Adherence to guideline recommendations for Barrett's esophagus (BE) surveillance endoscopies: Effects of dedicated BE endoscopy lists.

Background and study aims For non-dysplastic Barrett's Esophagus (BE) patients, guidelines recommend endoscopic surveillance every 3 to 5 years with four-quadrant random biopsies every 2 cm of BE length. Adherence to these guidelines is low in clinical practice. Pooling BE surveillance endoscopies on dedicated endoscopy lists performed by dedicated endoscopists could possibly enhance guideline adherence, detection of visible lesions, and dysplasia detection rates (DDRs). Patients and methods Data were used from the ACID-study (Netherlands Trial Registry NL8214), a prospective trial of BE surveillance in the Netherlands. BE patients with known or previously treated dysplasia were excluded. Guideline adherence, detection of visible lesions, and DDRs were compared for patients on dedicated and general endoscopy lists. Results A total of 1,244 patients were included, 318 on dedicated lists and 926 on general lists. Endoscopies on dedicated lists showed significantly higher adherence to the random biopsy protocol (85% vs. 66%, P <0.01) and recommended surveillance intervals (60% vs. 47%, P <0.01) compared to general lists. Detection of visible lesions (8.8% vs. 8.1%, P =0.79) and DDRs were not significantly different (6.9% and 6.6%, P =0.94). None (0.0%) of the patients scheduled on dedicated lists and 10 (1.1%) on general lists were diagnosed with esophageal adenocarcinoma ( P =0.07). In multivariable analysis, dedicated lists were significantly associated with biopsy protocol adherence and adherence to surveillance interval recommendations with odds ratios of 4.45 (95% confidence interval [CI] 2.07-9.57) and 1.64 (95% CI 1.03-2.61), respectively. Conclusions Dedicated endoscopy lists are associated with better adherence to the random biopsy protocol and surveillance interval recommendations.

Long-term oncological outcomes of endoscopic full-thickness resection after previous incomplete resection of low-risk T1 CRC (LOCAL-study): study protocol of a national prospective cohort study.

BACKGROUND: T1 colorectal cancer (CRC) without histological high-risk factors for lymph node metastasis (LNM) can potentially be cured by endoscopic resection, which is associated with significantly lower morbidity, mortality and costs compared to radical surgery. An important prerequisite for endoscopic resection as definite treatment is the histological confirmation of tumour-free resection margins. Incomplete resection with involved (R1) or indeterminate (Rx) margins is considered a strong risk factor for residual disease and local recurrence. Therefore, international guidelines recommend additional surgery in case of R1/Rx resection, even in absence of high-risk factors for LNM. Endoscopic full-thickness resection (eFTR) is a relatively new technique that allows transmural resection of colorectal lesions. Local scar excision after prior R1/Rx resection of low-risk T1 CRC could offer an attractive minimal invasive strategy to achieve confirmation about radicality of the previous resection or a second attempt for radical resection of residual luminal cancer. However, oncologic safety has not been established and long-term data are lacking. Besides, surveillance varies widely and requires standardization. METHODS/DESIGN: In this nationwide, multicenter, prospective cohort study we aim to assess feasibility and oncological safety of completion eFTR following incomplete resection of low-risk T1 CRC. The primary endpoint is to assess the 2 and 5 year luminal local tumor recurrence rate. Secondary study endpoints are to assess feasibility, percentage of curative eFTR-resections, presence of scar tissue and/or complete scar excision at histopathology, safety of eFTR compared to surgery, 2 and 5 year nodal and/or distant tumor recurrence rate and 5-year disease-specific and overall-survival rate. DISCUSSION: Since the implementation of CRC screening programs, the diagnostic rate of T1 CRC is steadily increasing. A significant proportion is not recognized as cancer before endoscopic resection and is therefore resected through conventional techniques primarily reserved for benign polyps. As such, precise histological assessment is often hampered due to cauterization and fragmentation and frequently leads to treatment dilemmas. This first prospective trial will potentially demonstrate the effectiveness and oncological safety of completion eFTR for patients who have undergone a previous incomplete T1 CRC resection. Hereby, substantial surgical overtreatment may be avoided, leading to treatment optimization and organ preservation. Trial registration Nederlands Trial Register, NL 7879, 16 July 2019 ( https://trialregister.nl/trial/7879 ).

