Nationwide practice in CT-based preoperative staging of colon cancer and concordance with definitive pathology.

INTRODUCTION: In an era of exploring patient-tailored treatment options for colon cancer, preoperative staging is increasingly important. This study aimed to evaluate completeness and reliability of CT-based preoperative locoregional colon cancer staging in Dutch hospitals. MATERIALS AND METHODS: Patients who underwent elective oncological resection of colon cancer without neoadjuvant treatment in 77 Dutch hospitals were evaluated between 2011 and 2021. Completeness of T-stage was calculated for individual hospitals and stratified based on a 60% cut-off. Concordance between routine CT-based preoperative locoregional staging (cTN) and definitive pathological staging (pTN) was examined. RESULTS: A total of 59,558 patients were included with an average completeness of 43.4% and 53.4% for T and N-stage, respectively. Completeness of T-stage improved from 4.9% in 2011-2014 to 74.4% in 2019-2021. Median completeness for individual hospitals was 53.9% (IQR 27.3-80.5%) and were not significantly different between low and high-volume hospitals. Sensitivity and specificity for T3-4 tumours were relatively low: 75.1% and 76.0%, respectively. cT1-2 tumours were frequently understaged based on a low negative predictive value of 56.8%. Distinction of cT4 and cN2 disease had a high specificity (>95%), but a very low sensitivity (<50%). Positive predictive values of <60% indicated that cT4 and cN1-2 were often overstaged. Completeness and time period did not influence reliability of staging. CONCLUSION: Completeness of locoregional staging of colon cancer improved during recent years and varied between hospitals independently from case volume. Discriminating cT1-2 from cT3-4 tumours resulted in substantial understaging and overstaging, additionally cT4 and cN1-2 were overstaged in >40% of cases.

Thermal Contaminants in Coffee Induced by Roasting: A Review.

Roasting is responsible for imparting the main characteristics to coffee, but the high temperatures used in the process can lead to the formation of several potentially toxic substances. Among them, polycyclic aromatic hydrocarbons, acrylamide, furan and its derivative compounds, α-dicarbonyls and advanced glycation end products, 4-methylimidazole, and chloropropanols stand out. The objective of this review is to present a current and comprehensive overview of the chemical contaminants formed during coffee roasting, including a discussion of mitigation strategies reported in the literature to decrease the concentration of these toxicants. Although the formation of the contaminants occurs during the roasting step, knowledge of the coffee production chain as a whole is important to understand the main variables that will impact their concentrations in the different coffee products. The precursors and routes of formation are generally different for each contaminant, and the formed concentrations can be quite high for some substances. In addition, the study highlights several mitigation strategies related to decreasing the concentration of precursors, modifying process conditions and eliminating/degrading the formed contaminant. Many of these strategies show promising results, but there are still challenges to be overcome, since little information is available about advantages and disadvantages in relation to aspects such as costs, potential for application on an industrial scale and impacts on sensory properties.

Patient selection for urgent endoscopic retrograde cholangio-pancreatography by endoscopic ultrasound in predicted severe acute biliary pancreatitis (APEC-2): a multicentre prospective study.

OBJECTIVE: Routine urgent endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic biliary sphincterotomy (ES) does not improve outcome in patients with predicted severe acute biliary pancreatitis. Improved patient selection for ERCP by means of endoscopic ultrasonography (EUS) for stone/sludge detection may challenge these findings. DESIGN: A multicentre, prospective cohort study included patients with predicted severe acute biliary pancreatitis without cholangitis. Patients underwent urgent EUS, followed by ERCP with ES in case of common bile duct stones/sludge, within 24 hours after hospital presentation and within 72 hours after symptom onset. The primary endpoint was a composite of major complications or mortality within 6 months after inclusion. The historical control group was the conservative treatment arm (n=113) of the randomised APEC trial (Acute biliary Pancreatitis: urgent ERCP with sphincterotomy versus conservative treatment, patient inclusion 2013-2017) applying the same study design. RESULTS: Overall, 83 patients underwent urgent EUS at a median of 21 hours (IQR 17-23) after hospital presentation and at a median of 29 hours (IQR 23-41) after start of symptoms. Gallstones/sludge in the bile ducts were detected by EUS in 48/83 patients (58%), all of whom underwent immediate ERCP with ES. The primary endpoint occurred in 34/83 patients (41%) in the urgent EUS-guided ERCP group. This was not different from the 44% rate (50/113 patients) in the historical conservative treatment group (risk ratio (RR) 0.93, 95% CI 0.67 to 1.29; p=0.65). Sensitivity analysis to correct for baseline differences using a logistic regression model also showed no significant beneficial effect of the intervention on the primary outcome (adjusted OR 1.03, 95% CI 0.56 to 1.90, p=0.92). CONCLUSION: In patients with predicted severe acute biliary pancreatitis without cholangitis, urgent EUS-guided ERCP with ES did not reduce the composite endpoint of major complications or mortality, as compared with conservative treatment in a historical control group. TRIAL REGISTRATION NUMBER: ISRCTN15545919.

