Salvage surgery in post-chemoradiation laryngeal and hypopharyngeal carcinoma: outcome and review.

Our objective was to evaluate recurrence patterns of hypopharyngeal and laryngeal carcinoma after chemoradiation and options for salvage surgery, with special emphasis on elderly patients. In a retrospective study all patients who underwent chemoradiation for hypopharyngeal and laryngeal carcinoma in a tertiary care academic center from 1990 through 2010 were evaluated. Primary outcome measures were the survival and complication rates of patients undergoing salvage surgery, especially in elderly patients. Secondary outcome measures were the predictors for salvage surgery for patients with locoregional recurrence after failed chemoradiotherapy. A review of the literature was performed. Of the 136 included patients, 60 patients had recurrent locoregional disease, of whom 22 underwent salvage surgery. Fifteen patients underwent a total laryngectomy with neck dissection(s) and 7 neck dissection without primary tumour surgery. Independent predictors for salvage surgery within the group of 60 patients with recurrent disease, were age under the median of 59 years (p = 0.036) and larynx vs. hypopharynx (p = 0.002) in multivariate analyses. The complication rate was 68% (14% major and 54% minor), with fistulas in 23% of the patients. Significantly more wound related complications occurred in patients with current excessive alcohol use (p = 0.04). Five-year disease free control rate of 35%, overall survival rate of 27% and disease specific survival rate of 35% were found. For the 38 patients who were not suitable for salvage surgery, median survival was 12 months. Patients in whom the tumour was controlled had a 5-year overall survival of 70%. In patients selected for salvage surgery age was not predictive for complications and survival. In conclusion, at two years follow-up after chemoradiation 40% of the patients were diagnosed with recurrent locoregional disease. One third underwent salvage surgery with 35% 5-year disease specific survival and 14% major complications. Older patients selected for salvage surgery had a similar complication rate and survival as younger patients.

The Asher-McDade Aesthetic Index in Comparison With Two Scoring Systems in Nonsyndromic Complete Unilateral Cleft Lip and Palate Patients.

OBJECTIVE: To compare the Asher-McDade aesthetic index with 2 systems used to score the appearance of the nasolabial area in patients with a complete cleft lip and palate. DESIGN: Retrospective analysis of the results of complete unilateral cleft lip and palate patients. SETTING: Academic Center for Dentistry of Amsterdam and the VU University Medical Center. PATIENTS: Six-year-olds with complete unilateral cleft lip and palate. MAIN OUTCOME MEASURES: Cleft lip and palate patients assessed using the scoring system proposed by Prahl et al, a 5-point ordinal scale, and the scoring system proposed by Asher-McDade et al by 6 judges, 3 orthodontists, and 3 plastic surgeons. A calculation of intra- and interobserver reliability was made. A comparison was made of all the assessment methods using Kendalls' tau. RESULTS: Photographs of 55 children (38 boys and 17 girls) with complete unilateral cleft lip and palate were assessed. For the scoring system of Prahl et al, interobserver reliability varied from 0.43 to 0.53, for the 5-point scale between 0.45 and 0.57, and for the scoring system by Asher-McDade et al these varied between 0.52 and 0.66. Multiple significant correlations were found between the used scoring systems. CONCLUSION: It can be concluded that the Asher-McDade aesthetic index is still superior to the other scoring systems used in this study. However, all 3 scoring systems can reliably be used when 3 or more observers are used.

Comparison of two scoring systems in the assessment of nasolabial appearance in cleft lip and palate patients.

