Body Composition and Dose-limiting Toxicity in Colorectal Cancer Chemotherapy Treatment; a Systematic Review of the Literature. Could Muscle Mass be the New Body Surface Area in Chemotherapy Dosing?

Chemotherapy dosing is traditionally based on body surface area calculations; however, these calculations ignore separate tissue compartments, such as the lean body mass (LBM), which is considered a big pool of drug distribution. In our era, colorectal cancer patients undergo a plethora of computed tomography scans as part of their diagnosis, staging and monitoring, which could easily be used for body composition analysis and LBM calculation, allowing for personalised chemotherapy dosing. This systematic review aims to evaluate the effect of muscle mass on dose-limiting toxicity (DLT), among different chemotherapy regimens used in colorectal cancer patients. This review was carried out according to the PRISMA guidelines. MEDLINE and EMBASE databases were searched from 1946 to August 2019. The primary search terms were 'sarcopenia', 'myopenia', 'chemotherapy toxicity', 'chemotherapy dosing', 'dose limiting toxicity', 'colorectal cancer', 'primary colorectal cancer' and 'metastatic colorectal cancer'. Outcomes of interest were - DLT and chemotoxicity related to body composition, and chemotherapy dosing on LBM. In total, 363 studies were identified, with 10 studies fulfilling the selection criteria. Seven studies were retrospective and three were prospective. Most studies used the same body composition analysis software but the chemotherapy regimens used varied. Due to marked study heterogeneity, quantitative data synthesis was not possible. Two studies described a toxicity cut-off value for 5-fluorouracil and one for oxaliplatin based on LBM. The rest of the studies showed an association between different body composition metrics and DLTs. Prospective studies are required with a larger colorectal cancer cohort, longitudinal monitoring of body composition changes during treatment, similar body composition analysis techniques, agreed cut-off values and standardised chemotherapy regimens. Incorporation of body composition analysis in the clinical setting will allow early identification of sarcopenic patients, personalised dosing based on their LBM and early optimisation of these patients undergoing chemotherapy.

Contact X-ray Brachytherapy as an Adjunct to a Watch and Wait Approach is an Affordable Alternative to Standard Surgical Management of Rectal Cancer for Patients with a Partial Clinical Response to Chemoradiotherapy.

AIMS: Emerging evidence suggests that contact X-ray brachytherapy (CXB) may increase the clinical complete response rate and durability when administered after standard chemoradiotherapy in patients with rectal cancer. The addition of CXB in partial responders is therefore probably cost-effective. The affordability of widening access to CXB in the UK, however, has not been evaluated. MATERIALS AND METHODS: Decision analytical modelling with Monte Carlo simulation was used to evaluate long-term costs for the management of patients with rectal cancers who were given a CXB boost when a clinical complete response was not initially achieved following chemoradiotherapy in order to facilitate a watch and wait approach. A third-party payer (National Health Service) perspective was adopted, probabilistic sensitivity analysis was carried out and a scenario analysis was performed to investigate the effect of the number of referral centres and number of patients treated with CXB. RESULTS: We estimate that 818 (95% confidence interval 628-1021) patients per year are eligible for CXB as an adjunct to a watch and wait approach in England and Wales. As this management is less costly than surgical management for each individual patient, the more patients treated, the more affordable the technology. Even if as few as 125 patients are treated nationally in 15 centres, the cost of implementing this technology would be less than £4 million. If the average number of patients treated in each centre is 30, this technology would be cost saving within 5 years. CONCLUSIONS: The cost of CXB is not prohibitive according to the National Institute for Health and Care Excellence threshold for implementation of new technology and may even be cost saving within 5 years compared with standard surgical management, depending on the uptake of the technology and the number of referral centres.

Robotics in cardiac surgery.

A summary of its uses in mitral valve surgery and coronary artery revascularisation.

Cerebral embolization, silent cerebral infarction and neurocognitive decline after thoracic endovascular aortic repair.