Air- and Water-Stable Heteroleptic Copper (I) Complexes Bearing Bis(indazol-1-yl)methane Ligands: Synthesis, Characterisation, and Computational Studies.

A series of four novel heteroleptic Cu(I) complexes, bearing bis(1H-indazol-1-yl)methane analogues as N,N ligands and DPEPhos as the P,P ligand, were synthesised in high yields under mild conditions and characterised by spectroscopic and spectrometric techniques. In addition, the position of the carboxymethyl substituent in the complexes and its effect on the electrochemical and photophysical behaviour was evaluated. As expected, the homoleptic copper (I) complexes with the N,N ligands showed air instability. In contrast, the obtained heteroleptic complexes were air- and water-stable in solid and solution. All complexes displayed green-yellow luminescence in CH2Cl2 at room temperature due to ligand-centred (LC) phosphorescence in the case of the Cu(I) complex with an unsubstituted N,N ligand and metal-to-ligand charge transfer (MLCT) phosphorescence for the carboxymethyl-substituted complexes. Interestingly, proper substitution of the bis(1H-indazol-1-yl)methane ligand enabled the achievement of a remarkable luminescent yield (2.5%) in solution, showcasing the great potential of this novel class of copper(I) complexes for potential applications in luminescent devices and/or photocatalysis.

The mechanism of macroautophagy: The movie.

This animated movie presents the mechanism of macroautophagy, hereafter autophagy, by showing the molecular features of the formation of autophagosomes, the hallmark organelle of this intracellular catabolic pathway. It is based on our current knowledge and it also illustrates how autophagosomes can recognize and eliminate selected cargoes.

Aggressive fluid hydration plus non-steroidal anti-inflammatory drugs versus non-steroidal anti-inflammatory drugs alone for post-endoscopic retrograde cholangiopancreatography pancreatitis (FLUYT): a multicentre, open-label, randomised, controlled trial.