OBJECTIVE: The aim of this study was to determine the reliability of 2 scoring systems. DESIGN: This study used a retrospective analysis of the results of complete unilateral cleft lip and palate patients. SETTING: The study was conducted at the VU Medical Center and the Academic Center for Dentistry of Amsterdam. PATIENTS: Patients were complete unilateral cleft lip and palate patients at the age of 6 years. MAIN OUTCOME MEASURES: Assessment of the nose and lip together and separately with a numerical photographic reference scoring system and with a 5-point ordinal scale without the use of a reference photograph by 6 judges. Intraobserver and interobserver reliability was calculated; both ways of assessment were compared by using Kendall tau. RESULTS: Photographs were available of 55 children (6 years old, 38 boys and 17 girls) with a complete unilateral cleft lip and palate. The interobserver reliabilities of the lip and nose together were 0.53 and, for the nose and lip separately, 0.51 and 0.43, respectively with the use of the numerical scale. In the 5-point scale, these were 0.55 for the nose and lip together and 0.57 and 0.45 for the nose and lip separately, respectively. Furthermore, it was found that the lip dominates in the scorings of the lip and nose together (linear regression analysis). CONCLUSIONS: The 2 tested systems are equivalent in their reliability and outcome. The lip is dominating in the overall scorings. It is advocated to use the 5-point scale without the use of a reference photograph and to assess the lip and nose separately.

The effect of substitution therapy on symptoms in patients with hypothyroidism following treatment for laryngeal and hypopharyngeal carcinomas.

Hypothyroidism is a well-known complication following treatment of laryngeal or hypopharyngeal carcinomas, and may cause various psychological and physical problems that negatively affect quality of life. The aim of this study was to evaluate the effect of substitution therapy on symptoms in patients with hypothyroidism. A study-specific questionnaire on physical and psychological problems (before and after substitution therapy) was sent to 70 patients who had been treated between 1977 and 2008 with clinical or subclinical hypothyroidism. Ninety-four percent returned the questionnaire. Symptoms on energy levels were reported most often (67% always tired and 70% lack of energy). Moodiness and emotional and physical symptoms were reported more often in substituted (sub)clinical hypothyroidism. Substitution therapy resulted in an improvement of energy (P = 0.013), sense of general interest and enjoyment (P = 0.022) and a reduction of puffy face (P = 0.041). Most symptoms in patients with thyroid dysfunction do not improve after substitution therapy. Nevertheless, due to its impact on health-related quality of life and the low burden of substitution therapy, screening for hypothyroidism and subsequent substitution therapy remains important.

Interobserver agreement in detailed prenatal diagnosis of congenital heart disease by telemedicine using four-dimensional ultrasound with spatiotemporal image correlation.

OBJECTIVE: To evaluate the clinical accuracy of four-dimensional (4D) echocardiography in the detailed prenatal diagnosis of congenital heart disease (CHD) in a telemedicine setting. METHODS: Ten second-trimester spatiotemporal image correlation (STIC) volumes were sent to three observers in different tertiary care centers with expertise in 4D echocardiography. The 10 volumes were selected based on the type of diagnosis to cover a wide spectrum of CHD anomalies, and also included one normal fetal heart. Observers were asked to provide the diagnosis, the postprocessing modalities used and the time spent on examination, and to give a rating of the confidence for the diagnosis on a 5-point Likert scale. They were free to consult other colleagues, including pediatric cardiologists, but were blinded to the prenatal diagnosis and the neonatal outcome. A diagnostic scoring system was used to evaluate different aspects of the heart defects. The results were compared with neonatal echocardiography or postmortem findings ('gold standard'). RESULTS: In two cases all observers correctly diagnosed all details of the volume datasets. The observer with the best performance reached perfect agreement in six cases and nearly perfect agreement in three. The volumes were most frequently studied by sectional planes and were analyzed in a median time of 11.0 (range, 2.5-30.0) min. The median confidence score was 4.0 (range, 1.0-5.0). CONCLUSIONS: In a telemedicine setting using STIC volumes, fetal cardiac anomalies can be diagnosed correctly by an expert. However, details required for adequate counseling and planning of postnatal care may be missed. STIC by telemedicine is a promising modality, although not accurate enough for exclusive use in clinical decision making regarding treatment, prognosis or termination of pregnancy.

