Prospective study on stereotactic body radiotherapy for small pancreatic neuroendocrine tumors: tolerance and effectiveness analysis.

INTRODUCTION: Surgery is the standard treatment for pancreatic neuroendocrine tumors (pNETs), obtaining favorable results but associating high morbidity and mortality rates. This study assesses stereotactic body radiation therapy (SBRT) as a radical approach for small (< 2 cm) nonfunctioning pNETs. MATERIALS AND METHODS: From January 2017 to June 2023, 20 patients with small pNETs underwent SBRT in an IRB-approved study. Endpoints included local control, tolerance, progression-free survival, and overall survival (OS). Diagnostic assessments comprised endoscopy, CT scans, OctreScan or PET-Dotatoc, abdominal MRI, and histological confirmatory samples. RESULTS: In a 30-month follow-up of 20 patients (median age 55.5 years), SBRT was well-tolerated with no grade > 2 toxicity. 40% showed morphological response, 55% remained stable. Metabolically, 50% achieved significant improvement. With a median OS of 41.5 months, all patients were alive without local or distant progression or need for surgical resection. CONCLUSION: SBRT is a feasible and well-tolerated approach for small neuroendocrine pancreatic tumors, demonstrating effective local control. Further investigations are vital for validation and extension of these findings.

Harmonizing Definitions and Perspectives in Extreme Liver Surgery: A Delphi Experts Consensus.

OBJECTIVE: To propose to our community a common language about extreme liver surgery. BACKGROUND: The lack of a clear definition of extreme liver surgery prevents convincing comparisons of results among centers. METHODS: We used a two-round Delphi methodology to quantify consensus among liver surgery experts. For inclusion in the final recommendations, we established a consensus when the positive responses (agree and totally agree) exceeded 70%. The study steering group summarized and reported the recommendations. In general, a five-point Likert scale with a neutral central value was used, and in a few cases multiple choices. Results are displayed as numbers and percentages. RESULTS: A two-round Delphi study was completed by 38 expert surgeons in complex hepatobiliary surgery. The surgeon´s median age was 58 years old (52-63) and the median years of experience was 25 years (20-31). For the proposed definitions of total vascular occlusion, hepatic flow occlusion and inferior vein occlusion, the degree of agreement was 97%, 81% and 84%, respectively. In situ approach (64%) was the preferred, followed by ante situ (22%) and ex situ (14%). Autologous or cadaveric graft for hepatic artery or hepatic vein repair were the most recommended (89%). The use of veno-venous bypass or portocaval shunt revealed the divergence depending on the case. Overall, 75% of the experts agreed with the proposed definition for extreme liver surgery. CONCLUSION: Obtaining a consensus on the definition of extreme liver surgery is essential to guarantee the correct management of patients with highly complex hepatobiliary oncological disease. The management of candidates for extreme liver surgery involves comprehensive care ranging from adequate patient selection to the appropriate surgical strategy.

Preoperative and postoperative 3D reconstruction for surgical management of a post-cholecystectomy biliary stricture.

Cholecystectomy-related iatrogenic biliary injuries cause intricate postoperative complications that can significantly affect a patient's life, often leading to chronic liver disease and biliary stenosis. These patients require a multidisciplinary approach with intervention from radiologists, endoscopists and surgeons experienced in hepatobiliary reconstruction. Symptoms vary from none to jaundice, pruritus and ascending cholangitis. The best strategy for the management of biliary stricture is based on optimal preoperative planning. Our patient presented 1 year after an iatrogenic lesion was induced during a cholecystectomy, and was managed with a complex common bile duct reconstruction through a Roux-en-Y hepaticojejunostomy. The three-dimensional (3D) model reconstruction of the biliary tract was pivotal in the planning of the patient's surgery, providing additional preoperative and intraoperative assistance throughout the procedure. The 3D model's description of detailed spatial relations between the bile duct and the vascular structure in the liver hilum enabled a correct surgical dissection and safe execution of the anastomosis.

Light and shadow of watch-and-wait strategy in rectal cancer: oncological result, clinical outcomes, and cost-effectiveness analysis.

