The impact of fluorescence angiography on anastomotic leak rate following transanal total mesorectal excision for rectal cancer: a comparative study.

BACKGROUND: Anastomotic leak (AL) is the most feared complication in colorectal surgery. Indocyanine green (ICG) fluorescence angiography allows for real-time intraoperative evaluation of bowel perfusion. This study aimed to assess the impact of ICG on perioperative outcomes in patients treated with transanal total mesorectal excision (TaTME) for rectal cancer. METHODS: Comparative study based on a retrospective analysis of prospectively collected data, to validate the use of ICG assessment (ICGA) during TaTME (November/2011-June/2018). The primary outcome was the clinical AL rate. The secondary outcomes included modification of proximal colonic transection, anastomotic redo, additional surgical maneuvers and surgical morbidity. RESULTS: Two hundred and eighty-four patients were included, 204 (71.8%) in non-ICG group and 80 (28.2%) in ICG group. No significant differences were found in patient and tumor features. Mean anastomotic height was 4.85 cm vs. 5.04 cm (p = 0.500), diverting stoma was constructed in 205 patients (72.1% vs. 72.5%; p = 0.941). Fluorescence angiography modified the surgical plan in 23 patients (28.7%). AL was diagnosed in 23 patients (11.3%) in the non-ICG group and in two patients (2.5%) in the ICG group (p = 0.020). Postoperative intraabdominal collection was diagnosed in 19 patients (7.4% vs. 5.1%; p = 0.490), and reintervention was needed in 24 patients (10.8% vs. 7.6%; p = 0.420). Median length of hospital stay was 6.0 (IQR 5.0-9) vs. 4.0 (IQR 3.0-8.5) (p = 0.005). ICGA was found as independent protective factor for AL in the multivariate analysis of the whole cohort (n = 284) (OR 0.142; 95% CI 0.032-0.633; p = 0.010). CONCLUSION: ICG fluorescence angiography modified the proximal colonic transection in more than one-quarter of patients, leading to a significant decrease of AL rate.

Three-year outcome after transanal versus laparoscopic total mesorectal excision in locally advanced rectal cancer: a multicenter comparative analysis.

BACKGROUND: For patients with mid and distal rectal cancer, robust evidence on long-term outcome and causal treatment effects of transanal total mesorectal excision (TaTME) is lacking. This multicentre retrospective cohort study aimed to assess whether TaTME reduces locoregional recurrence rate compared to laparoscopic total mesorectal excision (LapTME). METHODS: Consecutive patients with rectal cancer within 12 cm from the anal verge and clinical stage II-III were selected from three institutional databases. Outcome after TaTME (Nov 2011 - Feb 2018) was compared to a historical cohort of patients treated with LapTME (Jan 2000 - Feb 2018) using the inverse probability of treatment weights method. The primary endpoint was three-year locoregional recurrence. RESULTS: A total of 710 patients were analysed, 344 in the TaTME group and 366 in the LapTME group. At 3 years, cumulative locoregional recurrence rates were 3.6% (95% CI, 1.1-6.1) in the TaTME group and 9.6% (95% CI, 6.5-12.7) in the LapTME group (HR = 0.4; 95% CI, 0.23-0.69; p = 0.001). Three-year cumulative disease-free survival rates were 74.3% (95% CI, 68.8-79.8) and 68.6% (95% CI, 63.7-73.5) (HR = 0.82; 95% CI, 0.65-1.02; p = 0.078) and three-year overall survival 87.2% (95% CI, 82.7-91.7) and 82.2% (95% CI, 78.0-86.2) (HR = 0.74; 95% CI, 0.53-1.03; p = 0.077), respectively. In patients who underwent sphincter preservation procedures, TaTME was associated with a significantly better disease-free survival (HR = 0.78; 95% CI, 0.62-0.98; p = 0.033). CONCLUSIONS: These findings suggest that TaTME may improve locoregional recurrence and disease-free survival rates among patients with mid and distal locally advanced rectal cancer.

Associated thoracic injury in patients with a clavicle fracture: a retrospective analysis of 1461 polytrauma patients.

