Study of sterically crowded alkanes: assessment of non-empirical density functionals including double-hybrid cost-effective methods.

We theoretically study the homolytic dissociation reactions of sterically crowded alkanes of increasing size, carrying three different (bulky) substituents such as tert-butyl, adamantane, and [1.1.1]propellanyl, employing a family of parameter-free functionals ranging from semi-local, to hybrid and double-hybrid models. The study is complemented with the interaction between a pair of HC(CH3)3 molecules at repulsive and attractive regions, as an example of a system composed by a pair of weakly bound sterically crowded alkanes. We also assessed the effect of incorporating reliable dispersion corrections (i.e., D4 or NL) for all the functionals assessed, as well as the use of a tailored basis set (DH-SVPD) for non-covalent interactions, which provides the best trade-off between accuracy and computational cost for a seemingly extended applications to branched or crowded systems. Overall, the PBE-QIDH/DH-SVPD and r2SCAN-QIDH/DH-SVPD methods represent an excellent compromise providing relatively low, and thus very competitive, errors at a fraction of the cost of other quantum-chemical methods in use.

Axial-equatorial equilibrium in substituted cyclohexanes: a DFT perspective on a small but complex problem.

In Chemistry, complexity is not necessarily associated to large systems, as illustrated by the textbook example of axial-equatorial equilibrium in mono-substituted cyclohexanes. The difficulty in modelling such a simple isomerization is related to the need for reproducing the delicate balance between two forces, with opposite effects, namely the attractive London dispersion and the repulsive steric interactions. Such balance is a stimulating challenge for density-functional approximations and it is systematically explored here by considering 20 mono-substituted cyclohexanes. In comparison to highly accurate CCSD(T) reference calculations, their axial-equatorial equilibrium is studied with a large set of 48 exchange-correlation approximations, spanning from semilocal to hybrid to more recent double hybrid functionals. This dataset, called SAV20 (as Steric A-values for 20 molecules), allows to highlight the difficulties encountered by common and more original DFT approaches, including those corrected for dispersion with empirical potentials, the 6-31G*-ACP model, and our cost-effective PBE-QIDH/DH-SVPD protocol, in modeling these challenging interactions. Interestingly, the performance of the approaches considered in this contribution on the SAV20 dataset does not correlate with that obtained with other more standard datasets, such as S66, IDISP or NC15, thus indicating that SAV20 covers physicochemical features not already considered in previous noncovalent interaction benchmarks.

Diagnostic value of ascites immunohistochemistry in carcinomatosis of unknown origin.

We present the case of a patient diagnosed with carcinomatosis when admitted urgently for an occlusive condition. It is the immunohistochemistry that clarifies which is the primary tumor. Sigma neoplasia was initially suspected to recur due to operative findings. It was surprising that the primary tumor was of pulmonary origin. It became known thanks to the immunohistochemical cytology of the ascetic fluid.

Ovarian metastasis from pancreatic ductal carcinoma.

A clinical case is presented about a rare presentation of pancreatic cancer. Firstly, pancreatic cancer rarely metastasizes to the ovary, and when it does, it usually presents in the form of peritoneal carcinomatosis and bilateral involvement. However, the initial radiological diagnosis was primary pancreatic carcinoma with a synchronous primary ovarian carcinoma. Once analyzed pathologically, it was concluded that it was ovarian metastasis from pancreatic cancer. Given the diagnostic difficulty along with the patient's long survival, an exceptional case is presented.

Dysphagia secondary to neuroendocrine carcinoma: a rare esophageal tumor.

We present two clinical cases, a 68-year-old male and a 55-year-old female, who are being studied for progressive solid food dysphagia. The initial gastroscopy revealed a polypoid lesion in the first case and a partially stenosing lesion in the second case. Both lesions were located in the mid-esophagus and presented a normal mucosa. Histological diagnosis confirmed an esophageal neuroendocrine carcinoma (NEC) of large cell and small cell types, respectively.

Extraosseous Ewing's sarcoma of the pancreas.