BACKGROUND: Silent cerebral infarction is brain injury detected incidentally on imaging; it can be associated with cognitive decline and future stroke. This study investigated cerebral embolization, silent cerebral infarction and neurocognitive decline following thoracic endovascular aortic repair (TEVAR). METHODS: Patients undergoing elective or emergency TEVAR at Imperial College Healthcare NHS Trust and Guy's and St Thomas' NHS Foundation Trust between January 2012 and April 2015 were recruited. Aortic atheroma graded from 1 (normal) to 5 (mobile atheroma) was evaluated by preoperative CT. Patients underwent intraoperative transcranial Doppler imaging (TCD), preoperative and postoperative cerebral MRI, and neurocognitive assessment. RESULTS: Fifty-two patients underwent TEVAR. Higher rates of TCD-detected embolization were observed with greater aortic atheroma (median 207 for grade 4-5 versus 100 for grade 1-3; P = 0·042), more proximal landing zones (median 450 for zone 0-1 versus 72 for zone 3-4; P = 0·001), and during stent-graft deployment and contrast injection (P = 0·001). In univariable analysis, left subclavian artery bypass (ß coefficient 0·423, s.e. 132·62, P = 0·005), proximal landing zone 0-1 (ß coefficient 0·504, s.e. 170·57, P = 0·001) and arch hybrid procedure (ß coefficient 0·514, s.e. 182·96, P < 0·001) were predictors of cerebral emboli. Cerebral infarction was detected in 25 of 31 patients (81 per cent) who underwent MRI: 21 (68 per cent) silent and four (13 per cent) clinical strokes. Neurocognitive decline was seen in six of seven domains assessed in 15 patients with silent cerebral infarction, with age a significant predictor of decline. CONCLUSION: This study demonstrates a high rate of cerebral embolization and neurocognitive decline affecting patients following TEVAR. Brain injury after TEVAR is more common than previously recognized, with cerebral infarction in more than 80 per cent of patients.

Computational study of aortic hemodynamics for patients with an abnormal aortic valve: The importance of secondary flow at the ascending aorta inlet.

Blood flow in the aorta is helical, but most computational studies ignore the presence of secondary flow components at the ascending aorta (AAo) inlet. The aim of this study is to ascertain the importance of inlet boundary conditions (BCs) in computational analysis of flow patterns in the thoracic aorta based on patient-specific images, with a particular focus on patients with an abnormal aortic valve. Two cases were studied: one presenting a severe aortic valve stenosis and the other with a mechanical valve. For both aorta models, three inlet BCs were compared; these included the flat profile and 1D through-plane velocity and 3D phase-contrast magnetic resonance imaging derived velocity profiles, with the latter being used for benchmarking. Our results showed that peak and mean velocities at the proximal end of the ascending aorta were underestimated by up to 41% when the secondary flow components were neglected. The results for helical flow descriptors highlighted the strong influence of secondary velocities on the helical flow structure in the AAo. Differences in all wall shear stress (WSS)-derived indices were much more pronounced in the AAo and aortic arch (AA) than in the descending aorta (DAo). Overall, this study demonstrates that using 3D velocity profiles as inlet BC is essential for patient-specific analysis of hemodynamics and WSS in the AAo and AA in the presence of an abnormal aortic valve. However, predicted flow in the DAo is less sensitive to the secondary velocities imposed at the inlet; hence, the 1D through-plane profile could be a sufficient inlet BC for studies focusing on distal regions of the thoracic aorta.

A Cost-Effectiveness Analysis of Contact X-ray Brachytherapy for the Treatment of Patients with Rectal Cancer Following a Partial Response to Chemoradiotherapy.