BACKGROUND: The watch-and-wait (WW) strategy is a potential option for patients with rectal cancer who obtain a complete clinic response after neoadjuvant therapy. The aim of this study is to analyze the long-term oncological outcomes and perform a cost-effectiveness analysis in patients undergoing this strategy for rectal cancer. MATERIAL AND METHODS: The data of patients treated with the WW strategy were prospectively collected from January 2015 to January 2020. A control group was created, matched 1:1 from a pool of 480 patients undergoing total mesorectal excision. An independent company carried out the financial analysis. Clinical and oncological outcomes were analyzed in both groups. Outcome parameters included surgical and follow-up costs, quality-adjusted life years (QALYs), and the incremental cost per QALY gained or the incremental cost-effectiveness ratio (ICER). RESULTS: Forty patients were included in the WW group, with 40 patients in the surgical group. During a median follow-up period of 36 months, metastasis-free survival (MFS) and overall survival (OS) were similar in the two groups. In the WW group, nine (22%) local regrowths were detected in the first 2 years. The permanent stoma rate was slightly higher after salvage surgery in the WW group compared to the surgical group (48.5% vs 20%, p < 0.01). The cost-effectiveness analysis was slightly better for the WW group, especially for low rectal cancer compared to medium-high rectal cancer (ICER = - 108,642.1 vs ICER = - 42,423). CONCLUSIONS: The WW strategy in locally advanced rectal cancer offers similar oncological outcomes with respect to the surgical group and excellent results in quality of life and cost outcomes, especially for low rectal cancer. Nonetheless, the complex surgical field during salvage surgery can lead to a high permanent stoma rate; therefore, the careful selection of patients is mandatory.

New era of robotic surgery: first case in Spain of right hemicolectomy on Hugo RAS surgical platform.

We describe the first robot-assisted right hemicolectomy performed in Spain using the new Hugo RAS (robotic-assisted surgery) (Medtronic, Minneapolis, Minnesota, USA). No conversion was registered, and no intraoperative complications or technical failures of the system were recorded. The operative time was 200 min, the docking time was 5 min and the length of the hospital stay was 8 days. We conclude that a right hemicolectomy using the Hugo RAS system is safe and feasible. Our earlier experience provides important skills for those who are starting to use this new robotic system.

First-reported case of vaginal late recurrence of Wilms tumor treated with complete pelvic exenteration.

Late relapses of Wilms tumour are extremely uncommon but still represent possible events. Even more rarely Wilms tumours present as extrarenal neoplasms, for which it could be difficult to diagnose and treat them promptly.We present a unique case of late recurrence of Wilms tumour 16 years after the primary diagnosis, with location in the gynaecological system. The relapse presented as a vaginal mass, and it gradually raised up to involve the majority of pelvic organs. We accurately studied the tumour extension, even realising a 3D preoperative reconstruction, and we managed to evaluate the patient with a multidisciplinary team involving general surgeons, urologists, gynaecologists and plastic surgeons. We finally decided for an extended surgical approach and realised a complete pelvic exenteration. Three months after surgery, the patient is in a good general condition, without major surgical complications and with no radiological signs of pelvic tumour relapse.

Can 3D imaging modeling recognize functional tissue and predict liver failure? A retrospective study based on 3D modelling of the major hepatectomies after hepatic modulation.

BACKGROUND: Thanks to the introduction of radiomics, 3d reconstruction can be able to analyse tissues and recognise true hypertrophy from non-functioning tissue in patients treated with major hepatectomies with hepatic modulation.The aim of this study is to evaluate the performance of 3D Imaging Modelling in predict liver failure. METHODS: Patients submitted to major hepatectomies after hepatic modulation at Sanchinarro University Hospital from May 2015 to October 2019 were analysed. Three-dimensional reconstruction was realised before and after surgical treatment. The volumetry of Future Liver Remnant was calculated, distinguishing in Functional Future Liver Remnant (FRFx) i.e. true hypertrophy tissue and Anatomic Future Liver Remnant (FRL) i.e. hypertrophy plus no functional tissue (oedema/congestion) These volumes were analysed in patients with and without post hepatic liver failure. RESULTS: Twenty-four procedures were realised (11 ALPPS and 13 PVE followed by major hepatectomy). Post hepatic liver failure grade B and C occurred in 6 patients. The ROC curve showed a better AUC for FRFxV (74%) with respect to FRLV (54%) in prediction PHLF > B. The increase of anatomical FRL (iFRL) was superior in the ALPPS group (120%) with respect to the PVE group (73%) (p = 0,041), while the increase of functional FRFX (iFRFx) was 35% in the ALLPS group and 46% in the PVE group (p > 0,05), showing no difference in the two groups. CONCLUSION: The 3D reconstruction model can allow optimal surgical planning, and through the use of specific algorithms, can contribute to differential functioning liver parenchyma of the FLR.