[Dutch observation scales to assess cognitive abilities of the aged]. / Nederlandstalige observatieschalen voor onderzoek van cognitief functioneren van ouderen.

Assessment of complex geriatric health problems by nurses is important for diagnosis, especially assessment of cognitive functioning through daily observations. However, it is unclear which Dutch observation scales are available to assess cognitive abilities. In this study, we present an overview of these scales. A systematic review was performed. Beforehand we determined criteria for inclusion of scales and we searched through Dutch and English databases up till May 2005. Thirteen behavioural observation scales were found. The number of dimensions of cognitive functioning assessed in the scales varied greatly, from two to eight in number. Memory and psychomotor behaviour were always included; consciousness and thinking were frequently included, while alertness, perception, executive functions and language were least included. Extensive assessment of cognitive functioning is highly relevant for a geriatric hospital ward in which patients are admitted for diagnosis. Of all scales that we traced, the A-one is the most extensive: all eight dimensions are included. Little is known about the potential for using the A-one scale in nursing practice; further exploration is indicated. For now, nurses should become acquainted with the different dimensions of cognitive functioning and start to integrate observations in these dimensions in their reporting.

[Scabies outbreak in a hospital and in 8 health-care institutions caused by an elderly patient with scabies crustosa]. / Uitbraak van scabiës in i ziekenhuis en 8 zorginstellingen door een geriatrische patiënt met scabies crustosa.

An outbreak of scabies in a teaching hospital, two nursing homes and six health-care institutions for the elderly, occurred in the Nijmegen area in the Netherlands, between September 2004 and April 2005. In November 2004 the diagnosis of scabies crustosa (scabies norvegica) was made in the index patient - a 78-year-old woman. An atypical presentation, without much itching, as is not infrequently seen in elderly patients, resulted in there being a considerable delay before the diagnosis was made. This resulted in a total of 51 people, both in and outside the hospital, becoming infected. Based on article 7 of the Dutch Infectious Diseases Act, the Municipal Health Service (GGD) advised institutions on the policy and carried out both source and contact tracing. According to this Act notification and cooperation between hospital, care institutions and the GGD are of importance for the effective handling of epidemics. Systemic treatment with ivermectin is the main alternative to local treatment in outbreaks in institutions.

5-aminolevulinic acid photodynamic therapy versus argon plasma coagulation for ablation of Barrett's oesophagus: a randomised trial.

BACKGROUND: Photochemical and thermal methods are used for ablating Barrett's oesophagus (BO). The aim of this study was to compare 5-aminolevulinic acid induced photodynamic therapy (ALA-PDT) with argon plasma coagulation (APC) with respect to complete reversal of BO. METHODS: Patients with BO (32 no dysplasia and eight low grade dysplasia) were randomised to one of three treatments: (a) ALA-PDT as a single dose of 100 J/cm(2) at four hours (PDT100; n = 13); (b) ALA-PDT as a fractionated dose of 20 and 100 J/cm(2) at one and four hours, respectively (PDT20+100; n = 13); or (c) APC at a power setting of 65 W in two sessions (APC; n = 14). If complete elimination of BO was not achieved by the designated treatment, the remaining BO was treated by a maximum of two sessions of APC. RESULTS: Mean endoscopic reduction of BO at six weeks was 51% (range 20-100%) in the PDT100 group, 86% (range 0-100%) in the PDT20+100 group, and 93% (range 40-100%) in the APC group (PDT100 v PDT20+100, p<0.005; PDT100 v APC, p<0.005; and PDT20+100 v APC, NS) with histologically complete ablation in 1/13 (8%) patients in the PDT100 group, 4/12 (33%) in the PDT20+100 group, and 5/14 (36%) in the APC group (NS). Remaining BO was additionally treated with APC in 23/40 (58%) patients. Histological examination at 12 months revealed complete ablation in 9/11 (82%) patients in the PDT100 group, in 9/10 (90%) patients in the PDT20+100 group, and in 8/12 (67%) patients in the APC group (NS). At 12 months, no dysplasia was detected. Side effects (that is, pain (p<0.01), and nausea and vomiting (p<0.05)) and elevated liver transaminases (p<0.01) were more common after PDT than APC therapy. One patient died three days after treatment with PDT, presumably from cardiac arrhythmia. CONCLUSION: APC alone or ALA-PDT in combination with APC can lead to complete reversal of Barrett's epithelium in at least two thirds of patients when administered in multiple treatment sessions. As the goal of treatment should be complete reversal of Barrett's epithelium, we do not recommend these techniques for the prophylactic ablation of BO.

