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Bacterial infection of hernia mesh with the formation of biofilms presents a barrier to antibiotic treatment with subsequent surgical intervention and hospitalization. Hence, in the current study, we examined the effect of BromAc, a mucolytic agent, on the dissolution of biofilm formed by three different strains of Pseudomonas aeruginosa. Pseudomonas aeruginosa was carefully grown on hernia mesh and treated with various concentrations of bromelain, NAC, and their combinations at 37 °C over 4 h in vitro. Then, the biofilm dissolution activities of the agents were evaluated. Moreover, the combination index (CI) was analyzed to determine the synergy of the bromelain and NAC combination. The results indicated that biofilms were more susceptible to degradation by bromelain, whilst NAC showed growth enhancement in two of the strains. However, in combination (BromAc), the three strains were dramatically affected by the agents, with more than 80% debridement fir a suitable combination of bromelain and NAC that was also strain-specific. Hence, the current study shows that the biofilms formed by these three strains of Pseudomonas aeruginosa were adversely affected by a single treatment of BromAc, with more than 80% debridement, indicating that subsequent treatment may abolish the biofilm completely.

Background: There is a paucity of studies evaluating perioperative systemic chemotherapy in conjunction with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colorectal cancer peritoneal metastases (CRCPM). The aim was to evaluate neoadjuvant and/or adjuvant systemic therapy in CRCPM. Methods: Patients with CRCPM from 39 treatment centres globally from January 1, 1991, to December 31, 2018, who underwent CRS+HIPEC were identified and stratified according to neoadjuvant/adjuvant use. Crude data analysis, propensity score matching (PSM) and Cox-proportional hazard modelling was performed. Findings: Of 2093 patients, 1613 were included in neoadjuvant crude evaluation with 708 in the PSM cohort (354 patients/arm). In the adjuvant evaluation, 1176 patients were included in the crude cohort with 778 in the PSM cohort (389 patients/arm). The median overall survival (OS) in the PSM cohort receiving no neoadjuvant vs neoadjuvant therapy was 37.0 months (95% CI: 32.6-42.7) vs 34.7 months (95% CI: 31.2-38.8, HR 1.08 95% CI: 0.88-1.32, p = 0.46). The median OS in the PSM cohort receiving no adjuvant therapy vs adjuvant therapy was 37.0 months (95% CI: 32.9-41.8) vs 45.7 months (95% CI: 38.8-56.2, HR 0.79 95% CI: 0.64-0.97, p = 0.022). Recurrence-free survival did not differ in the neoadjuvant evaluation but differed in the adjuvant evaluation - HR 1.04 (95% CI: 0.87-1.25, p = 0.66) and 0.83 (95% CI: 0.70-0.98, p = 0.03), respectively. Multivariable Cox-proportional hazard modelling in the crude cohorts showed hazard ratio 1.08 (95% CI: 0.92-1.26, p = 0.37) for administering neoadjuvant therapy and 0.86 (95% CI: 0.72-1.03, p = 0.095) for administering adjuvant therapy. Interpretation: Neoadjuvant therapy did not confer a benefit to patients undergoing CRS+HIPEC for CRCPM, whereas adjuvant therapy was associated with a benefit in this retrospective setting.

Rituximab is widely used to treat autoimmunity but clinical response varies. Efficacy is determined by the efficiency of B-cell depletion, which may depend on various Fc gamma receptor (FcγR)-dependent mechanisms. Study of FcγR is challenging due to the complexity of the FCGR genetic locus. We sought to assess the effect of FCGR variants on clinical response, B-cell depletion and NK-cell-mediated killing in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).A longitudinal cohort study was conducted in 835 patients [RA = 573; SLE = 262]. Clinical outcome measures were two-component disease activity score in 28-joints (2C-DAS28CRP) for RA and British Isles Lupus Assessment Group (BILAG)-2004 major clinical response (MCR) for SLE at 6 months. B-cells were evaluated by highly-sensitive flow cytometry. Single nucleotide polymorphism and copy number variation for genes encoding five FcγRs were measured using multiplex ligation-dependent probe amplification. Ex vivo studies assessed NK-cell antibody-dependent cellular cytotoxicity (ADCC) and FcγR expression.In RA, carriage of FCGR3A-158V and increased FCGR3A-158V copies were associated with greater 2C-DAS28CRP response (adjusted for baseline 2C-DAS28CRP). In SLE, MCR was associated with increased FCGR3A-158V, OR 1.64 (95% CI 1.12-2.41) and FCGR2C-ORF OR 1.93 (95% CI 1.09-3.40) copies. 236/413 (57%) patients with B-cell data achieved complete depletion. Homozygosity for FCGR3A-158V and increased FCGR3A-158V copies were associated with complete depletion in combined analyses. FCGR3A genotype was associated with rituximab-induced ADCC, and increased NK-cell FcγRIIIa expression was associated with improved clinical response and depletion in vivo. Furthermore, disease status and concomitant therapies impacted both NK-cell FcγRIIIa expression and ADCC.FcγRIIIa is the major low affinity FcγR associated with rituximab response. Increased copies of the FCGR3A-158V allele (higher affinity for IgG1), influences clinical and biological responses to rituximab in autoimmunity. Enhancing FcγR-effector functions could improve the next generation of CD20-depleting therapies and genotyping may stratify patients for optimal treatment protocols.Medical Research Council, National Institute for Health and Care Research, Versus Arthritis.

As the subsea well intervention sector ascends from a double-dip downturn, operators are motivated to execute projects with increased agility. By adopting new rationale and supported by strategic partnerships, an enhanced focus on operating efficiency is targeted. This paper discusses how operators can – deliver predictable operational expenditure (opex) results, safeguarding life-of-field economics through routine interventions and robust risk mitigation – align objectives with service providers through technology, strategy, and process – realize value of integrated alliances in the subsea intervention sector. Reliability is the cornerstone on which operational integrity is established. Repeatability is the foundation on which partnerships are formed, forging a synchronized philosophy; pledging operational efficiency as commanded in a dynamic environment; bringing to market a holistic, multileveled, multiskilled solution to subsea interventions; and uniting product and operational experts to evaluate the range of scope requirements selecting fit-for-purpose solutions, delivered with synchronized processes. Here we describe how this approach, coupled with repeatable field-proven product and service reliability and driven by true customer-centric thinking, minimizes operating risk to deliver predictable outcomes. This ethos is demonstrated in action via three case studies that discuss the benefits of combining customer expertise with product and operational specialists during the initiation and planning phases of subsea well intervention projects. The shared examples demonstrate how inculcating a continuous improvement mindset and applying lessons learned to product design, process, and procedures can drive operating efficiency to new levels. Campaigns executed in 2020 by the supplier delivered best-in-class results, exceeding customer expectations. The campaign represented the first fully synchronized service operation on the Q5000 intervention vessel at 90% operating efficiency. In addition, they demonstrated outstanding versatility by outperforming budget on the first deployment of the 15,000 psi intervention riser system (IRS) from the Q4000 intervention vessel. Less than 1% operating nonproductive time (NPT) was attributed to the well access package for the campaign. Sustaining this level of success via collaborative performance management is the next step on the roadmap to ensure this becomes the new normal. Conclusions drawn from customer feedback indicated expectations were surpassed, and that synchronicity is the key that unlocks the door to sustainability in the subsea deepwater intervention sector.

