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Purpose: Recently introduced hybrid 2-[18 F]-fluoro-2-deoxy-D-glucose (18 F-FDG) Positron Emission Tomography (PET) combined with Magnetic Resonance Imaging (MRI) may aid in proper diagnosis and staging of perihilar cholangiocarcinoma (pCCA). The aim of this study is to assess the effect of 18 F-FDG PET/MRI on diagnosis and clinical decision making in the pre-operative work up of pCCA. Methods: In this single-centre pilot study patients with presumed resectable pCCA underwent state-of-the-art 18 F-FDG hybrid PET/MRI using digital silicone photomultiplier detectors integrated within a 3-Tesla bore. Data were collected on several baseline and imaging characteristics. The primary outcome measure was the added diagnostic information and the effect on clinical decision making. Secondary aim was to correlate quantitative PET signal intensity to patient- and tumour characteristics. High and low SUVmax subgroups related to the mean value were made. Significance of lesion- and patient characteristics with the high and low SUVmax subgroups, as well as TLR and TBR, was evaluated with Fisher's exact test or Mann-Whitney-U test. Results: In total 14 patients were included (mean age 62.4 years, 64% male). Final diagnosis was pCCA in 10 patients (71.4%), follicular lymphoma in one patient (7.1%) and benign disease in the remaining three patients. FDG-PET/MRI added valuable diagnostic information in six (43%) patients and affected clinical decision making in two of these patients (14%) by increasing confidence for malignancy which lead to the decision for surgery on short term. High SUVmax values were seen in half of cases with pCCA and half of cases with non-cancerous lesions. In addition, high SUVmax values were directly associated with primary sclerosing cholangitis when present (p = 0.03). Conclusion: Simultaneous 18 F-FDG-PET/MRI added diagnostic information in six of fourteen patients and influenced clinical decision making in two patients (14%) with presumed resectable pCCA. [ABSTRACT FROM AUTHOR]

Aim: To facilitate midline fascial closure in complex abdominal wall surgery, component separation techniques (CST) are usually required. However, CST is associated with an enlarged morbidity. Prehabilitation could increase the compliance of the abdominal wall and thereby decrease the necessity of myofascial release. This can be accomplished by administration of botulinum toxin type A (BTA) in the lateral abdominal wall musculature. The aim of this study was to determine the effect of BTA on the subsequent necessity to perform CST in patients with complex abdominal wall hernias. Methods: Patients with a complex abdominal wall hernia, planned to undergo CST between July 2020 and November 2022 were included. Outcome of procedures with 300U of BTA 4 (2–6) weeks prior to surgery, were retrospectively analyzed by comparison with propensity matched subjects of an historical group. Hernia width difference was assessed by CT and operative details were included. Results: A total of 13 patients with a median hernia width of 12 cm (IQR 9–14, range 24) were prehabilitated with BTA between July 2020 and November 2022. A CST was planned for all, however not required in 6/13 patients (46%) to accomplish midline fascial closure. A mean elongation of lateral abdominal wall musculature of 4.01 cm was seen in patients not requiring CST. Compared to the propensity score matched control group, a 27% reduction (p = 0.08) in the need for CST was observed. Conclusion: There is a tendency for decrease of necessity for CST by preoperatively administered BTA in patients with complex abdominal wall defects. Although small, as this study used propensity matched comparison, further exploration of BTA should be encouraged. [ABSTRACT FROM AUTHOR]

Background: Patients often need admission at an Intensive Care Unit (ICU), immediately after complex abdominal wall reconstruction (CAWR). Lack of ICU resources requires adequate patient selection for a planned postoperative ICU admission. Risk stratification tools like Fischer score and Hernia Patient Wound (HPW) classification may improve patient selection. This study evaluates the decision-making process in a multidisciplinary team (MDT) on justified ICU admissions for patients after CAWR. Methods: A pre-Covid-19 pandemic cohort of patients, discussed in a MDT and subsequently underwent CAWR between 2016 and 2019, was analyzed. A justified ICU admission was defined by any intervention within the first 24 h postoperatively, considered not suitable for a nursing ward. The Fischer score predicts postoperative respiratory failure by eight parameters and a high score (> 2) warrants ICU admission. The HPW classification ranks complexity of hernia (size), patient (comorbidities) and wound (infected surgical field) in four stages, with increasing risk for postoperative complications. Stages II–IV point to ICU admission. Accuracy of the MDT decision and (modifications of) risk-stratification tools on justified ICU admissions were analyzed by backward stepwise multivariate logistic regression analysis. Results: Pre-operatively, the MDT decided a planned ICU admission in 38% of all 232 CAWR patients. Intra-operative events changed the MDT decision in 15% of all CAWR patients. MDT overestimated ICU need in 45% of ICU planned patients and underestimated in 10% of nursing ward planned patients. Ultimately, 42% went to the ICU and 27% of all 232 CAWR patients were justified ICU patients. MDT accuracy was higher than the Fischer score, HPW classification or any modification of these risk stratification tools. Conclusion: A MDT's decision for a planned ICU admission after complex abdominal wall reconstruction was more accurate than any of the other risk-stratifying tools. Fifteen percent of the patients experienced unexpected operative events that changed the MDT decision. This study demonstrated the added value of a MDT in the care pathway of patients with complex abdominal wall hernias. [ABSTRACT FROM AUTHOR]

Purpose: Surgical site occurrences after transversus abdominis release in ventral hernia repair are still reported up to 15%. Evidence is rising that preoperative improvement of risk factors might contribute to optimal patient recovery. A reduction of complication rates up to 40% has been reported. The aim of this study was to determine whether prehabilitation has a favorable effect on the risk on wound and medical complications as well as on length of stay. Methods: A retrospective cohort study was performed in a tertiary referral center for abdominal wall surgery. All patients undergoing ventral hernia repair discussed at multidisciplinary team (MDT) meetings between 2015 and 2019 were included. Patients referred for a preconditioning program by the MDT were compared to patients who were deemed fit for operative repair by the MDT, without such a program. Endpoints were patients, hernia, and procedure characteristics as well as length of hospital stay, wound and general complications. Results: A total of 259 patients were included of which 126 received a preconditioning program. Baseline characteristics between the two groups were statistically significantly different as the prehabilitated group had higher median BMI (28 vs 30, p < 0.001), higher HbA1c (41 vs 48, p = 0.014), more smokers (4% vs 25%, p < 0.001) and higher HPW classes due to more patient factors (14% vs 48%, p < 0.001). There were no significant differences in intra-operative and postoperative outcome measures. Conclusions: This study showed prehabilitation facilitates patients with relevant comorbidities achieving the same results as patients without those risk factors. The indication of a preconditioning program might be effective at the discretion of an MDT meeting. Further research could focus on the extent of such program to assess its value. [ABSTRACT FROM AUTHOR]

