Neoadjuvant FOLFOXIRI prior to chemoradiotherapy for high-risk ("ugly") locally advanced rectal cancer: study protocol of a single-arm, multicentre, open-label, phase II trial (MEND-IT).

BACKGROUND: The presence of mesorectal fascia (MRF) invasion, grade 4 extramural venous invasion (EMVI), tumour deposits (TD) or extensive or bilateral extramesorectal (lateral) lymph nodes (LLN) on MRI has been suggested to identify patients with indisputable, extensive locally advanced rectal cancer (LARC), at high risk of treatment failure. The aim of this study is to evaluate whether or not intensified chemotherapy prior to neoadjuvant chemoradiotherapy improves the complete response (CR) rate in these patients. METHODS: This multicentre, single-arm, open-label, phase II trial will include 128 patients with non-metastatic high-risk LARC (hr-LARC), fit for triplet chemotherapy. To ensure a study population with indisputable, unfavourable prognostic characteristics, hr-LARC is defined as LARC with on baseline MRI at least one of the following characteristics; MRF invasion, EMVI grade 4, enlarged bilateral or extensive LLN at high risk of an incomplete resection, or TD. Exclusion criteria are the presence of a homozygous DPD deficiency, distant metastases, any chemotherapy within the past 6 months, previous radiotherapy within the pelvic area precluding standard chemoradiotherapy, and any contraindication for the planned treatment. All patients will be planned for six two-weekly cycles of FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) prior to chemoradiotherapy (25 × 2 Gy or 28 × 1.8 Gy with concomitant capecitabine). A resection will be performed following radiological confirmation of resectable disease after the completion of chemoradiotherapy. A watch and wait strategy is allowed in case of a clinical complete response. The primary endpoint is the CR rate, described as a pathological CR or a sustained clinical CR one year after chemoradiotherapy. The main secondary objectives are long-term oncological outcomes, radiological and pathological response, the number of resections with clear margins, treatment-related toxicity, perioperative complications, health-related costs, and quality of life. DISCUSSION: This trial protocol describes the MEND-IT study. The MEND-IT study aims to evaluate the CR rate after intensified chemotherapy prior to concomitant chemoradiotherapy in a homogeneous group of patients with locally advanced rectal cancer and indisputably unfavourable characteristics, defined as hr-LARC, in order to improve their prognosis. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04838496 , registered on 02-04-2021 Netherlands Trial Register: NL9790. PROTOCOL VERSION: Version 3 dd 11-4-2022.

The outcome of pulmonary hypertension and its association with pulmonary artery dilatation.

BACKGROUND: Pulmonary artery (PA) dilatation is often seen in pulmonary hypertension (PH) and is considered a long-term consequence of elevated pressure. The PA dilates over time and therefore may reflect disease severity and duration. Survival is related to the stage of the disease at the time of diagnosis and therefore PA diameter might be used to predict prognosis. This study evaluates the outcome of patients with pulmonary arterial hypertension (PAH) and chronic thrombo-embolic pulmonary hypertension (CTEPH) and investigates whether PA diameter at the time of diagnosis is associated with mortality. METHODS: Patients visiting an outpatient clinic of a tertiary centre between 2004 and 2018 with a cardiac catheterisation confirmed diagnosis of PAH or CTEPH and a CT scan available for PA diameter measurement were included. PA diameter and established predictors of survival were collected (New York Heart Association (NYHA) class, N­terminal pro-brain natriuretic peptide (NT-proBNP) level and 6­min walking distance (6MWD)). RESULTS: In total 217 patients were included (69% female, 71% NYHA class ≥III). During a median follow-up of 50 (22-92) months, 54% of the patients died. Overall survival was 87% at 1 year, 70% at 3 years and 58% at 5 years. The mean PA diameter was 34.2 ± 6.2 mm and was not significantly different among all the diagnosis groups. We found a weak correlation between PA diameter and mean PA pressure ( r = 0.23, p < 0.001). Male sex, higher age, shorter 6MWD and higher NT-proBNP level were independently associated with mortality, but PA diameter was not. CONCLUSION: The prognosis of PAH and CTEPH is still poor. Known predictors of survival were confirmed, but PA diameter at diagnosis was not associated with survival in PAH or CTEPH patients.