ALDH2 is a key enzyme in alcohol metabolism that protects cells from acetaldehyde toxicity. Using iHS and FST statistics, we identified regulatory acting variants affecting ALDH2 gene expression under positive selection in populations of European ancestry. Several SNPs (rs3184504, rs4766578, rs10774625, rs597808, rs653178, rs847892, rs2013002) that function as eQTLs for ALDH2 in various tissues showed evidence of positive selection. Very large pairwise FST values indicated high genetic differentiation at these loci between populations of European ancestry and populations of other global ancestries. Estimating the timing of positive selection on the beneficial alleles suggests that these variants were recently adapted approximately 3000 to 3700 years ago. The derived beneficial alleles are in complete linkage disequilibrium with the derived ALDH2 promoter variant rs886205, which is associated with higher transcriptional activity. The SNPs rs4766578 and rs847892 are located in binding sequences for the transcription factor HNF4A, which is an important regulatory element of ALDH2 gene expression. In contrast to the missense variant ALDH2 rs671 (ALDH2*2), which is common only in East Asian populations and is associated with greatly reduced enzyme activity and alcohol intolerance, the beneficial alleles of the regulatory variants identified in this study are associated with increased expression of ALDH2. This suggests adaptation of Europeans to higher alcohol consumption.

INTRODUCTION AND OBJECTIVE:Pathogenic/likely pathogenic (P/LP) germline genetic variants occur in ∼10-15% of all prostate cancer (PCa) patients. However, complicated and restrictive testing guideli...

Gemcitabine (GEM) is commonly chosen for treating pancreatic cancer. However, its use is limited by toxicity. Earlier in vitro studies with GEM in combination with Bromelain (Brom) and Acetylcysteine (Ac) indicated a substantial reduction in IC(50). In this study, immunocytochemistry and Western blot were used to explore the mechanistic effects of Brom and Ac (BromAc(®)) in vitro. Then, we explored the efficacy and safety of BromAc(®) only and with GEM in a pancreatic cancer model in vivo. Immunocytochemistry results revealed a reduction in both MUC1 and MUC4 post-treatment. There was a decrease in VEGF, MMP-9, NF-κβ and cleavage of PARP. There was also a decrease in the cell cycle regulators Cyclin B and D as well as TGF-β and the anti-apoptotic Bcl-2. In vivo, the low and high doses of BromAc(®) alone and with chemotherapy agents were safe. A very significant reduction in pancreatic tumour volume, weight, and ki67 were seen with BromAc(®) therapy and was equal to treatment with GEM alone and better than treatment with 5-FU. In addition, tumour density was significantly reduced by BromAc(®). In conclusion, the anticancer effect of BromAc(®) is probably related to its mucin depletion activity as well as its effect on proteins involved in cell cycle arrest, apoptosis and modulation of the tumour microenvironment. The in vivo results are encouraging and are considered the first evidence of the efficacy of BromAc(®) in pancreatic cancer. These results also provide some mechanistic leads of BromAc(®).

Surgical mesh infections from ventral hernia repairs are common in obese patients. Definitive management includes the surgical removal of mesh; however, obese patients are often poor surgical candidates with limited therapeutic options. We report the case of a 64-year-old male with an abdominal wall seroma secondary to an infected surgical mesh. This was on a background of multiple abdominal wall reconstructions for previous strangulated ventral hernias. A nonoperative novel approach utilizing bromelain percutaneously in conjunction with antibiotics successfully resolved the infected seroma. The purpose of this case is to detail the potential clinical application of bromelain in surgical site infections involving surgical prosthesis. We illustrate the successful use of bromelain as a nonoperative alternative for abdominal infections or when all other surgical and conservative therapies have been exhausted.

Early recurrence (ER) is defined as development of loco-regional peritoneal disease within 12-month of the initial CRS/PIC. Our aims were to identify overall survival (OS), recurrence-free survival (RFS) and independent prognostic factors associated with ER in PM of appendiceal neoplasm.A prospectively-maintained database for patients with appendiceal neoplasm undergoing cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) from year 1996-2018 was retrospectively analysed.208 female and 185 male patients were identified. With a median follow-up of 40-month, 40.2% of the patients developed ER. The median OS for ER was 24 months compared to late (LR) at 64 months. Median OS was not reached in non-recurrence (NR). 5-year survival for ER was less favourable compared to LR and NR (19.3%vs54.6%vs94%). No patients in ER group survived beyond 10-year. Independent negative predictors associated with ER on multivariate analysis were male patient (p = 0.013), blood transfusion of8 units (p = 0.013), elevated preoperative CEA levels (5 ng/ml; p = 0.002) and hard intraoperative tumour consistency (p 0.001). Protective factor was a combination of CC1, hard tumour consistency and use of EPIC (p = 0.039). Independent prognostic factors that predicted recurrence of appendiceal PM were PCI20 (p = 0.049), non-use of EPIC (p = 0.012), hard tumour consistency (p = 0.004) and use of previous chemotherapy (p = 0.023).ER following CRS and PIC of appendiceal PM is associated with reduced survival outcomes. Our data alludes to the importance of optimising the risk factors in order to delay loco-regional recurrence and improve long-term survival of these patients.

The purpose of this study was to examine the influence of participation in social media networks on theatrical movie attendance, with particular attention paid to the fear-of-missing-out (FoMO) and...

Objectives To assess the impact of short and long term outcomes of diaphragmatic interventions in cyto-reductive surgery (CRS) and intra-peritoneal chemotherapy (IPC). Methods 1230 consecutive CRS/IPC procedures were preformed between 1996 and 2018 in Sydney, Australia. Redo procedures and incomplete cyto-reductions were excluded. Among these, 599 underwent diaphragmatic intervention. Preoperative heterogeneity was assessed for in 6 parameters and addressed with propensity score matching. CRS/IPC requiring diaphragmatic interventions were compared to CRS/IPC without diaphragmatic involvement. Ten perioperative outcomes were measured. Overall survival was assessed based on diagnosis type. Results Intraoperative results revealed a significant increase in operative hours (7.85 vs. 7.28, p = 0.033). Transfusion requirements were insignificantly different. Postoperatively, increased grade III and IV complications (36% vs. 26%, p = 0.052) were noted. There was no difference with regards to intensive care stay, hospital length of stay, hospital death and return to theatre. In terms of respiratory specific complications, an increased incidence of pneumothorax (13% vs. 3%, p = 0.001) and pleural effusions (24% vs. 16%, p = 0.043) were noted, whilst the differences in pneumonia were insignificant. Overall survival revealed diaphragm interventions; did not affect survival outcomes in colorectal cancers (p = 0.750, RR = 1.077, CI 0.683–1.697) and increased relative risk in low-grade appendiceal mucinous neoplasms (p = 0.025, RR = 2.437, CI 1.121–5.298). Conclusion After our three-tiered research strategy, we conclude that despite the marginal increase in short term morbidity; diaphragmatic interventions do not decrease survival in colorectal cancers and diaphragmatic disease in LAMNs maybe an independent prognosticator of disease aggression.