Background: During ileal pouch-anal anastomosis (IPAA) surgery for ulcerative colitis (UC), rectal dissection can be performed via close rectal dissection (CRD) or in a total mesorectal excision plane (TME). Although CRD should protect autonomic nerve function, this technique may be more challenging than TME. The aim of this study was to compare long-term outcomes of patients undergoing CRD and TME. Methods: This single-centre retrospective cohort study included consecutive patients who underwent IPAA surgery for UC between January 2002 and October 2017. Primary outcomes were chronic pouch failure (PF) among patients who underwent CRD and TME and the association between CRD and developing chronic PF. Chronic PF was defined as a pouch-related complication occurring ≥ 3 months after primary IPAA surgery requiring redo pouch surgery, pouch excision or permanent defunctioning ileostomy. Secondary outcomes were risk factors and causes for chronic PF. Pouch function and quality of life were assessed via the Pouch dysfunction score and Cleveland global quality of life score. Results: Out of 289 patients (155 males, median age 37 years [interquartile range 26.5–45.5 years]), 128 underwent CRD. There was a shorter median postoperative follow-up for CRD patients than for TME patients (3.7 vs 10.9 years, p < 0.01). Chronic PF occurred in 6 (4.7%) CRD patients and 20 (12.4%) TME patients. The failure-free pouch survival rate 3 years after IPAA surgery was comparable among CRD and TME patients (96.1% vs. 93.5%, p = 0.5). CRD was a no predictor for developing chronic PF on univariate analyses (HR 0.7 CI-95 0.3–2.0, p = 0.54). A lower proportion of CRD patients developed chronic PF due to a septic cause (1% vs 6%, p = 0.03). Conclusions: Although differences in chronic PF among CRD and TME patients were not observed, a trend toward TME patients developing chronic pelvic sepsis was detected. Surgeons may consider performing CRD during IPAA surgery for UC. [ABSTRACT FROM AUTHOR]

This letter discusses the potential benefits of psychological prehabilitation in complex abdominal wall reconstruction surgery. The authors argue that while current approaches focus on physical comorbidities, addressing mental health before surgery could lead to improved patient outcomes. However, the authors note that there is currently no literature on psychological prehabilitation in this specific context, and more research is needed to determine its effectiveness and design. The authors propose incorporating psychological screening into a multidisciplinary approach to better understand and address patient risk factors. [Extracted from the article]

This article, published in the journal Endoscopy, discusses the diagnostic accuracy of different biopsy techniques for the diagnosis of indeterminate biliary duct strictures (IBDS). The study compared the diagnostic yield of digital single operator cholangioscopy (d-SOC) guided single standard biopsies to those obtained via bite-on-bite-biopsy (BBB) technique in patients with IBDS. The results showed that both biopsy techniques had similar accuracy, with no significant difference in diagnostic yield. However, prior manipulation of the IBDS, such as stent placement or prior tissue acquisition, was associated with a decreased yield. Overall, the study provides valuable insights into the optimal biopsy technique for diagnosing IBDS. [Extracted from the article]

Purpose: MYC gene rearrangements in diffuse large B-cell lymphoma (DLBCL) patients are associated with poor prognosis. Our aim was to compare patterns of 2[18F]fluoro-2-deoxy-D-glucose positron emission tomography computed tomography (PET/CT) response in MYC + and MYC- DLBCL patients. Methods: Interim PET/CT (I-PET) and end of treatment PET/CT (EoT-PET) scans of 81 MYC + and 129 MYC- DLBCL patients from 2 HOVON trials were reviewed using the Deauville 5-point scale (DS). DS1-3 was regarded as negative and DS4-5 as positive. Standardized uptake values (SUV) and metabolic tumor volume (MTV) were quantified at baseline, I-PET, and EoT-PET. Negative (NPV) and positive predictive values (PPV) were calculated using 2-year overall survival. Results: MYC + DLBCL patients had significantly more positive EoT-PET scans than MYC- patients (32.5 vs 15.7%, p = 0.004). I-PET positivity rates were comparable (28.8 vs 23.8%). In MYC + patients 23.2% of the I-PET negative patients converted to positive at EoT-PET, vs only 2% for the MYC- patients (p = 0.002). Nine (34.6%) MYC + DLBCL showed initially uninvolved localizations at EoT-PET, compared to one (5.3%) MYC- patient. A total of 80.8% of EoT-PET positive MYC + patients showed both increased lesional SUV and MTV compared to I-PET. In MYC- patients, 31.6% showed increased SUV and 42.1% showed increased MTV. NPV of I-PET and EoT-PET was high for both MYC subgroups (81.8–94.1%). PPV was highest at EoT-PET for MYC + patients (61.5%). Conclusion: MYC + DLBCL patients demonstrate aberrant PET response patterns compared to MYC- patients with more frequent progression during treatment after I-PET negative assessment and new lesions at sites that were not initially involved. Trial registration number and date of registration: HOVON-84: EudraCT: 2006–005,174-42, retrospectively registered 01–08-2008. HOVON-130: EudraCT: 2014–002,654-39, registered 26–01-2015 [ABSTRACT FROM AUTHOR]