BACKGROUND: Pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Prophylactic rectal administration of non-steroidal anti-inflammatory drugs (NSAIDs) is considered as standard of care to reduce the risk of post-ERCP pancreatitis. It has been suggested that aggressive hydration might further reduce this risk. Guidelines already recommend aggressive hydration in patients who are unable to receive rectal NSAIDs, although it is laborious and time consuming. We aimed to evaluate the added value of aggressive hydration in patients receiving prophylactic rectal NSAIDs. METHODS: FLUYT, a multicentre, open-label, randomised, controlled trial done across 22 Dutch hospitals, included patients aged between 18 and 85 years with moderate to high risk of post-ERCP pancreatitis. Patients were randomly assigned (1:1) by a web-based module with varying block sizes to a combination of aggressive hydration and rectal NSAIDs (100 mg diclofenac or indomethacin; aggressive hydration group) or rectal NSAIDs (100 mg diclofenac or indomethacin) alone (control group). Randomisation was stratified according to treatment centre. Aggressive hydration comprised 20 mL/kg intravenous Ringer's lactate solution within 60 min from the start of ERCP, followed by 3 mL/kg per h for 8 h. The control group received normal intravenous saline with a maximum of 1·5 mL/kg per h and 3 L per 24 h. The primary endpoint was post-ERCP pancreatitis and was analysed on a modified intention-to-treat basis (including all patients who underwent randomisation and an ERCP and for whom data regarding the primary outcome were available). The trial is registered with the ISRCTN registry, ISRCTN13659155. FINDINGS: Between June 5, 2015, and June 6, 2019, 826 patients were randomly assigned, of whom 388 in the aggressive hydration group and 425 in the control group were included in the modified intention-to-treat analysis. Post-ERCP pancreatitis occurred in 30 (8%) patients in the aggressive hydration group and in 39 (9%) patients in the control group (relative risk 0·84, 95% CI 0·53-1·33, p=0·53). There were no differences in serious adverse events, including hydration-related complications (relative risk 0·99, 95% CI 0·59-1·64; p=1·00), ERCP-related complications (0·90, 0·62-1·31; p=0·62), intensive care unit admission (0·37, 0·07-1·80; p=0·22), and 30-day mortality (0·95, 0·50-1·83; p=1·00). INTERPRETATION: Aggressive periprocedural hydration did not reduce the incidence of post-ERCP pancreatitis in patients with moderate to high risk of developing this complication who routinely received prophylactic rectal NSAIDs. Therefore, the burden of laborious and time-consuming aggressive periprocedural hydration to further reduce the risk of post-ERCP pancreatitis is not justified. FUNDING: Netherlands Organisation for Health Research and Development and Radboud University Medical Center.

Surface charge modulation of rifampicin-loaded PLA nanoparticles to improve antibiotic delivery in Staphylococcus aureus biofilms.

BACKGROUND: After the golden age of antibiotic discovery, bacterial infections still represent a major challenge for public health worldwide. The biofilm mode of growth is mostly responsible for chronic infections that current therapeutics fail to cure and it is well-established that novel strategies must be investigated. Particulate drug delivery systems are considered as a promising strategy to face issues related to antibiotic treatments in a biofilm context. Particularly, poly-lactic acid (PLA) nanoparticles present a great interest due to their ability to migrate into biofilms thanks to their submicronic size. However, questions still remain unresolved about their mode of action in biofilms depending on their surface properties. In the current study, we have investigated the impact of their surface charge, firstly on their behavior within a bacterial biofilm, and secondly on the antibiotic delivery and the treatment efficacy. RESULTS: Rifampicin-loaded PLA nanoparticles were synthetized by nanoprecipitation and characterized. A high and superficial loading of rifampicin, confirmed by an in silico simulation, enabled to deliver effective antibiotic doses with a two-phase release, appropriate for biofilm-associated treatments. These nanoparticles were functionalized with poly-L-lysine, a cationic peptide, by surface coating inducing charge reversal without altering the other physicochemical properties of these particles. Positively charged nanoparticles were able to interact stronger than negative ones with Staphylococcus aureus, under planktonic and biofilm modes of growth, leading to a slowed particle migration in the biofilm thickness and to an improved retention of these cationic particles in biofilms. While rifampicin was totally ineffective in biofilms after washing, the increased retention capacity of poly-L-lysine-coated rifampicin-loaded PLA nanoparticles has been associated with a better antibiotic efficacy than uncoated negatively charged ones. CONCLUSIONS: Correlating the carrier retention capacity in biofilms with the treatment efficacy, positively charged rifampicin-loaded PLA nanoparticles are therefore proposed as an adapted and promising approach to improve antibiotic delivery in S. aureus biofilms.

Molecular Dynamics Studies of Poly(Lactic Acid) Nanoparticles and Their Interactions with Vitamin E and TLR Agonists Pam1CSK4 and Pam3CSK4.