AIMS: Following chemoradiotherapy in patients with rectal cancer, the addition of contact X-ray brachytherapy (CXB) in partial responders might increase the proportion of patients with a clinical complete response (cCR) and who are thus suitable for watch and wait management. However, the long-term cost-effectiveness of this approach has not been evaluated. MATERIALS AND METHODS: Decision analytical modelling and a Markov simulation were used to compare long-term costs, quality-adjusted life years (QALYs) and cost-effectiveness from a third-party payer (National Health Service) perspective for treatment strategies after chemoradiotherapy; watch and wait with CXB when a cCR was not initially achieved after external beam radiotherapy (EBRT) (WWCXB), watch and wait with EBRT alone (WWEBRT) and radical surgery for all patients. The effect of uncertainty in model parameters and patient demographics was investigated. RESULTS: WWCXB had a higher QALY payoff than both radical surgery and WWEBRT and was less costly in most scenarios and demographic cohorts. In all plausible scenarios, WWCXB was the most cost-effective, at a threshold of £20 000/QALY. This finding was insensitive to uncertainty associated with model parameters. CONCLUSIONS: WWCXB is likely to be cost-effective compared with both WWEBRT alone and radical surgery. These findings support the use of CXB boost as an adjunct to a watch and wait strategy.

Component analysis of enhanced recovery pathways for esophagectomy.

The objective of this systematic review is to identify key components of enhanced recovery protocols (ERP) that lead to improved length of hospital stay (LOS) following esophagectomy. Relevant electronic databases were searched for studies comparing clinical outcome from esophagectomy followed by a conventional pathway versus ERP. Relevant outcome measures were compared and metaregression was performed to identify the key ERP components associated with reduced in LOS. Thirteen publications were included, ERP was associated with no changes in in-hospital mortality, total complications, anastomotic leak, or pulmonary complications compared with a conventional pathway, however LOS was reduced in the ERP group. Metaregression identified that immediate extubation was associated with reduced LOS (OR = -0.51, 95%CI -0.77 to -0.25; P < 0.01). Several postoperative factors were associated with a significant reduction in length of hospital stay, and in order of most important were (i) gastrograffin swallow ≤5 days (OR = -4.27, 95%CI -4.50 to -4.03); (ii) mobilization on postoperative day ≤1 (OR = -2.49, 95%CI -2.63 to -2.34); (iii) removal of urinary catheter ≤2 days (OR = -0.99, 95%CI -1.15 to -0.84); (iv) oral intake with at least sips of fluid ≤1 day (OR = -0.96, 95%CI -1.24 to -0.68); (v) enteral diet with feeding jejunostomy or gastrostomy ≤ 1 day (OR = -0.57, 95%CI -0.80 to -0.35) and (vi) epidural removal ≤ 4 days (OR = -0.17, 95%CI -0.27 to -0.07). Several core ERP components and principles appear to be associated with LOS reduction. These elements should form a part of the core ERP for the specialty, while surgical teams incorporate other elements through an iterative process.

On the choice of outlet boundary conditions for patient-specific analysis of aortic flow using computational fluid dynamics.

Boundary conditions (BCs) are an essential part in computational fluid dynamics (CFD) simulations of blood flow in large arteries. Although several studies have investigated the influence of BCs on predicted flow patterns and hemodynamic wall parameters in various arterial models, there is a lack of comprehensive assessment of outlet BCs for patient-specific analysis of aortic flow. In this study, five different sets of outlet BCs were tested and compared using a subject-specific model of a normal aorta. Phase-contrast magnetic resonance imaging (PC-MRI) was performed on the same subject and velocity profiles extracted from the in vivo measurements were used as the inlet boundary condition. Computational results obtained with different outlet BCs were assessed in terms of their agreement with the PC-MRI velocity data and key hemodynamic parameters, such as pressure and flow waveforms and wall shear stress related indices. Our results showed that the best overall performance was achieved by using a well-tuned three-element Windkessel model at all model outlets, which not only gave a good agreement with in vivo flow data, but also produced physiological pressure waveforms and values. On the other hand, opening outlet BCs with zero pressure at multiple outlets failed to reproduce any physiologically relevant flow and pressure features.

