Avoiding Unnecessary Major Rectal Cancer Surgery by Implementing Structural Restaging and a Watch-and-Wait Strategy After Neoadjuvant Radiochemotherapy.

BACKGROUND: Pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) is found in 15-20% of patients with locally advanced rectal cancer. A watch-and-wait (W&W) strategy has been introduced as an alternative strategy to avoid surgery for selected patients with a clinical complete response at multidisciplinary response evaluation. The primary aim of this study was to evaluate the efficacy of the multidisciplinary response evaluation by comparing the proportion of patients with pCR since the introduction of the structural response evaluation with the period before response evaluation. METHODS: This retrospective cohort study enrolled patients with locally advanced rectal cancer who underwent nCRT between January 2009 and May 2018, categorizing them into cohort A (period 2009-2015) and cohort B (period 2015-2018). The patients in cohort B underwent structural multidisciplinary response evaluation with the option of the W&W strategy. Proportion of pCR (ypT0N0), time-to-event (pCR) analysis, and stoma-free survival were evaluated in both cohorts. RESULTS: Of the 259 patients in the study, 21 (18.4%) in cohort A and in 8 (8.7%) in cohort B had pCR (p = 0.043). Time-to-event analysis demonstrated a significant pCR decline in cohort B (p < 0.001). The stoma-free patient rate was 24% higher in cohort B (p < 0.001). CONCLUSION: Multidisciplinary clinical response evaluation after nCRT for locally advanced rectal cancer led to a significant decrease in unnecessary surgery for the patients with a complete response.

Feasibility of volatile organic compound in breath analysis in the follow-up of colorectal cancer: A pilot study.

BACKGROUND: Colorectal carcinoma (CRC) has a worldwide incidence of 1.4 million patients and a large share in cancer-related mortality. After curative treatment, the risk of recurrence is 30-65%. Early detection may result in curative treatment. However, current follow-up (FU) examinations have low sensitivity ranging from 49 to 85% and are associated with high costs. Therefore, the search for a new diagnostic tool is justified. Analysis of volatile organic compound in exhaled air through an electronic nose (eNose) is a promising new patient-friendly diagnostic tool. We studied whether the eNose under investigation, the Aeonose™, is able to detect local recurrence or metastases of CRC. METHODS: In this cross-sectional study we included 62 patients, all of whom underwent curative treatment for CRC in the past 5 years. Thirty-six of them had no metastases and 26 had extraluminal local recurrence or metastases of CRC, detected during FU. Breath testing was performed and machine learning was used to predict extraluminal recurrences or metastases, and based on the receiver operating characteristics (ROC)-curve both sensitivity and specificity were calculated. RESULTS: The eNose identified extra luminal local recurrences or metastases of CRC with a sensitivity and specificity of 0.88 (CI 0.69-0.97) and 0.75 (CI 0.57-0.87), respectively, with an overall accuracy of 0.81. DISCUSSION: This eNose may be a promising tool in detecting extraluminal local recurrences or metastases in the FU of curatively treated CRC. However, a well-designed prospective study is warranted to show its accuracy and predictive value before it can be used in clinical practice.

Limited human epidermal growth factor receptor 2 discordance in metastatic breast cancer patients treated with trastuzumab, a population based study.

BACKGROUND: Accurate assessment of the human epidermal growth factor receptor 2 (HER2) in breast cancer is essential for proper treatment decisions. HER2 positivity confirmation rates in breast cancer trials by central testing pathology laboratories were reported to be approximately 85%. The aim of our study was to assess in a population based sample concordance of HER2 status in metastatic breast cancer (MBC) patients locally tested HER2 positive and treated with trastuzumab. Moreover cost-effectiveness of in situ hybridisation (ISH) in patients with an immunohistochemical score 3+ (IHC3+) was explored. METHODS: MBC patients treated between 2005 and 2009 with trastuzumab-based therapy in North East Netherlands were identified by a survey of hospital pharmacies. Primary tumour samples were retested centrally for HER2 status using 1 immunohistochemical (IHC) method and two methods using ISH on tissue micro-arrays. Potential discordant patients were retested on whole tumour slides. HER2 positivity was defined as: (1) ISH amplification (according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) clinical practice Guideline Update) and (2) when ISH failed an IHC score of 3+. Cost-effectiveness was estimated using potential ISH and treatment costs. RESULTS: HER2 status could be retested in 174 of 194 (90%) patients. The HER2 concordance rate was 87%. The 21 discordant patients were in the 67% due to primary HER2 testing with only IHC. Overall survival of HER2 discordant and concordant patients was not significantly different (18 versus 25months, p=0.131). Structural ISH in the case of IHC3+ has an estimated potential saving of €87,710 per 100 patients. CONCLUSION: HER2 concordance in a population based study is comparable to those described in selected populations. Discordance is mostly due to testing with only IHC. ISH in the case of IHC3+ is cost-effective.