The diagnostic accuracy of local staging in colon cancer based on computed tomography (CT): evaluating the role of extramural venous invasion and tumour deposits.

PURPOSE: The shift from adjuvant to neoadjuvant treatment in colon cancer demands the radiological selection of patients for systemic therapy. The aim of this study was to evaluate the accuracy of the CT-based TNM stage and high-risk features, including extramural venous invasion (EMVI) and tumour deposits, in the identification of patients with histopathological advanced disease, currently considered for neoadjuvant treatment (T3-4 disease). METHODS: All consecutive patients surgically treated for non-metastatic colon cancer between January 2018 and January 2020 in a referral centre for colorectal cancer were identified retrospectively. All tumours were staged on CT according to the TNM classification system. Additionally, the presence of EMVI and tumour deposits on CT was evaluated. The histopathological TNM classification was used as reference standard. RESULTS: A total of 176 patients were included. Histopathological T3-4 colon cancer was present in 85.0% of the patients with CT-detected T3-4 disease. Histopathological T3-4 colon cancer was present in 96.4% of the patients with CT-detected T3-4 colon cancer in the presence of both CT-detected EMVI and CT-detected tumour deposits. Histopathological T0-2 colon cancer was present in 50.8% of the patients with CT-detected T0-2 disease, and in 32.4% of the patients without CT-detected EMVI and tumour deposits. CONCLUSION: The diagnostic accuracy of CT-based staging was comparable with previous studies. The presence of high-risk features on CT increased the probability of histopathological T3-4 colon cancer. However, a substantial part of the patients without CT-detected EMVI and tumour deposits was diagnosed with histopathological T3-4 disease. Hence, more accurate selection criteria are required to correctly identify patients with locally advanced disease.

Paediatric community-acquired septic shock: results from the REPEM network study.

UNLABELLED: INTRODUCTION AND PURPOSE OF THE STUDY: With this study we aimed to describe a "true world" picture of severe paediatric 'community-acquired' septic shock and establish the feasibility of a future prospective trial on early goal-directed therapy in children. During a 6-month to 1-year retrospective screening period in 16 emergency departments (ED) in 12 different countries, all children with severe sepsis and signs of decreased perfusion were included. RESULTS: A 270,461 paediatric ED consultations were screened, and 176 cases were identified. Significant comorbidity was present in 35.8 % of these cases. Intensive care admission was deemed necessary in 65.7 %, mechanical ventilation in 25.9 % and vasoactive medications in 42.9 %. The median amount of fluid given in the first 6 h was 30 ml/kg. The overall mortality in this sample was 4.5 %. Only 1.2 % of the survivors showed a substantial decrease in Paediatric Overall Performance Category (POPC). 'Severe' outcome (death or a decrease ≥2 in POPC) was significantly related (p < 0.01) to: any desaturation below 90 %, the amount of fluid given in the first 6 h, the need for and length of mechanical ventilation or vasoactive support, the use of dobutamine and a higher lactate or lower base excess but not to any variables of predisposition, infection or host response (as in the PIRO (Predisposition, Infection, Response, Organ dysfunction) concept). CONCLUSION: The outcome in our sample was very good. Many children received treatment early in their disease course, so avoiding subsequent intensive care. While certain variables predispose children to become septic and shocked, in our sample, only measures of organ dysfunction and concomitant treatment proved to be significantly related with outcome. We argue why future studies should rather be large multinational prospective observational trials and not necessarily randomised controlled trials.

Improved response rate in patients with prognostically poor locally advanced rectal cancer after treatment with induction chemotherapy and chemoradiotherapy when compared with chemoradiotherapy alone: A matched case-control study.