Anorectal function evaluation and predictive factors for faecal incontinence in 600 patients.

AIM: Anorectal function was assessed in patients with and without faecal incontinence (FI) . Risk factors predictive for FI were determined. METHOD: Between 2003 and 2009, all consecutive patients referred were assessed by questionnaire, anorectal manometry and anal endosonography. Predictive factors were identified and used to develop a statistical model to predict FI. RESULTS: Of 600 patients (519 women), 285 (48%) were faecally incontinent. In comparison with continent women, incontinent women (mean Vaizey score 15.4), were older, had more liquid stools, more deliveries, more urinary incontinence, lower anal pressures, shorter sphincter length, smaller rectal capacity and more sphincter defects. Incontinent men (mean Vaizey score 15.3) were older and had lower anal pressures. Incontinent and continent patients showed an overlap in test results. Predictors in women were age, stool consistency, anal pressures, rectal capacity, and internal and external sphincter defects. The area under the ROC-curve was 0.84 (P < 0.001; 95% confidence interval, 0.80-0.87). Using a cut off point of 0.4, FI was predicted with sensitivity, specificity, positive and negative predictive values of 86%, 68%, 74% and 82%, respectively. The model was studied in five women with a temporary stoma and was accurate in predicting FI after stoma closure. CONCLUSION: Incontinent patients have lower pressures, smaller rectal capacity and more sphincter defects than controls, but show a large overlap. Our model shows a relatively high sensitivity and negative predictive value for predicting FI in women. The model seems promising in the patients studied with a temporary stoma.

Paratracheal lymph node dissection during laryngectomy after previous (chemo)radiotherapy: a retrospective analysis of complications and histopathological results.

OBJECTIVES: To evaluate complications and histopathological results of paratracheal lymph node dissection (PTLND) at laryngectomy after (chemo)radiotherapy. DESIGN, SETTING AND PARTICIPANTS: In a retrospective analysis, complications and histopathological results of paratracheal lymph node dissections were analysed in 191 patients with a recurrent or second primary laryngeal or hypopharyngeal carcinoma following radiotherapy with or without chemotherapy. MAIN OUTCOME MEASURES: The percentage of complications in patients with bilateral, unilateral or without PTLND. RESULTS: Forty-seven patients underwent laryngectomy with bilateral paratracheal lymph node dissection, 52 with unilateral and 92 without paratracheal lymph node dissection. Although the difference in total complications was not significant, significantly more fistulae developed in patients with bilateral paratracheal lymph node dissection (40%versus 22%; P =0.016). In multivariate analysis, this difference maintained significant (P = 0.038). Pathological examination of the lymph node dissection specimen showed tumour in 3 of the 96 ipsilateral dissections (3%) and in 1 of the 50 contralateral dissections (2%). This suggests that if unilateral instead of a bilateral paratracheal lymph node dissection had been performed, 17% less fistulae would have occurred in this group of patients, while paratracheal lymph node (PTLN) metastases would have been missed in one patient. Three of four patients with paratracheal lymph nodeparatracheal lymph node metastases had glottic carcinoma, all with subglottic extension. CONCLUSION: Because of the low incidence of lymph node metastases and the increased risk of fistulae, there is a need for a strict selection of patients who need a bilateral paratracheal lymph node dissection at laryngectomy after previous (chemo)radiotherapy.

Salvage laryngectomy: oncological and functional outcome.