Background: This study examines the impact of intraoperative macroscopic tumour consistency on short-term and long-term outcomes after cytoreductive surgery (CRS) with intraperitoneal chemotherapy (IPC) for appendiceal adenocarcinoma with peritoneal metastases. Methods: Macroscopic intraoperative tumour consistency was classified in three groups as soft (jelly-like geltatinous tumours), hard (hard tumour nodules without gelatinous features) and intermediate (both soft and hard features). In-hospital mortality, major morbidity, intensive care unit (ICU), high dependency unit (HDU) and total hospital stay, disease-free survival (DFS) and overall survival (OS) were compared. Results: The three groups had similar perioperative short-term outcomes. Patients with soft, intermediate and hard tumours revealed differences in OS (p

Purpose CRS/HIPEC has evolved as an effective method for management of selected patients with peritoneal metastatic disease. Abdominal wall resection (AWR) is often required, and may require complex reconstructions, such as component separation (CST) leading to wound dehiscence (WD) and wound complications (WC). The purpose of our study was to analyse factors contributing to wound complications and wound recurrence (WR). Methods Retrospective review of a prospective database of 1074 patients undergoing CRS/HIPEC procedures from 1996 to 2017 at St George Hospital. Results AWR and reconstruction for abdominal wall metastases was performed in 197 (18.3%) patients. Tumour types included mesothelioma, appendiceal, colorectal and ovarian cancers. Grade III WC were found in 21 (10.6%). WD was found in 14 (7.1%) compared to 30 (3.4%) in 877 patients without AWR (p = 0.028). Midline WR was seen in 26 (13.3%) with AWR and mean time to recurrence of 18 months. Multivariable’ regression analysis showed age (OR 1.06, 95%CI 1.01–1.11, p = 0.022) and CST (OR 9.63, 95%CI 2.55–36.23, p = 0.001) were independent predictors of Grade III WC, and CST (OR 4.19, 95%CI 1.27–13.86, p = 0.019) was an independent predictor of WD after AWR. The presence of a higher prior surgical score (PSS) 2–3 (OR 2.74, 95%CI 1.16–6.49, p = 0.022) was an independent predictor of midline WR post AWR. Conclusion This study demonstrates that patients undergoing AWR have a higher incidence of postoperative WD. CST was associated with an increased incidence of Grade III WC and WD. Patients with a higher PSS were more likely to develop midline wound recurrence.

BACKGROUND/AIM An update on the incidence, risk factors, clinical sequalae, and management of postoperative pancreatic fistula (POPF) following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). PATIENTS AND METHODS Retrospective analysis of prospectively collected data from the St George CRS/HIPEC database. RESULTS Sixty-five (5.7%) out of 1,141 patients developed a POPF. Patients with POPFs were older, had a higher peritoneal cancer index, longer operation time, and required more units of blood intraoperatively. Splenectomy and distal pancreatectomy were significant risk factors for developing POPFs. While there was no effect on overall long-term survival in POPF patients, they did suffer higher rates of Clavien-Dindo grade 3/4 complications, in-hospital deaths, and longer hospital length of stay. Of the 65 POPF patients, 23 were taken back to theatre, 48 required radiological drains and 7 underwent endoscopic retrograde cholangiopancreatography. CONCLUSION There are multiple risk factors for developing POPFs that are non-modifiable. While POPFs are associated with increased postoperative morbidity, long-term survival does not appear to be affected.

B cell depletion using rituximab is widely used to treat autoimmune diseases, but patient response varies. The efficacy of rituximab is limited by the efficiency of depletion. Strategies to improve response include altering rituximab dosing, switching anti-CD20-mAb, alternative B cell targets, or non-B cell targeted therapies. Implementing an appropriate strategy requires understanding of the mechanism(s) of resistance to depletion and, if this varies between individuals, a means to test for it. Rituximab kills B cells via a variety of Fcγ receptor (FcγR)-dependent mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), as well as non-FcγR mechanisms. We conducted a longitudinal cohort study in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) using two national registries. Qualitative and quantitative FCGR functional variants were measured using multiplexed ligation-dependent probe amplification, supplemented by novel FCGR2C assays.We provide consistent evidence that FCGR3A, specifically increased number of copies of the FCGR3A-158V allele, was the major FcγR gene associated with rituximab response, including clinical response in RA and SLE and depth of B cell depletion in the combined cohort. In SLE, we provide preliminary data suggesting increased FCGR2C ORF copies were also associated with improved clinical response. Furthermore, we demonstrated the impact of disease status and concomitant therapies on both natural killer cell FcγRIIIa expression and rituximab-induced ADCC; demonstrating increased FcγRIIIa expression and FCGR3A genotype were independently associated with clinical response and B cell depletion. Our findings highlight the importance of enhancing FcγR-effector functions, may help stratify patients, and support ongoing development of next-generation CD20 depleting therapeutics.One Sentence SummaryThe high affinity FcγRIIIa allotype on NK cells explains depth of B cell depletion and clinical response in rituximab therapy for autoimmune disease

Single-agent doxorubicin currently forms part of standard care for patients with sarcomas. However, efficacy is limited by the presence of dose-dependent cardiotoxicity and toxicity to renal, hepatic, and neurological systems. Therefore, there is a pressing need for novel drug regimens which can provide increased efficacy and safety. BromAc is a novel drug combination developed as a mucolytic agent which has demonstrated anticancer activity both in vitro and in vivo in several cancers. Here, we investigated the efficacy of BromAc in combination with doxorubicin for four subtypes of sarcoma. Cell proliferation, alongside western blot for a variety of cell cycle, apoptosis, and autophagy biomarkers assays was performed following treatment of cell lines in vitro at various concentrations of BromAc and doxorubicin. The impact of drug treatment on MUC1 and MUC4 levels was assessed through immune-cytological methods. Drug agent synergy was assessed through the Chou-Talalay framework. BromAc treatment in combination with doxorubicin was more efficacious than single-agent doxorubicin, with synergistic effects observed. The immuno-cytological analysis demonstrated significant mucin depletion following treatment with BromAc and doxorubicin used in combination, providing a potential mechanistic underpinning for the observed anticancer effects.

