Pharyngocutaneous fistula: the incidence and the risk factors.

A pharyngocutaneous fistula is the most common complication following laryngectomy. A wide range of potential risk factors has been suggested. The purpose of this study was to determine the incidence and risk factors for the fistula at the Department of Otorhinolaryngology and Head and Neck Surgery in Ljubljana, Slovenia between 2007 and 2012. Charts from patients treated for head and neck cancer by laryngectomy were retrospectively reviewed. Comprehensive clinicopathologic data were collected including potential risk factors related to the patient, disease, surgery and postoperative period. The patients were categorised into the group with the fistula (a study group) and without it (a control group). The incidence of the fistula was calculated and the groups were statistically compared according to potential risk factors using the Chi square test, Fisher exact test, T test, Mann-Whitney U test and binary logistic regression analysis. Hundred fifty-eight patients were included. The incidence of the fistula was 30.4 %. In the primary laryngectomy group the incidence was 22.6 %, whereas in the salvage laryngectomy group 44.6 % (p = 0.006). The independent predictors for the fistula were history of head and neck cancer (p = 0.001), invasion of piriform sinus (p = 0.020) and surgical wound infection (p < 0.001). The timing of surgical wound infection could be of some importance. In the PCF group, it started on the 5th postoperative day, whereas in the control group on the 7th postoperative day (p = 0.063). Decreasing the rate of surgical wound infection could diminish the fistula rate.

Intra-articular patient-controlled analgesia improves early rehabilitation after knee surgery.

The influence of patient-controlled intra-articular analgesia with ropivacaine, morphine and ketorolac (RMK) on postoperative pain relief and early rehabilitation after anterior cruciate ligament reconstruction was studied. Twenty six patients, randomized into two groups, were enrolled in a placebo-controlled, double-blind study. At the end of surgery a catheter was placed intra-articularly and connected to a patient-controlled pump, programmed to deliver 10 mL bolus and 60 min lockout interval. RMK group received 0.25% ropivacaine, morphine 0.2 mg/mL and ketorolac 1 mg/mL; P group saline. Pain was measured with 10 cm visual analog scale. At pain scores > 3 cm, all patients were instructed to self-administer morphine intravenously using a patient-controlled pump. Daily rescue morphine consumption was noted and 48 h rehabilitation programme was evaluated. Daily morphine consumption was significantly lower in the RMK group (p < 0.001). At 24h after surgery, the patients in the RMK group experienced significantly less pain (p < 0.05). The patients in the RMK group achieved higher maximum degree of knee flexion in supine (p < 0.001) and in prone position (p < 0.05) compared to placebo group and better pain free flexion with assistance on day 1 (p < 0.05) and 2 (p > 0.05). The results show that patient-controlled intra-articular analgesia with RMK combination provides effective pain relief following anterior cruciate ligament reconstruction and improves early physical rehabilitation.

Atrial fibrillation is an independent determinant of increased NT-proBNP levels in outpatients with signs and symptoms of heart failure.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is increasingly used in the diagnosis and prognostic assessment of heart failure; however, the possible influence of atrial fibrillation on BNP is still a matter of controversy. We assessed the influence of atrial fibrillation on NT-proBNP levels in outpatients with signs and symptoms of heart failure. METHODS: Consecutive outpatients (n = 306) referred to a university hospital heart-failure clinic for evaluation of signs and symptoms of heart failure underwent clinical and echocardiographic assessment and had their NT-proBNP levels determined in a sandwich chemiluminescent immunoassay with two antibodies on an Elecsys analyzer. The influence of atrial fibrillation on NT-proBNP levels was assessed using a non-parsimonious linear regression model with propensity score adjustments to balance for possible confounders. RESULTS: Atrial fibrillation was associated with increased NT-proBNP levels in patients with (median concentration 1944 vs. 1390 pg/ml) and without (1093 vs. 172 pg/ml) underlying structural disease (P < 0.001). In a linear regression model with a propensity score, atrial fibrillation emerged as an independent determinant of NT-proBNP levels (P = 0.023), even after allowing for possible confounders (left ventricular ejection fraction and end-diastolic diameter, left atrial diameter, mitral insufficiency, age, sex, NYHA class or heart rate). CONCLUSIONS: Atrial fibrillation is an independent determinant of increased NT-proBNP levels. This association should be taken into account when NT-proBNP levels are used in the diagnosis of heart failure in patients with atrial fibrillation.

Knee anterior laxity: a risk factor for traumatic knee injury among sportswomen?

