Ontogeny of Hepatic Transporters and Drug-Metabolizing Enzymes in Humans and in Nonclinical Species.

The liver represents a major eliminating and detoxifying organ, determining exposure to endogenous compounds, drugs, and other xenobiotics. Drug transporters (DTs) and drug-metabolizing enzymes (DMEs) are key determinants of disposition, efficacy, and toxicity of drugs. Changes in their mRNA and protein expression levels and associated functional activity between the perinatal period until adulthood impact drug disposition. However, high-resolution ontogeny profiles for hepatic DTs and DMEs in nonclinical species and humans are lacking. Meanwhile, increasing use of physiologically based pharmacokinetic (PBPK) models necessitates availability of underlying ontogeny profiles to reliably predict drug exposure in children. In addition, understanding of species similarities and differences in DT/DME ontogeny is crucial for selecting the most appropriate animal species when studying the impact of development on pharmacokinetics. Cross-species ontogeny mapping is also required for adequate translation of drug disposition data in developing nonclinical species to humans. This review presents a quantitative cross-species compilation of the ontogeny of DTs and DMEs relevant to hepatic drug disposition. A comprehensive literature search was conducted on PubMed Central: Tables and graphs (often after digitization) in original manuscripts were used to extract ontogeny data. Data from independent studies were standardized and normalized before being compiled in graphs and tables for further interpretation. New insights gained from these high-resolution ontogeny profiles will be indispensable to understand cross-species differences in maturation of hepatic DTs and DMEs. Integration of these ontogeny data into PBPK models will support improved predictions of pediatric hepatic drug disposition processes. SIGNIFICANCE STATEMENT: Hepatic drug transporters (DTs) and drug-metabolizing enzymes (DMEs) play pivotal roles in hepatic drug disposition. Developmental changes in expression levels and activities of these proteins drive age-dependent pharmacokinetics. This review compiles the currently available ontogeny profiles of DTs and DMEs expressed in livers of humans and nonclinical species, enabling robust interpretation of age-related changes in drug disposition and ultimately optimization of pediatric drug therapy.

Postoperative inflammatory response in colorectal cancer surgery: a meta-analysis.

PURPOSE: Surgical removal of the cancerous tissue remains the cornerstone of curative treatment for colorectal cancer and results in an inflammatory response. An exaggerated inflammatory response has been implicated in the promotion of tumor proliferation and has shown associations with postoperative complications. Literature on the preferred surgical technique to minimize inflammatory response is inconclusive. Therefore, the aim of this study was to assess the inflammatory response and postoperative incidence of infectious complications following surgery for colorectal cancer. METHODS: Embase, PubMed, and Cochrane databases were searched for RCTs that reported inflammatory parameters as a function of surgical modality only. Data related to CRP or IL-6 levels on postoperative days 1 and 3 and data related to postoperative infections were subject to a pairwise meta-analysis to compare open versus laparoscopic techniques. RESULTS: The literature search and screening process yielded 4151 studies. Ten studies met criteria, including 568 patients. Only studies on laparoscopic and open surgery were found. Pooled analyses found lower Il-6 and CRP levels on postoperative day 1 and lower CRP levels on postoperative day 3 for laparoscopic surgery compared to open surgery. However, there was no difference in incidence of postoperative infectious complications. CONCLUSION: The findings of this study indicate a superior inflammatory profile for laparoscopic surgery compared to an open approach for colorectal cancer surgery. For future research, it would be worthwhile to conduct a randomized controlled trial to compare the postoperative inflammatory response and related clinical outcomes between minimally invasive surgical approaches, including laparoscopic and robot-assisted surgery.

Assessing the learning curve of robot-assisted total mesorectal excision: a multicenter study considering procedural safety, pathological safety, and efficiency.

