The impact on postoperative outcomes of intraoperative fluid management strategies during cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: The impact of intraoperative fluid management during cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) on postoperative outcomes has been poorly investigated. This study aimed to retrospectively evaluate the impact of intraoperative fluid management strategy on postoperative outcomes and survival. METHODS: 509 patients undergoing CRS and HIPEC at Uppsala University Hospital/Sweden 2004-2017 were categorized into two groups according to the intraoperative fluid management strategy: pre-goal directed therapy (pre-GDT) and goal directed therapy (GDT), where a hemodynamic monitor (CardioQ or FloTrac/Vigileo) was used to optimize fluid management. Impact on morbidity, postoperative hemorrhage, length-of-stay and survival was analyzed. RESULTS: The pre-GDT group received higher fluid volume compared to the GDT group (mean 19.9 vs. 16.2 ml/kg/h, p < 0.001). Overall postoperative morbidity Grade III-V was higher in the GDT group (30% vs. 22%, p = 0.03). Multivariable adjusted odds ratio (OR) for Grade III-V morbidity was 1.80 (95%CI 1.10-3.10, p = 0.02) in the GDT group. Numerically, more cases of postoperative hemorrhage were found in the GDT group (9% vs. 5%, p = 0.09), but no correlation was observed in the multivariable analysis 1.37 (95%CI 0.64-2.95, p = 0.40). An oxaliplatin regimen was a significant risk factor for postoperative hemorrhage (p = 0.03). Mean length of stay was shorter in the GDT group (17 vs. 26 days, p < 0.0001). Survival did not differ between the groups. CONCLUSION: While GDT increased the risk for postoperative morbidity, it was associated with shortened hospital stay. Intraoperative fluid management during CRS and HIPEC did not affect the postoperative risk for hemorrhage, while the use of an oxaliplatin regimen did.

A short- and long-term follow-up study of intersphincteric NASHA Dx implants for fecal incontinence.

BACKGROUND: The bulking agent NASHA Dx injected into the submucosal layer is effective in the treatment of fecal incontinence (FI) at short-and medium-term follow-up but efficacy after injection in the intersphincteric location is unknown. The aim of this study was to determine the short- and long-term efficacy and safety of NASHA Dx injected into the intersphincteric location for FI. METHODS: Patients were recruited from referrals to our Department for treatment of FI in November 2008-January 2010. Eligible patients were injected with 8 ml of NASHA Dx. Patients with a subtotal treatment effect were retreated after 2-4 weeks. The change in number of fecal incontinence episodes, the proportion of responders defined as at least 50% decrease in number of FI episodes and side effects were the main outcome measures. RESULTS: Sixteen patients, 15 women and 1 man with a median age of 68, 5 (range 44-80) years and a median CCFIS of 15 (range 10-19) were included in the study. The median number of incontinence episodes decreased from 21.5 (range 8-61) at baseline to 10 (range 0-30) at 6 months (p = 0.003) and 6 (range 0-44) at 12 months (p = 0.05). The median number of incontinence episodes in the 11 patients completing the 10-year follow-up was 26.5 (range 0-68). The percentage of responders at 12 months and 10 years were 56% and 27%, respectively. Mild to moderate pain at the injection site was described by 69%. There was one case of mild infection, successfully treated with antibiotics and one implant had to be removed due to dislocation. CONCLUSIONS: NASHA Dx as an intersphincteric implant improves incontinence symptoms in the short term with moderate side effects and can be used alone or as an adjunct to other treatment modalities. Long-term efficacy was observed in 27%.

Morbidity following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal metastases with or without early postoperative intraperitoneal chemotherapy: A propensity score matched study.