The purpose of this study was to investigate if knee anterior laxity, measured with an arthrometer, is a risk factor for traumatic knee injury in sportswomen. To allow a more complete analysis, other, easily measured variables such as anthropometry, lower leg characteristics, sport exposure and menstrual cycle characteristics were also evaluated as possible risk factors. Subjects were Slovenian sportswomen aged between 11 and 41 years participating in basketball, team handball and volleyball (N = 540). Sportswomen were tested in the pre-season and followed for one season. The data collection included: written informed consent, background questionnaire, anthropometric tests, leg dominance assessment, navicular drop test (measurement of foot pronation), passive knee extension assessment and measurement of knee anterior laxity with a KT arthrometer. Several sets of data analysis were performed including logistic regression analysis in order to build a model for predicting traumatic knee injury among sportswomen. Height and average hours of training per week were found to differ significantly (P < 0.05) between injured and uninjured sportswomen. More sportswomen injured their non-dominant leg. Traumatic knee injuries among Slovenian sportswomen participating in basketball, team handball and volleyball are associated with higher amounts of training, greater body height and greater knee anterior laxity. Only 1% of the variability in traumatic knee injuries among sportswomen were explained with those variables suggesting that there are many other variables associated with traumatic knee injuries among sportswomen than were tested in this study.

Alveolar echinococcosis: from a deadly disease to a well-controlled infection. Relative survival and economic analysis in Switzerland over the last 35 years.

BACKGROUND/AIMS: Alveolar echinococcosis (AE) is a serious liver disease. The aim of this study was to explore the long-term prognosis of AE patients, the burden of this disease in Switzerland and the cost-effectiveness of treatment. METHODS: Relative survival analysis was undertaken using a national database with 329 patient records. 155 representative cases had sufficient details regarding treatment costs and patient outcome to estimate the financial implications and treatment costs of AE. RESULTS: For an average 54-year-old patient diagnosed with AE in 1970 the life expectancy was estimated to be reduced by 18.2 and 21.3 years for men and women, respectively. By 2005 this was reduced to approximately 3.5 and 2.6 years, respectively. Patients undergoing radical surgery had a better outcome, whereas the older patients had a poorer prognosis than the younger patients. Costs amount to approximately Euro108,762 per patient. Assuming the improved life expectancy of AE patients is due to modern treatment the cost per disability-adjusted life years (DALY) saved is approximately Euro6,032. CONCLUSIONS: Current treatments have substantially improved the prognosis of AE patients compared to the 1970s. The cost per DALY saved is low compared to the average national annual income. Hence, AE treatment is highly cost-effective in Switzerland.

Risk assessment of trisomy 21 by maternal age and fetal nuchal translucency thickness in 7,096 unselected pregnancies in Slovenia.

AIM: To evaluate the screening for trisomy 21 by maternal age and nuchal translucency in a low-risk population. METHODS: Screening was performed in 7,096 singleton pregnancies. The estimated risk for trisomy 21, the detection rate (DR), false positive rate (FPR) and the cut-off nuchal translucency thickness to obtain a 5% FPR were calculated. RESULTS: The median maternal age was 28.6 years. The estimated risk for trisomy 21 was 1 in 300 or greater in 2.4% (171 of 7,096) of all pregnancies and in 75% (9 of 12) of trisomy 21 pregnancies. The DR for all aneuploidies was 83.3%, and 75% for trisomy 21. The estimated FPR at risk 1 in 300 for the whole population in 2004 was 3.8%. It is predicted to remain below 4% at least until 2007; to achieve a 5% FPR in 2007 the risk limit 1 in 400 is proposed. CONCLUSIONS: Screening for trisomy 21 in a low-risk population in Slovenia gives comparable results to those in other countries. The only result that varies is the percentage of screen positive patients at the risk limit 1 in 300. We believe the risk limit should be specifically estimated for each country based on its population distribution of maternal age.

Low performance of the MSKCC nomogram in preoperatively ultrasonically negative axillary lymph node in breast cancer patients.

BACKGROUND AND OBJECTIVES: In order to predict the nonsentinel lymph node (NSLN) metastases in sentinel lymph node (SLN) positive patients a nomogram was created at the Memorial Sloan Kettering Cancer Centre (MSKCC). The aim of our study was to validate the MSKCC nomogram in patients grouped by the preoperative ultrasound (US) examination of the axillary lymph nodes. METHODS: The MSKCC nomogram was validated separately in three groups of patients: (US-0) only clinically preoperatively negative axillary lymph nodes (126 patients), (US-1) US negative axillary lymph nodes (109 patients), and (US-2) US suspicious but fine needle aspiration biopsy (FNAB) negative axillary lymph nodes (41 patients). RESULTS: The predicted probability underestimates the actual probability with the mean absolute error equal to 0.116 in the US-0 group (P = 0.003), and overestimates the actual probability (mean absolute error equal to 0.084) in US-1 group (P = 0.033) and US-2 group (mean absolute error is 0.110) (P = 0.275). CONCLUSION: We found that the MSKCC nomogram overestimates the probability of the NSLN metastases in breast cancer patients with (i) preoperatively US negative or (ii) US suspicious, but FNAB negative axillary lymph nodes. We also found that MSKCC nomogram has only limited value in patients with only clinically negative axillary lymph nodes.