[The malignant side of chronic inflammatory bowel disease]. / De maligne kant van chronisch inflammatoir darmlijden.

Patients with chronic inflammatory bowel disease (IBD) have a higher risk of colorectal carcinoma, and present with this malignancy at a younger age than non-IBD individuals. In three patients, two men aged 20 and 36 years and one woman aged 34 years, colorectal cancer developed at a young age, following a long history of ulcerative colitis. Surveillance for colorectal cancer in IBD patients needs to be performed by regular colonoscopy with extensive biopsy sampling for the detection of dysplasia, regarded by many as predictive for colon carcinoma. Whenever a dysplasia-associated lesion or mass or a highgrade dysplasia is identified, there is a strong indication for colectomy. When low-grade dysplasia is found, the findings should be discussed with the patient and it should be decided whether the patient should resume surveillance or opt for colectomy.

[Acute liver failure ascribed to nefazodone: importance of 'postmarketing surveillance' for recently introduced drugs]. / Acuut leverfalen toegeschreven aan nefazodon: het belang van 'postmarketing surveillance' bij recentelijk geïntroduceerde geneesmiddelen.

A 50-year-old man developed acute liver failure 7 months after nefazodone treatment was initiated. There was no evidence of any aetiology apart from the exposure to the antidepressant drug nefazodone, while the results of repeated histological examinations of the liver were compatible with serious progressive drug-induced hepatitis. This diagnosis was initially disregarded because in the literature no patients with nefazodone-induced hepatitis were reported. However, the drug had only recently been introduced, which meant that relatively infrequent adverse drug reactions might not have been published. Further analyses of databases of the marketing pharmaceutical industry and of the World Health Organization revealed more cases of liver toxicity ascribed to nefazodone, which showed that liver failure may indeed be associated with nefazodone use. Consequently, prescribing doctors have been warned by the pharmaceutical company about this possible adverse drug reaction.

In vivo model systems in P-glycoprotein-mediated multidrug resistance.

In this article we review the in vivo model systems that have been developed for studying P-glycoprotein-mediated multidrug resistance (MDR) in the preclinical setting. Rodents have two mdr genes, both of which confer the MDR phenotype: mdr 1a and mdr 1b. At gene level they show strong homology to the human MDR1 gene and the tissue distribution of their gene product is very similar to P-glycoprotein expression in humans. In vivo studies have shown the physiological roles of P-glycoprotein, including protection of the organism from damage by xenobiotics. Tumors with intrinsic P-glycoprotein expression, induced MDR or transfected with an mdr gene, can be used as syngeneic or xenogenic tumor models. Ascites, leukemia, and solid MDR tumor models have been developed. Molecular engineering has resulted in transgenic mice that express the human MDR1 gene in their bone marrow and in knockout mice missing a murine mdr gene. The data on pharmacokinetics, efficacy, and toxicity of chemosensitizers of P-glycoprotein in vivo are described. Results from studies using monoclonal antibodies directed against P-glycoprotein and other miscellaneous approaches for modulation of MDR are mentioned. The importance of in vivo studies prior to clinical trials is being stressed and potential pitfalls due to differences between species are discussed.

Pharmacokinetics of the multidrug-resistance-converting drug dexniguldipine and its pyridine metabolite M-1 in the plasma, tumor, and renal tissue of tumor-bearing Wag/Rij rats.