The purpose of the research was to evaluate postoperative complications, functional outcome and survival after salvage laryngectomy. Second, to evaluate the management of the neck in combination with a laryngectomy in this group of patients. A retrospective analysis of all patients who underwent total laryngectomy for residual or recurrent squamous cell laryngeal carcinoma after (chemo)radiotherapy between November 1990 and June 2007 was performed. Of the 120 patients that were included, the complication rate was 56% (33% major and 23% minor). In univariate analyses, T-stage (p=0.05), bilateral neck dissection (p=0.09) and ASA score (p=0.08) showed a trend for postoperative major complications. Lymph node metastases were found in 26% of the neck dissection specimens, with a trend towards more regional disease at higher initial N-stage (p=0.06) and T-stage (p=0.08). Five-year disease specific survival was 58%. In univariate analyses pre-operative chemoradiation (vs. radiation) (p=0.0001), N3 neck (p=0.001) and positive surgical margins (p=0.02) were significant predictors for a worse disease specific survival, but only positive surgical margins (p<0.001) maintained significance in multivariate analysis. Eighty-seven percent of the patients were able to produce speech using a voice prosthesis, and 84% of the patients were able to have a 'normal' or 'soft' diet. There was an almost significant increase in mean body mass index (BMI) 6-12 months postoperative (p=0.057). Laryngectomy after radiotherapy offers good survival, with a substantial risk of complications and good functional outcome.

Diverticulosis and diverticulitis form no risk for polyps and colorectal neoplasia in 4,241 colonoscopies.

BACKGROUND AND AIMS: There are conflicting data concerning the association between diverticular disease and colorectal carcinoma (CRC). This study was performed to determine the prevalence and association of diverticulosis, diverticulitis, polyps, and CRC. MATERIALS AND METHODS: In a cross-sectional, retrospective study, we analyzed the colonoscopy reports of complete colonoscopies and patho-histological results of all patients referred for colonoscopy in a period of 3 months in 18 hospitals in The Netherlands. Diverticulosis was defined as three or more diverticula present and diverticulitis as diverticulosis with inflammation. Polyps were also coded according to localization and size. Advanced neoplastic lesions were defined as polyps >or=10 mm in diameter and/or villous architecture and/or adenomas with high grade dysplasia and/or invasive cancer. Actual and previous described CRC were registered. RESULTS: A total of 4,241 patients were included in the study [1,996 (47%) male], mean age of 59 and range 18-95. Diverticula, diverticulitis, and polyps were seen in 1,052 (25%), 75 (2%), and 1,282 (30%) patients, respectively. No association was found between patients with polyps and those with and without diverticulosis (p=0.478). Invasive adenocarcinoma and adenomas >or=10 mm were most frequently observed. CRC was present in 372 (9%) patients. Negative relation between diverticulosis and CRC and invasive adenocarcinoma was observed. No association was found between polyps and CRC and patients with diverticulitis and CRC. In conclusion, there is no relation between patients with diverticulosis and higher incidence of polyps or CRC when using age-stratified analysis. No increased risk for polyps or CRC was found in patients with diverticulitis.

2-Deoxy-2[F-18]FDG-PET for detection of recurrent laryngeal carcinoma after radiotherapy: interobserver variability in reporting.

PURPOSE: To evaluate accuracy and interobserver variability in the assessment of 2-deoxy-2[F-18]fluoro-D-glucose-positron emission tomography (FDG-PET) for detection of recurrent laryngeal carcinoma after radiotherapy. PROCEDURES: Eleven experienced nuclear physicians from eight centres assessed 30 FDG-PET scans on the appearance of local recurrence (negative/equivocal/positive). Conservative (equivocal analysed as negative) and sensitive (equivocal analysed as positive) assessment strategies were compared to the reference standard (recurrence within 6months after PET). RESULTS: Seven patients had proven recurrences. For the conservative and sensitive strategy, the mean sensitivity was 87% and 97%, specificity 81% and 63%, positive predictive values 61% and 46% and negative predictive values 96% and 99%, respectively. Interobserver variability showed a reasonable relation in comparison to the reference standard (kappa = 0.55). CONCLUSIONS: FDG-PET has acceptable interobserver agreement and yields good negative predictive value for detection of recurrent laryngeal carcinoma. It could therefore be used as first diagnostic step and may reduce futile invasive diagnostics.

Resorbability of rigid beta-tricalcium phosphate wedges in open-wedge high tibial osteotomy: a retrospective radiological study.