Robot-assisted cholecystectomy with the new HUGO™ robotic-assisted system: first worldwide report with system description, docking settings, and video.

Robotic surgery has gained worldwide acceptance in the past decade, and several studies have shown that this technique is safe and feasible. The innovation of this system is the open surgical console with an HD-3D display, a system tower, and four independent arm carts. We describe the first robot-assisted cholecystectomy performed with the new Hugo RAS (robotic-assisted surgery) system (Medtronic, Minneapolis, MN, USA) in Spain. The procedure was completed without conversion. No intraoperative complication or technical failure of the system was recorded. The operative time was 70 min. The docking time was 3 min. Hospital length of stay was 1 days. This case report shows the safety and feasibility of cholecystectomy with the Hugo RAS system and provides relevant data that may be of help to early adopters of this surgical platform.

Pancreatic head resection with segmental duodenectomy for the treatment of benign and malign pancreatic diseases. Case series experience of a single center.

INTRODUCTION AND IMPORTANCE: Duodenum-preserving pancreatic resections (DPPHR) is a reasonable surgical option for benign or low-grade malignant tumours of the pancreatic head. Several techniques have been proposed, with or without common biliary duct preservation. CASE PRESENTATION: We report for the first time two cases of pancreas divisum treated with this technique and we illustrate two other cases of pancreatic disease in which this procedure was realized from January 2015 to January 2020 in the HM Sanchinarro University Hospital. CLINICAL DISCUSSION: Pancreatic head resection with pancreatic parenchyma sparing, and duodenal preservation has been commonly accepted in the treatment of benign pancreatic head disease. CONCLUSION: This technique offers a wide application in the treatment of pancreatic and duodenal benign disease, including pancreatic malformation such as pancreas divisum and duodenal tumour that require segmental resection, in order to assure complete pancreatic head resection and to avoid duodenal and biliary duct ischemia.

Robot-assisted Nissen fundoplication with the new HUGO™ Robotic assisted system: First worldwide report with system description, docking settings and video.

BACKGROUND: Robotic surgery has gained worldwide acceptance over the past decade, with several studies showing that this technique is safe and feasible. METHODS: We describe the first robot-assisted Nissen fundoplication for hiatal hernia performed with the new Hugo™ RAS (Robotic assisted surgery) system (Medtronic, Minneapolis, MN, USA) in Spain. The innovation of this system is the open surgical console with a 3D-HD display, a system tower and four independent arm carts. RESULTS: The surgical procedures were completed without conversion. No intraoperative complications or technical failures of the system were recorded. The operative time was 97 min, the docking time was 3 min, and the length of hospital stay was three days. CONCLUSIONS: This case report shows the safety and feasibility of Nissen fundoplication for hiatal hernia with the Hugo™ RAS system and provides relevant data that may assist early adopters of this surgical platform.

Closed hyperthermic intraperitoneal chemotherapy with CO2 recirculation system compared with the open Coliseum technique in peritoneal malignity treatment.