IntroductionDespite optimal patient selection and surgical effort, recurrence is seen in over 70% of patients undergoing cytoreductive surgery (CRS) for peritoneal metastases (PM). Apart from the Peritoneal Cancer Index (PCI), completeness of cytoreduction and tumour grade, there are other factors like disease distribution in the peritoneal cavity, pathological response to systemic chemotherapy (SC), lymph node metastases and morphology of PM which may have prognostic value. One reason for the underutilisation of these factors is that they are known only after surgery. Identifying clinical predictors, specifically radiological predictors, could lead to better utilisation of these factors in clinical decision making and the extent of peritoneal resection performed for different tumours. This study aims to study these factors, their impact on survival and identify clinical and radiological predictors.Methods and analysisThere is no therapeutic intervention in the study. All patients with biopsy-proven PM from colorectal, appendiceal, gastric and ovarian cancer and peritoneal mesothelioma undergoing CRS will be included. The demographic, clinical, radiological, surgical and pathological details will be collected according to a prespecified format that includes details regarding distribution of disease, morphology of PM, regional node involvement and pathological response to SC. In addition to the absolute value of PCI, the structures bearing the largest tumour nodules and a description of the morphology in each region will be recorded. A correlation between the surgical, radiological and pathological findings will be performed and the impact of these potential prognostic factors on progression-free and overall survival determined. The practices pertaining to radiological and pathological reporting at different centres will be studied.Ethics and disseminationThe study protocol has been approved by the Zydus Hospital ethics committee (27 July, 2020) and Lyon-Sud ethics committee (A15-128).Trial registration numberCTRI/2020/09/027709; Pre-results.

Doxorubicin loaded DC beads (microspheres) has been used for treating un-resectable tumours by transarterial chemoembolization (TACE). We have shown that bromelain, an enzyme from the pineapple plant, enhances the cytotoxic effect of a number of chemotherapeutic drugs and in an earlier study we have demonstrated that it can be loaded into DC beads. Therefore, in the current study we have investigated how certain physical and chemical parameters affect its loading and release for future development of DC beads in cancer therapy. Aliquots of 40-60 µL of DC beads (100-300 µm) were treated to bromelain in distilled water and various parameters such as pH of solution, bromelain concentration, temperature, loading period, presence/absence of agitation and the cytotoxic effect of bromelain loaded beads were investigated. Further release kinetics was also studied with additional investigation of pH effect on the proteolytic activity of bromelain. Results indicate that higher loading of bromelin was achieved in the beads at lower pH, higher concentration of bromelain, with agitation, 24 hours loading and ambient room temperature. Proteolytic activity of bromelain was maximal at pH 4.5 whilst cytotoxicity was at par if not better in the bromelain loaded DC beads. Release kinetics indicated that bromelain can be delivered over several hours. Hence, we conclude that bromelain can be loaded more efficiently with manipulation of certain parameters with noticeable cytotoxicity in tumour cells.

ObjectiveGemcitabine (GEM) is commonly chosen for treating pancreatic cancer. However, its use is limited by toxicity. Earlier in vitro studies with GEM in combination with Bromelain (Brom) and Acetylcysteine (Ac) indicated a substantial reduction in IC50. Here, we investigated the efficacy and safety of Brom and Ac (BromAc) in the pancreatic cancer model in vivo.DesignBoth low dose and high dose studies for safety and efficacy of BromAc and GEM were conducted in nude mice. Body weight, wellbeing and tumor volume were monitored. At autopsy, tumor weight, tumor density, percentage of tumor necrosis, expression of Ki67 antigen, and immunohistological evaluation of vital organs were compared between the treatment groups.ResultsThe low and high doses of BromAc alone and with chemotherapy agents were safe. A very significant reduction in pancreatic tumor volume, weight, and ki67 were seen with BromAc therapy and was equal to treatment with GEM alone and better than treatment with 5-FU. In addition, tumor density was significantly reduced by BromAc.ConclusionThese encouraging results are the first in vivo evidence of the efficacy of BromAc in pancreatic cancer and provide some mechanistic leads.

IntroductionDespite optimal patient selection and surgical effort, recurrence is seen in over 70% of patients undergoing cytoreductive surgery(CRS) for peritoneal metastases (PM). Apart from the peritoneal cancer index(PCI), completeness of cytoreduction and tumor grade, there are other factors like disease distribution in the peritoneal cavity, pathological response to systemic chemotherapy(SC), lymph node metastases and morphology of PM which may have prognostic value. One reason for the underutilization of these factors is that they are known only after surgery. Identifying clinical predictors, specifically radiological predictors, could lead to better utilization of these factors in clinical decision making and the extent of peritoneal resection performed for different tumors. This study aims to study these factors, their impact on survival and identify clinical and radiological predictors. Methods and analysisThere is no therapeutic intervention in the study. All patients with biopsy proven PM from colorectal, appendiceal, gastric and ovarian cancer and peritoneal mesothelioma undergoing CRS will be included. The demographic, clinical, radiological, surgical and pathological details will be collected according to a pre-specified format that includes details regarding distribution of disease, morphology of PM, regional node involvement and pathological response to SC. In addition to the absolute value of PCI, the structures bearing the largest tumor nodules and a description of the morphology in each region will be recorded. A correlation between the surgical, radiological and pathological findings will be performed and the impact of these potential prognostic factors on progression-free and overall survival determined. The practices pertaining to radiological and pathological reporting at different centers will be studied. Ethics and disseminationThe study protocol has been approved by the Zydus Hospital ethics committee (27th July, 2020) and Lyon-sud ethics committee (A15-128). It is registered with the clinical trials registry of India (CTRI/2020/09/027709).The results will be published in peer-reviewed scientific journals.Strength and limitationsA prospective correlation between the radiological, surgical and pathological findings in patients undergoing CRS will be performed which has not been done before.Being prospective in nature it will also enable us to evaluate the impact of the current treatment practices on the clinical end-pointsThere is fixed protocol for radiological and pathological evaluation for which there are no specific guidelinesThe data collection format will capture all the relevant data but this may affect compliance.Despite the large sample size planned for each primary site, the heterogeneity of treatment protocols may be a limiting factor while evaluating the impact on survival.