Dutch virtual integration of healthcare information.

OBJECTIVES: As information technology creates opportunities for cooperation which crosses the boundaries between healthcare institutions, it will become an integral part of the Dutch healthcare system. Along with many involved organizations in healthcare the National IT Institute for Healthcare in the Netherlands (NICTIZ) is working on the realization of a national IT infrastructure for healthcare and a national electronic patient record (EPR). METHODS: An underlying national architecture is designed to enable the Dutch EPR virtually, not in a national database, nor on a patient's smartcard. The required secure infrastructure provides generic functions for healthcare applications: patient identification, authentication and authorization of healthcare professionals. RESULTS: The first national applications in the EPR program using a national index of where patient data is stored, are the electronic medication record and the electronic record for after hours GP services. The rollout of the electronic medication record and electronic record for after hours GP services has been started in 2007. CONCLUSIONS: To guarantee progress of electronic data exchange in healthcare in the Netherlands we have primarily opted for two healthcare applications: the electronic medication record and the electronic record for after hours GP services. The use of a national switch-point containing the registry of where to find what information, guarantees that the professional receives the most recent information and omits large databases to contain downloaded data. Proper authorization, authentication as well as tracing by the national switchpoint also ensures a secure environment for the communication of delicate information.

Management of chemotherapy-induced adverse effects in the treatment of colorectal cancer.

The anticancer agents fluorouracil, raltitrexed, irinotecan and oxaliplatin show limited efficacy in the treatment of colorectal cancer and may be associated with substantial toxicity. Therefore, the prevention and reduction of chemotherapy-induced adverse effects is of major significance, in accordance with the increasing concern for the quality of life of patients with cancer. Therapeutic drug monitoring of fluorouracil and chronomodulation of fluorouracil and oxaliplatin, have been effective in reducing the incidence and gravity of adverse effects in several clinical trials. However, these concepts have not been implemented in clinical practice yet. At the present time, dose adaptation and supportive measures are the main tools for toxicity control in the treatment of colorectal cancer. In this review, supportive measures for alleviation of the adverse effects of fluorouracil, raltitrexed, irinotecan and oxaliplatin, respectively, are described, based on study results. The main adverse effects of these agents are myelosuppression, oral mucositis, diarrhoea, acute cholinergic syndrome, nausea and emesis, neurotoxicity, hand-foot syndrome and other cutaneous adverse effects, ocular toxicity, cardiotoxicity, small bowel toxicity, asthenia, elevated liver transaminase levels and alopecia. The incidence and gravity of these adverse effects are more or less related to the agent and administration schedule involved. The supportive measures and recommendations include the use of specific drugs, alterations of administration schedule and several nonpharmacological methods. In addition, guidelines for dosage adjustments when toxicity occurs are presented. For optimal management of adverse effects, patients should be considered individually, while patients, nurses and physicians should cooperate to identify and treat adverse effects in an early stage of their development.

[Tamoxifen: does a wider range of indications require more careful monitoring?]. / Tamoxifen; ruimere indicaties, uitgebreidere controle?

Two patients, premenopausal women aged 48 years and 37 years, who were treated with tamoxifen following a mammary carcinoma operation, experienced abdominal complaints, hot flushes, vaginal discharge, an irregular menstrual cycle and/or concern about the increased risk of ovarian carcinoma. Transvaginal ultrasonography of the ovaries and laboratory tests indicated ovarian overstimulation. Both patients temporarily stopped using tamoxifen; in one of the patients both ovaries were ablated. The range of indications for treatment with tamoxifen has in recent years been extended to premenopausal patient groups and the length of treatment has been increased from two to five years. We recommend more extensive checks when prescribing tamoxifen to premenopausal patients in view of the possible adverse effects of ovarian stimulation associated with this treatment.

Risk factors determining chemotherapeutic toxicity in patients with advanced colorectal cancer.