Key message: We identified cryptic early blight resistance introgressions in tomato breeding lines and demonstrated efficient genotypic selection for resistance in the context of a tomato breeding program. Early blight is a widespread and problematic disease affecting tomatoes (Solanum lycopersicum). Caused by the fungal pathogen Alternaria linariae (syn. A. tomatophila), symptoms include lesions on tomato stems, fruit, and foliage, often resulting in yield losses. Breeding tomatoes with genetic resistance would enhance production sustainability. Using cross-market breeding populations, we identified several quantitative trait loci (QTL) associated with early blight resistance. Early blight resistance putatively derived from 'Campbell 1943′ was confirmed in modern fresh market tomato breeding lines. This resistance offered substantial protection against early blight stem lesions (collar rot) and moderate protection from defoliation. A distinctive and potentially novel form of early blight foliar resistance was discovered in a processing tomato breeding line and is probably derived from S. pimpinellifolium via 'Hawaii 7998'. Additional field trials validated the three most promising large-effect QTL, EB-1.2, EB-5, and EB-9. Resistance effects for EB-5 and EB-9 were consistent across breeding populations and environments, while EB-1.2's effect was population specific. Using genome-wide marker-assisted backcrossing, we developed fresh market tomato lines that were near-isogenic for early blight QTL. Resistance in these lines was largely mediated by just two QTL, EB-5 and EB-9, that together captured 49.0 and 68.7% of the defoliation and stem lesion variance, respectively. Our work showcases the value of mining cryptic introgressions in tomato lines, and across market classes, for use as additional sources of disease resistance. [ABSTRACT FROM AUTHOR]

Introduction Adalimumab is effective for maintenance of remission in patients with Crohn’s disease (CD) at a dose of 40mg subcutaneously every 2 weeks. However, adalimumab is associated with (long-term) adverse events and is costly. The aim of this study is to demonstrate noninferiority and cost-effectiveness of disease activity guided adalimumab interval lengthening compared to standard dosing of every other week (EOW). Methods and analysis The Lengthening Adalimumab Dosing Interval (LADI) study is a pragmatic, multicentre, open label, randomised controlled non-inferiority trial. Non-inferiority is reached if the difference in cumulative incidence of persistent (>8 weeks) flares does not exceed the non-inferiority margin of 15%. 174CD patients on adalimumab maintenance therapy in longterm (>9 months) clinical and biochemical remission will be included (C-reactive protein (CRP) <10mg/L, faecal calprotectin (FC) <150 µg/g, Harvey-Bradshaw Index (HBI) <5). Patients will be randomised 2:1 into the intervention (adalimumab interval lengthening) or control group (adalimumab EOW). The intervention group will lengthen the adalimumab administration interval to every 3 weeks, and after 24 weeks to every 4 weeks. Clinical and biochemical disease activity will be monitored every 12 weeks by physician global assessment, HBI, CRP and FC. In case of disease flare, dosing will be increased. A flare is defined as two of three of the following criteria; FC>250 µg/g, CRP≥10 mg/l, HBI≥5. Secondary outcomes include cumulative incidence of transient flares, adverse events, predictors for successful dose reduction and cost effectiveness. Ethics and dissemination The study is approved by the Medical Ethics Committee Arnhem-Nijmegen, the Netherlands (registration number NL58948.091.16). Results will be published in peer-reviewed journals and presented at international conferences. [ABSTRACT FROM AUTHOR]

BRCA1/2 MUTATIONS IMPACT ON THE DEVELOPMENT OF BREAST IMPLANT-ASSOCIATED LYMPHOMA (BIA-ALCL) IN WOMEN WITH BREAST CANCER RECONSTRUCTED WITH TEXTURED BREAST IMPLANTS B Introduction: b Breast Implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a subtype of T-cell lymphoma arising as a seroma and/or mass in relation to the capsule of textured breast implants. Here we analyze the risk of BIA-ALCL occurrence related to BRCA in a large population of women with implants followed long term after breast cancer (BC) mastectomy. [Extracted from the article]

Many marine animals depend upon a larval phase of their life cycle to locate suitable habitat, and larvae use light detection to influence swimming behaviour and dispersal. Light detection is mediated by the opsin genes, which encode light-sensitive transmembrane proteins. Previous studies suggest that r-opsins in the eyes mediate locomotory behaviour in marine protostomes, but few have provided direct evidence through gene mutagenesis. Larvae of the marine annelid Capitella teleta have simple eyespots and are positively phototactic, although the molecular components that mediate this behaviour are unknown. Here, we characterize the spatio-temporal expression of the rhabdomeric opsin genes in C. teleta and show that a single rhabdomeric opsin gene, Ct-r-opsin1, is expressed in the larval photoreceptor cells. To investigate its function, Ct-r-opsin1 was disrupted using CRISPR/CAS9 mutagenesis. Polymerase chain reaction amplification and DNA sequencing demonstrated efficient editing of the Ct-r-opsin1 locus. In addition, the pattern of Ct-r-opsin1 expression in photoreceptor cells was altered. Notably, there was a significant decrease in larval phototaxis, although the eyespot photoreceptor cell and associated pigment cell formed normally and persisted in Ct-r-opsin1-mutant animals. The loss of phototaxis owing to mutations in Ct-r-opsin1 is similar to that observed when the entire photoreceptor and pigment cell are deleted, demonstrating that a single r-opsin gene is sufficient to mediate phototaxis in C. teleta. These results establish the feasibility of gene editing in animals like C. teleta, and extend previous work on the development, evolution and function of the C. teleta visual system. Our study represents one example of disruption of animal behaviour by gene editing through CRISPR/CAS9 mutagenesis, and has broad implications for performing genome editing studies in a wide variety of other understudied animals. [ABSTRACT FROM AUTHOR]

Burkitt lymphoma is an aggressive B cell malignancy accounting for 1-2% of all adult lymphomas. Treatment with dose-intensive, multi-agent chemotherapy is effective but associated with considerable toxicity. In this observational study, we compared real-world efficacy, toxicity, and costs of four frequently employed treatment strategies for Burkitt lymphoma: the Lymphome Malins B (LMB), the Berlin-Frankfurt-Münster (BFM), the HOVON, and the CODOX-M/IVAC regimens. We collected data from 147 adult patients treated in eight referral centers. Following central pathology assessment, 105 of these cases were accepted as Burkitt lymphoma, resulting in the following treatment groups: LMB 36 patients, BFM 19 patients, HOVON 29 patients, and CODOX-M/IVAC 21 patients (median age 39 years, range 14-74; mean duration of follow-up 47 months). There was no significant difference between age, sex ratio, disease stage, or percentage HIV-positive patients between the treatment groups. Five-year progression-free survival (69%, p = 0.966) and 5-year overall survival (69%, p = 0.981) were comparable for all treatment groups. Treatment-related toxicity was also comparable with only hepatotoxicity seen more frequently in the CODOX/M-IVAC group (p = 0.004). Costs were determined by the number of rituximab gifts and the number of inpatients days. Overall, CODOX-M/IVAC had the most beneficial profile with regards to costs, treatment duration, and percentage of patients completing planned treatment. We conclude that the four treatment protocols for Burkitt lymphoma yield nearly identical results with regards to efficacy and safety but differ in treatment duration and costs. These differences may help guide future choice of treatment. [ABSTRACT FROM AUTHOR]