PURPOSE: Evidence regarding the learning curve of robot-assisted total mesorectal excision is scarce and of low quality. Case-mix is mostly not taken into account, and learning curves are based on operative time, while preferably clinical outcomes and literature-based limits should be used. Therefore, this study aims to assess the learning curve of robot-assisted total mesorectal excision. METHODS: A retrospective study was performed in four Dutch centers. The primary aim was to assess the safety of the individual and institutional learning curves using a RA-CUSUM analysis based on intraoperative complications, major postoperative complications, and compound pathological outcome (positive circumferential margin or incomplete TME specimen). The learning curve for efficiency was assessed using a LC-CUSUM analysis for operative time. Outcomes of patients before and after the learning curve were compared. RESULTS: In this study, seven participating surgeons performed robot-assisted total mesorectal excisions in 531 patients. Learning curves for intraoperative complications, postoperative complications, and compound pathological outcome did not exceed predefined literature-based limits. The LC-CUSUM for operative time showed lengths of the learning curve ranging from 12 to 35 cases. Intraoperative, postoperative, and pathological outcomes did not differ between patients operated during and after the learning curve. CONCLUSION: The learning curve of robot-assisted total mesorectal excision based on intraoperative complications, postoperative complications, and compound pathological outcome did not exceed predefined limits and is therefore suggested to be safe. Using operative time as a surrogate for efficiency, the learning curve is estimated to be between 12 and 35 procedures.

End effects in low aspect ratio Taylor-Couette flow.

Taylor-Couette flow with a low aspect ratio cylinder suffers from end effects due to the finite-span of the gap between the cylinder sides and the secondary flow in the region below the inner cylinder. We experimentally explore these end effects by varying the cylinder aspect ratio between 6.67 and 40 for a range of wall gap widths and bottom gap heights. For these geometries, end effects (i.e. non-ideal Taylor-Couette flow) can be substantial due to both features of the finite-span and the bottom secondary flow. In some cases, the finite-span effects extended between 20% and 30% of the way into the Taylor-Couette flow region, and the secondary flow at the bottom accounted for nearly half of the total measured torque. By taking these effects into consideration, our high aspect ratio results agreed well with those obtained by Taylor (Taylor 1936 Proc. R. Soc. Lond. A 157, 546-564. (doi:10.1098/rspa.1936.0215)) at considerably higher aspect ratios. This article is part of the theme issue 'Taylor-Couette and related flows on the centennial of Taylor's seminal Philosophical Transactions paper (part 1)'.

Laparoscopic Versus Robot-Assisted Versus Transanal Low Anterior Resection: 3-Year Oncologic Results for a Population-Based Cohort in Experienced Centers.

BACKGROUND: Laparoscopic, robot-assisted, and transanal total mesorectal excision are the minimally invasive techniques used most for rectal cancer surgery. Because data regarding oncologic results are lacking, this study aimed to compare these three techniques while taking the learning curve into account. METHODS: This retrospective population-based study cohort included all patients between 2015 and 2017 who underwent a low anterior resection at 11 dedicated centers that had completed the learning curve of the specific technique. The primary outcome was overall survival (OS) during a 3-year follow-up period. The secondary outcomes were 3-year disease-free survival (DFS) and 3-year local recurrence rate. Statistical analysis was performed using Cox-regression. RESULTS: The 617 patients enrolled in the study included 252 who underwent a laparoscopic resection, 205 who underwent a robot-assisted resection, and 160 who underwent a transanal low anterior resection. The oncologic outcomes were equal between the three techniques. The 3-year OS rate was 90% for laparoscopic resection, 90.4% for robot-assisted resection, and 87.6% for transanal low anterior resection. The 3-year DFS rate was 77.8% for laparoscopic resection, 75.8% for robot-assisted resection, and 78.8% for transanal low anterior resection. The 3-year local recurrence rate was in 6.1% for laparoscopic resection, 6.4% for robot-assisted resection, and 5.7% for transanal procedures. Cox-regression did not show a significant difference between the techniques while taking confounders into account. CONCLUSION: The oncologic results during the 3-year follow-up were good and comparable between laparoscopic, robot-assisted, and transanal total mesorectal technique at experienced centers. These techniques can be performed safely in experienced hands.

Obese outbred mice only partially benefit from diet normalization or calorie restriction as preconception care interventions to improve metabolic health and oocyte quality.

