 g per minute) was lower than in contralateral homologous regions (44.1±11.1 mL/100 g per minute; P<0.001) in all patients. The primary end point of perihematoma relative CBF in the <150 mm Hg target group (0.86±0.12) was not significantly lower than that in the <180 mm Hg group (0.89±0.09; P=0.19; absolute difference, 0.03; 95% confidence interval -0.018 to 0.078). There was no relationship between the magnitude of BP change and perihematoma relative CBF in the <150 mm Hg (R=0.00005; 95% confidence interval, -0.001 to 0.001) or <180 mm Hg target groups (R=0.000; 95% confidence interval, -0.001 to 0.001). CONCLUSIONS: Rapid BP lowering after a moderate volume of ICH does not reduce perihematoma CBF. These physiological data indicate that acute BP reduction does not precipitate cerebral ischemia in ICH patients. Clinical Trial Registration Information- URL:http://clinicaltrials.gov. Unique Identifier: NCT00963976.