Making relative survival analysis relatively easy.

In survival analysis we are interested in time from the beginning of an observation until certain event (death, relapse, etc.). We assume that the final event is well defined, so that we are never in doubt whether the final event has occurred or not. In practice this is not always true. If we are interested in cause-specific deaths, then it may sometimes be difficult or even impossible to establish the cause of death, or there may be different causes of death, making it impossible to assign death to just one cause. Suicides of terminal cancer patients are a typical example. In such cases, standard survival techniques cannot be used for estimation of mortality due to a certain cause. The cure to the problem are relative survival techniques which compare the survival experience in a study cohort to the one expected should they follow the background population mortality rates. This enables the estimation of the proportion of deaths due to a certain cause. In this paper, we briefly review some of the techniques to model relative survival, and outline a new fitting method for the additive model, which solves the problem of dependency of the parameter estimation on the assumption about the baseline excess hazard. We then direct the reader's attention to our R package relsurv that provides functions for easy and flexible fitting of all the commonly used relative survival regression models. The basic features of the package have been described in detail elsewhere, but here we additionally explain the usage of the new fitting method and the interface for using population mortality data freely available on the Internet. The combination of the package and the data sets provides a powerful informational tool in the hands of a skilled statistician/informatician.

Stefin a and stefin B: markers for prognosis in operable squamous cell carcinoma of the head and neck.

PURPOSE: The aim of this study was to test the hypothesis about the protective role of high stefin A and stefin B concentrations in operable carcinoma of the head and neck. METHODS AND MATERIALS: Stefins A and B concentrations were measured in tissue cytosols of nontumorous mucosa and primary tumors from 92 patients. For quantitative analysis of stefins in tumor cytosols, commercially available enzyme-linked immunosorbent assays were used. RESULTS: Stefin A was upregulated in 53 patients (higher concentrations were measured in tumor samples than in nontumorous mucosa) and was downregulated in 39 patients. The corresponding numbers for stefin B were 49 and 43, respectively. A significantly higher proportion of downregulated cases were found among patients with disease re-appearance. In the Cox model, high stefin A concentrations appeared as independent predictors for favorable disease-free survival. Assuming a "broken stick" model, a significant increase in the recurrence rate after the threshold of 1063 ng/mgp (the 64th percentile in the group) was found, the hazard ratio reaching 3% of the reference value with doubling of the level of stefin A. These results were reconfirmed after pooling the data with two historical data sets into a uniform series involving 182 patients. CONCLUSIONS: A group of patients at high risk for disease progression was identified, characterized by the downregulated stefin A protein in the tumor compared with the nontumorous mucosa. Stefin A was recognized as a promising candidate marker for prognosis in patients with operable carcinoma of the head and neck.

Infliximab reduces the number of activated mucosal lymphocytes in patients with Crohn's disease.

BACKGROUND: Infliximab is an effective treatment for Crohn's disease in patients with poor prior response to conventional therapy. The mechanism by which infliximab induces clinical improvement is not completely known. AIM: The aim of the study was to investigate the influence of infliximab on immunological parameters in peripheral blood and inflamed intestinal mucosa. METHODS: Twenty-five patients with Crohn's disease (11 with luminal and 14 with fistular form) underwent treatment with infliximab. The lymphocyte populations from the peripheral blood and the inflamed intestinal mucosa were analysed by flow cytometry before treatment and 14 days later. RESULTS: After treatment, the peripheral blood analysis showed a significant increase in the percentage of CD19 cells and the concentrations of CD3, CD4, CD8 and activated (HLA DR positive) T cells, while the percentage of NK cells was reduced. In the inflamed mucosa, a significant decrease in the percentage of activated T cells and expression of HLA I molecules by epithelial cells was noted. CONCLUSIONS: Infliximab profoundly downregulates inflammation in the intestinal mucosa of patients with Crohn's disease. This effect is manifested by a reduction of activated T cells, main producers of proinflammatory cytokines, in the inflamed mucosa.

Peripheral arterial disease and ankle-brachial pressure index as predictors of mortality in residents of Metlika County, Slovenia.