Poly(lactic acid) (PLA) nanoparticles (NPs) are widely investigated due to their bioresorbable, biocompatible and low immunogen properties. Interestingly, many recent studies show that they can be efficiently used as drug delivery systems or as adjuvants to enhance vaccine efficacy. Our work focuses on the molecular mechanisms involved during the nanoprecipitation of PLA NPs from concentrated solutions of lactic acid polymeric chains, and their specific interactions with biologically relevant molecules. In this study, we evaluated the ability of a PLA-based nanoparticle drug carrier to vectorize either vitamin E or the Toll-like receptor (TLR) agonists Pam1CSK4 and Pam3CSK4, which are potent activators of the proinflammatory transcription factor NF-κB. We used dissipative particle dynamics (DPD) to simulate large systems mimicking the nanoprecipitation process for a complete NP. Our results evidenced that after the NP formation, Pam1CSK4 and Pam3CSK4 molecules end up located on the surface of the particle, interacting with the PLA chains via their fatty acid chains, whereas vitamin E molecules are buried deeper in the core of the particle. Our results allow for a better understanding of the molecular mechanisms responsible for the formation of the PLA NPs and their interactions with biological molecules located either on their surfaces or encapsulated within them. This work should allow for a rapid development of better biodegradable and safe vectorization systems with new drugs in the near future.

Urgent endoscopic retrograde cholangiopancreatography with sphincterotomy versus conservative treatment in predicted severe acute gallstone pancreatitis (APEC): a multicentre randomised controlled trial.

BACKGROUND: It remains unclear whether urgent endoscopic retrograde cholangiopancreatography (ERCP) with biliary sphincterotomy improves the outcome of patients with gallstone pancreatitis without concomitant cholangitis. We did a randomised trial to compare urgent ERCP with sphincterotomy versus conservative treatment in patients with predicted severe acute gallstone pancreatitis. METHODS: In this multicentre, parallel-group, assessor-masked, randomised controlled superiority trial, patients with predicted severe (Acute Physiology and Chronic Health Evaluation II score ≥8, Imrie score ≥3, or C-reactive protein concentration >150 mg/L) gallstone pancreatitis without cholangitis were assessed for eligibility in 26 hospitals in the Netherlands. Patients were randomly assigned (1:1) by a web-based randomisation module with randomly varying block sizes to urgent ERCP with sphincterotomy (within 24 h after hospital presentation) or conservative treatment. The primary endpoint was a composite of mortality or major complications (new-onset persistent organ failure, cholangitis, bacteraemia, pneumonia, pancreatic necrosis, or pancreatic insufficiency) within 6 months of randomisation. Analysis was by intention to treat. This trial is registered with the ISRCTN registry, ISRCTN97372133. FINDINGS: Between Feb 28, 2013, and March 1, 2017, 232 patients were randomly assigned to urgent ERCP with sphincterotomy (n=118) or conservative treatment (n=114). One patient from each group was excluded from the final analysis because of cholangitis (urgent ERCP group) and chronic pancreatitis (conservative treatment group) at admission. The primary endpoint occurred in 45 (38%) of 117 patients in the urgent ERCP group and in 50 (44%) of 113 patients in the conservative treatment group (risk ratio [RR] 0·87, 95% CI 0·64-1·18; p=0·37). No relevant differences in the individual components of the primary endpoint were recorded between groups, apart from the occurrence of cholangitis (two [2%] of 117 in the urgent ERCP group vs 11 [10%] of 113 in the conservative treatment group; RR 0·18, 95% CI 0·04-0·78; p=0·010). Adverse events were reported in 87 (74%) of 118 patients in the urgent ERCP group versus 91 (80%) of 114 patients in the conservative treatment group. INTERPRETATION: In patients with predicted severe gallstone pancreatitis but without cholangitis, urgent ERCP with sphincterotomy did not reduce the composite endpoint of major complications or mortality, compared with conservative treatment. Our findings support a conservative strategy in patients with predicted severe acute gallstone pancreatitis with an ERCP indicated only in patients with cholangitis or persistent cholestasis. FUNDING: The Netherlands Organization for Health Research and Development, Fonds NutsOhra, and the Dutch Patient Organization for Pancreatic Diseases.

Predicting a 'difficult cholecystectomy' after mild gallstone pancreatitis.