STUDY QUESTION: Can diet normalization or a calorie-restricted diet for 2 or 4 weeks be used as a preconception care intervention (PCCI) in Western-type diet-induced obese Swiss mice to restore metabolic health and oocyte quality? SUMMARY ANSWER: Metabolic health and oocyte developmental competence was already significantly improved in the calorie-restricted group after 2 weeks, while obese mice that underwent diet normalization showed improved metabolic health after 2 weeks and improved oocyte quality after 4 weeks. WHAT IS KNOWN ALREADY: Maternal obesity is linked with reduced metabolic health and oocyte quality; therefore, infertile obese women are advised to lose weight before conception to increase pregnancy chances. However, as there are no univocal guidelines and the specific impact on oocyte quality is not known, strategically designed studies are needed to provide fundamental insights in the importance of the type and duration of the dietary weight loss strategy for preconception metabolic health and oocyte quality. STUDY DESIGN, SIZE, DURATION: Outbred female Swiss mice were fed a control (CTRL) or high-fat/high-sugar (HF/HS) diet. After 7 weeks, some of the HF mice were put on two different PCCIs, resulting in four treatment groups: (i) only control diet for up to 11 weeks (CTRL_CTRL), (ii) only HF diet for up to 11 weeks (HF_HF), (iii) switch at 7 weeks from an HF to an ad libitum control diet (HF_CTRL) and (iv) switch at 7 weeks from an HF to a 30% calorie-restricted control diet (HF_CR) for 2 or 4 weeks. Metabolic health and oocyte quality were assessed at 2 and 4 weeks after the start of the intervention (n = 8 mice/treatment/time point). PARTICIPANTS/MATERIALS, SETTING, METHODS: Changes in body weight were recorded. To study the impact on metabolic health, serum insulin, glucose, triglycerides, total cholesterol and alanine aminotransferase concentrations were measured, and glucose tolerance and insulin sensitivity were analyzed at PCCI Weeks 2 and 4. The quality of in vivo matured oocytes was evaluated by assessing intracellular lipid droplet content, mitochondrial activity and localization of active mitochondria, mitochondrial ultrastructure, cumulus cell targeted gene expression and oocyte in vitro developmental competence. MAIN RESULTS AND THE ROLE OF CHANCE: Significant negative effects of an HF/HS diet on metabolic health and oocyte quality were confirmed (P < 0.05). HF_CTRL mice already showed restored body weight, serum lipid profile and glucose tolerance, similar to the CTRL_CTRL group after only 2 weeks of PCCI (P < 0.05 compared with HF_HF) while insulin sensitivity was not improved. Oocyte lipid droplet volume was reduced at PCCI Week 2 (P < 0.05 compared with HF_HF), while mitochondrial localization and activity were still aberrant. At PCCI Week 4, oocytes from HF_CTRL mice displayed significantly fewer mitochondrial ultrastructural abnormalities and improved mitochondrial activity (P < 0.05), while lipid content was again elevated. The in vitro developmental capacity of the oocytes was improved but did not reach the levels of the CTRL_CTRL mice. HF_CR mice completely restored cholesterol concentrations and insulin sensitivity already after 2 weeks. Other metabolic health parameters were only restored after 4 weeks of intervention with clear signs of fasting hypoglycemia. Although all mitochondrial parameters in HF_CR oocytes stayed aberrant, oocyte developmental competence in vitro was completely restored already after 2 weeks of intervention. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: In this study, we applied a relevant HF/HS Western-type diet to induce obesity in an outbred mouse model. Nevertheless, physiological differences should be considered when translating these results to the human setting. However, the in-depth study and follow-up of the metabolic health changes together with the strategic implementation of specific PCCI intervals (2 and 4 weeks) related to the duration of the mouse folliculogenesis (3 weeks), should aid in the extrapolation of our findings to the human setting. WIDER IMPLICATIONS OF THE FINDINGS: Our study results with a specific focus on oocyte quality provide important fundamental insights to be considered when developing preconception care guidelines for obese metabolically compromised women wishing to become pregnant. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Flemish Research Fund (FWO-SB grant 1S25020N and FWO project G038619N). The authors declare there are no conflicts of interest.