INTRODUCTION: The addition of induction chemotherapy (ICT) to neoadjuvant chemoradiotherapy (CRT) has the potential to improve outcomes in patients with locally advanced rectal cancer (LARC). However, patient selection is essential to prevent overtreatment. This study compared the complete response (CR) rate after treatment with and without ICT of LARC patients with prognostically poor characteristics. METHODS: All LARC patients who were treated with neoadjuvant CRT, whether or not preceded by ICT, and who underwent surgery or were considered for a wait-and-see strategy between January 2016 and March 2020 in the Catharina Hospital Eindhoven, were retrospectively selected. LARC was defined as any T4 tumour, or a T2/T3 tumour with extramural venous invasion and/or tumour deposits and/or N2 lymph node status, and/or mesorectal fascia involvement (T3 tumours only). Case-control matching was performed based on the aforementioned characteristics. RESULTS: Of 242 patients, 178 (74%) received CRT (CRT-group) and 64 patients (26%) received ICT followed by CRT (ICT-group). In the ICT-group, 3 patients (5%) did not receive the minimum of three cycles. In addition, in this selected cohort, compliance with radiotherapy was 100% in the ICT-group and 97% in the CRT-group. The CR rate was 30% in the ICT-group and 15% in the CRT-group (p = 0.011). After case-control matching, the CR rate was 28% and 9%, respectively (p = 0.013). CONCLUSION: Treatment including ICT seemed well tolerated and resulted in a high CR rate. Hence, this treatment strategy may facilitate organ preservation and improve survival in LARC patients with prognostically poor characteristics.

Work ability assessment in prolonged depressive illness.

BACKGROUND: Major depressive disorder (MDD) is a complex disease and therefore the assessment of work ability in patients with MDD is complicated. A checklist has been developed to support such assessment. AIMS: To assess the mean score and variation of work ability assessments undertaken by Dutch insurance physicians (IPs) in five real case history vignettes of MDD patients on long-term sick leave, with and without the aid of a checklist. METHODS: In a post-test-only randomized experiment, 25 IPs assessed work ability for five cases on a scale of 0-100 without the use of the checklist, while 21 IPs used the checklist. Differences between groups in mean and absolute variation of work ability were tested with independent t-tests. Intraclass correlation (ICC) analysis was used to determine inter-rater reliability. RESULTS: When using the checklist, the mean work ability score of all vignettes was 3-12 points higher than without its use. There was no difference in the variation in work ability scores per vignette and between groups. ICC was 0.64 for both groups. CONCLUSIONS: The use of the checklist increased the mean score of work ability but had no effect on the variation in scores between assessors. The inter-rater reliability was moderate, independent of the use of the checklist.

Anesthesia and perioperative management for a patient with Ullrich syndrome undergoing surgery for scoliosis.

Ullrich syndrome is a rare congenital hypotonic-sclerotic muscular disorder in which affected children develop a slowly progressive scoliosis and contractures and limpness of joints. The disease causes increasingly invalidating contractures and hardening of the muscles of the neck and trunk. While this neuromuscular type of scoliosis is progressive, patients rarely attain the point of surgery due to their compromised general medical condition. This may explain the current lack of outcome data and the paucity of information on perioperative management for patients with Ullrich syndrome undergoing major surgery. The purpose of this report was therefore to describe our first experience with the perioperative and anesthetic management of a 15-year-old boy presenting with Ullrich syndrome and a secondary invalidating scoliosis. The specific challenges of this condition characterized by severe restrictive lung disease and a challenging airway abnormality are discussed.

Federal polices affecting vaccine research and production.

The federal government is the single most important determinant of the extent of vaccine research, development, and use in the United States. Federal actions having a positive effect include the finacing of vaccine research and development and of major public immunization programs. Federal policies that may be contributing to a decline in the private sector's commitment to vaccine development include an unwillingness to resolve certain liability issues. The nation depends heavily on vaccines to prevent several childhood diseases. For that and other reasons, decisive government efforts are needed to help stimulate the creation of new vaccines and to ensure the continued supply and use of existing safe and efficacious vaccines.

Characterisation of exposure to total and hexavalent chromium of welders using biological monitoring.