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis can be performed in two ways: first, the standard open abdominal technique (Open HIPEC); or second, the closed technique. In recent years, a new technique has been introduced to perform closed HIPEC; the Peritoneal Recirculation System (PRS-1.0 Combat) with CO2 recirculation technology (PRS Closed HIPEC). The objective of this study is to present our experience with the PRS Closed HIPEC by comparing the intraoperative, postoperative and oncological results with the standard Open HIPEC technique (the Coliseum technique). METHODS: Data on patients undergoing CRS and HIPEC at the Sanchinarro University Hospital, Madrid from October 2012 to June 2021 were collected in a prospective database. The inclusion criteria were patients with primary or recurrent peritoneal metastases in gastrointestinal malignancies or ovarian cancer. The presence of an unresectable peritoneal carcinomatosis, the coexistence of another oncological disease, unresectable and distant metastases were the exclusion criteria. RESULTS: From October 2014 to June 2021, 84 patients underwent CRS and HIPEC at the Sanchinarro University Hospital, Madrid with curative intent. Since the introduction of the PRS Closed HIPEC technique in 2016, 65 patients have been treated. Before the introduction of PRS Closed HIPEC, 19 cases were performed using the Coliseum technique (the Open HIPEC group). The intraoperative results were similar in the two groups. Complete cytoreduction was achieved in all cases in the Open HIPEC group and in 98% in the PRS Closed HIPEC group. The rate of major complications was similar between the groups. Median Overall Survival (OS) resulted better in the Closed HIPEC group (67 months) with respecto to the Open group (43 months) (p < 0,001). Median Disease-Free Survival (DFS) was 15 months in the Open HIPEC group and 40 months in the PRS Closed HIPEC group (p < 0.001). CONCLUSION: The Peritoneal Recirculation System with CO2 recirculation technology (PRS Closed HIPEC) is a reproducible and safe technique and may represent a valid alternative for the administration of HIPEC.

Radiofrequency-assisted transection of the pancreas versus stapler in distal pancreatectomy: study protocol for a multicentric randomised clinical trial (TRANSPAIRE).

INTRODUCTION: To date, no pancreatic stump closure technique has been shown to be superior to any other in distal pancreatectomy. Although several studies have shown a trend towards better results in transection using a radiofrequency device (radiofrequency-assisted transection (RFT)), no randomised trial for this purpose has been performed to date. Therefore, we designed a randomised clinical trial, with the hypothesis that this technique used in distal pancreatectomies is superior in reducing clinically relevant postoperative pancreatic fistula (CR-POPF) than mechanical closures. METHODS AND ANALYSIS: TRANSPAIRE is a multicentre randomised controlled trial conducted in seven Spanish pancreatic centres that includes 112 patients undergoing elective distal pancreatectomy for any indication who will be randomly assigned to RFT or classic stapler transections (control group) in a ratio of 1:1. The primary outcome is the CR-POPF percentage. Sample size is calculated with the following assumptions: 5% one-sided significance level (α), 80% power (1-ß), expected POPF in control group of 32%, expected POPF in RFT group of 10% and a clinically relevant difference of 22%. Secondary outcomes include postoperative results, complications, radiological evaluation of the pancreatic stump, metabolomic profile of postoperative peritoneal fluid, survival and quality of life. Follow-ups will be carried out in the external consultation at 1, 6 and 12 months postoperatively. ETHICS AND DISSEMINATION: TRANSPAIRE has been approved by the CEIM-PSMAR Ethics Committee. This project is being carried out in accordance with national and international guidelines, the basic principles of protection of human rights and dignity established in the Declaration of Helsinki (64th General Assembly, Fortaleza, Brazil, October 2013), and in accordance with regulations in studies with biological samples, Law 14/2007 on Biomedical Research will be followed. We have defined a dissemination strategy, whose main objective is the participation of stakeholders and the transfer of knowledge to support the exploitation of activities. REGISTRATION DETAILS: ClinicalTrials.gov Registry (NCT04402346).

A directed genome evolution method to enhance hydrogen production in Rhodobacter capsulatus.