Local recurrence of robot-assisted total mesorectal excision: a multicentre cohort study evaluating the initial cases.

PURPOSE: Evidence regarding local recurrence rates in the initial cases after implementation of robot-assisted total mesorectal excision is limited. This study aims to describe local recurrence rates in four large Dutch centres during their initial cases. METHODS: Four large Dutch centres started with the implementation of robot-assisted total mesorectal excision in respectively 2011, 2012, 2015, and 2016. Patients who underwent robot-assisted total mesorectal excision with curative intent in an elective setting for rectal carcinoma defined according to the sigmoid take-off were included. Overall survival, disease-free survival, systemic recurrence, and local recurrence were assessed at 3 years postoperatively. Subsequently, outcomes between the initial 10 cases, cases 11-40, and the subsequent cases per surgeon were compared using Cox regression analysis. RESULTS: In total, 531 patients were included. Median follow-up time was 32 months (IQR: 19-50]. During the initial 10 cases, overall survival was 89.5%, disease-free survival was 73.1%, and local recurrence was 4.9%. During cases 11-40, this was 87.7%, 74.1%, and 6.6% respectively. Multivariable Cox regression did not reveal differences in local recurrence between the different case groups. CONCLUSION: Local recurrence rate during the initial phases of implantation of robot-assisted total mesorectal procedures is low. Implementation of the robot-assisted technique can safely be performed, without additional cases of local recurrence during the initial cases, if performed by surgeons experienced in laparoscopic rectal cancer surgery.

Maternal metabolic health and fertility: we should not only care about but also for the oocyte!

Metabolic disorders due to obesity and unhealthy lifestyle directly alter the oocyte's microenvironment and impact oocyte quality. Oxidative stress and mitochondrial dysfunction play key roles in the pathogenesis. Acute effects on the fully grown oocytes are evident, but early follicular stages are also sensitive to metabolic stress leading to a long-term impact on follicular cells and oocytes. Improving the preconception health is therefore of capital importance but research in animal models has demonstrated that oocyte quality is not fully recovered. In the in vitro fertilisation clinic, maternal metabolic disorders are linked with disappointing assisted reproductive technology results. Embryos derived from metabolically compromised oocytes exhibit persistently high intracellular stress levels due to weak cellular homeostatic mechanisms. The assisted reproductive technology procedures themselves form an extra burden for these defective embryos. Minimising cellular stress during culture using mitochondrial-targeted therapy could rescue compromised embryos in a bovine model. However, translating such applications to human in vitro fertilisation clinics is not simple. It is crucial to consider the sensitive epigenetic programming during early development. Research in humans and relevant animal models should result in preconception care interventions and in vitro strategies not only aiming at improving fertility but also safeguarding offspring health.

Comparison of laparoscopic versus robot-assisted versus transanal total mesorectal excision surgery for rectal cancer: a retrospective propensity score-matched cohort study of short-term outcomes.

BACKGROUND: Laparoscopic total mesorectal excision (TME) surgery for rectal cancer has important technical limitations. Robot-assisted and transanal TME (TaTME) may overcome these limitations, potentially leading to lower conversion rates and reduced morbidity. However, comparative data between the three approaches are lacking. The aim of this study was to compare short-term outcomes for laparoscopic TME, robot-assisted TME and TaTME in expert centres. METHODS: Patients undergoing rectal cancer surgery between 2015 and 2017 in expert centres for laparoscopic, robot-assisted or TaTME were included. Outcomes for TME surgery performed by the specialized technique in the expert centres were compared after propensity score matching. The primary outcome was conversion rate. Secondary outcomes were morbidity and pathological outcomes. RESULTS: A total of 1078 patients were included. In rectal cancer surgery in general, the overall rate of primary anastomosis was 39.4, 61.9 and 61.9 per cent in laparoscopic, robot-assisted and TaTME centres respectively (P < 0.001). For specialized techniques in expert centres excluding abdominoperineal resection (APR), the rate of primary anastomosis was 66.7 per cent in laparoscopic, 89.8 per cent in robot-assisted and 84.3 per cent in TaTME (P < 0.001). Conversion rates were 3.7 , 4.6 and 1.9 per cent in laparoscopic, robot-assisted and TaTME respectively (P = 0.134). The number of incomplete specimens, circumferential resection margin involvement rate and morbidity rates did not differ. CONCLUSION: In the minimally invasive treatment of rectal cancer more primary anastomoses are created in robotic and TaTME expert centres.