PURPOSE: During primary survey the main goal is to ascertain life-threatening injuries. A chest X-ray is recommended in all polytrauma patients as thoracic injury plays an important role in mortality. However, treatment-dictating injuries are often missed on the chest X-ray. In contrast, clavicle fractures should be relatively easy to diagnose on a chest X-ray. We previously showed that clavicle fractures occur in approximately 10 % of all polytrauma patients in our population. The aim was to compare polytrauma patients, with and without a clavicle fracture, to investigate if a clavicle fracture is associated with concomitant thoracic injury. METHODS: A retrospective cohort study of polytrauma patients (ISS ≥ 16) from 2007 until 2011. Thoracic injuries were defined as: ribfracture, pneumothorax, lung contusion, sternum fracture, hemothorax, myocardial contusion, thoracic aorta injury and thoracic spine injury. RESULTS: Of 1461 polytrauma patients in 160 patients a clavicle fracture was diagnosed, and 95 % was diagnosed on chest X-ray. Patients with a clavicle fracture had a higher mean Injury Severity Score (ISS) (29.2 ± 10.1 vs. 24.9 ± 9.1; P < 0.001). Additional thoracic injuries were more prevalent in patients with a clavicle fracture (76 vs. 47 %; OR 3.6; 95 % CI 2.45-5.24) and they had a higher rate of thoracic injury with an AIS ≥ 3 (66 vs. 41 %; OR 2.8; 95 % CI 1.97-3.93). CONCLUSIONS: The clavicle can be seen as the gatekeeper of the thorax. In polytrauma patients, a clavicle fracture is easily diagnosed during primary survey and may indicate underlying thoracic injury, as the rate and extent of concomitant thoracic injury are high.

Impact of deep brain stimulation of the ventral anterior limb of the internal capsule on cognition in depression.

BACKGROUND: Preliminary studies report no negative and a possible positive impact of deep brain stimulation (DBS) on cognition of patients with treatment-resistant depression (TRD). However, these studies neither controlled for practice effects nor compared active with sham stimulation. METHOD: To address these limitations, we compared 25 TRD patients, who underwent DBS of the ventral anterior limb of the internal capsule (vALIC), with 21 healthy controls (HCs) matched on gender, age and education level. Both groups did subtests of the Cambridge Neuropsychological Test Automated Battery assessing verbal and visuospatial memory, attention, cognitive flexibility, psychomotor functioning, planning and object naming. TRD patients were tested 3 weeks prior to DBS surgery (baseline), 3 weeks following surgery (T1) and following 52 weeks of DBS optimization (T2). HCs were tested at baseline, 6 weeks following baseline (T1) and 20-24 weeks following baseline (T2). Subsequently, TRD patients entered a randomized, double-blind crossover phase, in which they were tested in an active and a sham stimulation phase. RESULTS: TRD patients did not improve on a test of immediate verbal recognition from baseline to T1, whereas HCs did (group x time: p = 0.001). Both TRD patients and HCs improved over sessions on tests measuring delayed verbal recall, visuospatial memory, planning and object naming (all p < 0.01). Active and sham stimulation did not have an impact on any of the tests differentially. CONCLUSIONS: vALIC DBS neither has a lasting positive nor negative impact on cognition in TRD patients. DBS surgery might have a temporary negative effect on verbal memory.

Isolated hip fracture care in an inclusive trauma system: A trauma system wide evaluation.