Antitumour therapy in advanced colorectal cancer has limited efficacy. For decades, fluorouracil has been the main anticancer drug for the treatment of colorectal cancer. Recently, however, new agents have been introduced: raltitrexed, irinotecan and oxaliplatin. Currently, the dosage for an individual patient is calculated from the estimated body surface area of the patient. Toxicity, however, frequently necessitates decreasing the dosage, extending the dose interval or even discontinuing treatment. Risk factors with predictive value for toxicity have been identified in several studies. These risk factors are often determined by the pharmacokinetic and pharmacodynamic properties of the drug. In this review, the risk factors for toxicity of the cytotoxic agents used in the treatment of advanced colorectal cancer are considered. For fluorouracil, age, gender, performance status, genetic polymorphism of dihydropyridine dehydrogenase, drug administration schedule, circadian rhythm of plasma concentrations, history of previous chemotherapy-related diarrhoea, xerostomia, low neutrophil levels, and drug-drug interactions have been identified as affecting chemotherapeutic toxicity. For raltitrexed, gender and renal and hepatic impairment, and for oxaliplatin, renal impairment and circadian rhythm of plasma concentrations, respectively, can be considered as risk factors for toxicity. In addition, age, performance status, bilirubinaemia, genetic polymorphism of uridine 5'-diphosphate-glucuronyltransferase-1A1 and drug administration schedule have been shown to be related to irinotecan toxicity. The available literature suggests that dose adjustment based on these risk factors can be used to individualise the dose in order to decrease toxicity and to improve the therapeutic index. This also applies to therapeutic drug monitoring, which has been shown to be effective controlling the toxicity of fluorouracil in some studies. Future research is warranted to assess the potential advantage of dose individualisation of chemotherapy founded on risk factors, over direct dose calculation from the estimated body surface area, with regard to toxicity, therapeutic index, and quality of life, in patients with advanced colorectal cancer.

The angiogenic factor bFGF impairs leukocyte adhesion and rolling under flow conditions.

Recirculation of leukocytes is mediated by the intricately regulated expression of adhesion molecules on both the vessel wall and leukocyte membranes. In the present paper it is demonstrated that tumor angiogenesis factors impair leukocyte rolling and adhesion under flow conditions. Three lines of evidence presented in this paper support this finding; (i) treatment of cultured endothelial cells (EC) with the angiogenic factor basic fibroblast growth factor (bFGF) results in decreased ICAM-1 expression and decreased numbers of adhering leukocytes under flow conditions. (ii) flow induced upregulation of endothelial ICAM-1 in the presence of bFGF does not yield ICAM-1 levels higher than on resting EC. (iii) bFGF decreases the TNFalpha mediated induction of E-selectin and ICAM-1 expression, resulting in decreased rolling and firm adhesion of leukocytes on the endothelial surface. For ICAM-1 it is demonstrated that bFGF inhibits TNFalpha induced levels of mRNA, and that this effects is transcriptionally regulated. These findings support our earlier described hypothesis that angiogenic factors are involved in the tumor derived escape mechanism from immune surveillance, since we demonstrate here that these mechanisms are operative under physiologic flow conditions.

[Colonic varices: an unusual cause of occult blood loss]. / Colonvarices: een zeldzame oorzaak van occult bloedverlies.

A man aged 81 known to suffer from atrial fibrillation - the treatment for which included acetylsalicylic acid - and chronic obstructive pulmonary disease, was hospitalized because of a respiratory infection. Since he had iron deficiency anaemia and the case history mentioned "intestinal bleeding', supplementary examinations were carried out. Endoscopy revealed colonic varices; because of the absence of portal hypertension and other disorders related to colonic varices, the varices were classified as idiopathic. In view of the extensiveness of the lesions, it was decided to refrain from endoscopic sclerotherapy and to adopt an expectative policy.

Severe bronchomalacia in a 65-year-old man treated with stent insertion instead of surgical bronchoplasty.

Bronchomalacia in adults is rare. A case is reported here of a 65-year-old man with severe cough and mucostasis, caused by a benign bronchomalacia of the ventral wall of the left main bronchus. This was treated successfully with the insertion of a silicone Dumon stent as an alternative to surgical bronchoplasty.

Effects of low-dose EPA-E on glycemic control, lipid profile, lipoprotein(a), platelet aggregation, viscosity, and platelet and vessel wall interaction in NIDDM.

OBJECTIVE: To assess the effects of low-dose eicosapentaenoic acid-ethyl-ester on diabetes regulation, lipid metabolism, blood rheology, and platelet reactivity. RESEARCH DESIGN AND METHODS: In a double-blind, randomized, placebo-controlled study, 24 NIDDM subjects received 1800 mg of EPA-E, 900 mg of EPA-E, or a placebo (1656 mg olive oil) daily for 8 wk. RESULTS: The EPA:arachidonic acid plasma ratio increased over an 8-wk period, then declined after a 4-wk wash-out period in the fish-oil groups in a dose-dependent way. Platelet-activating factor-induced platelet aggregation decreased from 75 +/- 7% at wk 0 to 35 +/- 21% at wk 8 in the 900-mg group (P = 0.016) and from 72 +/- 11 to 40 +/- 30% in the 1800-mg group (P = 0.039), but did not change in the placebo group. No effects on ADP- or collagen-induced aggregation could be attributed to EPA-E. In the 1800-mg group low-density-lipoprotein cholesterol increased significantly, without concomitant rise in apolipoprotein B. Triglycerides, glycemic control, lipoprotein (a), blood and plasma viscosity, erythrocyte deformability, and platelet adhesion to and aggregate formation on extracellular endothelial cell matrix were not significantly influenced. CONCLUSIONS: Purified EPA-E in doses of 900 and 1800 mg reduces Platelet-activating factor-induced platelet aggregation without negatively affecting glycemic control. Low-density-lipoprotein cholesterol was elevated in the 1800-mg group.