The results of this study showed similar and acceptable short-term results for laparoscopic, robot-assisted and transanal total mesorectal excision performed in expert centres. In centres with robot-assisted or transanal technique, more primary anastomoses were made.

Capacity of Trolox to improve the development and quality of metabolically compromised bovine oocytes and embryos invitro during different windows of development.

Trials to improve oocyte developmental competence under metabolic stress by using antioxidants may start before or after oocyte maturation. In the present conceptual study, we aimed to identify the most efficient timing of antioxidant application in relation to a metabolic insult using a bovine invitro embryo production model. Pathophysiological concentrations of palmitic acid (PA) were used to induce metabolic stress during oocyte maturation or embryo development. Trolox (TR; antioxidant) treatment prior to, during or after the PA insult was tested to evaluate the protective, neutralising and rescuing capacity of TR respectively. Changes in embryo developmental competence, mitochondrial activity, reactive oxygen species (ROS) concentrations, blastocyst cell allocation and apoptosis and cell stress-related gene expression were monitored. The improvement in developmental capacity was most obvious when oocytes were preloaded with TR before the PA insult. This protective effect could be explained by the observed combination of increased mitochondrial activity with reduced ROS production. This resulted in blastocysts with normal cell counts and apoptosis, as well as increased nuclear factor erythroid 2-related factor 2 (NRF2) expression (a marker for redox regulatory processes) and normalised the expression of the mitochondrial transcription factor A (TFAM), a marker of mitochondrial biogenesis. These results indicate that 'pretreatment' of oocytes with antioxidants produces embryos that seem to be more resilient to a metabolic stress insult.

[Pregnancy and psychiatry: a description of patients and the conducted interventions seen at a POP-clinic]. / Zwangerschap en psychiatrie; beschrijving van patiënten en interventies op een POP-poli.

BACKGROUND: Pregnancy and the postpartum period is a vulnerable phase in life for women and can influence the development or course of a psychiatric disorder. These patients can receive extra guidance during this period by the POP-collaboration (Psychiatry, Obstetrics and Pediatrics) in many hospitals. AIM: To describe the characteristics of patients who received psychiatric consultation by the POP-collaboration at the LUMC and the interventions that were conducted. METHOD: Data of patients who were seen at the psychiatric (outpatient) clinic for POP-guidance between 1 January 2016 and 1 April 2020 were analyzed. RESULTS: 292 patients were seen in 310 guidance programs at the psychiatric (outpatient) clinic. Patients referred preconceptionally or during the pregnancy mostly suffered anxiety or unipolar mood disorders. Postpartum it concerned mostly psychotic disorders and bipolar mood disorders. A majority had two or more psychiatric disorders. Interventions were psycho-education, supportive contact, collaboration with their own health-professionals, adjustment of the current treatment, making a prevention plan, a prolonged stay at hospital after childbirth or (rarely) an admission to the psychiatric ward. CONCLUSION: Patients seen for guidance by the POP-collaboration at the LUMC are a vulnerable patient population with frequently complex psychopathology, and need personalized psychoeducation, supervision and treatment.

[Lithium use in women with bipolar disorder during peripartum]. / Lithiumgebruik bij vrouwen met een bipolaire stoornis tijdens het peripartum overzichtsartikel.