Inhalation exposure to total and hexavalent chromium (TCr and HCr) was assessed by personal air sampling and biological monitoring in 53 welders and 20 references. Median inhalation exposure levels of TCr were 1.3, 6.0, and 5.4 microg/m(3) for welders of mild steel (MS, <5% alloys), high alloy steel (HAS, >5% alloys), and stainless steel (SS, >26% alloys), respectively. The median exposures to HCr compounds were 0.23, 0.20, and 0.08 microg/m(3), respectively. Median concentrations of TCr in urine, blood plasma and erythrocytes were elevated in all welders, compared with the corresponding median concentrations in the reference group (p<0.005). The TCr levels observed in plasma were two-fold higher in welders of SS and HAS than in welders of MS (p<0.01). Exposure to HCr as indicated by median total content of Cr in erythrocytes was 10 microg/L in welders of SS, MS and HAS. Uptake of TCr during the shift was confirmed for welders of SS by a median increase of urinary TCr from pre- to post-shift of 0.30 microg/g creatinine. For welders of MS and HAS as a group TCr was not increased.

Work ability in sick-listed patients with major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is often a chronic relapsing disease resulting in work disability. For evaluation purposes a practical set of aspects of work ability would be helpful. AIM: To identify the most important disease-specific aspects of work ability for sick-listed employees with MDD. METHODS: An expert brainstorming session identified the specific abilities that were thought to be associated with work ability in sick-listed employees with MDD and that could also be associated with the items of the Hamilton Rating scale for Depression. Sixty-four insurance physicians (IPs) were then selected to participate in a two-round Delphi study. The aim of the first Delphi round was to identify the abilities that were thought to be important by at least 80% of the IPs. In the second Delphi round, the abilities ranked in the top 10 by at least 55% of the IPs were identified as being the most important items. RESULTS: Sixty-one IPs participated in the two Delphi rounds. The most important abilities to be evaluated in work ability evaluation for sick-listed employees with MDD were to take notice, to sustain attention, to focus attention, to complete operations, to think in a goal-directed manner, to remember, to perform routine operations, to undertake structured work activities, to recall and to perform autonomously. CONCLUSION: According to 55% of the IPs, there were 10 important aspects of work ability that have to be considered in a work ability evaluation of sick-listed employees with MDD.

[Serious and sometimes fatal consequences of high-altitude pulmonary oedema]. / Ernstige en soms fatale gevolgen van hoogtelongoedeem.

Three women aged 25, 34 and 22 years respectively, experienced high-altitude pulmonary oedema during a climbing holiday. The first patient presented with complaints arising from a fast ascent to high altitude and was treated with acetazolamide and rapid descent. She recovered without any complications. The second patient developed symptoms during the night, which were not recognised as high-altitude pulmonary oedema. The next morning she died while being transported down on a stretcher without having received any medication or oxygen. The third case was not a specific presentation of high-altitude pulmonary oedema but autopsy revealed pulmonary oedema. This woman had already been higher up on the mountain before she developed complications. The cases illustrate the seriousness of this avoidable form of high altitude illness. The current Dutch national guidelines advise against the use of medication by lay people. A revision is warranted: travellers to high altitude should be encouraged to carry acetazolamide, nifedipine and corticosteroids on the trip. Travel guides ought to be trained to use these drugs. In addition climbing travellers should be encouraged to adopt appropriate preventive behaviour and to start descending as soon as signs of high-altitude pulmonary oedema develop.

Prognostic factors for work ability in sicklisted employees with chronic diseases.

OBJECTIVE: Identifying prognostic factors for work ability in sicklisted employees with myocardial infarction (MI), chronic low back pain (cLBP) and major depressive disorder (MDD) in order to establish an objective basis for work ability evaluation. DESIGN: Systematic literature search in PubMed database (1 January 1990 to 1 July 2006) with the Yale prognostic research filter. Inclusion criteria were as follows: (1) work-disabled employees; (2) MI, cLBP or MDD patients; (3) longitudinal designs; and (4) return to work or compensation status as outcome measure. RESULTS: four studies on mi met the inclusion criteria and described the following prognostic factors for work ability in the acute phase of the disease and disablement: lower age; male gender; no financial basis on which to retire; lower physical job demands; fewer somatic complaints; no anxiety attacks; no diabetes; no heart failure; no atrial fibrillation; no Q waves; and a short time interval between MI and presentation at the occupational medicine clinic. Two studies on cLBP met the inclusion criteria and described the following prognostic factors for work ability after 3 months' work disablement: lower age; male gender; no treatment before sick listing; surgery in the first year of sick listing; being a breadwinner; less pain; better general health; higher job satisfaction; lower physical and/or psychological demands at work; and a higher decision latitude at work. No relevant MDD studies were found. CONCLUSION: In the earlier phases of work disablement in MI and cLBP patients, only a few studies describe disease-specific, environmental and personal prognostic factors for return to work. No studies describe prognostic factors for MDD. More evidence is needed on the topic of prognostic factors for return to work in employees with chronic diseases.