Solid-supported membranes have become a common tool to study lipid membrane properties in a controlled environment. One particular example is the study of membrane curvature and its effect on lipid sorting. Here we simulate solid-supported membranes using the coarse grain molecular dynamics Martini force field.We characterize basic properties of the solid surfaces and lipid membranes deposited on them. Subsequently we construct large, solid ridges and use them to induce curvature in DOPC membranes. We study membrane properties, such as lateral diffusion and tail order parameters, relative to the curved membrane. Finally, we study the effect of the induced curvature on lateral lipid sorting in a ternary lipid membrane. Thus, we obtain comprehensive and microscopic insight into the impact of curvature on a lipid membrane in terms of structure and dynamics. [ABSTRACT FROM AUTHOR]

Aim To examine the effects of current smoking status on disease characteristics in patients with Crohn's disease (CD). Method CD patients were asked to fill in a questionnaire about their smoking habits. Their disease characteristics were obtained from medical records. Results The questionnaires were sent to 614 CD patients, and 263 completed the questionnaire. Of them, 252 were included in the statistical analysis. Compared to respondents who never smoked, current smokers had a trend toward the use of more tumour necrosis factor (TNF)-inhibitors, being diagnosed with fistulas, and undergoing bowel surgery more often. Eighty-percent of current smokers were willing to quit smoking. Conclusion The authors found significant differences in the development of fistulas and having bowel surgery in smokers compared with patients who stopped smoking. No differences were found in the use of TNF-inhibitors. Moreover, the proportion of patients willing to quit smoking was high. Therefore, programmes supporting patients to quit smoking may be advocated. [ABSTRACT FROM AUTHOR]

An important part of the scientific literature looks upon undercover policing from a normative, critical point of view. These studies frequently problematize undercover operations as a necessary evil. Yet what do we actually know about the practice of the execution of undercover operations and about the results they yield for criminal investigations? Not much. Little empirical research has been done on this subject. This article analyses the implementation and results of undercover operations in the Netherlands. The empirical data consist of all covert policing operations in the Netherlands in 2004. The authors address the following questions: how often is this method of investigation deployed; what different types of undercover operations exist; and what results have these operations produced? Furthermore, they examine the history of undercover policing and look into the legislative debate. Finally, they explore some possible future developments in the use of undercover operations. [ABSTRACT FROM AUTHOR]

In the past decades, telecommunications traffic has grown explosively. There has been an enormous expansion of the use of mobile phones. In addition, the way in which these phones are used has changed as well. An ever growing number of mobile phones is connected to the Internet, and a growing share of communications take place through the Internet. As a result, communication gets increasingly fragmented, because of the various ways and channels available for communication. In this article, the authors discuss the possible implications of these developments for the use of the telephone tap as an investigative tool during criminal investigations. Furthermore, the authors examine the ways in which the internet tap can support or replace the use of the telephone tap. Finally, alternative investigation tools are discussed that might compensate the changing results of the telephone tap. [ABSTRACT FROM AUTHOR]

Secondary peripheral chondrosarcoma is the result of malignant transformation of a pre-existing osteochondroma, the most common benign bone tumor. Osteochondromas are caused by genetic abnormalities in EXT1 or EXT2: homozygous deletion of EXT1 characterizes sporadic osteochondromas (non-familial/solitary), and germline mutations in EXT1 or EXT2 combined with loss of heterozygosity define hereditary multiple osteochondromas. While cells with homozygous inactivation of EXT and wild-type cells shape osteochondromas, the cellular composition of secondary peripheral chondrosarcomas and the role of EXT in their formation have remained unclear. We report using a targeted-tiling-resolution oligo-array-CGH (array comparative genomic hybridization) that homozygous deletions of EXT1 or EXT2 are much less frequently detected (2/17, 12%) in sporadic secondary peripheral chondrosarcomas than expected based on the assumption that they originate in sporadic osteochondromas, in which homozygous inactivation of EXT1 is found in ∼80% of our cases. FISH with an EXT1 probe confirmed that, unlike sporadic osteochondromas, cells from sporadic secondary peripheral chondrosarcomas predominantly retained one (hemizygous deleted loci) or both copies (wild-type) of the EXT1 locus. By immunohistochemistry, we confirm the presence of cells with dysfunctional EXT1 in sporadic osteochondromas and show cells with functional EXT1 in sporadic secondary peripheral chondrosarcomas. These immuno results were verified in osteochondromas and secondary peripheral chondrosarcomas in the setting of hereditary multiple osteochondromas. Our data therefore point to a model of oncogenesis in which the osteochondroma creates a niche in which wild-type cells with functional EXT are predisposed to acquire other mutations giving rise to secondary peripheral chondrosarcoma, indicating that EXT-independent mechanisms are involved in the pathogenesis of secondary peripheral chondrosarcoma. [ABSTRACT FROM AUTHOR]

Background: Previous reports correlated microalbuminuria with disease activity in patients with Crohn's disease (CD). The aim of the present study is to determine the value of microalbuminuria as a marker for relapses in quiescent CD. Methods: In a 1-year prospective maintenance trial with oral budesonide in patients with CD in remission, microalbuminuria was measured at randomization, after 2, 6 and 12 months, plus at the time of a relapse. The association of microalbuminuria with the course of disease was analyzed with logistic regression analysis. Time-dependent Cox regression was undertaken to study the association between microalbuminuria and relapse. Results: We included a total of 139 patients. At randomization, microalbuminuria was present in 8 patients. During a 1-year follow-up, 29 patients relapsed and in 11% (3/29), microalbuminuria was present during the relapse. We found no statistically significant association between microalbuminuria and relapse (odds ratio 0.92, 95% confidence interval (CI) 0.76-1.13). Time-dependent Cox regression analysis also revealed no statistical predictive value for microalbuminuria (hazard ratio 1.29, 95% CI 0.37-4.39, p = 0.68). Conclusion: Microalbuminuria was moderately prevalent in quiescent CD patients, but it could not be associated with disease characteristics or the type of medication before randomization, nor as a predictor for relapses. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We report the selection of enfuvirtide-resistant human immunodeficiency virus type 1 in cerebrospinal fluid, resulting in subsequent loss of viral suppression in the plasma. This case report emphasizes the potential danger of low-level penetration of entry inhibitors into the central nervous system. [ABSTRACT FROM AUTHOR]