AIM: To test how the presence of peripheral arterial disease predicted mortality of middle-aged and elderly residents of Metlika county, a rural area in southeastern Slovenia. METHODS: In 1987, we interviewed and examined a representative cohort of 646 subjects aged 45-80 years at inclusion without overt coronary or cerebrovascular disease, for cardiovascular risk factors and measured the ankle-brachial pressure index (ABPI). Peripheral arterial disease was defined as ABPI<0.90. The subjects were followed up 15 years or until death. All-cause mortality and cardiovascular mortality were assessed and compared between subjects with and without peripheral arterial disease in a multivariate model. RESULTS: There were 580 subjects with normal ABPI and 66 subjects with peripheral arterial disease, among which 49 were asymptomatic and 17 had intermittent claudication. Because subjects with peripheral arterial disease were on average 10 years older than those without peripheral arterial disease, the mere presence of peripheral arterial disease was not an independent predictor of mortality. However, there was a significant interaction of peripheral arterial disease with age, with a more pronounced adverse prognostic effect of peripheral arterial disease in younger than in older age groups. For a 55-year-old subject with peripheral arterial disease, the hazard ratio of dying from any cause in the follow-up period was 2.44 (95% confidence interval [CI], 1.15-4.96) in comparison to an age-matched subject without peripheral arterial disease, but at 75 years of age, the hazard ratio decreased to only 0.71 (95% CI, 0.46-1.09). For cardiovascular mortality, the hazard ratio in the presence of peripheral arterial disease was 6.05 (95% CI, 1.87-16.27) at 55 years and 0.92 (95% CI, 0.54-1.52) at 75 years. Among patients with peripheral arterial disease, each decrement of ABPI at inclusion by 0.10 significantly increased the cardiovascular mortality after 15 years by 30% (P = 0.038). CONCLUSION: Peripheral arterial disease, even asymptomatic, is an important predictor of adverse cardiovascular prognosis in relatively young patients. Reduced ABPI is a strong, independent predictor of cardiovascular mortality in all patients with peripheral arterial disease.

Relative survival analysis in R.

Relative survival techniques are used to compare the survival experience in a study cohort with the one expected should they follow the background population mortality rates. The techniques are especially useful when the cause-specific death information is not accurate or not available since they provide a measure of excess mortality in a group of patients with a certain disease. There are several approaches to modeling relative survival, but there is no widely used statistical package that would incorporate the relevant techniques. The existing software was mostly written by the authors of different methods, in different computer languages and with different requirements for the data input, which makes it almost impossible for a user to choose between available models. We describe our R package relsurv that provides functions for easy and flexible fitting of several relative survival regression models.

Goodness of fit of relative survival models.

Additive regression models are preferred over multiplicative models in the analysis of relative survival data. Such preferences are mainly grounded in practical experience with mostly cancer registries data, where the basic assumption of the additivity of hazards is more likely to be met. Also, the interpretation of coefficients is more meaningful in additive than in multiplicative models. Nonetheless, the question of goodness of fit of the assumed model must still be addressed, and while there is an abundance of methods to check the goodness of fit of multiplicative models, the respective arsenal for additive models is almost empty. We propose here a variety of procedures for testing the null hypothesis of a good fit. These are based on partial residuals defined similarly to Schoenfeld residuals familiar for Cox model diagnostics. The tests have appropriate sizes under the null hypothesis, and good power under different alternatives. We investigate their performance through simulations and apply the methods to data from a study into survival of colon cancer patients.

Density of Demodex folliculorum in perioral dermatitis.

The role of Demodex folliculorum in perioral dermatitis is not satisfactory explained. Our purpose was to assess the density of D. folliculorum in perioral dermatitis and evaluate the relationship of the mite count to previous therapy with topical steroids. A standardized skin surface biopsy of the chin was performed in 82 female patients with perioral dermatitis and in 70 control female subjects. Patients who received previous topical steroid therapy had a significantly higher mite density than the patients who had received no topical steroids (p<0.001). In the latter group of patients, the mite density did not differ significantly from that of the control group (p=0.629). Mite density increased significantly with the length of treatment with topical steroids (p<0.001). Our results suggest that increased density of D. folliculorum in perioral dermatitis is a secondary phenomenon, associated with topical steroid therapy.

Augmented convex hull plots: Rationale, implementation in R and biomedical applications.

The paper addresses the possibility to replace cluttered multi-group scatter-plots with augmented convex hull plots. By replacing scatter-plot points with convex hulls, space is gained for visualization of descriptive statistics with error bars or confidence ellipses within the convex hulls. An informative addition to the plot is calculation of the area of convex hull divided by corresponding group size as a bivariate dispersion measure. Marginal distributions can be depicted on the sides of the main plot in established ways. Bivariate density plots might be used instead of convex hulls in the presence of outliers. Like any scatter-plot type visualization, the technique is not limited to raw data -- points can be derived from any dimension reduction technique, or simple functions can be used as axes instead of original dimensions. The limited possibilities for producing such plots in existing software are surveyed, and our general and flexible implementation in R -- the publicly available chplot function -- is presented. Examples based on our daily biostatistical consulting practice illustrate the technique with various options.