We present the clinical case of a 21-year-old male with abdominal pain in the left hypochondrium radiating to the ipsilateral lumbar area and a weight loss of 2kg over a month, secondary to a large palpable intra-abdominal mass in the examination. TAC revealed a large solid mass with necrotic-cystic component which depended of the pancreas, infiltrated the spleen, enveloped the celiac trunk and affected to the splenic vases. Inmunohistochemical and molecular study confirmed the diagnosis extraosseus Ewing sarcoma (EES).

Multisocietal European consensus on the terminology, diagnosis, and management of patients with synchronous colorectal cancer and liver metastases: an E-AHPBA consensus in partnership with ESSO, ESCP, ESGAR, and CIRSE.

BACKGROUND: Contemporary management of patients with synchronous colorectal cancer and liver metastases is complex. The aim of this project was to provide a practical framework for care of patients with synchronous colorectal cancer and liver metastases, with a focus on terminology, diagnosis, and management. METHODS: This project was a multiorganizational, multidisciplinary consensus. The consensus group produced statements which focused on terminology, diagnosis, and management. Statements were refined during an online Delphi process, and those with 70 per cent agreement or above were reviewed at a final meeting. Iterations of the report were shared by electronic mail to arrive at a final agreed document comprising 12 key statements. RESULTS: Synchronous liver metastases are those detected at the time of presentation of the primary tumour. The term 'early metachronous metastases' applies to those absent at presentation but detected within 12 months of diagnosis of the primary tumour, the term 'late metachronous metastases' applies to those detected after 12 months. 'Disappearing metastases' applies to lesions that are no longer detectable on MRI after systemic chemotherapy. Guidance was provided on the recommended composition of tumour boards, and clinical assessment in emergency and elective settings. The consensus focused on treatment pathways, including systemic chemotherapy, synchronous surgery, and the staged approach with either colorectal or liver-directed surgery as first step. Management of pulmonary metastases and the role of minimally invasive surgery was discussed. CONCLUSION: The recommendations of this contemporary consensus provide information of practical value to clinicians managing patients with synchronous colorectal cancer and liver metastases.

SOS1-RSX-QIDH: A spin-opposite-scaled range-separated-exchange quadratic-integrand double-hybrid density functional.

We develop and validate the SOS1-RSX-QIDH density functional, a one-parameter spin-opposite-scaled variant of the range-separated-exchange quadratic-integrand double-hybrid (RSX-QIDH) model. By entering into the family of spin-biased double hybrids, this new density functional benefits from an improved computational scaling that rivals with the one of hybrids, still conserving the accuracy of its RSX-QIDH version. As part of the latter family, this density functional is well-adapted to treat molecular systems that are particularly prone to self-interaction errors in their ground and excited states. In particular, we show that the SOS1-RSX-QIDH model is a good compromise to treat ground-state problems dealing with kinetics and has a real added value when applied to the evaluation of the excited-state properties of equilibrium and out-of-equilibrium molecular complexes. Even if spin-biased double hybrids are recognized to strongly underestimate noncovalent interactions, we notice and recommend coupling SOS1-RSX-QIDH with a nonlocal van der Waals potential, a combination that is here proved to compete with the best density-functional approximations currently in use.

Gastric gastrointestinal stromal tumor abscess.

A 70-year-old male with a large abscessed GIST is reported. Symptoms, laboratory results, diagnostic imaging and surgical field information are provided. It is a rare initial presentation of a GIST which we believe to be academically interesting.

The multi-societal European consensus on the terminology, diagnosis and management of patients with synchronous colorectal cancer and liver metastases: an E-AHPBA consensus in partnership with ESSO, ESCP, ESGAR, and CIRSE.