BACKGROUND: Combining hyperthermic intraperitoneal chemotherapy (HIPEC) treatment with early postoperative intraperitoneal chemotherapy (EPIC) may increase postoperative morbidity. This study aims to investigate postoperative morbidity after HIPEC+EPIC compared with HIPEC alone in patients with peritoneal metastases (PM). MATERIALS AND METHODS: This is a retrospective propensity score matched cohort study. All patients undergoing PM treatment at Uppsala University Hospital between February 2004 and December 2014 were included. Propensity score matching with a 1:1 ratio was performed using sex, primary tumor site, preoperative chemotherapy, peritoneal cancer index, completeness of cytoreduction score, and HIPEC regimen. Length of hospital stay, morbidity, reoperation rate, and readmission rate within 6 months were selected as endpoints. RESULTS: A total of 390 consecutive patients were divided in two arms: HIPEC+EPIC (n = 115) and HIPEC alone (n = 275). The propensity score matching (n = 190) was successful with balanced covariates: 95 patients/arm. The length of stay (LOS) was longer in the HIPEC + EPIC group in the total cohort (30 vs 24 days, p < 0.001), with a trend towards significance in the propensity matched group (29 vs 25 days, p = 0.062). No other differences in endpoints were found. CONCLUSION: HIPEC+EPIC is associated with a prolonged hospital stay, but with no statistically significant relevant increase in postoperative morbidity, reoperation rate or incidence of readmission.

Comparison of four surgical approaches for rectal prolapse: multicentre randomized clinical trial.

BACKGROUND: Several different procedures have been described for surgical treatment of rectal prolapse and consensus on the optimal approach has not been reached. The Swedish Rectal Prolapse Trial was performed with the aim to compare the outcomes after the most common surgical approaches to rectal prolapse. METHOD: A multicentre randomized trial was conducted from 2000 to 2009. Patients were randomized between a perineal or an abdominal approach for correction of rectal prolapse (randomization A) if eligible for any procedures. Patients considered unsuitable for random allocation were only included in randomizations B or C. Patients in randomization B (perineal group) were randomized to Delorme's or Altemeier's procedures and those in randomization C (abdominal group) to suture rectopexy or resection rectopexy. Primary outcomes were bowel function and quality of life, measured using Wexner incontinence score and RAND-36, and secondary outcomes were complications and recurrence at 3 years. RESULTS: During the study period, 134 patients were randomized: 18 in randomization A group, 80 in randomization B group and 54 in randomization C group; of these, 122 patients underwent surgery. Mean follow-up was 2.6 years. Improvements in Wexner and RAND-36 scores were seen but with no significant difference between the groups. Health change scores were significantly improved from baseline up to 1 year after surgery (P < 0.001). At 3 years, recurrence rates were two of seven patients for abdominal versus five of eight patients for perineal approach (P = 0.315), 18 of 31 patients (58 per cent) for Delorme's versus 15 of 30 patients (50 per cent) for Altemeier's (P = 0.611) and four of 19 patients (21 per cent) for suture rectopexy versus two of 21 patients (10 per cent) for resection rectopexy (P = 0.398). There were no significant differences regarding postoperative complications. CONCLUSION: For all procedures, significant improvements from baseline in health change scores were noted after surgery. Recurrence rates were higher than previously reported. Registration number: NCT04893642 (http://www.clinicaltrials.gov).

The incidence and prognostic importance of ovarian involvement in patients with peritoneal metastasis undergoing CRS-HIPEC.

BACKGROUND: Oophorectomy is a common procedure in women with peritoneal metastasis (PM) undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), which has unique consequences on hormonal balance and fertility before menopause. The objective of this study was to analyze histopathological results and the prognostic influence of ovarian involvement. MATERIAL AND METHODS: A prospective HIPEC database was used to identify 442 patients with PM from colorectal cancer, pseudomyxoma peritonei and appendix cancer scheduled for CRS-HIPEC between 2012 and 2019 at the University Hospital, Uppsala, Sweden. Statistical analyses were performed using the Chi-square test and Cox regression analysis. RESULTS: In all, 103 of 180 females underwent oophorectomy. Unilateral oophorectomy was performed in 19% (n = 20) and bilateral oophorectomy in 81% (n = 83). The median age was 61 (range 20-80). Benign ovarian histopathology was seen in 23% (n = 24). Of these, two patients were ≤35 years and 8 patients ≤50 years. The median peritoneal cancer index (PCI) was 16 in women undergoing oophorectomy, and 7 in those with no oophorectomy. Bilateral oophorectomy was associated with negative impact on overall survival (HR 4.84; 95% CI; 1.14-20.61). Malignant ovarian histopathology was also associated with a negative impact on overall survival (p = 0.043). CONCLUSION: Almost a quarter of the patients had benign histopathology after oophorectomy. This is crucial information for females with childbearing potential when planning for extensive surgery. Extensive pelvic peritoneal cancer growth resulted more often in bilateral oophorectomy which influenced survival negatively.