INTRODUCTION: Elderly patients with a hip fracture represent a large proportion of the trauma population; however, little is known about outcome differences between different levels of trauma care for these patients. The aim of this study is to analyse the outcome of trauma care in patients with a hip fracture within our inclusive trauma system. MATERIALS AND METHODS: Retrospective cohort study. Data were collected from the electronic patient documentation of patients, with an isolated hip fracture (aged ≥ 60), admitted to a level I or level II trauma centre between January 2008 and December 2012. Main outcomes were time to operative treatment, complications, mortality, and secondary surgical intervention rate. RESULTS: A total of 204 (level I) and 1425 (level II) patients were admitted. Significantly more ASA4 patients, by the American Society of Anesthesiologists (ASA) classification, were treated at the level I trauma centre. At the level II trauma centre, median time to surgical treatment was shorter (0 days; IQR 0-1 vs 1 day; IQR 1-2; P < 0.001), which was mainly influenced by postponement due to lack of operation room availability (14%, n = 28) and co-morbidities (13%, n = 26) present at the level I trauma centre. At the level II trauma centre, hospital stay was shorter (9 vs 11 days; P < 0.001) and the complication rate was lower (41%; n = 590 vs 53%; n = 108; P = 0.002), as was mortality (4%; n = 54 vs 7%; n = 15; P = 0.018). Secondary surgical intervention was performed less often at the level II trauma centre (6%; n = 91 vs 12%; n = 24; P = 0.005). However, no differences in secondary surgical procedures due to inadequate postoperative outcome or implant failure were observed. CONCLUSION AND RELEVANCE: The clinical pathway and the large volume of patients at the level II centre resulted in earlier surgical intervention, lower overall complication and mortality rate, and a shorter length of stay. Therefore, the elderly patient with a hip fracture should ideally be treated in the large-volume level II hospital with a pre-established clinical pathway. However, complex patients requiring specific care that can only be provided at the level I trauma centre may be treated there with similar operative results.

Accuracy of the field triage protocol in selecting severely injured patients after high energy trauma.

BACKGROUND: For optimal treatment of trauma patients it is of great importance to identify patients who are at risk for severe injuries. The Dutch field triage protocol for trauma patients, the LPA (National Protocol of Ambulance Services), is designed to get the right patient, in the right time, to the right hospital. Purpose of this study was to determine diagnostic accuracy and compliance of this triage protocol. STUDY DESIGN: Triage criteria were categorised into physiological condition (P), mechanism of trauma (M) and injury type (I). A retrospective analysis of prospectively collected data of all high-energy trauma patients from 2008 to 2011 in the region Central Netherlands is performed. Diagnostic parameters (sensitivity, specificity, negative predictive value, positive predictive value) of the field triage protocol for selecting severely injured patients were calculated including rates of under- and overtriage. Undertriage was defined as the proportion of severely injured patients (Injury Severity Score (ISS)≥16) who were transported to a level two or three trauma care centre. Overtriage was defined as the proportion of non-severely injured patients (ISS<16) who were transported to a level one trauma care centre. RESULTS: Overall sensitivity and specificity of the field triage protocol was 89.1% (95% confidence interval (CI) 84.4-92.6) and 60.5% (95% CI 57.9-63.1), respectively. The overall rate of undertriage was 10.9% (95%CI 7.4-15.7) and the overall rate of overtriage was 39.5% (95%CI 36.9-42.1). These rates were 16.5% and 37.7%, respectively for patients with M+I-P-. Compliance to the triage protocol for patients with M+I-P- was 78.7%. Furthermore, compliance in patients with either a positive I+ or positive P+ was 91.2%. CONCLUSION: The overall rate of undertriage (10.8%) was mainly influenced by a high rate of undertriage in the group of patients with only a positive mechanism criterion, therefore showing low diagnostic accuracy in selecting severely injured patients. As a consequence these patients with severe injury are undetected using the current triage protocol. As it has been shown that severely injured patients have better outcome in level one trauma care centres further optimisation of this protocol aiming at lowering undertriage is therefore essential, preferably without incrementing overtriage too much.

Risk factors for the development of lithium-induced polyuria.