Nitric oxide functions as an inhibitor of platelet adhesion under flow conditions.

BACKGROUND: Nitric oxide (NO) has been identified as endothelium-derived relaxing factor (EDRF), which, in addition to its relaxant effects on vascular smooth muscle cells, is also a potent inhibitor of platelet aggregation. An inhibitory role on platelet adhesion has been suggested from experiments with washed platelets under static conditions. We have determined whether endothelium-derived and exogenous NO also regulates platelet adhesion in whole blood under flow conditions. METHODS AND RESULTS: The effect of endothelium-derived NO was studied by the addition of specific inhibitors of NO production, L-N-monomethyl arginine (L-NMMA) and N-iminoethyl-L-ornithine (L-NIO), to a perfusion system in which both endothelial cells and their matrices were present. A concentration-dependent increase in platelet adhesion to the matrix was found with a maximum inhibition at a concentration of 2 mM L-NMMA and 0.1 mM L-NIO. The effect was dependent on the presence of endothelial cells, because no increase in platelet adhesion was observed in their absence. The effect of exogenous NO was tested in a specially devised perfusion system in which the NO was introduced at the site of adhesion by means of a porous membrane on which an extracellular matrix of endothelial cells was present. Inhibition of platelet adhesion by NO was found at all shear rates tested and after all perfusion periods. CONCLUSIONS: These results demonstrate that NO is a potent inhibitor of platelet adhesion under flow conditions and thereby contributes to the regulatory role of vascular endothelial cells on platelet-vessel wall interaction.

[Desmopressin in hemophilia A and Von Willebrand's disease]. / Desmopressine bij hemofilie A en de ziekte van Von Willebrand.

The treatment with desmopressin prior to surgery of patients with mild haemophilia A (HA) and Von Willebrand's disease (VWD) was retrospectively evaluated in a general hospital, from 1978 until 1987. From a group of 87 treated patients, 40 patients are reported (21 VWD, 19 HA) of which plasma factor VIII (FVIII) and Von Willebrand factor (VWF) concentrations were determined before, and twice after desmopressin treatment. Desmopressin was administered intravenously at a dose of 0.4 micrograms/kg body weight. Tranexamic acid was used only when surgery in the mouth cavity was performed, at a dose of 1 gram three times a day. Side effects were seen only in 5 patients (3 VWD, 2 HA). No significant difference between both groups was seen in bleeding tendency, transfusion necessity and side effects (chi 2 test). In both groups, FVIII and VWF concentrations increased significantly after 20 and 60 minutes following DDAVP administration (paired t-test). After 360 minutes, the FVIII concentration increased significantly in both groups, however, only in the VWD patients did VWF increase significantly. In neither group did initial FVIII concentrations correlate with the increase in FVIII (linear regression analysis). One female patient reacted differently to DDAVP, with a decrease in FVIII and VWF values. Desmopressin is a safe and effective agent in the management and prophylaxis of bleeding tendency in patients with mild HA and mild VWD.

Platelet adhesion to subendothelial structures under flow conditions: no effect of the lipoxygenase product 13-HODE.

It has been shown that endothelial cells can convert linoleic acid to 13-hydroxyoctadecadienoic acid (13-HODE) and it has been suggested that 13-HODE has non-thrombogenic properties. However, no direct evidence has been presented that indicates that 13-HODE indeed modulates platelet-vessel wall interaction. In this study we have bound a purified 13-HODE to a thrombogenic surface and its effect on platelet adhesion was studied and compared to the effects of an analogous hydroxy fatty acid, 15-hydroxyeicosatetraenoic acid (15-HETE). The effect of 13-HODE on platelet adhesion was studied both under static and flow conditions. In this report we show that binding of up to 40 times the physiological concentration to a thrombogenic surface has no inhibitory effect on platelet adhesion under static or flow conditions. We conclude that 13-HODE is not an important regulatory substance in platelet-subendothelium interaction, although this does not exclude it has a putative anti-adhesive role on intact endothelium.