Background: Systemic lupus erythematosus (SLE) shows marked population-specific disparities in disease prevalence, including substantial variation in manifestations and complications according to genetic ancestry. Several recent studies suggest that a substantial proportion of variation of gene expression shows genetic ancestry-associated differences in gene regulation on immune responses. Positive selection may act in a population-specific manner on expression quantitative trait loci (eQTLs) and thereby contributes to the difference in the differences of SLE prevalence and manifestation in human populations. We tested the hypothesises that some of the identified SLE risk polymorphisms display pleiotropic effects or polygenicity driven by positive selection. We performed a genome-wide scan for recent positive selection by using integrated Haplotype Score (iHS) statistics in different human populations. In addition, we estimated the timing of beneficial mutations to understand what possible selective pressures drive positive selection at SLE-associated loci. Results: We identified several SLE risk loci that are population-specifically under positive selection. Almost all SNPs that are under positive selection function as cis-eQTLs in different tissue types. We determined that adaptive eQTLs affect the expression of fewer genes than non-adaptive eQTLs, suggesting a limited range of effect of an eQTL at SLE risk sites that show signatures of positive selection. Furthermore, some positively selected SNPs are located in transcription factor binding sequences. The timing of positive selection for the studied loci suggests that both environmental and recent lifestyle changes during as well as after the Neolithic Transition may have become selectively effective. We propose a novel link between positively selected eQTLs at a certain SLE risk locus in Europeans and a physiological pathway not previously considered in SLE.Conclusions: We conclude that population-specific adaptive eQTLs contribute to the observed variation in specific manifestations and complications of SLE in different ethnicities. Our results suggest also that human populations adapt more rapidly to environmental and lifestyle stimuli via modification of gene expression without having to alter the genetic code.

In women, epithelial ovarian cancer is the leading cause of gynaecological malignancy-related deaths. Development of resistance to standard platinum and taxane based chemotherapy and recurrence of the disease necessitate development of novel drugs to halt disease progression. An established concept is to target molecular and signaling pathways that substantially contribute to development of drug resistance and disease progression. We have previously shown that, monepantel (MPL) a novel small molecule acetonitrile derivative is highly effective in suppressing growth, proliferation and colony formation of ovarian cancer cells. These effects are achieved through inhibition of the mTOR/p70S6K pathway in cancer cells. The present study was conducted to find in vivo corroboration and explore the effect of MPL om other growth stimulating putative signaling pathways. Here, female nude mice with subcutaneous OVCAR-3 xenografts were treated with 25 and 50 mg/kg doses of MPL administered (IP) three times weekly for 2 weeks. At the doses employed, MPL was modestly effective at suppressing tumor growth, but highly effective in inhibiting, mTOR, P70S6K and 4EBP1. There were also modest reductions in tumor cyclin D1 and retinoblastoma protein expression. Furthermore, it was found that MPL treatment causes down-regulation of IGF-1R, and c-MYC thus unveiling new dimensions to the growing antitumor actions of this potential anticancer drug. MPL treatment led to reduced tumor volume and weights without causing any detectable side effects. Coupled with the recent human safety data published on this molecule, expanded future trials are highly anticipated.

Systemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underlie the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertake a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture are identified. In addition to the human leukocyte antigen (HLA) region, nine disease loci show clear ancestral differences and implicate antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores perform significantly better when trained on ancestry-matched data sets. These analyses help to reveal the genetic basis for disparities in SLE among ancestral groups., The presentation of systemic lupus erythematosus has been known to differ by ancestry, but the underlying genetic factors remain unclear. Here, the authors report ancestry-specific susceptibility loci and better risk prediction when using data from matched ancestral groups.

SCOPUS: ar.j, info:eu-repo/semantics/published

Pseudomyxoma Peritonei (PMP) and Peritoneal Mesothelioma (PM) are both rare peritoneal malignancies. Currently, affected patients may be treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy offering long-term survival or even cure in selected patients. However, many issues regarding the optimal treatment strategy are currently under debate. To aid physicians involved in the treatment of these patients in clinical decision making, the PSOGI executive committee proposed to create a consensus statement on PMP and PM. This manuscript describes the methodology of the consensus process. The Delphi technique is a reliable method for attaining consensus on a topic that lacks scientific evidence through multiple voting rounds which feeds back responses to the participants in between rounds. The GRADE system provides a structured framework for presenting and grading the available evidence. Separate questionnaires were created for PMP and PM and sent during two voting rounds to 80 and 38 experts, respectively. A consensus threshold of 51.0% was chosen. After the second round, consensus was reached on 92.9%-100.0% of the questions. The results were presented and discussed in the plenary session at the PSOGI 2018 international meeting in Paris. A third round for the remaining issues is currently in progress. In conclusion, using the Delphi technique and GRADE methodology, consensus was reached in many issues regarding the treatment of PM and PMP amongst an international panel of experts. The main results will be published in the near future.

The combinations of Bromelain and Acetylcysteine (BromAc(®)) with cytotoxics such as Gemcitabine, 5-Fluorouracil or Oxaliplatin have shown a dramatic reduction in IC50 values in a variety of cancers, including colon cancer, suggesting the possibility of effective treatment without undesired side effects. In the current study, we investigated whether a similar effect is present in vivo using the colorectal cell line LS174T. Animals after acclimatization were randomized and allocated equally in the groups for the different studies (safety, dose-escalation, and efficacy). Drugs were delivered by the intraperitoneal route and animals were monitored for wellbeing. Separately, an efficacy study was conducted with intraperitoneal drug delivery after intraperitoneal tumor induction. At the termination of the experiment, tumors and other tissues were collected for evaluation. BromAc(®) was safe when delivered intraperitoneally in a rat model at the concentrations used. Subsequent investigations of these adjuvants in combination with Gemcitabine, Oxaliplatin, and 5-Fluorouracil in mice were also proven to be safe. Preliminary efficacy studies with Oxaliplatin and 5-Fluorouracil on tumor growth (LS174T) were negative. Gemcitabine was assessed with BromAc(®) showing an almost 71% tumor inhibition compared to controls. This in vivo study indicates that Gemcitabine at 2 mg/kg in combination with BromAc(®) 3 mg/300 mg/Kg was effective and safe, supporting its potential for future clinical application.

Bromelain consisting of a number of proteolytic enzymes possess anticancer and thrombotic properties. Hence, four chromatically separated fractions were examined for their proteolytic, anticancer and antithrombotic activity. Bromelain fractions were separated using ion-exchange column chromatography. Proteolytic properties were assessed using standard azocasein assay. Anticancer properties were first assessed using four different cell lines PANC-1, HEP 2B, HEP 3G and OVCAR-3 on cells grown in 96 well plates. Subsequently, fraction 2 and fraction 3 combined with gemcitabine were tested in ASPC-1 cells. Then cytotoxicity of fraction 3 was compared to bromelain in combination with doxorubicin and N-acetylcysteine on HEP G2 and HEP 3B cells. Finally, the anticoagulation effect of fraction 3 or bromelain combined with N-acetylcysteine was evaluated using human blood. Fraction 3 showed the highest proteolytic activity (5% greater than standard bromelain) whilst others were less active. Cytotoxicity as assessed by IC50 indicated fraction 3 to be the most potent whilst the others did not follow their proteolytic potency order. OVCAR-3 was the most sensitive amongst the cell lines. Fraction 3 showed higher potency in combination with gemcitabine in ASPC-1 cells compared to fraction 2. Similarly, fraction 3 in combination with doxorubicin showed higher toxicity when compared to bromelain. Fraction 3 or bromelain only showed thrombolytic activity in combination with N-acetylcysteine. Fraction 3 may be developed for clinical use since it showed better cytotoxicity compared to bromelain.