Nitrogenase-dependent H2 production by photosynthetic bacteria, such as Rhodobacter capsulatus, has been extensively investigated. An important limitation to increase H2 production using genetic manipulation is the scarcity of high-throughput screening methods to detect possible overproducing mutants. Previously, we engineered R. capsulatus strains that emitted fluorescence in response to H2 and used them to identify mutations in the nitrogenase Fe protein leading to H2 overproduction. Here, we used ultraviolet light to induce random mutations in the genome of the engineered H2-sensing strain, and fluorescent-activated cell sorting to detect and isolate the H2-overproducing cells from libraries containing 5 × 105 mutants. Three rounds of mutagenesis and strain selection gradually increased H2 production up to 3-fold. The whole genomes of five H2 overproducing strains were sequenced and compared to that of the parental sensor strain to determine the basis for H2 overproduction. No mutations were present in well-characterized functions related to nitrogen fixation, except for the transcriptional activator nifA2. However, several mutations mapped to energy-generating systems and to carbon metabolism-related functions, which could feed reducing power or ATP to nitrogenase. Time-course experiments of nitrogenase depression in batch cultures exposed mismatches between nitrogenase protein levels and their H2 and ethylene production activities that suggested energy limitation. Consistently, cultivating in a chemostat produced up to 19-fold more H2 than the corresponding batch cultures, revealing the potential of selected H2 overproducing strains.

Giant fibrovascular polyps of the esophagus. Trans oral versus surgical approach. Case report and systematic literature review.

INTRODUCTION: Giant fibrovascular esophageal polyp is a rare benign intraluminal tumour. The aim of this study is to perform a review of the most recent literature in order to describe and analyse the current range of possible diagnostics and treatment strategies. CASE REPORT: We present two cases of giant fibrovascular esophageal polyp treated with a combined minimally invasive transluminal approach at Sanchinarro University Hospital. Further, we perform a literature review. CONCLUSION: We present two cases of grant fibrovascular polyp submitted to minimally invasive transluminal approach. Furthermore, 54 original articles reporting 59 cases have been analysed. In the surgical group, an esophagotomy and polyp resection were performed in 31 (91 %) patients and a total esophagectomy in two patients (5,8 %). Severe morbidity occurred in two patients (5,8 %.) The median hospital stay was 9.25 days. A total of two (5,8 %) cases of recurrence have been registered. In the minimally invasive transluminal approach group, 27 patients had a polyp resection performed completely by endoscopy/transoral. There were no complications but there was one case of recurrence. CONCLUSION: The transluminal approach is safe and should be considered also in the treatment of large esophageal polyps.

Liver growth prediction in ALPPS - A multicenter analysis from the international ALPPS registry.

BACKGROUND: While ALPPS triggers a fast liver hypertrophy, it is still unclear which factors matter most to achieve accelerated hypertrophy within a short period of time. The aim of the study was to identify patient-intrinsic factors related to the growth of the future liver remnant (FLR). METHODS: This cohort study is composed of data derived from the International ALPPS Registry from November 2011 and October 2018. We analyse the influence of demographic, tumour type and perioperative data on the growth of the FLR. The volume of the FLR was calculated in millilitre and percentage using computed-tomography (CT) scans before and after stage 1, both according to Vauthey formula. RESULTS: A total of 734 patients were included from 99 centres. The median sFLR at stage 1 and stage 2 was 0.23 (IQR, 0.18-0.28) and 0.39 (IQR: 0.31-0.46), respectively. The variables associated with a lower increase from sFLR1 to sFLR2 were age˃68 years (p = .02), height ˃1.76 m (p ˂ .01), weight ˃83 kg (p ˂ .01), BMI˃28 (p ˂ .01), male gender (p ˂ .01), antihypertensive therapy (p ˂ .01), operation time ˃370 minutes (p ˂ .01) and hospital stay˃14 days (p ˂ .01). The time required to reach sufficient volume for stage 2, male gender accounts 40.3% in group ˂7 days, compared with 50% of female, and female present 15.3% in group ˃14 days compared with 20.6% of male. CONCLUSIONS: Height, weight, FLR size and gender could be the variables that most constantly influence both daily growths, the interstage increase and the standardized FLR before the second stage.

Case-matched analysis of robotic versus open surgical enucleation for pancreatic tumours: A comparative cost-effectiveness study.