The open-wedge high tibial osteotomy (OWHTO) is a well accepted treatment modality for patients with osteoarthritis of the medial compartment associated with genu varum. To fill in the osteotomy gap 30% macroporosity rigid beta-tricalcium phosphate (beta-TCP) is frequently used as a stable resorbable bone substitute. However, the resorbability of these beta-TCP wedges is not known. The aim of this study was to investigate this. Twenty-one OWHTO procedures in seventeen patients were performed with the use of 30% macroporosity rigid beta-TCP wedges. The osteotomies were fixed using an angle-stable locking plate. Conventional AP and lateral radiographs were examined in order to assess the resorbability of the 30% macroporosity rigid beta-TCP wedges as a function of time. A radiological classification system consisting of five phases was used to monitor the resorption of the 30% macroporosity rigid beta-TCP wedges. The mean duration of follow-up was 62 months (+/-23 range of 28-99). In all 21 cases, remnants of the 30% macroporosity rigid beta-TCP wedges were still present at maximum follow-up. Although the boundaries between 30% macroporosity rigid beta-TCP wedges and bone remained slightly visible, all osteotomies were completely consolidated and full osseointegration took place. In 16 out of 21 knees the fixation system was removed after a mean duration of 32 months (+/-19 range of 6-62). In six out of 21 knees a conversion to a knee arthroplasty was performed after a mean duration of 56 months (+/-18 range of 37-82). The OWHTO did not interfere with the placement of knee prostheses. Complete resorption of 30% macroporosity rigid beta-TCP wedges did not take place up to 8 years after operation.

Validation of the voice handicap index by assessing equivalence of European translations.

OBJECTIVE: We aimed to assess the equivalence of translations of the Voice Handicap Index (VHI). PATIENTS AND METHODS: Confirmatory factor analysis was used to assess equivalence of the US version and several translations including (1) Dutch, (2) Flemish Dutch (Belgium), (3) UK English, (4) French, (5) German, (6) Italian, (7) Portuguese and (8) Swedish. VHI questionnaires were gathered from 1,281 subjects. Patients were classified into 11 voice lesion categories. Patients with incomplete response (4%) and patients within voice lesion categories with small numbers were excluded from further analyses, leaving a cohort of 1,052 patients from 8 countries. RESULTS: The internal consistency of the VHI proved to be good. Confirmatory factor analysis across countries revealed that a 3-factor fixed measurement model best fitted the data; the 3 subscales appeared to highly intercorrelated, especially in the US data. The underlying structure of the VHI was also equivalent regarding various voice lesions, but distinct groups were recognized with respect to the height of the VHI scores, indicating that various voice lesions lead to a diversity of voice problems in daily life. CONCLUSION: The US VHI and the translations appeared to be equivalent, which means that the results from studies from the various included countries can be compared.

Elevated uterine activity increases the risk of fetal acidosis at birth.

OBJECTIVE: The objective of the study was to assess the role of uterine activity on fetal outcome. STUDY DESIGN: Intrauterine pressure (IUP) recordings from consecutive term singleton, vaginal deliveries collected between June 1, 1993, and July 1, 2004, were analyzed. One thousand four hundred thirty-three recordings were included. IUP data were obtained using HP 8040A and HP M1350 cardiotocographs. For each recording the uterine contraction curve was analyzed, and the following contraction parameters were determined: relaxation time; contraction duration, frequency, amplitude, and surface; Montevideo units; and active planimeter units and contraction frequency. IUP recordings and contraction parameters from deliveries ending with an umbilical artery pH of 7.11 or less were compared with those ending with an umbilical artery pH of 7.12 or greater. Statistical analyses were performed using Student's t test and logistic regression. RESULTS: An umbilical artery pH 7.11 or less at birth is associated with significant more uterine activity during the first and second stage of labor. CONCLUSION: Increased uterine activity is significantly associated with a higher incidence of an umbilical artery pH of 7.11 or less.