Background and objectivesSARS-CoV-2 infection is the cause of a worldwide pandemic, currently with limited therapeutic options. Whilst vaccines are at the forefront of the therapeutic initiative, drug repurposing remains a promising approach for SARS-CoV-2 treatment. BromAc (Bromelain & Acetylcysteine) has synergistic action against glycoproteins by the synchronous breakage of glycosidic linkages and disulfide bonds. The spike protein of SARS-CoV-2, formed of glycoprotein and disulfide bridges for stabilization, represents an attractive target as it is essential for binding to the ACE2 receptor in host cells present in nasal mucosa. We sought to determine the effect of BromAc on the Spike and Envelope proteins and its potential to reduce infectivity in host cells.DesignRecombinant Spike and Envelope proteins were treated by single agent and combination BromAc at 50 and 100 µg/20mg/mL and analyzed by electrophoresis. Ultraviolet analysis of disulfide bond reduction was performed for both Spike and Envelope proteins after treatment with Acetylcysteine. In vitro whole virus culture inactivation of pre-treated wild type and an S1/S2 Spike mutant SARS-CoV-2 with BromAc from 25 to 250 µg/20mg/mL was measured by cytopathic effect, cell lysis assay, and replication capacity by RT-PCR.ResultsRecombinant Spike and Envelope SARS-CoV-2 proteins were fragmented by BromAc at both 50 and 100 µg/20mg/mL whilst single agents had minimal effect. Spike and Envelope protein disulfide bonds were reduced by Acetylcysteine. In vitro whole virus culture of both wild type and Spike mutant SARS-CoV-2 demonstrated a concentration-dependent inactivation from BromAc treatment but not from single agents.ConclusionBromAc disintegrates SARS-CoV-2 Spike and Envelope proteins. In vitro tests on whole virus support this finding with inactivation of its replication capacity most strongly at 100 and 250 µg/20mg/mL BromAc, even in Spike mutant virus. Clinical testing through nasal administration in patients with early SARS-CoV-2 infection is imminent.Author SummaryThere is currently no suitable therapeutic treatment for early SARS-CoV-2 aimed to prevent disease progression. BromAc is under clinical development by the authors for mucinous cancers due to its ability to alter complex glycoproteins structure. The potential of BromAc on SARS-CoV-2 Spike and Envelope glycoproteins stabilized by disulfide bonds was examined and found to disintegrate recombinant Spike and Envelope proteins whilst reducing disulfide stabilizer bridges. BromAc also showed an inhibitory effect on wild-type and Spike mutant SARS-CoV-2 by inactivation of its replication capacity in vitro. Hence, BromAc may be an effective therapeutic agent for early SARS-CoV-2 infection, despite mutations, and even have potential as a prophylactic in people at high risk of infection.

This paper contributes to the literature on regional productivity, complementing previous education and skill-level perspectives with a novel approach analysing the impact of regional skill gaps and skill shortages. This allows us to reflect the idiosyncratic needs of the regional economic structure better, considering both the demand and supply side of the skills equation in localised labour markets. Controlling for unobserved time-invariant firm-level heterogeneity and other region–industry effects across a longitudinal data set for the period 2008–2014, our analysis reveals a negative direct effect of skill shortages on firm productivity. We further find negative spillover effects for both skill gaps and skill shortages in related industries and proximate regions. Results are also shown to be heterogeneous with respect to agglomeration levels and industrial sectors. Stronger negative effects are found in industries defined by a knowledge-intensive skill base, pointing to the loss of learning effects in the presence of skill deficiencies. Conversely, agglomeration effects appear to moderate the impact of skill deficiencies through more efficient matching in the local labour market. The findings presented thus suggest that policies aimed at improving productivity and addressing the increasing regional productivity divide cannot be reduced to a simple space-neutral support for higher education and skill levels but need to recognise explicitly the presence and characteristics of place-specific skills gaps and shortages.

Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease. Despite the significant progress made in identifying susceptibility genes for SLE, the genetic architecture of the disease is far from being understood. In this study, we set to replicate a number of suggestive association signals found in genome-wide association studies (GWASs) in additional independent cohorts. Replication studies were performed on Han Chinese cohorts from Hong Kong and Anhui, involving a total of 2,269 cases and 5,073 controls. We identified a missense variant in IRF3 (rs7251) reaching genome-wide significance through a joint analysis of GWAS and replication data (OR = 0.876, P = 4.40E-08). A significant correlation was observed between rs7251 and lupus nephritis (LN) by subphenotype stratification (OR = 0.785, P = 0.0128). IRF3 is a key molecule in type I interferon production upon nucleic acid antigen stimulations and may inhibit regulatory T cell differentiation. Further elucidation of the mechanism of this association could help us better understand the pathogenesis of SLE.

To determine the effect of signet ring cell (SRC) histopathology in appendix cancer with peritoneal dissemination on overall survival (OS) in patients undergoing cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC).Retrospective cohort study from a prospectively maintained database of patients that underwent CRS/HIPEC for appendix cancer from April 1999 to December 2019.255 patients were identified. 174 had high-grade disease with no SRC component, 35 with a low count of SRC and 46 with a high count of SRC. Median OS without SRC was 93.8 months vs 58.2 months for low count SRC and 23.7 months for high count SRC (P 0.001). 5-year OS was 60% for patients with no SRC, 35.5% and 10% in those with low count and high count SRC respectively. On multivariate analysis, presence of SRC and complete cytoreduction score were identified as independent factors that affect OS.The presence of SRC in appendix cancer with peritoneal dissemination is associated with worse OS when compared to an absence of SRC in patients undergoing CRS/HIPEC.

Uptake of drug-loaded micelles by tumour cell lines can be the crucial step in the creation of an efficient drug delivery system. Crosslinking of micelles has increasingly been proposed as a pathway to create stable nanoparticles. So far, little is known how crosslinking can affect the interaction of these nanocarriers with cells. The aim of this study is therefore to investigate the effect of crosslinking on exo- and endocytosis. RAFT (reversible addition fragmentation chain transfer) polymerization has been used to synthesize the block copolymer poly(methyl methacrylate)-block-poly(polyethylene glycol methyl ether methacrylate) PMMA-b-P(PEGMEMA), which was subsequently self-assembled into micelles of 20 nm. For comparison, the micelles were shell-crosslinked by incorporating methacrylic acid into the shell, which was used as a reactive group for crosslinking with 1,8-diaminooctane. The hydrodynamic diameter of the shell-crosslinked micelle was with 25 nm similar to that of the non-crosslinked one. Endocytosis of both micelles was significantly reduced by the presence of NaN3 or at 4 °C suggesting an energy dependent process. The internalization pathways of the block copolymer micelles in OVCAR-3 cells were elucidated using endocytosis inhibitors. Both nanoparticles, micelles and shell-crosslinked micelles, were internalized by caveolae mediated endocytosis while clathrin mediated endocytosis did not play a noticeable role. Shell-crosslinking therefore did not have an effect on endocytosis. However, a considerable difference was found in the exocytosis of both particles. While the micelle was lodged inside the cell for an extended period of time with less than 3% released in two hours, the shell-crosslinked micelle quickly exited the OVCAR-3 cells (25% in two hours). For comparison, a small molecule (Lucifer yellow) was found to be only marginally faster than the crosslinked micelles (40% in 2 h). These results could have implications on the use polymer–drug conjugates or drug carriers where the drug needs to be released before the polymer undergoes exocytosis.