BACKGROUND: Contemporary management of patients with synchronous colorectal cancer and liver metastases is complex. The aim of this project was to provide a practical framework for care of patients with synchronous colorectal cancer and liver metastases with a focus on terminology, diagnosis and management. METHODS: This project was a multi-organisational, multidisciplinary consensus. The consensus group produced statements which focused on terminology, diagnosis and management. Statements were refined during an online Delphi process and those with 70% agreement or above were reviewed at a final meeting. Iterations of the report were shared by electronic mail to arrive at a final agreed document comprising twelve key statements. RESULTS: Synchronous liver metastases are those detected at the time of presentation of the primary tumour. The term "early metachronous metastases" applies to those absent at presentation but detected within 12 months of diagnosis of the primary tumour with "late metachronous metastases" applied to those detected after 12 months. Disappearing metastases applies to lesions which are no longer detectable on MR scan after systemic chemotherapy. Guidance was provided on the recommended composition of tumour boards and clinical assessment in emergency and elective settings. The consensus focused on treatment pathways including systemic chemotherapy, synchronous surgery and the staged approach with either colorectal or liver-directed surgery as first step. Management of pulmonary metastases and the role of minimally invasive surgery was discussed. CONCLUSIONS: The recommendations of this contemporary consensus provide information of practical value to clinicians managing patients with synchronous colorectal cancer and liver metastases.

Clinical Outcomes After Total Pancreatectomy: A Prospective Multicenter Pan-European Snapshot Study.

OBJECTIVE: To assess outcomes among patients undergoing total pancreatectomy (TP) including predictors for complications and in-hospital mortality. BACKGROUND: Current studies on TP mostly originate from high-volume centers and span long time periods and therefore may not reflect daily practice. METHODS: This prospective pan-European snapshot study included patients who underwent elective (primary or completion) TP in 43 centers in 16 European countries (June 2018-June 2019). Subgroup analysis included cutoff values for annual volume of pancreatoduodenectomies (<60 vs ≥60).Predictors for major complications and in-hospital mortality were assessed in multivariable logistic regression. RESULTS: In total, 277 patients underwent TP, mostly for malignant disease (73%). Major postoperative complications occurred in 70 patients (25%). Median hospital stay was 12 days (IQR 9-18) and 40 patients were readmitted (15%). In-hospital mortality was 5% and 90-day mortality 8%. In the subgroup analysis, in-hospital mortality was lower in patients operated in centers with ≥60 pancreatoduodenectomies compared <60 (4% vs 10%, P = 0.046). In multivariable analysis, annual volume <60 pancreatoduodenectomies (OR 3.78, 95% CI 1.18-12.16, P = 0.026), age (OR 1.07, 95% CI 1.01-1.14, P = 0.046), and estimated blood loss ≥2L (OR 11.89, 95% CI 2.64-53.61, P = 0.001) were associated with in-hospital mortality. ASA ≥3 (OR 2.87, 95% CI 1.56-5.26, P = 0.001) and estimated blood loss ≥2L (OR 3.52, 95% CI 1.25-9.90, P = 0.017) were associated with major complications. CONCLUSION: This pan-European prospective snapshot study found a 5% inhospital mortality after TP. The identified predictors for mortality, including low-volume centers, age, and increased blood loss, may be used to improve outcomes.

Tackling an accurate description of molecular reactivity with double-hybrid density functionals.

In this Communication, we assess a panel of 18 double-hybrid density functionals for the modeling of the thermochemical and kinetic properties of an extended dataset of 449 organic chemistry reactions belonging to the BH9 database. We show that most of DHs provide a statistically robust performance to model barrier height and reaction energies in reaching the "chemical accuracy." In particular, we show that nonempirical DHs, such as PBE0-DH and PBE-QIDH, or minimally parameterized alternatives, such as ωB2PLYP and B2K-PLYP, succeed to accurately model both properties in a balanced fashion. We demonstrate, however, that parameterized approaches, such as ωB97X-2 or DSD-like DHs, are more biased to only one of both properties.

Adenosquamous cancer of the pancreas: A multicenter retrospective study.