The pharmacokinetics of oral dexniguldipine, a new multidrug-resistance-modifying agent under clinical evaluation, and its pyridine metabolite M-1 were determined in plasma, tumor, and renal tissue in Wag/Rij rats bearing a multidrug-resistant CC531 colon adenocarcinoma tumor under the renal capsule. The pharmacokinetics were studied in four experiments. After a single administration of dexniguldipine (30 mg/kg), tumors and kidneys were collected after 5 (experiment 1), 24 (experiment 2), and 48 h (experiment 3). In the fourth experiment, dexniguldipine was given once daily for 3 consecutive days at a dose of 30 mg/kg. In all experiments, plasma samples were collected at regular intervals. The concentrations of dexniguldipine and M-1 could be determined in plasma in most of the rats at up to 32 h after drug administration. The area under the curve (AUC) of dexniguldipine and M-1 varied by a factor of 2-6 in the four experiments. High tumor-tissue concentrations of dexniguldipine were observed. The concentrations were highest in the multiple-dose experiment (2014 +/- 1005 ng/g tissue). High degrees of correlation (> 0.8) were established between the concentrations of dexniguldipine measured in plasma and tumor as well as renal tissue. Overall, tumor-tissue concentrations of M-1 comprised one-third of the dexniguldipine concentrations measured.

Cyclosporin A enhances locoregional metastasis of the CC531 rat colon tumour.

The immunosuppressive drug cyclosporin A has been evaluated recently in phase II trials in cancer therapy as a reverter of P-glycoprotein-mediated multidrug resistance. As an immunosuppressive agent, cyclosporin A potentially can enhance tumour growth. We investigated this potency of cyclosporin A in the weakly immunogenic CC531 colon adenocarcinoma model, using the same dose that had previously been shown to intensify the antitumour activity of doxorubicin in vivo. In vitro cyclosporin A caused no growth acceleration and only in high doses was growth inhibition of CC531 cells observed. In vivo no evidence of growth enhancement was found in short-term assays but, after 4 weeks, rats treated with cyclosporin A had a significantly higher tumour load, mainly consisting of locoregional metastases. These experiments in the CC531 tumour model show that cyclosporin A, used as a reverter of multidrug resistance, may produce short-term improvement of antitumour activity but may also induce enhancement of tumour metastasis.

High renin and prorenin in plasma and pleural exudate of a patient with the ovarian hyperstimulation syndrome.

We present the case of a 35-year-old woman with a severe ovarian hyperstimulation syndrome (OHSS) as a complication of ovulation induction for primary infertility. The clinical picture showed massively enlarged ovaries, pleural effusion and haemoconcentration. She needed a thoracentesis for evacuation of the large pleural effusion. High levels of renin and prorenin were observed in plasma and pleural exudate.

Modulation of multidrug resistance with dexniguldipine hydrochloride (B8509-035) in the CC531 rat colon carcinoma model.

The chemosensitizing potency of dexniguldipine hydrochloride (B8509-035) on epidoxorubicin was assessed in a multidrug-resistant (MDR) tumour model, the intrinsic MDR rat colon carcinoma CC531. In vitro in the sulphorhodamine B cell-viability assay the cytotoxicity of epidoxorubicin was increased approximately 15-fold by co-incubation with 50 ng/ml dexniguldipine. In vivo concentrations of dexniguldipine 5 h after a single oral dose of 30 mg/kg were 72 (+/- 19 SD) ng/ml in plasma and 925 (+/- 495 SD) ng/g in tumour tissue. Levels of the metabolite of dexniguldipine, M-1, which has the same chemosensitizing potential, were 26 (+/- 6 SD) ng/ml and 289 (+/- 127 SD) ng/g respectively. The efficacy of treatment with 6 mg/kg epidoxorubicin applied intravenously combined with 30 mg kg-1 day-1 dexniguldipine administered orally for 3 days prior to epidoxorubicin injection was evaluated on tumours grown under the renal capsule. Dexniguldipine alone did not show antitumour effects in vivo. Dexniguldipine modestly, but consistently, potentiated the tumour-growth-inhibiting effect of epidoxorubicin, reaching statistical significance in two out of four experiments. In conclusion, these experiments show that dexniguldipine has potency as an MDR reverter in vitro and in vivo in this solid MDR tumour model.

[Acute pancreatitis caused by chylomicronemia syndrome]. / Acute pancreatitis door het chylomicronemie-syndroom.

Pancreatitis caused by chylomicronaemia was diagnosed in three patients, two men of 36 and 51 years and a woman of 33 years. All three patients had a combined hyperlipidaemia, with severely elevated levels of triglycerides and cholesterol. Secondary causes of hypertriglyceridaemia such as uncontrolled diabetes mellitus, alcohol abuse, and non-compliance with diet and lipid lowering drug therapy caused aggravation of the lipid disorder. It is important to consider chylomicronaemia as a possible cause of pancreatitis, as treatment of the lipid disorder with diet and, if necessary, drugs can prevent recurrence of pancreatitis.