Assessing the faecal source sensitivity and specificity of ruminant and human genetic microbial source tracking markers in the central Ethiopian highlands.

This study tested genetic microbial source tracking (MST) methods for identifying ruminant- (BacR) and human-associated (HF183/BacR287, BacHum) bacterial faecal contaminants in Ethiopia in a newly created regional faecal sample bank (n = 173). BacR performed well, and its marker abundance was high (100% sensitivity (Sens), 95% specificity (Spec), median log10 8·1 marker equivalents (ME) g-1 ruminant faeces). Human-associated markers tested were less abundant in individual human samples (median: log10 5·4 and 4·2 (ME + 1) g-1 ) and were not continuously detected (81% Sens, 91% Spec for BacHum; 77% Sens, 91% Spec for HF183/BacR287). Furthermore, the pig-associated Pig2Bac assay was included and performed excellent (100% Sens, 100% Spec). To evaluate the presence of MST targets in the soil microbiome, representative soil samples were tested during a whole seasonal cycle (n = 60). Only BacR could be detected, but was limited to the dry season and to sites of higher anthropogenic influence (log10 3·0 to 4·9 (ME + 1) g-1 soil). In conclusion, the large differences in marker abundances between target and non-target faecal samples (median distances between distributions ≥log10 3 to ≥log10 7) and their absence in pristine soil indicate that all tested assays are suitable candidates for diverse MST applications in the Ethiopian area.

Multiple stressor effects on benthic macroinvertebrates in very large European rivers - A typology-based evaluation of faunal responses as a basis for future bioassessment.

Two factors complicate the ecological status classification of very large rivers in Europe according to the EU Water Framework Directive: First, current assessment methods do not fully consider the specific ecology of very large rivers (such as lateral connectivity and the role of floodplains for ecological status). Second, most of Europe's very large rivers have been severely altered by human activities such as flood protection, damming and navigation. The aim of our study is to develop an assessment method for very large rivers by identifying suitable biological metrics as the basis for multi-metric bioassessment using benthic invertebrates. Based on the pan-European typology of very large rivers by Borgwardt et al. (2019), we established a river type-specific assessment approach using invertebrate samples from 25 European countries and 94 very large rivers. The frequency and intensity of eight pressures jointly acting on the sampling sites were described, and a selection of suitable invertebrate community metrics were correlated with the pressure intensities to establish pressure-response relationships. The very large river types differ in terms of relevant pressures and pressure combinations, with the invertebrate communities distinctly responding to these pressure patterns. Neozoa dominance correlated strongly with 'navigation', being a major pressure at very large rivers, which entails severe hydro-morphological alterations such as channelization, riparian vegetation alteration and impoundment. Under combined pressures, a critical community turnover became evident in terms of neozoa outnumbering EPT taxa and the ratio of hemilimnic invertebrates decreasing. We propose ten bioassessment metrics, including measures of biological diversity as well as newly generated indicators, for the development of a European type-specific assessment method for very large rivers.

Long-term functional results after excisional haemorrhoidectomy.