BACKGROUND: Lithium use during peripartum requires careful consideration due to a risk of teratogenic effects, adverse side effects and risk of neonatal complications. However, given the effectiveness of lithium, use during the peripartum period may be indicated. AIM: To provide an overview of the current evidence regarding the clinical use of lithium during peripartum, including risk of relapse in case of (dis)continuation and evolution of lithium levels. METHOD: A review was performed in the Medline and ScienceDirect database. RESULTS: Ten studies were included. Six studies concerned the risk of relapse in case of (dis)continuation of lithium during the peripartum. Four studies concerned the evolution of lithium levels throughout the peripartum. Lithium discontinuation during pregnancy leads to an increased risk of relapse during pregnancy and postpartum. At the same dose, lithium levels are lower than preconceptual in all trimesters. CONCLUSION: Risk and benefits of lithium use during the peripartum should be carefully considered, if possible prior to conception. Close monitoring of maternal lithium levels and renal function is necessary due to significant fluctuations during peripartum.

Increased long-term mortality after emergency colon resections.

AIM: Emergency surgery is a known predictor for 30-day mortality. However, its relationship with long-term mortality is still a matter of debate. The aim of this study was to analyse the effect of emergency surgery compared with elective surgery on long-term survival. METHOD: Data from the Dutch Colorectal Audit and the Dutch Cancer Centre registry of a large nonacademic teaching hospital were used to analyse outcomes of patients who underwent surgery for colon cancer from 2009 until 2017. Univariable and multivariable Cox regression were used to assess the effect of emergency surgery on long-term mortality with adjustment for patient, tumour and treatment characteristics. RESULTS: A total of 1139 patients with a median follow-up of 40 months (interquartile range 23-65 months) were included. Emergency surgery was performed in 158 patients (14%). The 5-year survival after emergency surgery was 46% compared with 72% after elective surgery. After adjusting for baseline differences there was an independent and significant association between emergency surgery and increased long-term mortality (hazard ratio 1.79, 95% CI 1.28-2.51, P = 0.001). CONCLUSION: Emergency surgery for colon cancer seems to lead to a significantly increased risk of long-term mortality compared with elective surgery. Detection and treatment of early symptoms that can lead to emergency surgery might be the way forward.

Routine postoperative intensive care unit admission after colorectal cancer surgery for the elderly patient reduces postoperative morbidity and mortality.

AIM: Older colorectal cancer (CRC) patients are at increased risk of postoperative morbidity and mortality. Routine postoperative overnight intensive care unit (ICU) admission might reduce this risk. This study aimed to examine the effect of routine overnight ICU admission after CRC surgery on postoperative adverse outcomes and costs in patients aged 80 years or older. METHODS: Patients aged 80 years or older who underwent CRC surgery in our centre were included in this observational cohort study. All patients in the period 2014-2017 with routine overnight ICU admission were assigned to the ICU cohort; all patients in the period 2009-2013 were assigned to the non-ICU cohort. Multivariable logistic regression was performed to compare the primary composite end-point (30-day mortality, serious complications and readmission) between the groups. Cost data from the literature were used to perform a cost analysis. RESULTS: A total of 242 patients were included, 125 in the ICU cohort and 117 in the non-ICU cohort. Routine overnight ICU admission was associated with a reduced risk of the composite end-point (OR 0.44, 95% CI 0.22-0.87, P = 0.02) after adjusting for important confounders. In the ICU cohort 28% of patients experienced ICU events requiring intervention; this was not associated with postoperative morbidity or mortality. The 9% reduction in the incidence of serious complications in the ICU cohort is sufficient to offset the additional costs of routine overnight ICU admission. CONCLUSION: Routine overnight ICU admission after CRC surgery in patients aged 80 years and older is associated with reduced risk of postoperative mortality and morbidity and seems to be cost-effective.

Larger Dose Reductions of Vancomycin Required in Neonates with Patent Ductus Arteriosus Receiving Indomethacin versus Ibuprofen.