[Initial results of immediate reconstruction of the breast following mastectomy]. / Eerste resultaten van directe reconstructie van de borst na mastectomie.

OBJECTIVE: Evaluation of the results of immediate reconstruction after mastectomy for breast cancer by means of a silicone implant. DESIGN: Retrospective analysis. SETTING: Department of Surgical Oncology of the Dr Daniël den Hoed Cancer Centre and Department of Surgery of the Zuiderziekenhuis, Rotterdam, the Netherlands. METHOD: From September 1990 till July 1993, 37 immediate reconstructions of the breast after mastectomy were performed in 35 patients by means of a silicone implant. Indications for the treatment, consequences for further oncological treatment, additional plastic surgery, and complications of the reconstruction were evaluated. RESULTS: The indications for mastectomy and immediate reconstruction were local recurrence after breast conservative treatment (6 operations), multifocal disease (8), extensive in situ carcinoma (8), non-radically removed tumour at lumpectomy (5), anticipated poor cosmetics after breast conservative treatment (6), prophylactic ablation of the breast (2), and patient preference (1). 5 patients received adjuvant systemic chemotherapy, which could be administered without delay, and without negative influence on the result of the breast reconstruction. Additional plastic surgical treatment consisting of reconstruction of the areolar complex and correction of the breast symmetry, was performed in 5 and 3 patients respectively. In 8 of the 37 reconstructions (22%) complications were encountered. The main complications were haematoma (2), infection (4), implant removal (3), capsular contracture (2), skin necrosis (2), and luxation of the implant (1). CONCLUSION: Immediate reconstruction after mastectomy is a valuable treatment modality in breast cancer.

The chemosensitizer cyclosporin A enhances the toxic side-effects of doxorubicin in the rat.

The feasibility of using chemosensitizers in the circumvention of P-glycoprotein-mediated multidrug resistance has been shown in many studies. We recently reported on the chemosensitizing effect of cyclosporin A (CsA) on doxorubicin in a rat solid tumour model. Using the same experimental design we investigated the side-effects of the combination treatment. During the 35-day experiment doxorubicin treatment caused dose-dependent weight loss, which was enhanced by combination treatment with CsA. The main doxorubicin-related side-effects were myelosuppression (transient leucopenia and thrombopenia) and nephrotoxicity. Damage to the kidney was severe, leading to a nephrotic syndrome and resulting in ascites, pleural effusion, hypercholesterolaemia and hypertriglyceridaemia. These toxicities were enhanced by the addition of the chemosensitizer CsA. Mild doxorubicin-related cardiomyopathy and minimal hepatotoxicity were seen on histological examination. There were no signs of enhanced toxicity of the combination treatment in tissues with known high expression levels of P-glycoprotein, like the liver, adrenal gland and large intestine. CsA had a low toxicity profile, as it only caused a transient rise in bilirubin. In conclusion, the chemosensitizer CsA enhanced the side-effects of the anticancer drug doxorubicin without altering the toxicity pattern. There was no evidence of a therapeutic gain by adding CsA to doxorubicin, compared to single-agent treatment with doxorubicin in 25%-33% higher doses, because of the enhanced toxicity of the combination treatment.

5'-Deoxy-5-fluorouridine increases daunorubicin uptake in multidrug-resistant cells and its activity is related with P-gp 170 expression.

Most anticancer agents fail to induce clear responses in the treatment of colorectal cancer. This can be explained by involvement of overexpression of the membrane glycoprotein, P-gp 170, which is associated with multidrug resistance (MDR), and/or with involvement of ras. Fluoropyrimidines are amongst the few options in the chemotherapeutic treatment of colorectal cancers. 5'-Deoxy-5-fluorouridine (dFUrd) needs intracellular activation via 5-fluorouracil into 5-fluoro-2'-deoxyuridine-5'-monophosphate and 5-fluorouridine-5'-triphosphate. In the present study, the cytotoxic activity of dFUrd in vitro and dFUrd combined with daunorubicin (DNR) was assessed with the (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium) bromide assay in cells with increased P-gp 170 expression versus controls. Surprisingly, dFUrd was most active in cells with high P-gp 170 expression, a finding which can not be explained by intracellular metabolic activity only. The results also show that dFUrd improves the DNR uptake in MDR-positive cells, and this is related with increased cytotoxicity of the anthracycline.