Meta-analysis of determinants of survival following treatment of recurrent hepatocellular carcinoma.

BACKGROUND: Intrahepatic recurrence of hepatocellular carcinoma (HCC) following resection is common. However, no current consensus guidelines exist to inform management decisions in these patients. Systematic review and meta-analysis of survival following different treatment modalities may allow improved treatment selection. This review aimed to identify the optimum treatment strategies for HCC recurrence. METHODS: A systematic review, up to September 2016, was conducted in accordance with MOOSE guidelines. The primary outcome was the hazard ratio for overall survival of different treatment modalities. Meta-analysis of different treatment modalities was carried out using a random-effects model, with further assessment of additional prognostic factors for survival. RESULTS: Nineteen cohort studies (2764 patients) were included in final data analysis. The median 5-year survival rates after repeat hepatectomy (525 patients), ablation (658) and transarterial chemoembolization (TACE) (855) were 35·2, 48·3 and 15·5 per cent respectively. Pooled analysis of ten studies demonstrated no significant difference between overall survival after ablation versus repeat hepatectomy (hazard ratio 1·03, 95 per cent c.i. 0·68 to 1·55; P = 0·897). Pooled analysis of seven studies comparing TACE with repeat hepatectomy showed no statistically significant difference in survival (hazard ratio 1·61, 0·99 to 2·63; P = 0·056). CONCLUSION: Based on these limited data, there does not appear to be a significant difference in survival between patients undergoing repeat hepatectomy or ablation for recurrent HCC. The results also identify important negative prognostic factors (short disease-free interval, multiple hepatic metastases and large hepatic metastases), which may influence choice of treatment.

Meta-analysis of adjuvant therapy following curative surgery for periampullary adenocarcinoma.

BACKGROUND: Periampullary cancers are uncommon malignancies, often amenable to surgery. Several studies have suggested a role for adjuvant chemotherapy and chemoradiotherapy in improving survival of patients with periampullary cancers, with variable results. The aim of this meta-analysis was to determine the survival benefit of adjuvant therapy for periampullary cancers. METHODS: A systematic review was undertaken of literature published between 1 January 2000 and 31 December 2015 to elicit and analyse the pooled overall survival associated with the use of either adjuvant chemotherapy or chemoradiotherapy versus observation in the treatment of surgically resected periampullary cancer. Included articles were also screened for information regarding stage, prognostic factors and toxicity-related events. RESULTS: A total of 704 titles were screened, of which 93 full-text articles were retrieved. Fourteen full-text articles were included in the study, six of which were RCTs. A total of 1671 patients (904 in the control group and 767 who received adjuvant therapy) were included. The median 5-year overall survival rate was 37·5 per cent in the control group, compared with 40·0 per cent in the adjuvant group (hazard ratio 1·08, 95 per cent c.i. 0·91 to 1·28; P = 0·067). In 32·2 per cent of patients who had adjuvant therapy, one or more WHO grade 3 or 4 toxicity-related events were noted. Advanced T category was associated worse survival (regression coefficient -0·14, P = 0·040), whereas nodal status and grade of differentiation were not. CONCLUSION: This systematic review found no associated survival benefit for adjuvant chemotherapy or chemoradiotherapy in the treatment of periampullary cancer.

Linked hospital and primary care database analysis of the impact of short-term complications on recurrence in laparoscopic inguinal hernia repair.