Background: Colonoscopic surveillance provides the best practical means for preventing colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients. Strong evidence for improved survival from surveillance programmes is sparse.Method: The aim of this study was to compare tumour stage and survival of IBD patients with CRC who were a part of a surveillance programme with those who were not. A nationwide pathology database (PALGA (pathologisch anatomisch landelijk geautomatiseerd archief)) was consulted to identify IBD patients with CRC treated in all eight university hospitals in The Netherlands over a period of 15 years. Patients were assigned to the surveillance group when they had undergone one or more surveillance colonoscopies before a diagnosis of CRC. Patients who had not undergone surveillance served as controls. Tumour stage and survival were compared between the two groups.Results: A total of 149 patients with IBD-associated CRC were identified. Twenty-three had had colonoscopic surveillance before CRC was discovered. The 5-year CRC-related survival rate of patients in the surveillance group was 100% compared with 74% in the non-surveillance group (P=0.042). In the surveillance group, only one patient died as a consequence of CRC compared with 29 patients in the control group (P=0.047). In addition, more early tumour stages were found in the surveillance group (P=0.004).Conclusions: These results provide evidence for improved survival from colonoscopic surveillance in IBD patients by detecting CRC at a more favourable tumour stage. [ABSTRACT FROM AUTHOR]

Birt–Hogg–Dubé syndrome is a hereditary syndrome characterized by benign disease of skin and lungs and a risk of malignant renal tumors. We describe a clinical and genetic study of a large Dutch family with a novel mutation in the FLCN gene. Renal cancer at very young age occurred in one branch of this family, while in other branches, cutaneous and pulmonary symptoms predominated. A variety of congenital anomalies and connective tissue abnormalities were observed, possibly associated with the gene mutation. [ABSTRACT FROM AUTHOR]

Background: For patients with acute colitis, the decision when and how to operate is difficult in most cases. It was the aim of this systematic review to analyze early mortality and morbidity of colectomy for severe acute colitis in order to identify opportunities to improve perioperative treatment and outcome.Methods: A systematic review of the available literature in the Medline and PubMed databases from 1975 to 2007 was performed. All articles were assessed methodologically; the articles of poor methodological quality were excluded. Articles on laparoscopic colectomy for acute colitis were analyzed separately.Results: In total, 29 studies met the criteria for the systematic review, describing a total of 2,714 patients, 1,257 of whom were operated on in an acute setting, i.e., urgent or emergency colectomy. Reported in-hospital mortality was 8.0%; the 30-day mortality was 5.2%. Morbidity was 50.8%. The majority of complications were of infectious and thromboembolic nature. Over the last three decades, there was a shift in indications from toxic megacolon, from 71.1% in 1975-1984 to 21.6% in 1995-2005, to severe acute colitis not responding to conservative treatment, from 16.5% in 1975-1984 to 58.1% in 1995-2007. Mortality decreased from 10.0% to 1.8%. Morbidity remained high, exceeding 40% in the last decade. Mortality after laparoscopic surgery was 0.6%. Complication rate varies from 16-37%.Conclusion: Colectomy for acute colitis is complicated by considerable morbidity. The incidence of adverse outcome has substantially decreased over the last three decades, but further improvements are still required. The retrospective nature of the included studies allows for a considerable degree of selection bias that limits robust and clinically sound conclusions about both conventional and laparoscopic surgery. [ABSTRACT FROM AUTHOR]

Objective Prognosis in women with ovarian cancer mainly depends on International Federation of Gynecology and Obstetrics stage and the ability to perform optimal cytoreductive surgery. Since ovarian cancer has a heterogeneous presentation and clinical course, predicting progression-free survival (PFS) and overall survival (OS) in the individual patient is difficult. The objective of this study was to determine predictors of PFS and OS in women with advanced stage epithelial ovarian cancer (EOC) after primary cytoreductive surgery and first-line platinum-based chemotherapy. Design Retrospective observational study. Setting Two teaching hospitals and one university hospital in the south-western part of the Netherlands. Population Women with advanced stage EOC. Methods All women who underwent primary cytoreductive surgery for advanced stage EOC followed by first-line platinum-based chemotherapy between January 1998 and October 2004 were identified. To investigate independent predictors of PFS and OS, a Cox’ proportional hazard model was used. Nomograms were generated with the identified predictive parameters. Main outcome measures The primary outcome measure was OS and the secondary outcome measures were response and PFS. Results A total of 118 women entered the study protocol. Median PFS and OS were 15 and 44 months, respectively. Preoperative platelet count ( P = 0.007), and residual disease <1 cm ( P = 0.004) predicted PFS with a optimism corrected c-statistic of 0.63. Predictive parameters for OS were preoperative haemoglobin serum concentration ( P = 0.012), preoperative platelet counts ( P = 0.031) and residual disease <1 cm ( P = 0.028) with a optimism corrected c-statistic of 0.67. Conclusion PFS could be predicted by postoperative residual disease and preoperative platelet counts, whereas residual disease, preoperative platelet counts and preoperative haemoglobin serum concentration were predictive for OS. The proposed nomograms need to be externally validated. [ABSTRACT FROM AUTHOR]

It has become clear that the biological and clinical behaviour of malignant lymphoma is not only determined by the properties of the tumour cells themselves but are also largely by the interaction of the tumour cells with their nonmalignant microenvironment. The composition and functional status of the tumour microenvironment is highly variable between different classes of malignant lymphoma and may provide both growth-supportive and growth suppressive signals via components of the adaptive and innate immune response. In this review, the functional interactions and clinical consequences of these insights are discussed in indolent and aggressive B-cell lymphomas and in classical Hodgkin’s lymphoma. [ABSTRACT FROM AUTHOR]