INTRODUCTION: Adenosquamous cancer of the pancreas (ASCP) is an aggressive, infrequent subtype of pancreatic cancer that combines a glandular and squamous component and is associated with poor survival. METHODS: Multicenter retrospective observational study carried out at three Spanish hospitals. The study period was: January 2010-August 2020. A descriptive analysis of the data was performed, as well as an analysis of global and disease-free survival using the Kaplan-Meier statistic. RESULTS: Of a total of 668 pancreatic cancers treated surgically, twelve were ASCP (1.8%). Patient mean age was 69.2±7.4 years. Male/female ratio was 1:1. The main symptom was jaundice (seven patients). Correct preoperative diagnosis was obtained in only two patients. Nine pancreatoduodenectomies and three distal pancreatosplenectomies were performed. 25% had major complications. Mean tumor size was 48.6±19.4mm. Nine patients received adjuvant chemotherapy. Median survival time was 5.9 months, and median disease-free survival was 4.6 months. 90% of patients presented recurrence. Ten of the twelve patients in the study (83.3%) died, with disease progression being the cause in eight. Of the two surviving patients, one is disease-free and the other has liver metastases. CONCLUSION: ASCP is a very rare pancreatic tumor with aggressive behavior. It is rarely diagnosed preoperatively. The best treatment, if feasible, is surgery followed by the standard chemotherapy regimens for pancreatic adenocarcinoma.

The Cost of Postoperative Complications and Economic Validation of the Comprehensive Complication Index: Prospective Study.

OBJECTIVE: To validate the Comprehensive Complication Index (CCI) via an assessment of its relation to postoperative costs. BACKGROUND: The CCI summarizes all the postoperative complications graded by the Clavien-Dindo classification (CDC) on a numerical scale. Its relation to hospital costs has not been validated to date. METHODS: Prospective observational cohort study, including all patients undergoing surgery at a general surgery service during the 1-year study period. All complications graded with the CDC and CCI and related to the initial admission, or until discharge if the patient was readmitted within 90 days of surgery, were included. The surgeries were classified according to their Operative Severity Score (OSS) and in 4 groups of homogeneous surgeries. All postoperative costs were recorded. RESULTS: In all, 1850 patients were included, of whom 513 presented complications (27.7%). The CDC and the CCI were moderately to strongly correlated with overall postoperative costs (OPCs) in all OSS groups (rs = 0.444-0.810 vs 0.445-0.820; P < 0.001), homogeneous surgeries (rs = 0.364-0.802 vs 0.364-0.813; P < 0.001), prolongation of postoperative stay (rs = 0.802 vs 0.830; P < 0.001), and initial operating room costs (rs = 0.448 vs 0.451; P < 0.001). This correlation was higher in emergency surgery. With higher CDC grades, the OPC tended to increase an upward trend. In the multivariate analysis, CDC, CCI, age, and duration of surgery were all associated with OPC (P < 0.001). CONCLUSIONS: In our environment, the CCI presented associations with OPC. This demonstration of its economic validity enhances its clinical validity.

Assessing challenging intra- and inter-molecular charge-transfer excitations energies with double-hybrid density functionals.

We investigate the performance of a set of recently introduced range-separated double-hybrid functionals, namely ωB2-PLYP, ωB2GP-PLYP, RSX-0DH, and RSX-QIDH models for hard-to-calculate excitation energies. We compare with the parent (B2-PLYP, B2GP-PLYP, PBE0-DH, and PBE-QIDH) and other (DSD-PBEP86) double-hybrid models as well as with some of the most widely employed hybrid functionals (B3LYP, PBE0, M06-2X, and ωB97X). For this purpose, we select a number of medium-sized intra- and inter-molecular charge-transfer excitations, which are known to be challenging to calculate using time-dependent density-functional theory (TD-DFT) and for which accurate reference values are available. We assess whether the high accuracy shown by the newest double-hybrid models is also confirmed for those cases too. We find that asymptotically corrected double-hybrid models yield a superior performance, especially for the inter-molecular charge-transfer excitation energies, as compared to standard double-hybrid models. Overall, the PBE-QIDH and its corresponding range-separated RSX-QIDH functional are recommended for general-purpose TD-DFT applications, depending on whether long-range effects are expected to play a significant role.