Simulated impact of a fish based shift in the population n--3 fatty acids intake on exposure to dioxins and dioxin-like compounds.

Due to the favourable health effects of LC n-3 PUFAs, marine products have been recognised as a food group of special importance in the human diet. However, seafood is susceptible to contamination by lipophilic organic pollutants. The objective of this study was to evaluate intake levels of PCDDs, PCDFs and dioxin-like PCBs, by a probabilistic Monte Carlo procedure, in relation to the recommendation on LC n-3 PUFAs given by Belgian Federal Health Council. Regarding the recommendation, two scenarios were developed differing in LC n-3 PUFAs intake: a 0.3 E% and a 0.46 E% scenario. Total exposure to dioxins and dioxin-like substances in the 0.3 E% LC n-3 PUFAs scenario ranges from 2.31 pg TEQ/kg bw/day at the 5th percentile, over 4.37 pg TEQ/kgbw/day at the 50th percentile to 8.41 pg TEQ/kgbw/day at the 95th percentile. In the 0.46 E% LC n-3 PUFAs scenario, 5, 50 and 95th percentile are exposed to 2.74, 5.52 and 9.98 pg TEQ/kgbw/day, respectively. Therefore, if the recommended LC n-3 PUFAs intake would be based on fish consumption as the only extra source, the majority of the study population would exceed the proposed health based guidance values for dioxins and dioxin-like substances.

Work-ability evaluation: a piece of cake or a hard nut to crack?

PURPOSE: To describe what aspects, categorized according to the ICF model, insurance physicians (IPs) take into account in assessing short- and long-term work-ability. METHOD: An interview study on a random sample of 60 IPs of the Dutch National Institute for Employee Benefit Schemes, stratified by region and years of experience. RESULTS: In determining work-ability, a wide range of aspects were used. In the case of musculoskeletal disease, 75% of the IPs considered the 'function and structures' component important. With psychiatric and other diseases, however, the 'participation factor' component was considered important by 85 and 80%, respectively. Aspects relating to the 'environmental factor' and 'personal factor' components were mentioned as important by fewer than 25%. In assessing the short- and long-term prognosis of work-ability, the 'disease or disorder' component was primarily used with a rate of over 75%. CONCLUSIONS: In determining work-ability, insurance physicians predominantly consider aspects relating to the 'functions and structures' and 'participation' components of the ICF model important. The 'environmental factor' and 'personal factor' components were not often mentioned. In assessing the short- and long-term prognosis of work-ability, the 'disease or disorder' component was predominantly used. It can be argued that 'environmental factors' and 'personal factors' should also more often be used in assessing work-ability.

[A painful knee that cannot bend]. / Een pijnlijke knie die niet kan buigen.

A 59-year-old woman was seen at the ER with a painful right knee locked in extension. This was caused by unloaded hyperextension in bed. Interlocking patellofemoral osteophytes and a superior patella dislocation tilted away from the femur were seen on the X-ray, which are both pathognomonic signs of a superior dislocation of the patella.

Comparison of nuclear DNA content in primary and metastatic papillary thyroid carcinoma.

Nuclear DNA values were determined in 40 primary papillary thyroid carcinomas, as well as in 52 corresponding local recurrences and metastases were observed either at the time of diagnosis or up to 20 years later. The patient population consisted of 34 survivors and 6 nonsurvivors. In survivors, both the primary tumors and their recurrences and metastases exhibited a majority of cells with DNA values within the normal diploid region, whereas nonsurvivors showed increased and scattered DNA values. In all cases, the primary tumors and the corresponding recurrences and metastases showed similar DNA distribution patterns even if many years had passed between the detection of the primary tumor and the metastases. The results indicate that in papillary thyroid carcinomas, the DNA distribution patterns in the primary tumor and the corresponding recurrences or metastases are generally similar throughout the entire period of disease.