OBJECTIVE: To study the effects of short-term complications on recurrence following laparoscopic inguinal hernia repair using routine data. BACKGROUND: Linked primary and secondary care databases can evaluate the quality of inguinal hernia surgery by quantifying short- and long-term outcome together. METHODS: Longitudinal analysis of linked primary care (Clinical Practice Research Datalink) and hospital administrative (Hospital Episodes Statistics) databases quantified 30-day complications (wound infection and bleeding) and surgery for recurrence after primary repair performed between 1st April 1997 and 31st March 2012. RESULTS: Out of 41,545 primary inguinal hernia repairs, 10.3% (4296/41,545) were laparoscopic. Complications were less frequent following laparoscopic (1.8%, 78/4296) compared with open (3.5%, 1288/37,249) inguinal hernia repair (p < 0.05). Recurrence was more frequent following laparoscopic (3.5%, 84/2541) compared with open (1.2%, 366/31,859) repair (p < 0.05). Time to recurrence was shorter for laparoscopic (26.4 months SD 28.5) compared with open (46.7 months SD 37.6) repair (p < 0.05). Overall, complications were associated with recurrence (3.2%, 44/1366 with complications; 1.7%, 700/40,179 without complications; p < 0.05). Complications did not significantly increase the risk of recurrence in open hernia repair (OR = 1.49; 95% CI 0.97-2.30, p = 0.069). Complications following laparoscopic repair was significantly associated with increased risk of recurrence (OR = 7.86; 95% CI 3.46-17.85, p < 0.05). CONCLUSIONS: Complications recorded in linked routine data predicted recurrence following laparoscopic inguinal hernia repair. Focus must, therefore, be placed on achieving good short-term outcome, which is likely to translate to better longer term results using the laparoscopic approach.

The psychological impact of symptoms related to esophagogastric cancer resection presenting in primary care: A national linked database study.

BACKGROUND: The objective was to evaluate incidence, risk factors and impact of postoperative symptoms following esophagogastric cancer resection in primary care. METHODS: Patients undergoing esophagogastrectomy for cancer from 1998 to 2010 with linked records in Clinical Practice Research Datalink, Hospital Episodes Statistics and Office of National Statistics databases were studied. The recording of codes for reflux, dysphagia, dyspepsia, nausea, vomiting, dumping, diarrhea, steatorrhea, appetite loss, weight loss, pain and fatigue were identified up to 12 months postoperatively. Psychiatric morbidity was also examined and its risk evaluated by logistic regression analysis. RESULTS: Overall, 58.6% (1029/1755) of patients were alive 2 years after surgery. Of these, 41.1% had recorded postoperative symptoms. Reflux, dysphagia, dyspepsia and pain were more frequent following esophagectomy compared with gastrectomy (p < 0.05). Complications (OR = 1.40 95%CI 1.00-1.95) and surgical procedure predicted postoperative symptoms (p < 0.05). When compared with partial gastrectomy, esophagectomy (OR = 2.03 95%CI 1.26-3.27), total gastrectomy (OR = 2.44 95%CI 1.57-3.79) and esophagogastrectomy (OR = 2.66 95%CI 1.85-2.86) were associated with postoperative symptoms (p < 0.05). The majority of patients with postoperative psychiatric morbidity had depression or anxiety (98%). Predictors of postoperative depression/anxiety included younger age (OR = 0.97 95%CI 0.96-0.99), complications (OR = 2.40 95%CI 1.51-3.83), psychiatric history (OR = 6.73 95%CI 4.25-10.64) and postoperative symptoms (OR = 1.78 95%CI 1.17-2.71). CONCLUSIONS: Over 40% of patients had symptoms related to esophagogastric cancer resection recorded in primary care, and were associated with an increase in postoperative depression and anxiety.

Anastomotic leaks can be detected within 5 days following ileorectal anastomosis: a case-controlled study in patients with familial adenomatous polyposis.