Ibuprofen and indomethacin are commonly used to induce ductus arteriosus closure in preterm neonates. Our group previously reported that ibuprofen decreased vancomycin clearance by 16%. In this study, we quantified the impact of indomethacin coadministration on vancomycin clearance by extending our vancomycin population pharmacokinetic model with a data set containing vancomycin concentrations measured in preterm neonates comedicated with indomethacin. The modeling data set includes concentration-time data of vancomycin administered alone or in combination with either ibuprofen or indomethacin collected in the neonatal intensive care units of UZ Leuven (Leuven, Belgium) and São Francisco Xavier Hospital (Lisbon, Portugal). The derived vancomycin pharmacokinetic model was subsequently used to propose dose adjustments that yield effective vancomycin exposure (i.e., area under the concentration-time curve from 0 to 24 h [AUC0-24] between 300 to 550 mg·h/liter, with a probability of <0.1 of subtherapeutic exposure) in preterm neonates with patent ductus arteriosus. We found that indomethacin coadministration reduced vancomycin clearance by 55%. Model simulations showed that the most recent vancomycin dosing regimen, which was based on an externally validated model, requires 20% and 60% decreases of the loading and maintenance doses of vancomycin, respectively, when aiming for optimized exposure in the neonatal population. By analyzing vancomycin data from preterm neonates comedicated with indomethacin, we found a substantial decrease in vancomycin clearance of 55% versus a previously reported 16% for ibuprofen. This decrease in clearance impacts vancomycin dosing, and we anticipate that other drugs eliminated by glomerular filtration are likely to be affected to a similar extent as vancomycin.

Age and surgical outcome of low-grade glioma in Sweden.

BACKGROUND: Low-grade gliomas (LGG) are slow-growing primary brain tumors that typically affect young adults. Advanced age is widely recognized as a poor prognostic factor in LGG. The impact of age on postoperative outcome in this patient group has not been systemically studied. METHODS: We performed a nationwide register-based study with data from the Swedish Brain Tumor Registry (SBTR) for all adults diagnosed with a supratentorial LGG (WHO grade II astrocytoma, oligoastrocytoma, or oligodendroglioma) during 2005-2015. Patient- and tumor-related characteristics, postoperative complications, and survival were compared between three different age groups (18-39 years, 40-59 years, and ≥60 years). RESULTS: We identified 548 patients; 204 patients (37.2%) aged 18-39 years, 227 patients (41.4%) aged 40-59 years, and 117 patients (21.4%) ≥60 years of age. Unfavorable preoperative prognostic factors (eg, functional status and neurological deficit) were more common with increased age (P < .001). In addition, overall survival was significantly impaired in those 60 years and above (P < .001). We observed a clear dose-response for age with separation of survival curves at 50 years. Biopsy was more common in patients ≥60 years (P < .001). Subgroup analysis of patients with resection revealed a higher amount of postoperative neurological deficits in older patients (P = .029). CONCLUSION: In general, older patients with LGG have several unfavorable prognostic factors compared with younger patients but seem to tolerate surgery in a comparable fashion. However, more neurological deficits were observed following resections in elderly. Our data further support a cutoff at 50 years rather than 40 years for selection of high-risk patients.

Can sidestream dark field (SDF) imaging identify subtle microvascular changes of the bowel during colorectal surgery?

BACKGROUND: Recognition of a non-viable bowel during colorectal surgery is a challenging task for surgeons. Identifying the turning point in serosal microcirculatory deterioration leading up to a non-viable bowel is crucial. The aim of the present study was to determine whether sidestream darkfield (SDF) imaging can detect subtle changes in serosal microcirculation of the sigmoid after vascular transection during colorectal surgery. METHODS: A prospective observational clinical study was performed at a single medical centre. All eligible participants underwent laparoscopic sigmoid resection and measurements were taken during the extra-abdominal phase. Microcirculation was measured at the transected bowel and 20 cm proximal to this point. Microcirculatory parameters such as Microvascular Flow Index (MFI), proportion of perfused vessels (PPV), perfused vessel density (PVD), total vessel density (TVD) and the Heterogeneity Index were determined. Data are presented as median (interquartile range) or mean ± standard deviation. RESULTS: A total of 60 SDF images were acquired for 10 patients. Perfusion parameters and perfused vessel density were significantly lower at the transected bowel compared with the non-transected measurements [MFI 2.29 (1.96-2.63) vs 2.96 (2.73-3.00), p = 0.007; PPV 74% (55-83) vs 94% (86-97), p = 0.007; and PVD 7.61 ± 2.99 mm/mm2 versus 10.67 ± 1.48 mm/mm2, p = 0.009]. Total vessel density was similar between the measurement locations. CONCLUSIONS: SDF imaging can identify changes of the bowel serosal microcirculation. Significantly lower serosal microcirculatory parameters of the vascular transected bowel was seen compared with the non-transected bowel. The ability of SDF imaging to detect subtle differences holds promise for future research on microvascular cut-off values leading to a non-viable bowel.

