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.

[Mediation in public healthcare: opportunities for improvement]. / Mediación en el sistema público de salud: oportunidades para mejorar.

BACKGROUND: Mediation in healthcare is a non-adversarial process to resolve a dispute risen between patients and health providers during medical attention Aim: To characterize the mediation process taking place in the public health system in Chile, from its start until 2017. MATERIAL AND METHODS: Cross-sectional descriptive study. Under the Transparency Law, information about mediation processes between 2005 and 2017 was requested to the State Defense Council (CDE in its Spanish acronym). This data was complemented with the information available on the website of this agency. RESULTS: Ninety four percent of the complaints filed at the CDE were deemed eligible for mediation. Only 19% of the concluded cases led to an agreement between the disputing parties. The agreements reached were mostly monetary compensation, medical assistance, and apologies/explanation of the facts. The average amount of compensation reached $14,862,088 (Chilean pesos). The most commonly claimed damage resulting from medical care was partial disability. The medical specialties more often claimed were Obstetrics and Gynecology, General Surgery, and Internal Medicine. CONCLUSIONS: The analysis of conducted mediations is a source of feedback for healthcare staff and health institutions. It would greatly contribute to prevent possible damage and medical conflicts, specially within the specialties with the most complaints. Improvements to the existing legislation are required to ensure free access for all the population.

5G-assisted telementored surgery.

Safe and effective implementation of remote surgery and telementoring can have significant limitations. Fifth-generation (5G) wireless networks could be useful in overcoming these drawbacks. As a proof of concept, the authors present technical and clinical details of two procedures assisted by telementoring using 5G that were also broadcast live. Secure remote access advice.

Combined transanal total mesorectal excision (taTME) with laparoscopic instruments and abdominal robotic surgery in rectal cancer.

Laparoscopic surgery for rectal cancer can be technically challenging. We describe a hybrid technique combining abdominal robotic dissection and transanal total mesorectal excision. This procedure was performed in a 50-year-old man with rectal adenocarcinoma at 5 cm from the dentate lane. Preoperative staging was T2N0M0. Surgery went well without complications, and estimated blood loss was less than 50 mL. Robotic surgical time was 90 min, and total operative time was 160 min. The patient was discharged on postoperative day 3. Pathology analysis revealed an intact mesorectum (TME grade 3) and a T2N0 tumor with negative margins. Hybrid surgery with pelvic robotic dissection and transanal total mesorectal excision was feasible, quick and safe in this patient and may be a method that can be developed further.

Transanal Hartmann reversal: a new technique.

BACKGROUND: Hartmann procedure consists in a sigmoidectomy followed by a terminal colostomy. However, the stoma is associated with complications and suboptimal quality of life, so the restoration of colonic continuity should be, at least, considered in any case. Open restoration has been associated with significant morbidity and mortality; therefore, many authors have described the advantages of laparoscopic Hartmann reversal. We want to go a step further showing our experience using a combined laparoscopic and transanal approach in an attempt to improve the surgical technique. METHODS: Patients with an end colostomy due to an emergency Hartmann procedure are selected for this intervention. This approach is performed simultaneously laparoscopically and transanally, with single-port devices, through the colostomy wound in the first case and trough anal canal in the second one. The previous stapler line is resected transanally and the proximal rectum and mesorectum are dissected until the peritoneal reflexion, where both teams work together to complete the adhesiolysis. Finally an end-to-end anastomosis is performed under laparoscopic control. RESULTS: As in patients with rectal cancer, dissection of the stump in Hartmann reversal procedure may be better and associated with shorter operative time. CONCLUSIONS: As with any new surgical procedure, it is probably too early to draw conclusions, but nowadays transanal combined with laparoscopic approach seems to be a safe and feasible technique to perform a Hartmann reversal.

Unraveling the clinicopathological and molecular changes induced by neoadjuvant chemotherapy and endocrine therapy in hormone receptor-positive/HER2-low and HER2-0 breast cancer.