AIM: To determine the earliest time point at which anastomotic leaks can be detected in patients undergoing total colectomy with primary ileorectal anastomosis for familial adenomatous polyposis. METHOD: This was a case-controlled study of 10 anastomotic leak patients vs 20 controls following laparoscopic total colectomy with ileorectal anastomosis for familial adenomatous polyposis (from 96 consecutive patients between 2006 and 2013). Panel time-series data regression was performed using a double subscript structure to include both variables. A generalized least squares multivariate approach was applied in a random effects setting to calculate correlations for observations, with anastomotic leak being the dependent variable. Univariate and multivariate regression calculations were then performed according to individual observations at each recorded time point. Time-series analysis was used to determine when a variable became significant in the leak group. RESULTS: Multivariate analysis identified a significant difference between leak and control groups in mean heart rate (P < 0.001), mean respiratory rate (P = 0.017) and mean urine output (P = 0.001). Time-point analysis showed that heart rate was significantly different between leak and control groups at postoperative day 4.25. Multivariate analysis identified a significant difference between groups in alanine transaminase (P = 0.006), bilirubin (P = 0.008), creatinine (P = 0.001), haemoglobin (P < 0.001) and urea (P = 0.007). There were no differences between groups with regard to markers of inflammation such as albumin, white blood cell count, neutrophil count and C-reactive protein. CONCLUSION: Anastomotic leaks can be detected early (within 4.5 days of surgery) through changes in physiological, blood test and observational parameters, providing an opportunity for early intervention in these patients to salvage the anastomosis.

Network meta-analysis of protocol-driven care and laparoscopic surgery for colorectal cancer.

BACKGROUND: Laparoscopic approaches and standardized recovery protocols have reduced morbidity following colorectal cancer surgery. As the optimal regimen remains inconclusive, a network meta-analysis was undertaken of treatments for the development of postoperative complications and mortality. METHODS: MEDLINE, Embase, trial registries and related reviews were searched for randomized trials comparing laparoscopic and open surgery within protocol-driven or conventional perioperative care for colorectal cancer resection, with complications as a defined endpoint. Relative odds ratios (ORs) for postoperative complications and mortality were estimated for aggregated data. RESULTS: Forty trials reporting on 11 516 randomized patients were included with the network. Open surgery within conventional perioperative care was the index for comparison. The OR relating to complications was 0·77 (95 per cent c.i. 0·65 to 0·91) for laparoscopic surgery within conventional care, 0·69 (0·48 to 0·99) for open surgery within protocol-driven care, and 0·43 (0·28 to 0·67) for laparoscopic surgery within protocol-driven care. Sensitivity analyses excluding trials of low rectal cancer and those with a high risk of bias did not affect the treatment estimates. Meta-analyses demonstrated that mortality risk was unaffected by perioperative strategy. CONCLUSION: Laparoscopic surgery combined with protocol-driven care reduces colorectal cancer surgery complications, but not mortality. The reduction in complications with protocol-driven care is greater for open surgery than for laparoscopic approaches. Registration number: CRD42015017850 (https://www.crd.york.ac.uk/PROSPERO).

Trials based on specific fracture configuration and surgical procedures likely to be more relevant for decision making in the management of fractures of the proximal humerus: Findings of a meta-analysis.

OBJECTIVES: The objective of this study was to perform a meta-analysis of all randomised controlled trials (RCTs) comparing surgical and non-surgical management of fractures of the proximal humerus, and to determine whether further analyses based on complexity of fracture, or the type of surgical intervention, produced disparate findings on patient outcomes. METHODS: A systematic review of the literature was performed identifying all RCTs that compared surgical and non-surgical management of fractures of the proximal humerus. Meta-analysis of clinical outcomes was performed where possible. Subgroup analysis based on the type of fracture, and a sensitivity analysis based on the type of surgical intervention, were also performed. RESULTS: Seven studies including 528 patients were included. The overall meta-analysis found that there was no difference in clinical outcomes. However, subgroup and sensitivity analyses found improved patient outcomes for more complex fractures managed surgically. Four-part fractures that underwent surgery had improved long-term health utility scores (mean difference, MD 95% CI 0.04 to 0.28; p = 0.007). They were also less likely to result in osteoarthritis, osteonecrosis and non/malunion (OR 7.38, 95% CI 1.97 to 27.60; p = 0.003). Another significant subgroup finding was that secondary surgery was more common for patients that underwent internal fixation compared with conservative management within the studies with predominantly three-part fractures (OR 0.15, 95% CI 0.04 to 0.63; p = 0.009). CONCLUSION: This meta-analysis has demonstrated that differences in the type of fracture and surgical treatment result in outcomes that are distinct from those generated from analysis of all types of fracture and surgical treatments grouped together. This has important implications for clinical decision making and should highlight the need for future trials to adopt more specific inclusion criteria.Cite this article: S. Sabharwal, N. K. Patel, D. Griffiths, T. Athanasiou, C. M. Gupte, P. Reilly. Trials based on specific fracture configuration and surgical procedures likely to be more relevant for decision making in the management of fractures of the proximal humerus: Findings of a meta-analysisBone Joint Res 2016;5:470-480. DOI: 10.1302/2046-3758.510.2000638.