Prevalence and awareness of functional and structural foot abnormalities in children and adolescents with type 1 diabetes.

BACKGROUND: The ISPAD guideline 2011/2014 advises annual podiatric screening to detect foot complications and identify other possible risk factors such as functional and structural foot abnormalities. The aim of this study was to assess the prevalence and awareness of neurovascular, functional and structural foot abnormalities in children and adolescents with type 1 diabetes mellitus (T1DM). METHODS: All patients aged 0-18 years with T1DM were invited for a foot examination and structured questionnaire by a certified podiatrist. RESULTS: Three of the examined patients (n=128) showed signs of possible long-term complications. Structural and functional foot problems were observed in 71.9% (n=92). Of all patients, 38.3% (n=49) required further treatment by a podiatrist. CONCLUSIONS: Functional and structural foot abnormalities are a frequent problem in children with T1DM in the southern part of the Netherlands. These abnormalities are an additional risk factor for developing long-term foot complications. Education in and implementation of the guideline are necessary.

Are disseminated tumor cells in bone marrow and tumor-stroma ratio clinically applicable for patients undergoing surgical resection of primary colorectal cancer? The Leiden MRD study.

PURPOSE: Current TNM staging does not appropriately identify high-risk colorectal cancer (CRC) patients. The aim of this study was to evaluate whether the presence of disseminated tumor cells (DTCs) in the bone marrow (BM) and the presence of stroma in the primary tumor, i.e., the tumor-stroma ratio (TSR), in patients undergoing surgical resection of primary CRC provides information relevant for disease outcome. METHODS: Patients with primary CRC (n = 125), consecutively admitted for curative resection between 2001 and 2007, were included in the study. All patients underwent BM aspiration before surgery. Detection of tumor cells was performed using immunocytochemical staining for cytokeratin (CK-ICC). The TSR was determined on diagnostic H&E stained sections of primary tumors. RESULTS: DTCs were detected in the BM of 23/125 patients (18 %). No association was found between BM status and overall survival (HR 0.97 (95 % CI 0.45-2.09), p = 0.93). Also, no significant difference was found in their 5-year survival rate (resp. 72 % and 68 % for BM-positive versus BM-negative patients). The TSR was found to be associated with a worse overall survival (HR 2.16, 95 % CI 1.02-4.57, p = 0.04) with 5-year survival rates of 84 % versus 62 % for stroma-low and stroma-high patients, respectively. No relation was found between the presence of DTCs and TSR. CONCLUSIONS: Our data indicate that the presence of DTCs in the BM of CRC patients is not associated with disease outcome. The TSR was, however, found to be associated with a worse overall survival, which indicates that for CRC the tumor microenvironment plays an important role in its behavior and prognosis.

A reference data base for multilead electrocardiographic computer measurement programs.

In an effort to standardize and evaluate the performance of electrocardiographic computer measurement programs, a 15 lead reference library has been developed based on simultaneously recorded standard 12 lead and orthogonal XYZ lead data. A set of 250 electrocardiograms (ECGs) with selected abnormalities was analyzed by a group of five referee cardiologists and 11 different 12 lead and 6 XYZ computer programs. Attention was focused on the exact determination of the onsets and offsets of P, QRS and T waves. The referees performed their task on highly amplified, selected complexes from the library in a two round process. Median results of the referees coincided best with the median derived from all programs. An analysis of stability proved that the combined program median was a robust reference. However, some individual program results were widely divergent. Paired t tests demonstrated earlier onset for P and QRS (p less than 0.001), as well as later offset for P and T waves in the median 12 lead than in the XYZ results. Significant differences also existed among results obtained by programs analyzing all standard ECG leads at one time, the so-called multilead programs, and those obtained by the conventional standard three lead analysis programs. As a consequence, the derived P, PR, QRS and QT interval measurements varied quite widely among the various programs. Significant differences were also observed among measurements of Q, R and S duration. Some programs showed Q waves that were on the average 6 ms (p less than 0.001) longer than those of others. This may significantly influence diagnostic performance.(ABSTRACT TRUNCATED AT 250 WORDS)