Primary diffuse large B-cell lymphomas of different immune-privileged sites (IP-DLBCLs) share many clinical and biological features, such as a relatively poor prognosis, preferential dissemination to other immune-privileged sites, and deletion of the HLA region, which suggests that IP-DLBCL represents a separate entity. To further investigate the nature of IP-DLBCL, we investigated site-specific genomic aberrations in 16 testicular, nine central nervous system (CNS), and 15 nodal DLBCLs using array CGH. We also determined minimal common regions of gain and loss. Using robust algorithms including multiple testing procedures and the ACE-it script, which is specifically designed for this task, the array CGH data were combined with gene expression data to explore pathways deregulated by chromosomal aberrations. Loss of 6p21.32-p25.3, including the HLA genes, was associated with both types of IP-DLBCL, whereas gain of 2p16.1-p25.3 was associated with nodal DLBCL. Gain of 12q15-q21.1 and 12q24.32-q24.33 was associated with CNS DLBCL and gain of 19q13.12-q13.43 with testicular DLBCL. Analysis of candidate genes in site-specific regions and minimal common regions revealed two major groups of genes: one involved in the immune response, including regulation of HLA expression, and the other involved in apoptosis, including the p53 pathway. Many of these genes were also involved in homozygous deletions or high-level gains. The presence of both shared and site-specific aberrations in CNS and testicular DLBCLs underlines the concept of IP-DLBCL but also indicates that IP-DLBCLs of the CNS and testis do not form a single entity. The observed aberrations emphasize the importance of the deregulation of anti-tumour immune response and apoptosis pathways. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Most invasive breast cancers are classified as invasive ductal carcinoma not otherwise specified (IDC NOS), whereas about 25% are defined as histological 'special types'. These special-type breast cancers are categorized into at least 17 discrete pathological entities; however, whether these also constitute discrete molecular entities remains to be determined. Current therapy decision-making is increasingly governed by the molecular classification of breast cancer (luminal, basal-like, HER2+). The molecular classification is derived from mainly IDC NOS and it is unknown whether this classification applies to all histological subtypes. We aimed to refine the breast cancer classification systems by analysing a series of 11 histological special types [invasive lobular carcinoma (ILC), tubular, mucinous A, mucinous B, neuroendocrine, apocrine, IDC with osteoclastic giant cells, micropapillary, adenoid cystic, metaplastic, and medullary carcinoma] using immunohistochemistry and genome-wide gene expression profiling. Hierarchical clustering analysis confirmed that some histological special types constitute discrete entities, such as micropapillary carcinoma, but also revealed that others, including tubular and lobular carcinoma, are very similar at the transcriptome level. When classified by expression profiling, IDC NOS and ILC contain all molecular breast cancer types (ie luminal, basal-like, HER2+), whereas histological special-type cancers, apart from apocrine carcinoma, are homogeneous and only belong to one molecular subtype. Our analysis also revealed that some special types associated with a good prognosis, such as medullary and adenoid cystic carcinomas, display a poor prognosis basal-like transcriptome, providing strong circumstantial evidence that basal-like cancers constitute a heterogeneous group. Taken together, our results imply that the correct classification of breast cancers of special histological type will allow a more accurate prognostication of breast cancer patients and facilitate the identification of optimal therapeutic strategies. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background and aim: To detect precancerous dysplasia or asymptomatic cancer, patients suffering from inflammatory bowel disease often undergo colonoscopic surveillance based on American or British guidelines. It is recommended that surveillance is initiated after 8-10 years of extensive colitis, or after 15-20 years for left-sided disease. These starting points, however, are not based on solid scientific evidence. Our aim was to assess the time interval between onset of inflammatory bowel disease (IBD) and colorectal carcinoma (CRC), and subsequently evaluate how many patients developed cancer before their surveillance was recommended to commence. Methods: A nationwide automated pathology database (PALGA) was consulted to identify patients with IBD- associated colorectal carcinoma in seven university medical centres in The Netherlands between January 1990 and June 2006. Data were collected retrospectively from patient charts. Time intervals between onset of disease and cancer diagnosis were calculated in months. Results: 149 patients were identified with confirmed diagnoses of IBD and CRC (ulcerative colitis n = 89/Crohn's disease n = 59/indeterminate colitis n = 1). Taking date of diagnosis as the entry point, 22% of patients developed cancer before the 8 or 15 year starting points of surveillance, and 28% if surveillance was commenced 10 or 20 years after diagnosis for extensive or left-sided disease, respectively. Using onset of symptoms to calculate the time interval, 17-22% of patients would present with cancer prior to the surveillance starting points. Conclusions: These results show that the diagnosis of colorectal cancer is delayed or missed in a substantial number of patients (17-28%) when conducting surveillance strictly according to formal guidelines. [ABSTRACT FROM AUTHOR]

Seliciclib (R-roscovitine) is a cyclin-dependent kinase inhibitor in clinical development. It triggers apoptosis by inhibiting de novo transcription of the short-lived Mcl-1 protein, but it is unknown how this leads to Bax/Bak activation that is required for most forms of cell death. Here, we studied the effects of seliciclib in B-cell chronic lymphocytic leukemia (B-CLL), a malignancy with aberrant expression of apoptosis regulators. Although seliciclib-induced Mcl-1 degradation within 4 h, Bax/Bak activation occurred between 16 and 20 h. During this period, no transcriptional changes in apoptosis-related genes occurred. In untreated cells, prosurvival Mcl-1 was engaged by the proapoptotic proteins Noxa and Bim. Upon drug treatment, Bim was quickly released. The contribution of Noxa and Bim as a specific mediator of seliciclib-induced apoptosis was demonstrated via RNAi. Significantly, 16 h after seliciclib treatment, there was accumulation of Bcl-2, Bim and Bax in the ‘mitochondria-rich’ insoluble fraction of the cell. This suggests that after Mcl-1 degradation, the remaining apoptosis neutralizing capacity of Bcl-2 is gradually overwhelmed, until Bax forms large multimeric pores in the mitochondria. These data demonstrate in primary leukemic cells hierarchical binding and crosstalk among Bcl-2 members, and suggest that their functional interdependence can be exploited therapeutically.Cell Death and Differentiation (2007) 14, 1958–1967; doi:10.1038/sj.cdd.4402211; published online 17 August 2007 [ABSTRACT FROM AUTHOR]