Objectives: To assess the individual treatment strategies among international experts in peritoneal carcinosis, specifically their decision-making in the process of patient selection for hyperthermic intraperitoneal chemotherapy (HIPEC) in women suffering from ovarian cancer, to identify relevant decision-making criteria, and to quantify the level of consensus for or against HIPEC. Methods: The members of the executive committee of the Peritoneal Surface Oncology Group International (PSOGI) were asked to describe the clinical conditions under which they would recommend HIPEC in patients with ovarian cancer and to describe any disease or patient characteristics relevant to their decision. All answers were then merged and converted into decision trees. The decision trees were then analyzed by applying the objective consensus methodology. Results: Nine experts in surgical oncology provided information on their multidisciplinary treatment strategy including HIPEC for patients with advanced ovarian cancer. Three of the total of 12 experts did not perform HIPEC. Five criteria relevant to the decision on whether HIPEC is performed were applied. In patients with resectable disease, a peritoneal cancer index (PCI) Discussion and Conclusion: Among surgical oncology experts in peritoneal surface malignancy and HIPEC, HIPEC plays an important role in primary and recurrent ovarian cancer, and the PCI is the most important criterion in this decision.

Highlights • Intractable intraoperative haemorrhage is a result of both surgical and coagulopathic (nonsurgical) components. • There is increasing off-label use of rFVIIa for ceasing refractory bleeding aside from its application in patient with haemophilia. • rFVIIa use may be associated with increased thromboembolic events according to some literature. • The use of topical haemostatic agent in conjunction with ICS may potentially lead to systemic clot formation upon re-infusion of the chemical. • Avoid use of cell saver suction while the surgical field is contaminated with topical clotting factors before irrigation with 0.9% sodium chloride., Introduction In modern surgical era, local haemostatic agents and blood components such as recombinant activated factor VII (rFVIIa) have expanded surgeons’ armamentarium in controlling “surgical” and “nonsurgical bleeding”. We report a case of intraoperative thrombosis and cardiac arrest involving use of local haemostatic agent in intraoperative cell salvage and rFVIIa administration in extended right hepatectomy. Presentation of case A 46-year-old lady underwent extended right hepatectomy using cardiopulmonary bypass (CPB) and autotransfusion with ICS for metastatic gastrointestinal stromal tumour. She became extremely coagulopathic following weaning of CPB despite an array of fluid and blood products replacements. Decision to administer rFVIIa as a measure to arrest bleeding was unsuccessful. Extensive systemic thrombosis occurred which resulted in cardiac arrest and mortality. Discussion The thromboembolic event was unclear but likely multifactorial. Two important hypotheses were the administration of rFVIIa and use of local haemostatic agent in ICS. Conclusion Reported incidence of thromboembolism with use of rFVIIa in refractory bleeding is variable. More randomised controlled trials are needed to ascertain the efficacy and safety profile of the haemostatic agent. At present, off-label use of rFVIIa should be guided by the risk:benefit profile on a case-to-case basis. The authors also feel strongly against the use of local haemostatic gel in conjunction with ICS due to potential systemic circulation of the thrombin.

Systemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underly the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertook a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture were identified. Nine disease loci showed clear ancestral group heterogeneity and implicated antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores performed significantly better when trained on matched ancestral data sets. These analyses help to reveal the genetic bases for disparities in SLE among ancestral groups.

Introduction:Low grade, intermediate risk non-muscle invasive bladder cancer (LG IR-NMIBC) is notable for a high rate of disease recurrence yet low risk of disease progression. Patients with LG IR-...

BACKGROUND Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is associated with significant postoperative ileus (POI). This study examined intraoperative gastrointestinal wall thickness (GWT) and its association with patient outcomes. PATIENTS AND METHODS A prospective study of patients undergoing CRS and HIPEC. Proximal and distal small intestine GWT, before and after HIPEC were recorded. RESULTS Thirty-four patients (mean age=56.1 years, 61.8% female) were recruited. After HIPEC, the mean proximal (4.5 vs. 3.0 mm, p=0.03) and distal (4.3 vs. 3.4 mm, p

Pseudomyxoma Peritonei (PMP) is a mucin producing cancer with appendix as primary site. Cytoreductive Surgery (CRS) combined with hyper-thermic intraperitoneal chemotherapy (HIPEC) is an established form of therapy known to prolong survival in patients with PMP and peritoneal carcinomatosis. Methods/patients In our case series, we present five cases of PMP with synchronous liver and peritoneal metastasis treated with CRS and HIPEC. It is a very rare condition which needs more research to be able to comment on overall survival.However, in our study, we found lower age, female gender and complete cytoreduction in surgery to be favourable predictors for improved morbidity.In our experience, CRS/HIPEC seem to be feasible for patients with PMP with synchronous liver and peritoneal metastasis.

COVID-19 is a lethal disease caused by the pandemic SARS-CoV-2, which continues to be a public health threat. COVID-19 is principally a respiratory disease and is often associated with sputum retention, for which there are limited therapeutic options. In this regard, we evaluated the use of BromAc®, a combination of Bromelain and Acetylcysteine (NAC). Both drugs present mucolytic effect and have been studied to treat COVID-19. Therefore, we sought to examine the mucolytic, antiviral, and anti-inflammatory effect of BromAc® in tracheal aspirate samples from critically ill COVID-19 patients requiring mechanical ventilation.MethodTracheal aspirate samples from COVID-19 patients were collected following next of kin consent and mucolysis, rheometry and cytokine storm analysis was performed.ResultsBromAc® displayed a robust mucolytic effect in a dose dependent manner. BromAc® showed anti-inflammatory activity, reducing the action of cytokine storm, chemokines including MIP-1alpha, CXCL8, MIP-1b, MCP-1 and IP-10, and regulatory cytokines IL-5, IL-10, IL-13 IL-1RA and total reduction for IL-9 compared to NAC alone and control. BromAc® acted on IL-6, demonstrating a reduction in G-CSF and VEGF-D at concentrations of 125 and 250µg.ConclusionThese results indicate robust mucolytic and anti-inflammatory effect of BromAc® in tracheal aspirates from critically ill COVID-19 patients, indicating its potential as a therapeutic strategy to COVID-19.