AIM: The aim of this work was to perform a long-term evaluation of a randomized trial focusing on functional aspects after excisional haemorrhoidectomy with a minimum follow-up of 9 years. METHOD: A questionnaire-based study including patients operated on for haemorrhoids in Sweden between 1999 and 2003. A total of 225 patients were randomized to Milligan's or Ferguson's operation. Twenty-six patients had died and 151 (76%) participated after a median follow-up of 10.7 years (range 9.2-12.6 years). RESULTS: Seventy-seven patients were in the Milligan group and 74 in the Ferguson group. Forty-eight (32%) reported recurrence. Anal bleeding was reported in 80% at baseline but in 28% at long-term follow-up (P < 0.0001). At baseline, 49% had spontaneous anal pain and 25% pain at defaecation. At follow-up, these figures were 17% and 11%. At follow-up, 19% described a sense of anal stenosis. At baseline, soiling was reported in 51% but in 20% at long-term follow-up (P < 0.001). Nineteen per cent used pads preoperatively and 6% at follow-up (P < 0.0001). Straining at defaecation was reported by 35% at baseline. At follow-up, this figure was 25% (P = 0.055). CONCLUSION: Symptoms associated with haemorrhoids were reduced at long-term follow-up. The most common problems were perceived recurrence and a sense of anal stenosis.

Abdominal decompression illness following repetitive diving: a case report and review of the literature.

The complete pathophysiology of decompression illness is not yet fully understood. What is known is that the longer a diver breathes pressurized air at depth, the more likely nitrogen bubbles are to form once the diver returns to surface [1]. These bubbles have varying mechanical, embolic and biochemical effects on the body. The symptoms produced can be as mild as joint pain or as significant as severe neurologic dysfunction, cardiopulmonary collapse or death. Once clinically diagnosed, decompression illness must be treated rapidly with recompression therapy in a hyperbaric chamber. This case report involves a middle-aged male foreign national who completed three dives, all of which incurred significant bottom time (defined as: "the total elapsed time from the time the diver leaves the surface to the time he/she leaves the bottom)" [2]. The patient began to develop severe abdominal and back pain within 15 minutes of surfacing from his final dive. This case is unique, as his presentation was very concerning for other medical catastrophes that had to be quickly ruled out, prior to establishing the diagnosis of severe decompression illness. After emergency department resuscitation, labs and imaging were obtained; abdominal decompression illness was confirmed by CT, revealing a significant abdominal venous gas burden.

Long-term outcome after segmental colonic resection for slow transit constipation.

PURPOSE: Colectomy with ileorectal anastomosis (IRA) is the most common surgical procedure for slow transit constipation (STC). A hemicolectomy has been suggested as an alternative to IRA with good short-term results. However, long-term results are unknown. The aim of this study was to evaluate the long-term results after hemicolectomy as a treatment for STC. METHODS: Fifty patients with STC were selected for right- or left-sided hemicolectomy after evaluation with colonic scintigraphy from 1993 to 2008. Living patients (n = 43) received a bowel function questionnaire and a questionnaire about patient-reported outcome. RESULTS: After a median follow-up of 19.8 years, 13 patients had undergone rescue surgery (n = 12) or used irrigation (n = 1) and were classified as failures. In all, 30 were evaluable for functional outcome and questionnaire data for 19 patients (due to 11 non-responding) could be analysed. Two reported deterioration after several years and were also classified as failures. Median stool frequency remained increased from 1 per week at baseline to 5 per week at long-term follow-up (p = 0.001). Preoperatively, all patients used laxatives, whereas 12 managed without laxatives at long-term follow-up (p = 0.002). There was some reduction in other constipation symptoms but not statically significant. In the patients' global assessment, 10 stated a very good result, seven a good result and two a poor result. CONCLUSIONS: Hemicolectomy for STC increases stool frequency and reduces laxative use. Long-term success rate could range between 17/50 (34%) and 35/50 (70%) depending on outcome among non-responders.

Quality of life and cost effectiveness in a randomized trial of patients with colorectal cancer and peritoneal metastases.