BACKGROUND: Cholecystectomy after gallstone pancreatitis may be technically demanding. The aim of this study was to investigate risk factors for a difficult cholecystectomy after mild pancreatitis. METHODS: This was a prospective study within a randomized controlled trial on the timing of cholecystectomy after mild gallstone pancreatitis. Difficulty of cholecystectomy was scored on a 0 to 10 visual analogue scale (VAS) by the senior attending surgeon. The primary outcome 'difficult cholecystectomy' was defined by presence of one or more of the following features: a VAS score ≥ 8, duration of surgery > 75 minutes, conversion or subtotal cholecystectomy. RESULTS: 249 patients were included in the primary analysis. A difficult cholecystectomy occurred in 82 patients (33%). In the 'same-admission cholecystectomy' group 29 of 112 cholecystectomies were difficult (26%) versus 49 of 127 patients (39%) who underwent surgery after 2 weeks (p = 0.037). After multivariable analysis, male sex (OR 1.80, 95% confidence interval [CI] 1.04-3.13; p = 0.037), prior sphincterotomy (OR 1.79, 95% CI 1.01-3.16; p = 0.046), and delaying cholecystectomy for at least two weeks (OR 1.81, 95% CI 1.04-3.16; p = 0.036) were independent predictors of a difficult cholecystectomy. CONCLUSION: Surgeons should anticipate a difficult cholecystectomy after mild gallstone pancreatitis in case of male sex, prior sphincterotomy and delayed cholecystectomy.

Colicky pain and related complications after cholecystectomy for mild gallstone pancreatitis.

BACKGROUND: Same-admission cholecystectomy is advised after gallstone pancreatitis to prevent recurrent pancreatitis, colicky pain and other complications, but data on the incidence of symptoms and complications after cholecystectomy are lacking. METHODS: This was a prospective cohort study during the previously published randomized controlled PONCHO trial on timing of cholecystectomy after mild gallstone pancreatitis. Data on healthcare consumption and questionnaires focusing on colicky pain and biliary complications were obtained during 6 months after cholecystectomy. Main outcomes were (i) postoperative colicky pain as reported in questionnaires and (ii) medical treatment for postoperative symptoms and gallstone related complications. RESULTS: Among 262 patients who underwent cholecystectomy after mild gallstone pancreatitis, 28 of 191 patients (14.7%) reported postoperative colicky pain. The majority of these were reported within 2 months after surgery and were single events. Overall, 25 patients (9.5%) required medical treatment for symptoms or gallstone related complications. Acute readmission was required in seven patients (2.7%). No predictors for the development of postoperative colicky pain were identified. DISCUSSION: Some 15% of patients experienced colicky pain after cholecystectomy for mild gallstone pancreatitis, which were mostly single events and rarely required readmission. These data may be used to better inform patients undergoing cholecystectomy for mild gallstone pancreatitis.

Fluid hydration to prevent post-ERCP pancreatitis in average- to high-risk patients receiving prophylactic rectal NSAIDs (FLUYT trial): study protocol for a randomized controlled trial.

BACKGROUND: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most common complication of ERCP and may run a severe course. Evidence suggests that vigorous periprocedural hydration can prevent PEP, but studies to date have significant methodological drawbacks. Importantly, evidence for its added value in patients already receiving prophylactic rectal non-steroidal anti-inflammatory drugs (NSAIDs) is lacking and the cost-effectiveness of the approach has not been investigated. We hypothesize that combination therapy of rectal NSAIDs and periprocedural hydration would significantly lower the incidence of post-ERCP pancreatitis compared to rectal NSAIDs alone in moderate- to high-risk patients undergoing ERCP. METHODS: The FLUYT trial is a multicenter, parallel group, open label, superiority randomized controlled trial. A total of 826 moderate- to high-risk patients undergoing ERCP that receive prophylactic rectal NSAIDs will be randomized to a control group (no fluids or normal saline with a maximum of 1.5 mL/kg/h and 3 L/24 h) or intervention group (lactated Ringer's solution with 20 mL/kg over 60 min at start of ERCP, followed by 3 mL/kg/h for 8 h thereafter). The primary endpoint is the incidence of post-ERCP pancreatitis. Secondary endpoints include PEP severity, hydration-related complications, and cost-effectiveness. DISCUSSION: The FLUYT trial design, including hydration schedule, fluid type, and sample size, maximize its power of identifying a potential difference in post-ERCP pancreatitis incidence in patients receiving prophylactic rectal NSAIDs. TRIAL REGISTRATION: EudraCT: 2015-000829-37 . Registered on 18 February 2015. ISRCTN: 13659155 . Registered on 18 May 2015.