Background A recent study reported that a non-synonymous single nucleotide polymorphism (rs11209026, p.Arg381Gln) located in the IL23R gene is a protective marker for inflammatory bowel disease. Aim To analyse the frequency of p.Arg381Gln in three independent European inflammatory bowel disease cohorts and to evaluate how this variant influences disease behaviour. Methods We assessed a European cohort of 919 inflammatory bowel disease patients and compared the IL23R p.Arg381Gln genotype frequency with 845 healthy controls. Inflammatory bowel disease patients originated from Germany [Crohn’s disease (CD): n = 318; ulcerative colitis (UC): n = 178], Hungary (CD: n = 148; UC: n = 118) and the Netherlands (CD: n = 157). Ethnically matched controls were included. We performed subtyping analysis in respect to CARD15 alterations and clinical characteristics. Results The frequency of the glutamine allele of p.Arg381Gln was significantly lower in inflammatory bowel disease patients compared with controls in a pooled analysis of all three cohorts ( P < 0.000001) as well as in the individual cohorts (Germany: P = 0.001, Hungary: P = 0.02 and the Netherlands: P = 0.0002). The p.Arg381Gln genotype distribution was similar between CD and UC. We did not observe either statistical interactions between p.Arg381Gln and CARD15 variants or any significant associations between p.Arg381Gln genotype and subphenotypes. Conclusions The p.Arg381Gln IL23R variant confers a protective effect against both CD and UC, but does not determine disease phenotype. [ABSTRACT FROM AUTHOR]

BIC is a primary microRNA (pri-miR-155) that can be processed to mature miR-155. In this study, we show the crucial involvement of protein kinase C (PKC) and nuclear factor-κB (NF-κB) in the regulation of BIC expression upon B-cell receptor triggering. Surprisingly, Northern blot analysis did not reveal any miR-155 expression upon induction of BIC expression in the Burkitt lymphoma-derived Ramos cell line, whereas other microRNAs were clearly detectable. Ectopic expression of BIC in Ramos and HEK293 cells resulted in miR-155 expression in HEK293, but not in Ramos cells, suggesting a specific block of BIC to miR-155 processing in Ramos. In line with the results obtained with Ramos, lack of miR-155 expression after induction of BIC expression was also observed in other Burkitt lymphoma cell lines, indicating a generic and specific blockade in the processing of BIC in Burkitt lymphoma. In contrast, induction of BIC expression in normal tonsillar B cells resulted in very high levels of miR-155 expression and induction of BIC expression in Hodgkin's lymphoma cell lines. It also resulted in elevated levels of miR-155. Our data provide evidence for two levels of regulation for mature miR-155 expression: one at the transcriptional level involving PKC and NF-κB, and one at the processing level. Burkitt lymphoma cells not only express low levels of BIC, but also prevent processing of BIC via an, as yet, unknown mechanism.Oncogene (2007) 26, 3769–3776. doi:10.1038/sj.onc.1210147; published online 18 December 2006 [ABSTRACT FROM AUTHOR]

Objectives: Suboptimal debulking (>1 cm residual tumor) results in poor survival rates for patients with an advanced stage of ovarian cancer. The purpose of this study was to develop a prediction model, based on simple preoperative parameters, for patients with an advanced stage of ovarian cancer who are at risk of suboptimal cytoreduction despite maximal surgical effort. Methods: Retrospective analysis of 187 consecutive patients with a suspected clinical diagnosis of advanced-stage ovarian cancer undergoing upfront debulking between January 1998 and December 2003. Preoperative parameters were Karnofsky performance status, ascites and serum concentrations of CA 125, hemoglobin, albumin, LDH and blood platelets. The main outcome parameter was residual tumor >1 cm. Univariate and multivariate logistic regression was employed for testing possible prediction models. A clinically applicable graphic model (nomogram) for this prediction was to be developed. Results: Serum concentrations of CA 125 and blood platelets in the group with residual tumor >1 cm were higher in comparison to the optimally cytoreduced group (p < 0.0001 and <0.01, respectively). Serum albumin and hemoglobin levels were lower in the group with residual tumor (p < 0.0001 and <0.05, respectively). The frequency of preoperative ascites was higher in the group with residual tumor (p < 0.0005). The prediction model, consisting of CA 125 and albumin, for remaining with residual tumor showed an area under the receiver operating characteristics curve of 0.79. A nomogram for probability of residual tumor >1 cm based on serum levels of CA 125 and albumin was established. Conclusion: Postoperative residual tumor despite maximal surgical effort can be predicted by preoperative CA 125 and serum albumin levels. With a nomogram based on these two parameters, probability of postoperative residual tumor in each individual patient can be predicted. This proposed nomogram may be valuable in daily routine practice for counseling and to select treatment modality. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the mechanism explaining the persistence of human immunodeficiency virus (HIV) type 1 variants with multiple protease inhibitor (PI)-resistance mutations in the absence of PI therapy. METHODS: Longitudinal genotypic analyses were performed on sequential samples obtained from 2 HIV-1-infected patients who had stopped PI therapy for 4 years. Replication capacity (RC) was determined using recombinant viruses. Subsequently, the effect that changing individual protease mutations back to wild type has on RC was analyzed. RESULTS: We observed prolonged persistence (up to 4 years) of viruses with multiple protease mutations after PI therapy was stopped, despite the fact that the RC of the viruses was severely reduced. Forcing the virus to evolve toward wild type by changing individual protease mutations to wild type was unsuccessful, because all variants displayed a decreased RC in comparison with that of their predecessors. CONCLUSIONS: We propose compensatory fixation as a mechanism for the in vivo persistence of variants with multiple PI-resistance mutations in the absence of PI therapy. Viruses with multiple PI mutations have (partially) compensated for the initial loss in RC. Therefore, reversion of a single mutation causes a (further) reduction in RC and, as a consequence, the route to wild type is blocked. Copyright © 2007 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