BACKGROUND: The characterization and comparison of gene expression and intrinsic subtype (IS) changes induced by neoadjuvant chemotherapy (NACT) and endocrine therapy in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-low versus HR+/HER2-0 breast cancer (BC) has not been conducted so far. Most evidence on the association of HER2 status with pathologic responses and prognosis in HR+/HER2-negative BC is controversial and restricted to NACT-treated disease. Similarly, a temporal heterogeneity in HER2 status has been described only with NACT. METHODS: We retrospectively recruited a consecutive cohort of 186 patients with stage I-IIIB HR+/HER2-negative BC treated with neoadjuvant therapy (NAT). Available diagnostic biopsies and surgical samples were characterized for main pathological features, PAM50 IS and ROR-P score, and gene expression. Associations with pathologic complete response, residual cancer burden-0/I, event-free survival (EFS) and overall survival (OS) based on HER2 status were assessed. Pre/post pathologic/molecular changes were analyzed in matched samples. RESULTS: The HER2-low (62.9%) and HER2-0 (37.1%) cohorts did not differ significantly in main baseline features, treatments administered, breast-conserving surgery, pathologic complete response and residual cancer burden-0/I rates, EFS, and OS. NAT induced, regardless of HER2 status, a significant reduction of estrogen receptor/progesterone receptor and Ki67 levels, a down-regulation of PAM50 proliferation- and luminal-related genes/signatures, an up-regulation of selected immune genes, and a shift towards less aggressive IS and lower ROR-P. Moreover, 25% of HER2-0 changed to HER2-low and 34% HER2-low became HER2-0. HER2 shifts were significant after NACT (P < 0.001), not neoadjuvant endocrine therapy (P = 0.063), with consistent ERBB2 mRNA level dynamics. HER2 changes were not associated with EFS/OS. CONCLUSIONS: HER2-low and HER2-0 status change after NAT in ∼30% of cases, mostly after NACT. Targeted adjuvant strategies should be investigated accordingly. Molecular downstaging with current chemo/endocrine agents and immunotherapy should not rely on HER2 immunohistochemical levels in HR+/HER2-negative BC. Instead, HER2-low-targeted approaches should be explored to pursue more effective and/or less toxic dimensional downstaging.

Total ammoniacal nitrogen biofiltration of wastewaters from aquaculture systems using Macrocystis spp.

The results of total ammoniacal nitrogen (NH(3) + NH(4) (+)) removal in aquaculture systems using two experimental sets, aquatic seedlings produced in laboratory controlled conditions and wild seaweed (Macrocystis spp.) in reproductive state, are shown in this work. Biofiltration assays were carried out using a load of total ammoniacal nitrogen (TAN) of 1 mg/L. Absorption rates were measured taking into account a previous surface characterization, which gave values of 44 ± 14 cm(2)/g and 18 ± 6 cm(2)/g for aquatic seedlings and wild algae, respectively. The following parameters were measured during the experimental runs: temperature, pH, O(2), illuminance or light intensity, salinity and total solids. TAN removals of 61% and 70% were achieved for the seedlings and Macrocystis spp., respectively, after 17 h of treatment. The TAN absorption results were expressed as a function of surface and mass achieving the following values: 3.0 nmol N cm(-2) h(-1) and 111 nmol N g(-1) h(-1) for the seedlings, and 6.9 nmol N cm(-2) h(-1) and 122.4 nmol N g(-1) h(-1) for the macroalgae. In the light of these biofiltration processes, the initial TAN concentration decreased by 90% for the seedlings and wild algae over approximately 110 and 41 h, respectively. In addition, TAN removals achieved with Macrocystis spp. were always higher than those obtained with aquatic seedlings for the same operating periods.

Antibiotic therapy in dogs and cats in general practice in the United Kingdom before referral.

OBJECTIVES: To describe antibiotic prescription by veterinarians in general practices in the United Kingdom before referral and analyse if UK antibiotic stewardship guidelines were followed. MATERIALS AND METHODS: The clinical records from dogs and cats referred to the Internal Medicine and Oncology departments of two referral hospitals were retrospectively reviewed. RESULTS: There were 917 cases included, of which 486 (53.0%) had been prescribed antibiotics for the presentation they were subsequently referred for. Bacterial culture or cytology to guide antibiotic prescription had been performed in 43 of 486 (8.8%) and nine of 486 cases (1.8%) respectively. In four cases, both cytology and culture were performed. For those animals who had received antibiotics, 344 of 486 (70.8%) prescriptions did not comply with UK antibiotic stewardship guidelines. Following investigations at a referral centre, a bacterial aetiology was found or suspected in 17.9% of the cases that received antibiotics. CLINICAL SIGNIFICANCE: Use of diagnostics, including culture and cytology, to prove or determine the likelihood of a bacterial aetiology was infrequently performed before referral and may have contributed to overprescription of antibiotics. Encouraging veterinarians to undertake appropriate diagnostics, in combination with education around compliance with antibiotic stewardship guidelines, might reduce antibiotic prescription.

Prognostic value of intrinsic subtypes in hormone-receptor-positive metastatic breast cancer: systematic review and meta-analysis.