BACKGROUND: Polyuria is common in patients with bipolar disorder treated with lithium. However, the risk factors for polyuria in these patients have not been established. AIMS: To estimate the prevalence of polyuria associated with the use of lithium and to identify additional risk factors. METHOD: A 4-month prospective follow-up study in an out-patient lithium clinic. The 75 participants were asked to provide 24-h urine samples; polyuria was defined as a urine volume greater than 3 litres per 24 h. Risk factors examined included demographic variables, medications and medical comorbidities. RESULTS: The prevalence of polyuria among lithium users was 37%. Concomitant use of serotonergic antidepressants was strongly associated with polyuria (odds ratio 4.25, 95% CI 1.15-15.68) compared with patients not using these agents. CONCLUSIONS: Our data confirm the high prevalence of lithium-induced polyuria. Physicians should be aware that concurrent use of serotonergic antidepressants and lithium significantly enhances the risk of its occurrence. Although limited polyuria is not harmful, it may be troublesome for the patient. In many cases cessation of lithium therapy is not an option because of difficulty in controlling the manic or depressive symptoms.

Effect of supersaturation and crystallization phenomena on the release properties of a controlled release device based on EVA copolymer.

This study describes the influence of steroid concentration, manufacturing and storage on the release properties of etonogestrel from polyethylene vinylacetate (EVA) based coaxial fibers. Coaxial fibers were manufactured by extrusion technology. As a consequence of the high extrusion temperatures large amounts of etonogestrel dissolve in the polymeric melt. Since the release from the coaxial fibers is directly proportional to the concentration gradient over the membrane, the amount of dissolved drug that recrystallizes upon cooling is of crucial importance. Therefore crystallization kinetics were studied using thermal analysis and hot stage microscopy. It was found that if the amount of etonogestrel is below a critical nucleation concentration at room temperature, the dissolved steroid remains in a supersaturated state. If on the other hand the amount of dissolved steroid is just above the critical nucleation concentration, the supersaturated steroid recrystallizes very slowly. It is concluded that the release of etonogestrel from an extruded coaxial fiber is a result of a complicated set of parameters, where, respectively process conditions, concentration of etonogestrel and both time and temperature of storage are of importance.

In vitro release properties of etonogestrel and ethinyl estradiol from a contraceptive vaginal ring.

The release properties of steroids from a combined contraceptive vaginal ring have been investigated. The product design is based on a coaxial fiber consisting of two types of polyethylene vinylacetate copolymers. Inside the core of the fiber, two steroids are present in a molecularly dissolved state. In order to design a controlled release system with specified release characteristics, values of diffusion coefficient and solubility are required. These data can either be determined during pre-formulation studies on e.g. polymeric flat films or from in-vitro release measurements of the actual coaxial fibers. It can be concluded from this study that polyethylene vinylacetate copolymers exhibit suitable properties to develop a controlled release system with the two steroids etonogestrel and ethinyl estradiol. It has been found that the permeability data obtained in the pre-formulation studies are useful in semi-quantitative terms, but deviate from the permeability data found from the in-vitro release of coaxial fibers. This is most likely due to differences in the polymeric structure of films and coaxial fibers. As a consequence, further studies should be initiated to evaluate the relationship between the manufacturing process and the resulting polymeric structure. It has also been found that the solubility and release of etonogestrel are influenced by the concentration of ethinyl estradiol. By investigating this phenomenon by thermoanalysis, it was shown that the steroids form an eutectic. The lower melting point of the steroids results in an increase in solubility and hence in altered permeability properties.

Ritanserin, a selective 5-HT2/1C antagonist, and negative symptoms in schizophrenia. A placebo-controlled double-blind trial.

The effectiveness of ritanserin, a selective 5-HT2 and 5-HT1c antagonist, in reducing negative symptoms in schizophrenia was investigated in a double-blind, placebo-controlled trial. Trial treatment was added to a stable neuroleptic treatment in 33 schizophrenic patients with predominantly negative symptoms. Ritanserin reduced the negative symptoms, as measured with the SANS. The main reduction was for the items facial expression, global affective flattening, and relationships with friends and peers. Also a reduction in total BPRS score was found, which approached statistical significance. Significant reductions were observed for the BPRS items emotional withdrawal and depressive mood. Ritanserin or other drugs blocking 5-HT2 and/or 5-HT1c receptors could be important in reducing specific symptoms in schizophrenic patients.

Body weight and/or endogenous estradiol as determinants of cortical bone mass and bone loss in healthy early postmenopausal women.