Influence of body composition profile on outcomes following colorectal cancer surgery.

BACKGROUND: Muscle depletion is characterized by reduced muscle mass (myopenia), and increased infiltration by intermuscular and intramuscular fat (myosteatosis). This study examined the role of particular body composition profiles as prognostic markers for patients with colorectal cancer undergoing curative resection. METHODS: Patients with colorectal cancer undergoing elective surgical resection between 2006 and 2011 were included. Lumbar skeletal muscle index (LSMI), visceral adipose tissue (VAT) surface area and mean muscle attenuation (MA) were calculated by analysis of CT images. Reduced LSMI (myopenia), increased VAT (visceral obesity) and low MA (myosteatosis) were identified using predefined sex-specific skeletal muscle index values. Univariable and multivariable Cox regression models were used to determine the role of different body composition profiles on outcomes. RESULTS: Some 805 patients were identified, with a median follow-up of 47 (i.q.r. 24·9-65·6) months. Multivariable analysis identified myopenia as an independent prognostic factor for disease-free survival (hazard ratio (HR) 1·53, 95 per cent c.i. 1·06 to 2·39; P = 0·041) and overall survival (HR 1·70, 1·25 to 2·31; P < 0·001). The presence of myosteatosis was associated with prolonged primary hospital stay (P = 0·034), and myopenic obesity was related to higher 30-day morbidity (P = 0·019) and mortality (P < 0·001) rates. CONCLUSION: Myopenia may have an independent prognostic effect on cancer survival for patients with colorectal cancer. Muscle depletion may represent a modifiable risk factor in patients with colorectal cancer and needs to be targeted as a relevant endpoint of health recommendations.

Multimodal therapy in children and adolescents with newly diagnosed atypical teratoid rhabdoid tumor: individual pooled data analysis and review of the literature.

Atypical teratoid rhabdoid tumour (ATRT) is a malignant tumour of the central nervous system with a dismal prognosis. There is no consensus on optimal treatment and different multimodal strategies are currently being used in an attempt to improve outcomes. To evaluate the impact of high-dose chemotherapy followed by autologous stem-cell rescue (HD48 SCR), radiotherapy (RT) at first line, intrathecal chemotherapy (IT) and extent of surgical resection upon recurrence-free survival (RFS) and overall survival (OS). An online database search identified prospective and retrospective studies focused on the treatment of children and adolescents with newly diagnosed ATRT. Clinical, therapeutic and outcome data were extracted and an individual pooled data analysis was conducted. Out of 389 publications, 12 manuscripts were included in our review. Data from 332 patients were analysed. Median age at diagnosis was 37 months (range 1-231). HD-SCR, RT and IT had been administered to 28.6% (58/203), 49.6% (118/238) and 21% (65/310) of the patients, respectively. Gross total resection (GTR) had been achieved in 46.5% (152/327) of the cases. In the multivariate analysis, hazard ratios (95% Confidence Interval) for HD-SCR were: RFS-HR = 0.570 (0.357-0.910) p = 0.019, and OS-HR = 0.388 (0.214-0.704) p = 0.002; and for RT: RFS-HR = 0.551 (0.351-0.866) p = 0.01, and OS-HR = 0.393 (0.216-0.712) p = 0.002. IT and GTR were not significantly associated with improved RFS or OS in the multivariate analysis. In our pooled data review, HD-SCR and RT at first line were associated with improved outcomes in children and adolescents with newly diagnosed ATRT.