Fast-Track Liver Transplantation: Six-year Prospective Cohort Study with an Enhanced Recovery After Surgery (ERAS) Protocol.

INTRODUCTION: Enhanced recovery after surgery (ERAS) has been shown to facilitate discharge, decrease length of stay, improve outcomes and reduce costs. We used this concept to design a comprehensive fast-track pathway (OR-to-discharge) before starting our liver transplant activity and then applied this protocol prospectively to every patient undergoing liver transplantation at our institution, monitoring the results periodically. We now report our first six years results. PATIENTS AND METHODS: Prospective cohort study of all the liver transplants performed at our institution for the first six years. Balanced general anesthesia, fluid restriction, thromboelastometry, inferior vena cava preservation and temporary portocaval shunt were strategies common to all cases. Standard immunosuppression administered included steroids, tacrolimus (delayed in the setting of renal impairment, with basiliximab induction added) and mycophenolate mofetil. Tacrolimus dosing was adjusted using a Bayesian estimation methodology. Oral intake and ambulation were started early. RESULTS: A total of 240 transplants were performed in 236 patients (191♂/45♀) over 74 months, mean age 56.3±9.6 years, raw MELD score 15.5±7.7. Predominant etiologies were alcohol (n = 136) and HCV (n = 82), with hepatocellular carcinoma present in 129 (54.7%). Nine patients received combined liver and kidney transplants. The mean operating time was 315±64 min with cold ischemia times of 279±88 min. Thirty-one patients (13.1%) were transfused in the OR (2.4±1.2 units of PRBC). Extubation was immediate (< 30 min) in all but four patients. Median ICU length of stay was 12.7 hours, and median post-transplant hospital stay was 4 days (2-76) with 30 patients (13.8%) going home by day 2, 87 (39.9%) by day 3, and 133 (61%) by day 4, defining our fast-track group. Thirty-day-readmission rate (34.9%) was significantly lower (28.6% vs. 44.7% p=0.015) in the fast-track group. Patient survival was 86.8% at 1 year and 78.6% at five years. CONCLUSION: Fast-Tracking of Liver Transplant patients is feasible and can be applied as the standard of care.

Pancreas-Preserving Total Duodenectomy: A Systematic Review.

BACKGROUND: The management of the pancreas in patients with duodenal trauma or duodenal tumors remains a controversial issue. Pancreas-preserving total duodenectomy (PPTD) requires a meticulous surgical technique. The most common indication is familial duodenal adenomatous polyposis (FAP). The aims of this study are to carry out a systematic review of the literature on the indications for PPTD and to highlight the risks and benefits compared with other more aggressive procedures. SUMMARY: A systematic literature review was performed following PRISMA recommendations of studies published in PubMed, Embase, and Cochrane library until May 2019. Thirty articles describing 211 patients were chosen. The mean age was 48 years. The surgical indication in 75% of patients was FAP. The mean operating time was 329 min and mean intraoperative bleeding 412 mL. Postoperative morbidity rate was 49.7% (76% Clavien-Dindo 97.8%. Key Messages: PPTD is indicated for patients with benign and premalignant duodenal lesions without involvement of the pancreatic head. It is a feasible procedure offering an alternative to other more aggressive procedures in selected patients. Mortality is below 1.5%.

Management of clinical chorioamnionitis: an evidence-based approach.