BACKGROUND: Enucleation has widely spread as an alternative strategy in the treatment of small pancreatic tumours and cystic lesions. To date there are limited data on perioperative outcomes after pancreatic enucleation performed using a minimally invasive robotic technique, particularly regarding the risk factors associated with postoperative pancreatic fistula (POPF). We perform a comparative study of robotic pancreatic enucleation (RPE) and open enucleation (OPE) with the aim of evaluating clinical and cost-effective outcomes. METHODS: This is a case-matched analysis of patients who underwent robotic and open pancreatic enucleation performed at Sanchinarro University Hospital, Madrid, from October 2014 to December 2021. Patient data were obtained retrospectively. Clinicopathologic characteristics and perioperative and postoperative outcomes were recorded and analysed. Two groups of demographically similar patients were analysed: the robotic group (n = 20) and the open group (n = 20). The patient characteristics of the two groups have been compared. From February 2015, quality-adjusted life years (QALYs) are also included and prospectively recorded in the database and used to measure the effectiveness of the treatment. RESULT: A total of 20 RPE and 20 OPE have been included. The incremental cost of the robotic approach versus open was €2617.85(CI 95% 1601.48; 3634.24) and the incremental utility was 0.0879 QALYs (CI 95% 0.0834; 0.0925). The estimated ICER for patients was €29,782.13 (CI 95% 17,313.29; 43,576.01) per QALY gained. Robotic resection resulted a shorter postoperative hospital stay, less wound infections, faster recovery diet and a similar operating time. The two groups had similar complication rates. Pathological data were similar for both procedures. CONCLUSION: RPE resulted in a shorter hospital stay and less blood loss and morbidity, comparable with the outcomes of open enucleation. RPE may also be acceptable in terms of cost-effectiveness.

A conformational role for NifW in the maturation of molybdenum nitrogenase P-cluster.

Reduction of dinitrogen by molybdenum nitrogenase relies on complex metalloclusters: the [8Fe:7S] P-cluster and the [7Fe:9S:Mo:C:homocitrate] FeMo-cofactor. Although both clusters bear topological similarities and require the reductive fusion of [4Fe:4S] sub-clusters to achieve their respective assemblies, P-clusters are assembled directly on the NifD2K2 polypeptide prior to the insertion of FeMo-co, which is fully assembled separately from NifD2K2. P-cluster maturation involves the iron protein NifH2 as well as several accessory proteins, whose role has not been elucidated. In the present work, two NifD2K2 species bearing immature P-clusters were isolated from an Azotobacter vinelandii strain in which the genes encoding NifH and the accessory protein NifZ were deleted, and characterized by X-ray absorption spectroscopy and EPR. These analyses showed that both NifD2K2 complexes harbor clusters that are electronically and structurally similar, with each NifDK unit containing two [4Fe:4S]2+/+ clusters. Binding of the accessory protein NifW parallels a decrease in the distance between these clusters, as well as a subtle change in their coordination. These results support a conformational role for NifW in P-cluster biosynthesis, bringing the two [4Fe:4S] precursors closer prior to their fusion, which may be crucial in challenging cellular contexts.

AnfO controls fidelity of nitrogenase FeFe protein maturation by preventing misincorporation of FeV-cofactor.

Azotobacter vinelandii produces three genetically distinct, but structurally and mechanistically similar nitrogenase isozymes designated as Mo-dependent, V-dependent, or Fe-only based on the heterometal contained within their associated active site cofactors. These catalytic cofactors, which provide the site for N2 binding and reduction, are, respectively, designated as FeMo-cofactor, FeV-cofactor, and FeFe-cofactor. Fe-only nitrogenase is a poor catalyst for N2 fixation, when compared to the Mo-dependent and V-dependent nitrogenases and is only produced when neither Mo nor V is available. Under conditions favoring the production of Fe-only nitrogenase a gene product designated AnfO preserves the fidelity of Fe-only nitrogenase by preventing the misincorporation of FeV-cofactor, which results in the accumulation of a hybrid enzyme that cannot reduce N2 . These results are interpreted to indicate that AnfO controls the fidelity of Fe-only nitrogenase maturation during the physiological transition from conditions that favor V-dependent nitrogenase utilization to Fe-only nitrogenase utilization to support diazotrophic growth.

Watch-and-Wait policy versus robotic surgery for locally advanced rectal cancer: A cost-effectiveness study (RECCOSTE).