USP7 inhibition alters homologous recombination repair and targets CLL cells independently of ATM/p53 functional status.

The role of deubiquitylase ubiquitin-specific protease 7 (USP7) in the regulation of the p53-dependent DNA damage response (DDR) pathway is well established. Whereas previous studies have mostly focused on the mechanisms underlying how USP7 directly controls p53 stability, we recently showed that USP7 modulates the stability of the DNA damage responsive E3 ubiquitin ligase RAD18. This suggests that targeting USP7 may have therapeutic potential even in tumors with defective p53 or ibrutinib resistance. To test this hypothesis, we studied the effect of USP7 inhibition in chronic lymphocytic leukemia (CLL) where the ataxia telangiectasia mutated (ATM)-p53 pathway is inactivated with relatively high frequency, leading to treatment resistance and poor clinical outcome. We demonstrate that USP7 is upregulated in CLL cells, and its loss or inhibition disrupts homologous recombination repair (HRR). Consequently, USP7 inhibition induces significant tumor-cell killing independently of ATM and p53 through the accumulation of genotoxic levels of DNA damage. Moreover, USP7 inhibition sensitized p53-defective, chemotherapy-resistant CLL cells to clinically achievable doses of HRR-inducing chemotherapeutic agents in vitro and in vivo in a murine xenograft model. Together, these results identify USP7 as a promising therapeutic target for the treatment of hematological malignancies with DDR defects, where ATM/p53-dependent apoptosis is compromised.

Same-admission versus interval cholecystectomy for mild gallstone pancreatitis (PONCHO): a multicentre randomised controlled trial.

BACKGROUND: In patients with mild gallstone pancreatitis, cholecystectomy during the same hospital admission might reduce the risk of recurrent gallstone-related complications, compared with the more commonly used strategy of interval cholecystectomy. However, evidence to support same-admission cholecystectomy is poor, and concerns exist about an increased risk of cholecystectomy-related complications with this approach. In this study, we aimed to compare same-admission and interval cholecystectomy, with the hypothesis that same-admission cholecystectomy would reduce the risk of recurrent gallstone-related complications without increasing the difficulty of surgery. METHODS: For this multicentre, parallel-group, assessor-masked, randomised controlled superiority trial, inpatients recovering from mild gallstone pancreatitis at 23 hospitals in the Netherlands (with hospital discharge foreseen within 48 h) were assessed for eligibility. Adult patients (aged ≥18 years) were eligible for randomisation if they had a serum C-reactive protein concentration less than 100 mg/L, no need for opioid analgesics, and could tolerate a normal oral diet. Patients with American Society of Anesthesiologists (ASA) class III physical status who were older than 75 years of age, all ASA class IV patients, those with chronic pancreatitis, and those with ongoing alcohol misuse were excluded. A central study coordinator randomly assigned eligible patients (1:1) by computer-based randomisation, with varying block sizes of two and four patients, to cholecystectomy within 3 days of randomisation (same-admission cholecystectomy) or to discharge and cholecystectomy 25-30 days after randomisation (interval cholecystectomy). Randomisation was stratified by centre and by whether or not endoscopic sphincterotomy had been done. Neither investigators nor participants were masked to group assignment. The primary endpoint was a composite of readmission for recurrent gallstone-related complications (pancreatitis, cholangitis, cholecystitis, choledocholithiasis needing endoscopic intervention, or gallstone colic) or mortality within 6 months after randomisation, analysed by intention to treat. The trial was designed to reduce the incidence of the primary endpoint from 8% in the interval group to 1% in the same-admission group. Safety endpoints included bile duct leakage and other complications necessitating re-intervention. This trial is registered with Current Controlled Trials, number ISRCTN72764151, and is complete. FINDINGS: Between Dec 22, 2010, and Aug 19, 2013, 266 inpatients from 23 hospitals in the Netherlands were randomly assigned to interval cholecystectomy (n=137) or same-admission cholecystectomy (n=129). One patient from each group was excluded from the final analyses, because of an incorrect diagnosis of pancreatitis in one patient (in the interval group) and discontinued follow-up in the other (in the same-admission group). The primary endpoint occurred in 23 (17%) of 136 patients in the interval group and in six (5%) of 128 patients in the same-admission group (risk ratio 0·28, 95% CI 0·12-0·66; p=0·002). Safety endpoints occurred in four patients: one case of bile duct leakage and one case of postoperative bleeding in each group. All of these were serious adverse events and were judged to be treatment related, but none led to death. INTERPRETATION: Compared with interval cholecystectomy, same-admission cholecystectomy reduced the rate of recurrent gallstone-related complications in patients with mild gallstone pancreatitis, with a very low risk of cholecystectomy-related complications. FUNDING: Dutch Digestive Disease Foundation.