BACKGROUND: The aim was to compare health-related quality-of-life (HRQOL) and cost-effectiveness between cytoreductive surgery with intraperitoneal chemotherapy (CRS + IPC) and systemic chemotherapy for patients with colorectal peritoneal metastases. METHODS: Patients included in the Swedish Peritoneal Trial comparing CRS + IPC and systemic chemotherapy completed the EORTC QLQ-C30 and SF-36 questionnaires at baseline, 2, 4, 6, 12, 18, and 24 months. HRQOL at 24 months was the primary endpoint. EORTC sum score, SF-36 physical and mental component scores at 24 months were calculated and compared for each arm and then referenced against general population values. Two quality-adjusted life-year (QALY) indices were applied (EORTC-8D and SF-6D) and an incremental cost-effectiveness ratio (ICER) per QALY gained was calculated. A projected life-time ICER per QALY gained was calculated using predicted survival according to Swedish population statistics. RESULTS: No statistical differences in HRQOL between the arms were noted at 24 months. Descriptively, survivors in the surgery arm had higher summary scores than the general population at 24 months, whereas survivors in the chemotherapy arm had lower scores. The projected life-time QALY benefit was 3.8 QALYs in favor of the surgery arm (p=0.06) with an ICER per QALY gained at 310,000 SEK (EORTC-8D) or 362,000 SEK (SF-6D) corresponding to 26,700-31,200 GBP. CONCLUSION: The HRQOL in patients with colorectal peritoneal metastases undergoing CRS + IPC appear similar to those receiving systemic chemotherapy. Two-year survivors in the CRS + IPC arm have comparable HRQOL to a general population reference. The treatment is cost-effective according to NICE guidelines.

Longitudinal assessment of hydropeaking impacts on various scales for an improved process understanding and the design of mitigation measures.

Hydropeaking is one of the main pressures on the aquatic ecology in alpine rivers. Beside studies on abiotic process and biotic response on the local scale there is a lack in process understanding on the reach scale. Especially longitudinal changes of hydropeaking impacts based on retention processes have not been studied yet. Thus, based on unsteady one-dimensional and two-dimensional depth averaged modelling it was targeted to investigate possible changes in vertical ramping velocity for the discussion of possible mitigation measures at the local scale. Here, we compared artificial and natural sheltering habitats in terms of peak flow. Additionally, the hydropeaking assessment on various river scales was supported by an evaluation of tributaries in an alpine river system. Based on the modelling results and the discussion of the impact assessment of hydropeaking in different case studies we state, that on the first 5km downstream of the turbine outlet a significant decrease in vertical ramping velocity occurs. In this reach, habitat improvements should focus on increasing retention processes considering the higher risk of stranding for juvenile fish and macroinvertebrates. For morphological mitigation measures at the local scale, it turned out that self-formed, near-natural morphology should be targeted in terms of mitigation measure design compared to artificial sheltering habitats. Abundance and biomass of macroinvertebrates are directly linked to substrate variability in self-formed sheltering habitats downstream of gravel bars. Moreover, we ascertained that tributaries are able to contribute to the 'ecological potential' in multi-stressed hydropeaking rivers by providing spawning and rearing habitats for fish. However, for a sustainable improvement of the aquatic environment on all relevant scales, both sediment and flood dynamics have to be considered as important drivers to establish self-formed sheltering habitats in terms of hydropeaking.

Habitat use and tolerance levels of macroinvertebrates concerning hydraulic stress in hydropeaking rivers - A case study at the Ziller River in Austria.

Artificial flow fluctuations due to the operation of hydropower plants, frequently described as hydropeaking, result in a constant decrease of biomass of specific macrozoobenthos (MZB) taxa. For the presented case study, we assessed three reaches in the Ziller River catchment. At each sampling reach we performed the Multi-Habitat-Sampling (MHS) method with a Water Framework Directive (WFD) compliant AQEM/MHS net according to the Austrian guideline. Additionally, a hydraulic-specific sampling was conducted with a modified Box (Surber) sampler. As a basis for predictive habitat modelling of the MZB fauna, we measured abiotic parameters like mean (v40) and bottom-near (vbottom) flow rate or water depth respectively, for each box sample. In addition, the choriotope type, representing grain size classes, was determined. One of the main results is, that the national status assessment was not capable to reflect the impact of pulse release at the investigated river stretches on the basis of status classes. Moreover, we figured out that 1) habitats of stagnophilic macroinvertebrate taxa are minimized in channelized stretches affected by hydropeaking, leading to heavy quantitative losses for populations, becoming apparent in significant decreases in total individual numbers and biomass for many taxa. 2) The minor respond of the ecological status class in affected stretches by applying the WFD compliant national assessment method for macroinvertebrates owes to the tolerance of rheobiont or rheophilic taxa commonly classified as indicators for good conditions regarding saprobity or degradation score. 3) A development of a stressor-specific sampling design is required as the MHS method largely ignores vulnerable habitats. 4) The habitat suitability of selected species provides efficient expertise for impact assessment and mitigation measure design in terms of predictive habitat modelling.