For over a century, centrifugal pumps (CP) have been used in various applications, from large industrial pumps to flow pumps for aquariums. However, the use of CP as blood pumps has a rather short history. Consequently, the hydraulic performance data for a blood CP are limited. The aim of our investigation was to study the hydraulic performance and the heat generation of three commercially available CP: Bio-Medicus Bio-Pump BP80 (Medtronic), Rotaflow (Jostra Medizintechnik), and DeltaStream™ DP2 (MEDOS Medizintechnik AQ). The study was performed using a circuit primed with a water-glycerin mixture with a dynamic viscosity of 0.00272 pa/s. Pressure-flow curves were obtained by a stepwise stagnation of the pump outlet or inlet. The temperature changes were observed using ThermaCAM SC2000 (Flir Systems). The pumps' performance in close to clinical conditions (‘operating region’) was analysed in this report. The ‘operating region’ in the case of the BP80 is positioned around the pressure-flow curve at a pump speed of 3000 rpm. In the case of the Rotaflow, the ‘operating region’ was between the pump pressure-flow curves at a speed of 3000 and 4000 rpm, and the DP2 was found between 7000 and 8000 rpm. The standard deviation of mean pressure through the pump was used to characterise the stability of the pump. In experiments with outlet stagnation, the BP80 demonstrated high negative association between flow and pressure variability (r=-/0.68, p <0.001). In experiments with the DP2, this association was positive (r=0.68, p < 0.001). All pumps demonstrated significantly higher variability of pressure in experiments with inlet stagnation in comparison to the experiments with outlet stagnation. The rise of relative temperature in the inlet of a pump was closely related to the flow rate. The heating of fluid was more pronounced in the ‘zero-flow’ mode, especially in experiments with inlet stagnation. In summary, (1) the ‘zero-flow’ regime, which is described in the manuals of some commercially-available pumps, is the use of the pump outside the allowable operating region. It is potentially dangerous and should, therefore, never be used in clinical settings. (2) Using centrifugal pumps for kinetic-assisted venous return can only be performed safely when the negative pressure at the inlet of the pump is monitored continuously. The maximum allowable negative pressure has to be defined for each type of pump, and must be based on pump performance. [ABSTRACT FROM AUTHOR]

Background: The differentiation of Alzheimer's disease (AD) from vascular dementia (VaD) is hampered by clinical diagnostic criteria with disappointing sensitivity and specificity. The objective of this study was to investigate whether cerebrospinal fluid (CSF) levels of total tau protein (t-tau), amyloid beta42 protein (Abeta42), and tau phosphorylated at threonine 181 (p-tau181) are useful biomarkers to distinguish AD patients from VaD patients.Methods: We measured CSF levels of p-tau181, Abeta42, and t-tau in 86 patients with a clinical diagnosis of AD or VaD and in 30 control participants.Results: Optimal differentiation between AD and VaD was achieved by using the ratio of the CSF levels of Abeta42 and p-tau181 (Q Abeta42/p-tau) with sensitivity, specificity, positive and negative predictive values all > or = 85%.Conclusions: Our results support further efforts to prospectively validate the use of Q Abeta42/p-tau as a biomarker to discriminate between AD and VaD. [ABSTRACT FROM AUTHOR]

Background: Accurate control of heparin anticoagulation is necessary during all stages of cardiopulmonary bypass (CPB). The activated clotting time, first described by Hattersley in 1966, is mostly used for determination of anticoagulation. Either celite or kaolin are used as activators. An ACT value of 480 sec is proposed to be the safe minimum level for anticoagulation during CPB. This study was designed to determine if the activated coagulation time (ACT) values of each analyser separately are repeatable, and to determine whether there exists a significant difference in ACT values measured by three different analysers: the GEM PCL (Instrumentation Laboratory), the Hemochron 801 (International Technidyne Corporation) and the ACT II Automated Coagulation Timer (Medtronic). Methods: All patients underwent cardiovascular surgical procedures requiring heparinisation (200–300 IU/kg). Blood samples for the measurement of the ACT were taken from all patients before and after heparinisation, during CPB, and after protamine administration. All samples were measured in duplicate with the three different analysers. To compare the activated clotting time data, the method described by Bland and Altman was used. The Pearson correlation coefficient was used to determine whether the differences were related to the average ACTs. p-Values B <0.05 were considered statistically significant. Results: The results showed that the three tested ACT analysers met the requirements of repeatability. The mean differences and standard deviations of the ACT values measured with the GEM PCL, the Hemochron 801, and the ACT II analyser were, respectively -8.78±37.61, -19.77±68.82, and -6.23±39.21, with p-values=0.177, 0.081 and 0.384, respectively. The Pearson correlation coefficients were too low (-0.012, -0.221 and -0.241, respectively) to show any correlation between the differences and the means. The ACT values measured with the Hemochron 801 were not significantly different from the ACT values measured with the ACT II analyser: ΔACT =-34.09 9±146.68, with p=0.132. However, the GEM PCL did not agree with the Hemochron 801: ΔACT=-80.2±143.06, with p=0.001, or the ACT II analyser: ΔACT = -119.13±138.51, with p <0.001. A rather strong correlation was evident between the differences and the means measured with the GEM PCL compared with the Hemochron 801 (r =0.68) and the ACT II analyser (r =0.76). Conclusions: All analysers used celite or kaolin as activator. However, it was evident that the ACT measurements depended also on the analyser that had been chosen. A precaution that ACT values could not always be interpreted in the same way seems to be necessary. [ABSTRACT FROM AUTHOR]

Gastric extranodal marginal zone lymphoma (EMZL) often shows prolonged localised disease, but the present study demonstrated the presence of tumour cells in peripheral blood (PB) of low stage patients. We studied the presence of tumour cells in PB in gastric lymphoma patients harbouring or lacking t(11;18)(q21;q21), by real-time immunoglobulin (Ig)H allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) and API2-MALT1 PCR. Tumour cells were exclusively detected in PB of t(11;18)(q21;q21)+-EMZL patients. The presence of tumour cells in PB and gastric biopsy follow-up samples showed a good correlation in these patients, suggesting clinical relevance for monitoring of tumour cells in PB of gastric t(11;18)(q21;q21)+-EMZL patients. [ABSTRACT FROM AUTHOR]