Voice in early glottic cancer compared to benign voice pathology.

The purpose of this study is to compare (Dutch) Voice Handicap Index (VHIvumc) scores from a selected group of patients with voice problems after treatment for early glottic cancer with patients with benign voice disorders and subjects from the normal population. The study included a group of 35 patients with voice problems after treatment for early glottic cancer and a group of 197 patients with benign voice disorders. Furthermore, VHI scores were collected from 123 subjects randomly chosen from the normal population. VHI reliability was high with high internal consistency and test-retest stability. VHI scores of glottic cancer patients were similar to those of patients with voice problems due to benign lesions. Both groups of patients were clearly deviant from the normal population. Within the normal population, 16% appeared to have not-normal voices. Based on ROC curves a cut-off score of 15 points was defined to identify patients with voice problems in daily life. A clinical relevant difference score of 10 points was defined to be used for individual patients and of 15 points to be used in study designs with groups. Patients with voice problems after treatment for early glottic cancer encounter the same amount of problems in daily life as the other voice-impaired patients. The VHI proved to be an adequate tool for baseline and effectiveness measurement of voice.

Expression profiling and prediction of distant metastases in head and neck squamous cell carcinoma.

BACKGROUND: For breast and prostate cancer, a gene expression signature of the tumour is associated with the development of distant metastases. Regarding head and neck squamous cell carcinoma (HNSCC), the only known risk factor is the presence of > or =3 tumour-positive lymph nodes. AIM: To evaluate whether a HNSCC gene expression signature can discriminate between the patients with and without distant metastases. METHODS: Patients with HNSCC with and without distant metastases had >3 tumour-positive lymph nodes, and did not differ with respect to other risk factors. Statistical analysis was carried out using Student's t test, as well as statistical analysis of microarrays (SAM), to assess the false discovery rate for each gene. These analyses were supplemented with a newly developed method that computed deviations from gaussian-order statistics (DEGOS). To validate the platform, normal mucosa of the head and neck was included as control. RESULTS: 2963 genes were differently expressed between HNSCC and normal mucosa (t test; p<0.01). More rigorous statistical analysis with SAM confirmed the differential expression of most genes. The comparison of genes in HNSCC with and without metastases showed 150 differently expressed genes (t test; p<0.01), none of which, however, could be confirmed using SAM or DEGOS. CONCLUSIONS: No evidence for a metastasis signature is found, and gene expression profiling of HNSCC has seemingly no value in determining the risk of developing distant metastases. The absence of such a signature can be understood when it is realised that, for HNSCC in contrast with breast cancer, the lymph nodes are a necessary in-between station for haematogenous spread.

The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia.

Cytarabine (ara-C) is the most effective agent for the treatment of acute myeloid leukaemia (AML). Aberrant expression of enzymes involved in the transport/metabolism of ara-C could explain drug resistance. We determined mRNA expression of these factors using quantitative-real-time-PCR in leukemic blasts from children diagnosed with de novo AML. Expression of the inactivating enzyme pyrimidine nucleotidase-I (PN-I) was 1.8-fold lower in FAB-M5 as compared to FAB-M1/2 (P=0.007). In vitro sensitivity to deoxynucleoside analogues was determined using the MTT-assay. Human equilibrative nucleoside transporter-1 (hENT1) mRNA expression and ara-C sensitivity were significantly correlated (rp=-0.46; P=0.001), with three-fold lower hENT1 mRNA levels in resistant patients (P=0.003). hENT1 mRNA expression also seemed to correlate inversely with the LC50 values of cladribine (rp=-0.30; P=0.04), decitabine (rp=-0.29; P=0.04) and gemcitabine (rp=-0.33; P=0.02). Deoxycytidine kinase (dCK) and cytidine deaminase (CDA) mRNA expression seemed to correlate with in vitro sensitivity to gemcitabine (rp=-0.31; P=0.03) and decitabine (rp=0.33; P=0.03), respectively. The dCK/PN-I ratio correlated inversely with LC50 values for gemcitabine (rp=-0.45, P=0.001) and the dCK/CDA ratio seemed to correlate with LC50 values for decitabine (rp=-0.29; 0.04). In conclusion, decreased expression of hENT1, which transports ara-C across the cell membrane, appears to be a major factor in ara-C resistance in childhood AML.