Evaluation of hydropeaking impacts on the food web in alpine streams based on modelling of fish- and macroinvertebrate habitats.

Hydropeaking as a result of peak-load electricity production has been identified as one of the most significant pressures in alpine streams. Scouring of macroinvertebrates leads to downstream transport of aquatic organisms (catastrophic drift). Additionally, invertebrates are affected by periodic drying of wetted area during the dewatering of gravel bars and exposed areas along the banks. Even though fish are physiologically better adapted to switch to suitable habitats, artificial flow fluctuations may be followed by lethal stranding and quick alteration in habitat quantity and quality. Nevertheless, the interactions between pressures on fish and macroinvertebrates in terms of hydropeaking have not been investigated so far. The aim of this paper is to evaluate effects of flow fluctuations on potential epibenthic feeding grounds. Therefore, we evaluated changes in habitat distribution resulting from rapid flow fluctuations in river reaches with different river morphological characteristics, for five different macroinvertebrate taxa. Additionally, microhabitats for brown trout at two different life stages were calculated using representative peaking events (seasonal analysis) based on mid- to long term times series. Moreover, GIS-analysis allowed the evaluation of hydropeaking impacts (interaction) on both, macroinvertebrates and fish. In this study, it could be documented that feeding from the benthos for juvenile and subadult brown trout is inhibited during peak flow and is therefore reduced to times of base flow. Moreover, potential benthic feeding areas occurring at base flow have been found to increase with the level of morphological heterogeneity within analyzed river reaches. Likewise, hydrological sensitivity testing in terms of reducing ∆Q at different levels was performed and revealed that possible positive effects required heterogeneous river morphology as a precondition. However, this approach might be applied for estimating the impacts of hydrological mitigation measures in hydropeaked rivers concerning physical condition and/or growth rate of salmonids considering the river morphology of the investigated stream.

Transcutaneous Vagus Nerve Stimulation (tVNS) for Treatment of Drug-Resistant Epilepsy: A Randomized, Double-Blind Clinical Trial (cMPsE02).

BACKGROUND: Various brain stimulation techniques are in use to treat epilepsy. These methods usually require surgical implantation procedures. Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive technique to stimulate the left auricular branch of the vagus nerve at the ear conch. OBJECTIVE: We performed a randomized, double-blind controlled trial (cMPsE02) to assess efficacy and safety of tVNS vs. control stimulation in patients with drug-resistant epilepsy. METHODS: Primary objective was to demonstrate superiority of add-on therapy with tVNS (stimulation frequency 25 Hz, n = 39) versus active control (1 Hz, n = 37) in reducing seizure frequency over 20 weeks. Secondary objectives comprised reduction in seizure frequency from baseline to end of treatment, subgroup analyses and safety evaluation. RESULTS: Treatment adherence was 84% in the 1 Hz group and 88% in the 25 Hz group, respectively. Stimulation intensity significantly differed between the 1 Hz group (1.02 ± 0.83 mA) and the 25 Hz group (0.50 ± 0.47 mA; p = 0.006). Mean seizure reduction per 28 days at end of treatment was -2.9% in the 1 Hz group and 23.4% in the 25 Hz group (p = 0.146). In contrast to controls, we found a significant reduction in seizure frequency in patients of the 25 Hz group who completed the full treatment period (20 weeks; n = 26, 34.2%, p = 0.034). Responder rates (25%, 50%) were similar in both groups. Subgroup analyses for seizure type and baseline seizure frequency revealed no significant differences. Adverse events were usually mild or moderate and comprised headache, ear pain, application site erythema, vertigo, fatigue, and nausea. Four serious adverse events were reported including one sudden unexplained death in epilepsy patients (SUDEP) in the 1 Hz group which was assessed as not treatment-related. CONCLUSIONS: tVNS had a high treatment adherence and was well tolerated. Superiority of 25 Hz tVNS over 1 Hz tVNS could not be proven in this relatively small study, which might be attributed to the higher stimulation intensity in the control group. Efficacy data revealed results that justify further trials with larger patient numbers and longer observation periods.