The objective was to study the independent relationships of body mass index and endogenous estradiol to cortical bone mineral density and the rate of cortical bone loss at the radius in healthy early postmenopausal women. Fifty-one healthy early postmenopausal women (aged 58-66 years) participated. The women were a subset of a population participating in a 10-year longitudinal study to elucidate the influence of dietary calcium on the rate of cortical bone loss. Cortical bone mineral density at the radius, body weight and body height were measured annually (1979-89). Concentrations of sex steroids were measured in serum samples collected during the last year of follow-up (1989). Endogenous estradiol levels, although significantly positively correlated with body mass index, were not independently related to bone mass indices of the radius. Body mass index, on the other hand, was found to be positively related to cortical bone mineral density and negatively to the rate of bone loss, even after adjustments had been made for confounding factors. Our results suggest that the level of total estradiol is not an important determinant of cortical bone mass indices in healthy early postmenopausal women. Other factors of overweight such as mechanical loading may be important.

Sequence-, time- and dose-dependent synergism of methotrexate and 6-mercaptopurine in malignant human T-lymphoblasts.

Methotrexate (MTX) and 6-mercaptopurine (6MP) are common drugs in the oral maintenance therapy of acute lymphoblastic leukemia (ALL). On the basis of their biochemical effects on cell metabolism, a sequence-dependent synergism might be anticipated. In order to investigate this hypothesis, MOLT-4 human malignant T-lymphoblasts were incubated with various concentrations of MTX. The time at which maximal increase of intracellular 5-phosphoribosyl-1-pyrophosphate (PRPP) levels was found correlated with the concentrations of MTX used. Determination of aminoimidazolecarboxamide ribonucleoside monophosphate (AICAR) levels and labeled glycine incorporation into purine metabolites revealed an incomplete inhibition of purine de novo synthesis after incubation with 0.02 microM MTX, and a complete inhibition with 0.2 microM MTX. After prolonged periods of incubation, glutamine exhaustion of the medium caused inhibition of purine de novo synthesis in MTX-untreated cells, with a concomitant increase of PRPP levels. Addition of glutamine to the medium prevented this phenomenon. The increased availability of PRPP after pretreatment with MTX can be used for enhanced intracellular incorporation of hypoxanthine and 6MP in their respective nucleotides. The time- and dose-dependent effects of MTX on PRPP levels correlated with the enhanced incorporation of hypoxanthine and 6MP. The data presented in this study demonstrate that a synergistic action of the combination of MTX and 6MP can be anticipated in malignant lymphoblasts with an active purine de novo synthesis depending on the concentration of MTX and on the time and sequence of administration of both drugs.

Sex difference in human growth hormone (GH) response to intravenous human pancreatic GH-releasing hormone administration in young adults.

Intravenous administration of a 100-micrograms dose of human pancreatic GH-releasing hormone (human pancreatic GHRH1-44, indicated by GHRH) disclosed a sex difference in GH responsiveness. The maximum GH increments [41 +/- 11 (SEM) vs. 15 +/- 4 ng/ml, P* less than 0.05] and the areas under the curves (419 +/- 105 vs. 148 +/- 53 area U, P* less than 0.05) were significantly higher in 12 men than in 10 women. No significant correlation was found in either group between the basal plasma estradiol or testosterone levels and the maximum or integrated GH response to GHRH. Serum PRL levels significantly increased in both groups within 5 min after GHRH injection (men, P less than 0.001 vs. t = 0; women, P less than 0.05 vs. t = 0). The areas under the curves of the PRL responses (355 +/- 184 vs. 189 +/- 73 area U) and the maximum PRL increments (58 +/- 18 vs. 36 +/- 6 mU/l, P* greater than 0.10) were similar. In conclusion, a sex difference in GH responsiveness to GHRH was found between young adult men and women. Recent in vivo and in vitro data reveal a similar sex difference in rodents and an enhancing effect of androgens, but not estrogens, on the GH response to GHRH. These findings support the theory that in humans testosterone also plays a key role in the genesis of this sex difference.