Feasibility of a randomized trial on adjuvant radio-iodine therapy in differentiated thyroid cancer.

BACKGROUND: Justification for adjuvant radio-iodine (I-131) therapy in differentiated thyroid cancer (DTC) is purely based on retrospective data. This is true for ablative therapy and even more so for high-dosage adjuvant schedules. Randomized trials on the latter application are considered impossible due to anticipated formidable sample sizes required in a disease with an overall excellent prognosis like DTC. OBJECTIVE: To develop and validate a model that could stratify for risk of recurrence, rather than survival, as is usually done in prognostic indices, and secondly, to use this model to estimate the sample size required for a randomized trial. DESIGN, PATIENTS AND RESULTS: From databases of three large Dutch centres, we identified 342 consecutive patients without known residual DTC after (near-) total thyroidectomy. Using Cox proportional hazards analysis, a model was validated that clearly distinguished risk categories of recurrence using commonly available baseline variables. The model included age, N stage at presentation and T stage in papillary carcinoma. According to this stratification, a subset of patients at substantial risk for relapse (30-40%) was identified. They could be eligible for a trial assessing the impact of high-dose adjuvant I-131 on recurrence rates. Assuming a clinically relevant effect of 30% reduction of relapses, 290 patients would have to be entered in either arm (alpha 0.05, power 80%). CONCLUSION: We conclude that even though a randomized trial on this issue will be difficult to design and conduct, sample size is not the main problem.

Asymmetrical dimethylarginine (ADMA) in critically ill patients: high plasma ADMA concentration is an independent risk factor of ICU mortality.

BACKGROUND AND AIMS: Accumulation of asymmetrical dimethylarginine (ADMA) has been linked to endothelial dysfunction, and is an important risk factor for cardiovascular disease. Its elimination from the body is dependent on urinary excretion and degradation by the enzyme dimethylarginine dimethylaminohydrolase. This enzyme is highly expressed in the liver, and in rat studies a high net hepatic uptake of asymmetrical dimethylarginine was found. In critically ill patients, we investigated the relation between indicators of renal and hepatic dysfunction and plasma ADMA concentration, and tested the association between ADMA concentration and outcome. METHODS: We prospectively collected blood samples from a cross-section of critically ill patients (n=52) with clinical evidence of dysfunction of more than two organs. We identified correlates of plasma ADMA concentration with laboratory values, organ failures score and outcome by univariate and multiple regression analyses. RESULTS: In critically ill patients, plasma ADMA concentration was independently related to the presence of hepatic failure (b=0.334, 95% CI: 0.207-0.461; P<0.001), and to lactic acid (b=0.395, 95% CI: 0.230-0.560; P<0.001) and bilirubin (b=0.121, 95% CI: 0.031-0.212; P=0.009) concentration as markers of hepatic function. Twenty-one (40%) patients deceased during their ICU stay. In a logistic regression model, plasma ADMA ranked as the first and strongest predictor for outcome, with a 17-fold (95% CI: 3-100) increased risk for ICU death in patients who were in the highest quartile for ADMA. CONCLUSIONS: In critically ill patients, plasma ADMA concentration is a strong and independent risk factor for ICU mortality, and hepatic dysfunction is the most prominent determinant of ADMA concentration in this population.

Second primary tumors in hereditary retinoblastoma: a register-based study, 1945-1997: is there an age effect on radiation-related risk?