Which Lymph Nodes Contain Metastases in Colon Cancer Patients? A Retrospective Histopathological Evaluation of 156 Patients.

BACKGROUND: We hypothesized that a reliable N0 status can be established by sampling and evaluating the largest lymph nodes in the resected large-bowel specimen of patients with colon cancer. PATIENTS AND METHODS: This was a retrospective analysis of all surgical colon cancer patients treated between 2008 and 2010, excluding those who had received neoadjuvant treatment. We analyzed the relationship between lymph node size and the presence of metastasis. Furthermore, we examined other prognostic factors for a histopathological N+ status. RESULTS: Our patient group consisted of 156 patients with a median age of 73 years (range = 29-91 years). A total of 2044 lymph nodes (a median of 12 per patient, range = 2-47 nodes) were harvested, 1803 (88.2%) without and 241 (11.8%) with tumor spread. Using a unique ranking model, we found that in 58 out of the 59 N+ patients (98.3%, 95% confidence interval = 90.9% to 99.9%), the largest tumor-positive node was among the 5 largest lymph nodes in the specimen. The examination of ≥10 lymph nodes had no effect on the chance of finding a positive lymph node compared with examination of <10 nodes (P = .46). CONCLUSION: In our study, the N-stage was determined by the 5 largest nodes in almost all specimens. The chance of finding a small tumor-positive node when the larger ones were clean was very small.

Lymph Node Yield in Colon Cancer: Individuals Can Make the Difference.

AIM: To investigate the influence of individual surgeons and pathologists on examining an adequate (i.e. ≥10) number of lymph nodes in colon cancer resection specimens. PATIENTS AND METHODS: The number of lymph nodes was evaluated in surgically treated patients for colon cancer at our hospital from 2008 through 2010, excluding patients who had received neo-adjuvant treatment. The patient group consisted of 156 patients with a median age of 73 (interquartile range (IQR) 63-82 years) and a median of 12 lymph nodes per patient (IQR 8-15). In 106 patients (67.9%), 10 or more nodes were histopathologically examined. RESULTS: At univariate analysis, the examination of ≥10 nodes was influenced by tumour size (p = 0.05), tumour location (p = 0.015), type of resection (p = 0.034), individual surgeon (p = 0.023), and pathologist (p = 0.005). Neither individual surgeons nor pathologists did statistically and significantly influence the chance of finding an N+ status. Age (p = 0.044), type of resection (p = 0.007), individual surgeon (p = 0.012) and pathologist (p = 0.004) were independent prognostic factors in a multivariate model for finding ≥10 nodes. CONCLUSION: Though cancer staging was not affected in this study, individual efforts by surgeons and pathologists play a critical role in achieving optimal lymph node yield through conventional methods.

PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains.

Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT) are transcriptional regulators required for efficient expression of several growth promoting and antiapoptotic genes as well as for cell-cycle progression. BET proteins are recruited on transcriptionally active chromatin via their two N-terminal bromodomains (BRD), a protein interaction module that specifically recognizes acetylated lysine residues in histones H3 and H4. Inhibition of the BET-histone interaction results in transcriptional downregulation of a number of oncogenes, providing a novel pharmacologic strategy for the treatment of cancer. Here, we present a potent and highly selective dihydroquinazoline-2-one inhibitor, PFI-1, which efficiently blocks the interaction of BET BRDs with acetylated histone tails. Cocrystal structures showed that PFI-1 acts as an acetyl-lysine (Kac) mimetic inhibitor efficiently occupying the Kac binding site in BRD4 and BRD2. PFI-1 has antiproliferative effects on leukemic cell lines and efficiently abrogates their clonogenic growth. Exposure of sensitive cell lines with PFI-1 results in G1 cell-cycle arrest, downregulation of MYC expression, as well as induction of apoptosis and induces differentiation of primary leukemic blasts. Intriguingly, cells exposed to PFI-1 showed significant downregulation of Aurora B kinase, thus attenuating phosphorylation of the Aurora substrate H3S10, providing an alternative strategy for the specific inhibition of this well-established oncology target.

Laparoscopic partial cholecystectomy for the difficult gallbladder: a systematic review.

BACKGROUND: In the setting of difficult dissection of Calot's triangle during laparoscopic cholecystectomy, conversion is commonly advocated. An alternative approach aimed at preventing bile duct injury is laparoscopic partial cholecystectomy (LPC). The safety and efficacy of this procedure are unclear. METHODS: A systematic review of the literature was performed independently by three researchers. The outcomes were conversion rate, hospital length of stay (LOS), bile duct injury, bile leak, symptomatic gallstones in the remnant gallbladder, need for reoperation, postoperative endoscopic retrograde cholangiopancreaticography (ERCP), percutaneous intervention, and mortality. RESULTS: The review included 15 publications, which reported on 625 patients. Four different operative techniques could be distinguished. Conversion to open (partial) cholecystectomy was performed in 10.4 % of the cases. The median LOS was 4.5 days (range, 0-48 days). The most common complication was postoperative bile leak, which occurred in 66 patients (10.6 %). One case of bile duct injury occurred. During the follow-up period, 2.2 % of the patients experienced recurrent symptoms of gallstones. Eight patients (2.7 %) underwent reoperation. Postoperative ERCP was performed for 26 (7.5 %) of 349 patients. A percutaneous intervention was performed for 5 (1.4 %) of 353 patients. Three deaths were described in the reviewed series (1 of pulmonary sepsis and 2 of myocardial infarctions). A rough comparison showed that fewer bile leaks, less need for ERCP, and less recurrent symptoms of gallstones seemed to occur when the cystic duct and gallbladder remnant were closed. CONCLUSIONS: Literature concerning LPC is scarce. Four different LPC techniques can be distinguished. When a difficult gallbladder is encountered during LC, LPC seems to be a safe and feasible alternative to conversion. Closing of the cystic duct, gallbladder remnant, or both seems to be preferable.

The impact of maternal age on the effects of prenatal alcohol exposure on attention.

BACKGROUND: Prenatal exposure to alcohol has a variety of morphologic and neurobehavioral consequences, yet more than 10% of women continue to drink during pregnancy, placing their offspring at risk for fetal alcohol spectrum disorders (FASD). Identification of at-risk pregnancies has been difficult, in part, because the presence and severity of FASD are influenced by factors beyond the pattern of alcohol consumption. Establishing maternal characteristics, such as maternal age, that increase the risk of FASD is critical for targeted pregnancy intervention. METHODS: We examined the moderating effect of maternal age on measures of attention in 462 children from a longitudinal cohort born to women with known alcohol consumption levels (absolute ounces of alcohol per day at conception) who were recruited during pregnancy. Analyses examined the impact of binge drinking, as average ounces of absolute alcohol per drinking day. Smoking and use of cocaine, marijuana, and opiates were also assessed. At 7 years of age, the children completed the Continuous Performance Test, and their teachers completed the Achenbach Teacher Report Form. RESULTS: After controlling for covariates, stepwise multiple regression analyses revealed a negative relation between levels of prenatal binge drinking and several measures of attention. The interaction between alcohol consumption and maternal age was also significant, indicating that the impact of maternal binge drinking during pregnancy on attention was greater among children born to older drinking mothers. CONCLUSION: These findings are consistent with previous findings that children born to older alcohol-using women have more deleterious effects of prenatal alcohol exposure on other neurobehavioral outcomes.