Metabolic phenotype-microRNA data fusion analysis of the systemic consequences of Roux-en-Y gastric bypass surgery.

BACKGROUND/OBJECTIVES: Bariatric surgery offers sustained marked weight loss and often remission of type 2 diabetes, yet the mechanisms of establishment of these health benefits are not clear. SUBJECTS/METHODS: We mapped the coordinated systemic responses of gut hormones, the circulating miRNAome and the metabolome in a rat model of Roux-en-Y gastric bypass (RYGB) surgery. RESULTS: The response of circulating microRNAs (miRNAs) to RYGB was striking and selective. Analysis of 14 significantly altered circulating miRNAs within a pathway context was suggestive of modulation of signaling pathways including G protein signaling, neurodegeneration, inflammation, and growth and apoptosis responses. Concomitant alterations in the metabolome indicated increased glucose transport, accelerated glycolysis and inhibited gluconeogenesis in the liver. Of particular significance, we show significantly decreased circulating miRNA-122 levels and a more modest decline in hepatic levels, following surgery. In mechanistic studies, manipulation of miRNA-122 levels in a cell model induced changes in the activity of key enzymes involved in hepatic energy metabolism, glucose transport, glycolysis, tricarboxylic acid cycle, pentose phosphate shunt, fatty-acid oxidation and gluconeogenesis, consistent with the findings of the in vivo surgery-mediated responses, indicating the powerful homeostatic activity of the miRNAs. CONCLUSIONS: The close association between energy metabolism, neuronal signaling and gut microbial metabolites derived from the circulating miRNA, plasma, urine and liver metabolite and gut hormone correlations further supports an enhanced gut-brain signaling, which we suggest is hormonally mediated by both traditional gut hormones and miRNAs. This transomic approach to map the crosstalk between the circulating miRNAome and metabolome offers opportunities to understand complex systems biology within a disease and interventional treatment setting.

Systematic review: the combined surgical and medical treatment of fistulising perianal Crohn's disease.

BACKGROUND: The management of perianal Crohn's fistulas represents a significant challenge. A combination of medical and surgical therapy, guided by radiology, is often required. AIM: To review systematically the literature to assess fistula healing rates with medical treatment (anti-TNF-α therapies ± immunomodulators) or surgical treatment alone, compared with combined medical and surgical treatment in fistulising perianal Crohn's disease (CD). METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used. Two independent reviewers searched the literature. RESULTS: Twenty-four articles were included. The total population was 1139 patients; 460 (40%) received single treatment with either medical or surgical therapy, and 679 (60%) received combined medical and surgical therapy. Eight studies compared single and combination therapy, with a total population of 797 patients (single therapy: n = 448, combination therapy: n = 349). In the single therapy group, 191/448 were in complete remission (43%). This was lower than the healing rate of the combination therapy group 180/349 (52%). No response to therapy was noted in 34% (153/448) of the single therapy group compared with 23% (80/349) of the combination group. CONCLUSIONS: Combined surgical and medical (anti-TNF-α ± immunomodulators) therapy may have additional beneficial effects on perianal fistula healing in patients with Crohn's disease, compared with surgery or medical therapy alone. A well-designed Crohn's perianal fistula clinical trial is required in a multidisciplinary medical and surgical setting, with clearly defined end points of clinical (and likely patient reported outcomes) and radiological healing.