This review aimed to examine the existing evidence about interventions proposed for the treatment of clinical chorioamnionitis, with the goal of developing an evidence-based contemporary approach for the management of this condition. Most trials that assessed the use of antibiotics in clinical chorioamnionitis included patients with a gestational age of ≥34 weeks and in labor. The first-line antimicrobial regimen for the treatment of clinical chorioamnionitis is ampicillin combined with gentamicin, which should be initiated during the intrapartum period. In the event of a cesarean delivery, patients should receive clindamycin at the time of umbilical cord clamping. The administration of additional antibiotic therapy does not appear to be necessary after vaginal or cesarean delivery. However, if postdelivery antibiotics are prescribed, there is support for the administration of an additional dose. Patients can receive antipyretic agents, mainly acetaminophen, even though there is no clear evidence of their benefits. Current evidence suggests that the administration of antenatal corticosteroids for fetal lung maturation and of magnesium sulfate for fetal neuroprotection to patients with clinical chorioamnionitis between 24 0/7 and 33 6/7 weeks of gestation, and possibly between 23 0/7 and 23 6/7 weeks of gestation, has an overall beneficial effect on the infant. However, delivery should not be delayed to complete the full course of corticosteroids and magnesium sulfate. Once the diagnosis of clinical chorioamnionitis has been established, delivery should be considered, regardless of the gestational age. Vaginal delivery is the safer option and cesarean delivery should be reserved for standard obstetrical indications. The time interval between the diagnosis of clinical chorioamnionitis and delivery is not related to most adverse maternal and neonatal outcomes. Patients may require a higher dose of oxytocin to achieve adequate uterine activity or greater uterine activity to effect a given change in cervical dilation. The benefit of using continuous electronic fetal heart rate monitoring in these patients is unclear. We identified the following promising interventions for the management of clinical chorioamnionitis: (1) an antibiotic regimen including ceftriaxone, clarithromycin, and metronidazole that provides coverage against the most commonly identified microorganisms in patients with clinical chorioamnionitis; (2) vaginal cleansing with antiseptic solutions before cesarean delivery with the aim of decreasing the risk of endometritis and, possibly, postoperative wound infection; and (3) antenatal administration of N-acetylcysteine, an antioxidant and antiinflammatory agent, to reduce neonatal morbidity and mortality. Well-powered randomized controlled trials are needed to assess these interventions in patients with clinical chorioamnionitis.

Range-separated hybrid and double-hybrid density functionals: A quest for the determination of the range-separation parameter.

We recently derived a new and simple route to the determination of the range-separation parameter in range-separated exchange hybrid and double-hybrid density functionals by imposing an additional constraint to the exchange-correlation energy to recover the total energy of the hydrogen atom [Brémond et al., J. Chem. Phys. 15, 201102 (2019)]. Here, we thoroughly assess this choice by statistically comparing the derived values of the range-separation parameters to the ones obtained using the optimal tuning (OT) approach. We show that both approaches closely agree, thus, confirming the reliability of ours. We demonstrate that it provides very close performances in the computation of properties particularly prone to the one- and many-electron self-interaction errors (i.e., ionization potentials). Our approach arises as an alternative to the OT procedure, conserving the accuracy and efficiency of a standard Kohn-Sham approach to density-functional theory computation.

Metabolic syndrome, non-alcoholic fatty liver disease and hepatocarcinoma.

The term "metabolic syndrome" refers to a group of alterations comprising central obesity reduced high-density lipoprotein cholesterol concentrations, elevated triglyceride concentrations, arterial hypertension, and hyperglycemia. This syndrome has established itself as one of the epidemics of the 21st century. Among its causative agents are insulin resistance, leptin and adiponectin, changes in microbiota, and epigenetics. Its incidence in the European population is estimated to be around 25%. Non-alcoholic fatty liver disease is the hepatic manifestation of metabolic syndrome; its prevalence parallels that of obesity, and it has increased exponentially in recent decades. Recently, several publications have linked metabolic risk factors with the onset and development of hepatocarcinoma, and so it is essential to determine whether patients with non-alcoholic fatty liver disease should follow a protocol for hepatocarcinoma screening. At present, the worldwide incidence of hepatocarcinoma in patients with non-alcoholic fatty liver disease without cirrhosis is only 2.7%. Screening for hepatocarcinoma in patients with non-alcoholic fatty liver disease and cirrhosis is mandatory, but the low incidence of hepatocarcinoma in patients without cirrhosis does not justify the systematic monitoring of this patient population. Current efforts are based on identifying subgroups of patients with non-alcoholic fatty liver disease and a higher-than-average risk of developing hepatocarcinoma.