Libertas: a phase II placebo-controlled study of NRL001 in patients with faecal incontinence showed an unexpected and sustained placebo response.

PURPOSE: Faecal incontinence (FI) is distressing, significantly reduces quality of life (QoL) and has few pharmacological treatments. The α1-adrenoceptor agonist NRL001 (1R,2S-methoxamine hydrochloride) improves anal sphincter tone. NRL001 efficacy was evaluated by changes in Wexner scores at week 4 vs. baseline in NRL001-treated patients compared with placebo. Impact of NRL001 on QoL and safety were also assessed. METHODS: Four hundred sixty-six patients received NRL001 (5, 7.5 or 10 mg) or placebo as suppository, once daily over 8 weeks. Wexner score, Vaizey score and QoL were analysed at baseline, week 4 and week 8. FI episodes and adverse events were recorded in diaries. RESULTS: At week 4, mean reductions in Wexner scores were -3.0, -2.6, -2.6 and -2.4 for NRL001 5, 7.5, 10 mg and placebo, respectively. All reduced further by week 8. As placebo responses also improved, there was no significant treatment effect at week 4 (p = 0.6867) or week 8 (p = 0.5005). FI episode frequency improved for all patients, but not significantly compared with placebo (week 4: p = 0.2619, week 8: p = 0.5278). All patients' QoL improved, but not significantly for all parameters (p > 0.05) except depression/self-perception at week 4 (p = 0.0102) and week 8 (p = 0.0069), compared with placebo. Most adverse events were mild and judged probably or possibly related to NRL001. CONCLUSIONS: All groups demonstrated improvement in efficacy and QoL compared with baseline. NRL001 was well-tolerated without serious safety concerns. Despite the improvement in all groups, there was no statistically significant treatment effect, underlining the importance of relating results to a placebo arm.

Adjunctive retigabine in refractory focal epilepsy: Postmarketing experience at four tertiary epilepsy care centers in Germany.

PURPOSE: Retigabine (RTG, ezogabine) is the first potassium channel-opening anticonvulsant drug approved for adjunctive treatment of focal epilepsies. We report on the postmarketing clinical efficacy, adverse events, and retention rates of RTG in adult patients with refractory focal epilepsy. METHODS: Clinical features before and during RTG treatment were retrospectively collected from patients treated at four German epilepsy centers in 2011 and 2012. RESULTS: A total of 195 patients were included. Daily RTG doses ranged from 100 to 1500 mg. Retigabine reduced seizure frequency or severity for 24.6% and led to seizure-freedom in 2.1% of the patients but had no apparent effect in 43.1% of the patients. Seizure aggravation occurred in 14.9%. The one-, two-, and three-year retention rates amounted to 32.6%, 7.2%, and 5.7%, respectively. Adverse events were reported by 76% of the patients and were mostly CNS-related. Blue discolorations were noted in three long-term responders. Three possible SUDEP cases occurred during the observation period, equalling an incidence rate of about 20 per 1000 patient years. CONCLUSIONS: Our results are similar to other pivotal trials with respect to the long-term, open-label extensions and recent postmarketing studies. Despite the limitations of the retrospective design, our observational study suggests that RTG leads to good seizure control in a small number of patients with treatment-refractory seizures. However, because of the rather high percentage of patients who experienced significant adverse events, we consider RTG as a drug of reserve.

Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial.