Background: At present, selected patients with resectable colorectal peritoneal metastases (CRC-PM) are increasingly treated with a combination therapy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of this study was to investigate the current worldwide practice.Methods: HIPEC experts from 19 countries were invited through the Peritoneal Surface Oncology Group International (PSOGI) to complete an online survey concerning their personal expertise and current hospital and country wide practice.Results: It is estimated that currently more than 3800 patients with CRC-PM (synchronous and metachronous) are annually treated with CRS and HIPEC in 430 centers. Integration of CRS and HIPEC in national guidelines varies, resulting in large treatment disparities between countries. Amongst the experts, there was general agreement on issues related to indication, surgical technique and follow up but less on systemic chemotherapy or proactive strategies.Conclusion: This international survey demonstrates that CRS and HIPEC is now performed on a large scale for CRC-PM patients. Variation in treatment may result in heterogeneity in surgical and oncological outcomes, emphasising the necessity to reach consensus on several issues of this comprehensive procedure. Future initiatives directed at achieving an international consensus statement are needed. (C) 2018 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

The impact of concomitant urologic procedures (UPs) on perioperative and long-term outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is uncertain.In total, 935 consecutive CRS/HIPEC procedures were performed between 1996 and 2016 in Sydney, Australia. Among these, 73 (7.8%) involved concomitant UP. The association of concomitant UP with 21 perioperative outcomes and overall survival was assessed using univariate and multivariate analyses.In-hospital mortality was 1.8%. Patients requiring UP were more likely to require transfusion of ≥5 units of red blood cells (P=0.031) and have a complete cytoreduction (79% vs. 60%, P0.001). On multivariate analysis, UP was not associated with in-hospital mortality (2.7% vs. 1.7%, P=0.407) or grade III/IV morbidity (52% vs. 41%, P=0.376). The incidence of ureteric fistula (4% vs. 1%, P=0.004), return to theater (26% vs. 14%, P=0.005) and digestive fistula (22% vs. 11%, P=0.005) was higher in the UP group. The addition of a UP did not significantly impact overall survival for appendiceal cancer (P=0.162), colorectal cancer (P=0.315), or pseudomyxoma peritonei (P=0.120).Addition of a UP was not associated with an increased risk of grade III/IV morbidity or poorer long-term survival after CRS/HIPEC.

BACKGROUND/AIM To assess the impact of short- and long-term outcomes of bilateral vs. unilateral diaphragm interventions in cyto-reductive surgery (CRS) and intra-peritoneal chemotherapy (IPC). PATIENTS AND METHODS A total of 652 CRS/IPC procedures, between 1996 and 2018, required diaphragm interventions. Among these, 388 underwent bilateral intervention. Preoperative heterogeneity was assessed in 6 parameters and addressed with propensity score matching. The association of each respective analysis was assessed with 11 outcomes. Overall survival was assessed based on histology. RESULTS CRS/IPC requiring bilateral diaphragmatic interventions illustrated significantly increased operative hours (9.6 vs. 8.6 hours, p

It is believed that the oncologic behavior of mucinous colorectal adenocarcinoma (MC) is different from non-mucinous adenocarcinoma (NMC). The aim of the study is to compare long-term survivals between patients with MC and those with NMC following cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC).This was a retrospective study of prospectively collected data of patients with peritoneal metastases of colorectal origin following CRS and IPC. Group I included patients with MC which was defined as being composed of50% extracellular mucin. Group II included those with NMC. Subgroup analysis was performed according to the location of primary tumor.A total of 213 patients were included in this study. The two groups had similar hospital mortality, high dependency unit stay. MC group had a significantly longer mean intensive care unit (ICU) stay (p = .037) and total hospital stay (p = .037). There was no significant difference in overall survival (OS) and disease-free survival (DFS) between two groups (p = .657 and p = .938, respectively). Multivariate analysis showed that the presence of mucin was not an independent negative prognostic factor for OS (p = .190).In summary, patients with MC had a similar long-term survival outcome with those with NMC following CRS and IPC.

Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population. In EUR we observed 50 different A—C—B—DRB1—DQA—DQB multilocus haplotype sequences per hundred individuals; in the AA sample, these multilocus haplotypes were twice as common compared to Europeans. We also observed a strong narrow class II signal in AA as opposed to the long-range LD observed in EUR that includes class I alleles. We performed a Bayesian model choice of the classical HLA alleles and a frequentist analysis that combined both single nucleotide polymorphisms (SNPs) and classical HLA alleles. Both analyses converged on a similar subset of risk HLA alleles: in EUR HLA– B*08:01 + B*18:01 + (DRB1*15:01 frequentist only) + DQA*01:02 + DQB*02:01 + DRB3*02 and in AA HLA–C*17:01 + B*08:01 + DRB1*15:03 + (DQA*01:02 frequentist only) + DQA*02:01 + DQA*05:01+ DQA*05:05 + DQB*03:19 + DQB*02:02. We observed two additional independent SNP associations in both populations: EUR rs146903072 and rs501480; AA rs389883 and rs114118665. The DR2 serotype was best explained by DRB1*15:03 + DQA*01:02 in AA and by DRB1*15:01 + DQA*01:02 in EUR. The DR3 serotype was best explained by DQA*05:01 in AA and by DQB*02:01 in EUR. Despite some differences in underlying HLA allele risk models in EUR and AA, SNP signals across the extended MHC showed remarkable similarity and significant concordance in direction of effect for risk-associated variants.

In an effort to cut costs, newspaper chains nationwide have consolidated design operations at a few sites. These design hubs have changed the newspaper production process and removed designers from newsrooms; yet, top designers are able to work with their peers in a major city to produce all titles for a chain. This study uses a quantitative analysis of front pages collected from 435 newspapers throughout the United States to examine the quality of newspaper designs at hub and nonhub-designed newspapers. It concludes that hub designed newspapers are generally better designed than nonhub newspapers.

Background Systemic lupus erythematous (SLE) is a complex autoimmune disease with female predominance, particularly affecting those of childbearing age. We performed analysis of three genome-wide genotyping datasets of populations of both Chinese and European origin. Methods This study involved 5695 cases and 10,357 controls in the discovery stage. The lead signal on chromosome X was followed by replication in three additional Asian cohorts, with 2300 cases and 4244 controls in total. Conditional analysis of the known associated loci on chromosome X was also performed to further explore independent signals. Results Single-nucleotide polymorphism rs13440883 in GPR173 was found to be significantly associated with SLE (Pmeta = 7.53 × 10− 9, ORmeta= 1.16), whereas conditional analysis provided evidence of a potential independent signal in the L1CAM-IRAK1-MECP2 region in Asian populations (rs5987175 [LCA10]). Conclusions We identified a novel SLE susceptibility locus on the X chromosome. This finding emphasizes the importance of the X chromosome in disease pathogenesis and highlights the role of sex chromosomes in the female bias of SLE. Electronic supplementary material The online version of this article (10.1186/s13075-018-1590-3) contains supplementary material, which is available to authorized users.