OBJECTIVE: The aim of this study is to evaluate the influence of age at external beam irradiation (EBRT) on the occurrence of second primary tumors (SPTs) inside and outside the irradiation field in hereditary retinoblastoma patients. DESIGN: Cross-sectional study. PARTICIPANTS: The study included 263 hereditary retinoblastoma patients born in The Netherlands between 1945 and 1997. METHODS: A national register-based follow-up cohort study was performed on hereditary retinoblastoma patients. Information on therapy, age at irradiation, and location of SPT was obtained from the register. The Kaplan-Meier method calculated cumulative incidences of SPT in three subgroups: irradiation before (early EBRT) and after 12 months of age (late EBRT), and no irradiation. The Mantel-Cox method determined the statistical significance of differences between the cumulative incidence curves. MAIN OUTCOME MEASURES: Development of SPT inside and outside a precisely defined irradiation field in relation to age at irradiation. Our definition excluded pineoblastoma as SPT, because they constitute part of a trilateral retinoblastoma; in addition, they lie outside the field of irradiation. RESULTS: The cumulative incidence of SPT at the age of 25 years was 22% (95% confidence intervals 13%-34%) in the early EBRT group, 3% (0%-14%) in the late EBRT group, and 5% (1%-16%) in the nonirradiated group (Mantel-Cox overall: P = 0.001; between early and late EBRT, P = 0.04). However, in early irradiated patients, the incidence of SPTs inside and outside the irradiation field was similar (11%), and the difference between early and late EBRT in incidence of SPT inside the field of irradiation was less prominent than overall (11% vs. 3%: P = 0.37). Sensitivity analysis showed the results depended on the way SPT, irradiation field, and, especially, pineoblastomas are defined. CONCLUSIONS: Hereditary retinoblastoma confers an increased risk for the development of SPT, especially in patients treated with EBRT before the age of 12 months. However, the presence of similar numbers of SPTs inside and outside the irradiation field suggests that irradiation is not the cause. In other words, this study does not show an age effect on radiation-related risk. Rather, early EBRT is probably a marker for other risk factors of SPT.

Effect of perioperative nutrition, with and without arginine supplementation, on nutritional status, immune function, postoperative morbidity, and survival in severely malnourished head and neck cancer patients.

BACKGROUND: Malnourished head and neck cancer patients are at increased risk of postoperative complications. OBJECTIVE: We studied the effect of perioperative, arginine-supplemented nutritional support on nutritional status, immune status, postoperative outcome, and survival in severely malnourished (weight loss >10% of body weight) head and neck cancer patients undergoing major surgery. DESIGN: Forty-nine patients were randomly assigned to receive 1) no preoperative and standard postoperative tube feeding, 2) standard preoperative and postoperative tube feeding, or 3) arginine-supplemented preoperative and postoperative tube feeding. RESULTS: Patients in both prefed groups received approximately 9 d of preoperative tube feeding, resulting in energy intakes of 110% and 113% of calculated needs (compared with 79% in the control group; P = 0.007). Compared with no preoperative feeding, preoperative enteral nutrition did not significantly improve nutritional status or any of the studied biochemical or immunologic indexes. Major postoperative complications occurred in 53%, 47%, and 59% of patients in study groups 1, 2, and 3 (NS). A trend was seen toward better survival in the arginine-supplemented group (P = 0.15). Secondary analysis showed that survivors had better human leukocyte antigen-DR expression on monocytes (P = 0.05) and higher endotoxin-induced cytokine production (P = 0.010 for tumor necrosis factor alpha and P = 0.042 for interleukin 6) at the start of the study than did patients who died. CONCLUSIONS: Nine days of preoperative tube feeding, with or without arginine, did not significantly improve nutritional status, reduce the surgery-induced immune suppression, or affect clinical outcome in severely malnourished head and neck cancer patients. Patients supplemented with arginine-enriched nutrition tended to live longer. Some markers of immune function may distinguish patients with good or bad prognoses.