INTRODUCTION: Complete surgical resection for locally advanced rectal cancer is the standard treatment after a clinical complete response following chemoradiotherapy. However, some novel clinical approaches could achieve better functional results, such as Robotic Resection, or avoiding surgical procedure and incrementing surveillance intensity, called Watch-and-Wait policy. We use computational techniques to compare these clinical approaches using quality adjusted life years (QALYs). METHODS: A Markov decision analytic model was used in order to perform a cost-utility analysis, comparing standard resection (SR), Robotic Rectal Resection (RRR) and Watch-and-Wait (WW) strategies, estimating the incremental cost-effectiveness ratio per QALY to be gained from patients reaching a clinical complete response to chemoradiotherapy. Model parameter estimates were informed by previously published studies comparing WW to SR and from our database of RRR versus SR. Lifetime incremental cost-utility ratio was calculated among approaches, and a sensitivity analysis were performed in order to estimate the model uncertainty. A willingness-to-pay of per one additional QALY gained was measured to determine which strategies would be most cost-effective. RESULTS: WW is a dominating option over SR ( -75,486. 75 € and +2.04 QALYs) and RRR ( -75,486. 75 € and +0.41 QALYs). The cost-effectiveness plane shows that WW does not always dominate over RRR or SR. WW saves costs in 99.98% of the simulations when compared with either SR or RRR but only 86.9% and 55.38% (respectively) of these fall within the SR quadrant. WW is only more effective than SR 55% of the time which implies a significant uncertainty due to the high utility value assigned to cCR after chemoradiotherapy in the RRR alternative. CONCLUSION: This study provides data of cost-effectiveness differences among Standard Surgery, Watch-and-Wait and Robotic Resection approaches in clinical complete response in locally advanced rectal cancer patients after neoadjuvant chemoradiotherapy, showing a benefit for Watch-and-Wait policy.

Specificity of NifEN and VnfEN for the Assembly of Nitrogenase Active Site Cofactors in Azotobacter vinelandii.

The nitrogen-fixing microbe Azotobacter vinelandii has the ability to produce three genetically distinct, but mechanistically similar, components that catalyze nitrogen fixation. For two of these components, the Mo-dependent and V-dependent components, their corresponding metal-containing active site cofactors, designated FeMo-cofactor and FeV-cofactor, respectively, are preformed on separate molecular scaffolds designated NifEN and VnfEN, respectively. From prior studies, and the present work, it is now established that neither of these scaffolds can replace the other with respect to their in vivo cofactor assembly functions. Namely, a strain inactivated for NifEN cannot produce active Mo-dependent nitrogenase nor can a strain inactivated for VnfEN produce an active V-dependent nitrogenase. It is therefore proposed that metal specificities for FeMo-cofactor and FeV-cofactor formation are supplied by their respective assembly scaffolds. In the case of the third, Fe-only component, its associated active site cofactor, designated FeFe-cofactor, requires neither the NifEN nor VnfEN assembly scaffold for its formation. Furthermore, there are no other genes present in A. vinelandii that encode proteins having primary structure similarity to either NifEN or VnfEN. It is therefore concluded that FeFe-cofactor assembly is completed within its cognate catalytic protein partner without the aid of an intermediate assembly site. IMPORTANCE Biological nitrogen fixation is a complex process involving the nitrogenases. The biosynthesis of an active nitrogenase involves a large number of genes and the coordinated function of their products. Understanding the details of the assembly and activation of the different nitrogen fixation components, in particular the simplest one known so far, the Fe-only nitrogenase, would contribute to the goal of transferring the necessary genetic elements of bacterial nitrogen fixation to cereal crops to endow them with the capacity for self-fertilization. In this work, we show that there is no need for a scaffold complex for the assembly of the FeFe-cofactor, which provides the active site for Fe-only nitrogenase. These results are in agreement with previously reported genetic reconstruction experiments using a non-nitrogen-fixing microbe. In aggregate, these findings provide a high degree of confidence that the Fe-only system represents the simplest and, therefore, most attractive target for mobilizing nitrogen fixation into plants.