Drug resistance in rat colon cancer cell lines is associated with minor changes in susceptibility to cytotoxic cells.

The development of resistance to anticancer drugs urges the search for different treatment modalities. Several investigators have reported the concomitant development of drug resistance and resistance to natural killer (NK), lymphokine-activated killer (LAK) or monocyte/macrophage cell lysis, while others described unchanged or even increased susceptibility. We investigated this subject in the rat colon carcinoma cell line, CC531-PAR, which is intrinsically multidrug-resistant (MDR), and in three sublines derived from this parental cell line: a cell line with an increased MDR phenotype (CC531-COL), a revertant line from CC531-COL (CC531-REV), which demonstrates enhanced sensitivity to anticancer drugs of the MDR phenotype, and an independently developed cisplatin-resistant line (CC531-CIS). In a 4-h 51Cr-release assay we found no difference in susceptibility to NK cell lysis. No significant differences in lysability by adherent LAK (aLAK) cells were observed in a 4-h assay. In a prolonged 20-h 51Cr-release assay an enhanced sensitivity to aLAK-cell-mediated lysis was observed in the revertant, P-glycoprotein-negative cell line and in the cisplatin-resistant cell line (CC531-CIS). None of the cell lines was completely resistant to lysis by aLAK cells. Therefore, a role for immunotherapy in the treatment of drug-resistant tumors remains a realistic option.

Therapeutic lymphadenectomy in melanomas of the head and neck.

This retrospective study describes patients with loco-regionally metastasized melanoma of the head and neck. All patients underwent a therapeutic lymph node dissection. The 3-year survival rate was 35%. Duration of disease-free interval, number of lymph nodes involved, and extent of neck dissection proved of no influence on survival rates. Locoregional recurrence occurred in 10 patients and always proved to be a sign of systemic dissemination. Ultimately, 19 patients developed systemic disease. More than 40% developed cerebral metastases and the cerebrum was the second most involved site. As cerebral involvement occurs often in head and neck melanoma, a computed tomography or magnetic resonance imaging scan of the brain is recommended in the routine work-up before lymph node dissection. Furthermore, because the extent of the surgical procedure had no influence on local recurrence rate and overall survival, a selective approach, preserving functional structures, is advocated.

In vitro and in vivo chemosensitizing effect of cyclosporin A on an intrinsic multidrug-resistant rat colon tumour.

Colon tumours are intrinsically resistant to chemotherapy and most of them express the multidrug transporter P glycoprotein (Pgp). Whether this Pgp expression determines their resistance to anticancer agents in patients is not known. We report here on the reversibility of intrinsic multidrug resistance in a syngeneic, solid tumour model. CC531 is a rat colon carcinoma that expresses Pgp, as was shown with the monoclonal antibody C-219. In vitro the sensitivity to doxorubicin, daunorubicin and colchicine was enhanced by the addition of the chemosensitizers verapamil and cyclosporin A (CsA), while the sensitivity to cisplatin was not enhanced. In a daunorubicin accumulation assay verapamil and CsA enhanced the daunorubicin content of CC531 cells. In vivo CsA was injected intramuscularly for 3 consecutive days at a dose of 20 mg kg-1 day-1. This resulted in whole-blood CsA levels above 2 mumol/l, while intratumoral CsA levels amounted to 3.6 mumol/kg. In a subrenal capsule assay the maximal tolerable dose of doxorubicin (4 mg/kg) significantly reduced tumour growth. Doxorubicin at 3 mg/kg was not effective, but in combination with CsA this dose was as effective as 4 mg/kg doxorubicin. These experiments show that adequate doses of the chemosensitizing drug CsA can be obtained in vivo, resulting in increased antitumoral activity of doxorubicin in vivo. The in vitro and in vivo data together suggest that the chemosensitization by CsA is mediated by Pgp. This finding may have implications for the application of CsA and CsA-like chemosensitizers in the clinical setting.