BACKGROUND: First-line treatment of isolated resectable colorectal peritoneal metastases remains unclear. This study (the Swedish peritoneal study) compares cytoreductive surgery and intraperitoneal chemotherapy (surgery arm) with systemic chemotherapy (chemotherapy arm). METHODS: Patients deemed resectable preoperatively were randomised to surgery and intraperitoneal 5-fluorouracil 550 mg/m(2)/d for 6 d with repeated courses every month or to systemic oxaliplatin and 5-fluorouracil regimen every second week. Both treatments continued for 6 months. Primary end-point was overall survival (OS) and secondary end-points were progression-free survival (PFS), and morbidity. RESULTS: The study terminated prematurely when 48 eligible patients (24/arm) were included due to recruitment difficulties. Two-year OS was 54% in the surgery arm and 38% in the chemotherapy arm (p = 0.04). After 5 years, 8 versus 1 patient were alive, respectively (p = 0.02). Median OS was 25 months versus 18 months, respectively, hazard ratio 0.51 (95% confidence interval: 0.27-0.96, p = 0.04). PFS in the surgery arm was 12 months versus 11 months in the chemotherapy arm (p = 0.16) with 17% versus 0% 5-year PFS. Grade III-IV morbidity was seen in 42% and 50% of the patients, respectively. No mortalities. CONCLUSIONS: Cytoreductive surgery with intraperitoneal chemotherapy may be superior to systemic oxaliplatin-based treatment of colorectal cancer with resectable isolated peritoneal metastases.(ClinicalTrials.gov nr:NCT01524094).

Long-term outcome after surgery for Crohn's anal fistula.

AIM: Treatment of Crohn's anal fistula remains challenging and little is known about factors associated with healing. The aim of this study was to assess the rate of healing after surgical treatment and analyse clinical variables related to healing. METHOD: A total of 119 patients [63 women, mean age 36 (±13.7) years] with histopathologically verified Crohn's disease underwent a surgical procedure for anal fistula at four main referral centres in Sweden, January 1998 to December 2009. Baseline and treatment-related variables were recorded and analysed for correlation with fistula healing at a final follow-up after a mean of 7.2 (median 7.1, 1.0-17.5) years. RESULTS: Of the 119 patients 62 (52%) were healed at final follow-up. Fourteen healed after one procedure and the remaining 48 healed after a further median of 4.0 (2-20) procedures. Ten (8%) patients were subjected to a proctectomy. Final healing was more common in patients operated with a procedure aiming at eradicating the fistula (P = 0.0001), without proctitis (P = 0.02) and a shorter duration of Crohn's disease (P = 0.0019). CONCLUSION: Long-term healing of a Crohn's anal fistula can be expected in about half of the patients, usually after repeated surgical treatment. The probability for cure was higher when a curative operation was performed in a patient without proctitis and with a shorter duration of Crohn's disease. An attempt to close a Crohn's anal fistula is thus often worthwhile.

Results after sacral nerve stimulation for chronic constipation.

BACKGROUND: Sacral nerve stimulation is an established treatment for fecal incontinence and initial reports describe successful results also in subjects with chronic constipation. METHODS: Consecutive patients with slow transit or outlet obstruction type constipation were offered external stimulation through a test electrode inserted in a sacral foramen during a 3-week period. The symptomatic evaluation was based on the number of bowel movements and a validated obstructed defecation score (ODS). A permanent implant was performed provided an overall 50% decrease in symptoms was observed. KEY RESULTS: In total, 44 patients with chronic constipation were treated with a 3-week test stimulation. Fifteen experienced a 50% reduction of symptoms and received a permanent implant. Four of the 15 with permanent implants were explanted during the course of the study. Five subjects (11% of original group) reported sustained symptom relief at final follow-up after a mean of 24 months (range 4-81). Mean ODS score did not change during the treatment. Patients with predominantly slow transit constipation or outlet obstruction did not differ concerning success rate. CONCLUSIONS & INFERENCES: Sacral nerve stimulation has limited efficacy in unselected patients with chronic constipation and cannot be recommended for treatment on routine basis.