BACKGROUND: In hormone receptor-positive (HoR+) breast cancer (BC), gene expression analysis identifies luminal A (LumA), luminal B (LumB), human epidermal growth factor receptor 2 (HER2)-enriched (HER2-E), basal-like (BL) intrinsic subtypes and a normal-like group. This classification has an established prognostic value in early-stage HoR+ BC. Here, we carried out a trial-level meta-analysis to determine the prognostic ability of subtypes in metastatic BC (MBC). MATERIALS AND METHODS: We systematically reviewed all the available prospective phase II/III trials in HoR+ MBC where subtype was assessed. The primary endpoint was progression-free survival (PFS)/time to progression (TTP) of the LumA subtype compared to non-LumA. Secondary endpoints were PFS/TTP of each individual subtype, according to treatment, menopausal and HER2 status and overall survival (OS). The random-effect model was applied, and heterogeneity assessed through Cochran's Q and I2. Threshold for significance was set at P < 0.05. The study was registered in PROSPERO (ID: CRD42021255769). RESULTS: Seven studies were included (2536 patients). Non-LumA represented 55.2% and was associated with worse PFS/TTP than LumA [hazard ratio (HR) 1.77, P < 0.001, I2 = 61%], independently of clinical HER2 status [Psubgroup difference (Psub) = 0.16], systemic treatment (Psub = 0.96) and menopausal status (Psub = 0.12). Non-LumA tumors also showed worse OS (HR 2.00, P < 0.001, I2 = 65%), with significantly different outcomes for LumB (PFS/TTP HR 1.46; OS HR 1.41), HER2-E (PFS/TTP HR 2.39; OS HR 2.08) and BL (PFS/TTP HR 2.67; OS HR 3.26), separately (PFS/TTP Psub = 0.01; OS Psub = 0.005). Sensitivity analyses supported the main result. No publication bias was observed. CONCLUSIONS: In HoR+ MBC, non-LumA disease is associated with poorer PFS/TTP and OS than LumA, independently of HER2, treatment and menopausal status. Future trials in HoR+ MBC should consider this clinically relevant biological classification.

Targeted colonic release formulations of mesalazine - A clinical pharmaco-scintigraphic proof-of-concept study in healthy subjects and patients with mildly active ulcerative colitis.

Colonic targeting of orally applied therapeutic drugs remains a challenge. Tablet coatings relying on gastrointestinal pH and colonic bacterial enzymes as triggers in association with an inner alkaline layer are expected to improve targeting efficiency. Mesalazine release from three differently coated tablets labelled with 1 MBq 153Sm was characterised in a single centre, open-label, parallel group study in nineteen healthy subjects and seven patients with mildly active ulcerative colitis. Two semi-organic and one aqueous-based outer coating with different ratios of enteric polymer and resistant starch were tested. All coatings showed comparable release lagtimes in biorelevant dissolution media and were not affected by neutron-activation of the samarium tracer. Mesalazine pharmacokinetics and gamma scintigraphy were used to characterise drug release, anatomical site of tablet disintegration and gastrointestinal transit. Initial tablet disintegration occurred at the ileo-caecal junction or beyond in 92 % of the subjects. Time to initial tablet disintegration was inversely correlated with maximal plasma concentrations and systemic mesalazine exposure. Although high inter-subject variability precluded detection of differences between solvent types and different enteric polymer to polysaccharide ratios, the dual pH and enzymatic triggered release system in combination with an inner alkaline layer promoted mesalazine release at the target site with high accuracy.

Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2.

The nfkb1 and nfkb2 genes encode closely related products regulating immune and inflammatory responses. Their role during development and differentiation remains unclear. The generation of nfkb1 null mice (p50-/-) resulted in altered immune responses, but had no effect on development. Similarly, nfkb2 knockout mice (p52-/-) did not show developmental defects (J.C. et al., manuscript submitted). We have investigated the potential for in vivo compensatory functions of these genes by generating double-knockout mice. The surprising result was that the animals developed osteopetrosis because of a defect in osteoclast differentiation, suggesting redundant functions of NF-kappaB1 and NF-kappaB2 proteins in the development of this cell lineage. The osteopetrotic phenotype was rescued by bone marrow transplantation, indicating that the hematopoietic component was impaired. These results define a new mouse osteopetrotic mutant and implicate NF-kappaB proteins in bone development, raising new directions in the treatment of bone disorders.

Tryptophan-enriched diet or 5-hydroxytryptophan supplementation given in a randomized controlled trial impacts social cognition on a neural and behavioral level.