Radiation-related toxicities and outcomes in endometrial cancer: are obese women at a disadvantage?

OBJECTIVE: To assess the impact of body mass index (BMI) on radiotherapy toxicities in endometrial cancer patients. METHODS: This was a retrospective cohort study of women diagnosed with endometrial cancer between January 2006 and December 2014 at the Royal Cornwall Hospital Trust. Women who received radiotherapy as part of their treatment, including external beam radiotherapy (EBRT) and/or vaginal brachytherapy were included. Radiation-related toxicities were graded according to the Radiation Therapy Oncology Group (RTOG) guidelines. Toxicity outcomes were compared across BMI groups-non-obese (BMI <30 kg/m2) and obese (BMI ≥30 kg/m2)-according to radiotherapy treatment received (EBRT, brachytherapy or a combination). RESULTS: Of a total of 159 women who received radiotherapy, 110 were eligible for inclusion in the study. Sixty-three women had a BMI <30 kg/m2 and 47 women were obese. Obese women had poorer Eastern Cooperative Oncology Group performance status (P = 0.021) and more comorbidities (P < 0.001) compared to the non-obese group. Total (any) toxicity rates were 60.3, 72.7 and 52.0% for EBRT and brachytherapy (N = 63), single-mode EBRT (N = 22) and brachytherapy (N = 25), respectively. BMI was not associated with the incidence of acute and late radiation toxicities in the different radiotherapy groups, and there were no differences in individual complications between the BMI groups. CONCLUSION: When comparing obese to non-obese women, obesity does not negatively impact the incidence of radiation toxicities in endometrial cancer. However, toxicities remain an important challenge as they are common and negatively influence the quality of life (QoL) of survivors. Future studies need to further explore the role of BMI and possible interventions to improve toxicities and QoL.

Posterior implant removal in patients with thoracolumbar spine fractures: long-term results.

PURPOSE: Debate remains whether posterior implants after thoracolumbar spine fracture stabilization should be removed routinely or only in symptomatic cases. Implant related problems might be resolved or even prevented but removal includes secondary risks. The aim of this study was to evaluate safety, patient satisfaction and quality of life after implant removal. METHODS: A retrospective cohort study was performed concerning 102 patients that underwent posterior implant removal after stabilization of a traumatic thoracolumbar fracture between 2003 and 2015. Patients were invited to fill in SF-36, EQ-5D and RMDQ questionnaires after implant removal. Additionally, questions concerning satisfaction were presented. Cobb angles before and after removal were measured and in- or decrease of symptoms was gathered from hospital charts. RESULTS: Mean age at removal was 38 years and time from implant removal to questionnaire was approximately 7 years, 62 patients filled in the questionnaires. Complications were present in 8% and quality of life was reported as fairly good. Patients had less back pain related disability compared to chronic low back pain patients. After removal there was a kyphosis increase which did not correspond with worsened clinical outcome. Removal decreased most symptoms and even asymptomatic patients reported benefit in most cases. An increase of symptoms after removal was reported in 11% of patients. CONCLUSION: Implant removal is generally safe and provides high patient satisfaction. Overall, patients have a fairly good quality of life. Most symptomatic and asymptomatic patients report benefit from removal. However, low risks of complications and increase of symptoms have to be weighted for individual patients.