Understanding of emotions and intentions are key processes in social cognition at which serotonin is an important neuromodulator. Its precursor is the essential amino acid tryptophan (TRP). Reduced TRP availability leads to weaker impulse control ability and higher aggression, while TRP supplementation promotes confidence. In a double-blind placebo-controlled fMRI study with 77 healthy adults, we investigated the influence of a 4 week TRP enriched diet and an acute 5-hydroxytryptophan (5-HTP) intake on two social-cognitive tasks, a moral evaluation and an emotion recognition task. With 5-HTP, immoral behavior without negative consequences was rated as more reprehensible. Additionally, during story reading, activation in insula and supramarginal gyrus was increased after TRP intake. No significant effects of TRP on emotion recognition were identified for the whole sample. Importantly, emotion recognition ability decreased with age which was for positive emotions compensated by TRP. Since the supramarginal gyrus is associated with empathy, pain and related information integration results could be interpreted as reflecting stricter evaluation of negative behavior due to better integration of information. Improved recognition of positive emotions with TRP in older participants supports the use of a TRP-rich diet to compensate for age related decline in social-cognitive processes.

IkappaBalpha overexpression delays tumor formation in v-rel transgenic mice.

We have previously shown that transgenic mice expressing the oncoprotein v-Rel under the control of a T cell-specific promoter develop T cell lymphomas. Tumor formation was correlated with the presence of p50/v-Rel and v-Rel/v-Rel nuclear kappaB-binding activity. Since experimental evidence has led to the suggestion of a potential tumor suppressor activity for IkappaBalpha, we have studied the role of IkappaBalpha in the transforming activity of v-Rel by overexpressing IkappaBalpha in v-rel transgenic mice. Overexpression of IkappaBalpha in v-rel transgenic mice resulted in an extended survival, and the development of cutaneous T cell lymphomas of CD8(+)CD4(-) phenotype. These phenotypic alterations were associated with a dramatic reduction of p50/v-Rel, but not v-Rel/v-Rel nuclear DNA binding activity and an increased expression of the intercellular adhesion molecule 1. Our results indicate that v-Rel homodimers are active in transformation and that the capacity of v-Rel-containing complexes to escape the inhibitory effect of IkappaBalpha may be a key element in its transforming capability.

Defects in macrophage recruitment and host defense in mice lacking the CCR2 chemokine receptor.

Chemokines are a structurally related family of cytokines that are important for leukocyte trafficking. The C-C chemokine monocyte chemoattractant protein-1 (MCP-1) is a potent monocyte activator in vitro and has been associated with monocytic infiltration in several inflammatory diseases. One C-C chemokine receptor, CCR2, has been identified that mediates in vitro responses to MCP-1 and its close structural homologues. CCR2 has also recently been demonstrated to be a fusion cofactor for several HIV isolates. To investigate the normal physiological function of CCR2, we generated mice with a targeted disruption of the ccr2 gene. Mice deficient for CCR2 developed normally and had no hematopoietic abnormalities. However, ccr2(-/-) mice failed to recruit macrophages in an experimental peritoneal inflammation model. In addition, these mice were unable to clear infection by the intracellular bacteria, Listeria monocytogenes. These results suggest that CCR2 has a nonredundant role as a major mediator of macrophage recruitment and host defense against bacterial pathogens and that MCP-1 and other CCR2 ligands are effectors of those functions.

Gastric hyperplasia and increased proliferative responses of lymphocytes in mice lacking the COOH-terminal ankyrin domain of NF-kappaB2.

The nfkb2 gene encodes the p100 precursor which produces the p52 protein after proteolytic cleavage of its COOH-terminal domain. Although the p52 product can act as an alternative subunit of NF-kappaB, the p100 precursor is believed to function as an inhibitor of Rel/NF-kappaB activity by cytoplasmic retention of Rel/NF-kappaB complexes, like other members of the IkappaB family. However, the physiological relevance of the p100 precursor as an IkappaB molecule has not been understood. To assess the role of the precursor in vivo, we generated, by gene targeting, mice lacking p100 but still containing a functional p52 protein. Mice with a homozygous deletion of the COOH-terminal ankyrin repeats of NF-kappaB2 (p100(-/-)) had marked gastric hyperplasia, resulting in early postnatal death. p100(-/-) animals also presented histopathological alterations of hematopoietic tissues, enlarged lymph nodes, increased lymphocyte proliferation in response to several stimuli, and enhanced cytokine production in activated T cells. Dramatic induction of nuclear kappaB-binding activity composed of p52-containing complexes was found in all tissues examined and also in stimulated lymphocytes. Thus, the p100 precursor is essential for the proper regulation of p52-containing Rel/NF-kappaB complexes in various cell types and its absence cannot be efficiently compensated for by other IkappaB proteins.