Speech perception 30 years after cisplatin-based chemotherapy in adults: limited clinical relevance of long-term ototoxicity?

BACKGROUND: Cisplatin-based chemotherapy (CBCT) can cause high-frequency hearing loss, but little is known about the development and clinical relevance of this hearing loss in survivors of adult-onset cancer with very long-term follow-up. This case-control study investigates hearing and speech perception both in quiet and with background noise 30-years after CBCT. PATIENTS AND METHODS: One-hundred-and-one patients (Cases) who received CBCT for testicular cancer between 1980 and 1994 were assessed with pure-tone audiometry (.125 - 8 kHz) and speech perception tests including hearing in noise test (HINT). Self-reported hearing and tinnitus was scored by participants. Results were compared with 30 age-matched controls. RESULTS: The median age of Cases and Controls was 60 (46 - 83) and 61 years (51 - 74), respectively. The median observation time for Cases was 30 years (22 - 37). Compared with Controls, Cases had 8 and 19 dB worse age-adjusted high-frequency hearing at 6 and 8 kHz, respectively (p <.05), while thresholds at lower frequencies did not differ. All but four Cases reached 100% speech perception with basic speech audiometry. There was no difference between Cases and Controls in speech perception neither in quiet nor with both speech and background noise from the front, although the within-group variance was greater among Cases. Cases scored slightly worse with speech from front and noise from either side. Self-reported hearing loss (both hearing loss in general and specifically with background noise), and tinnitus were about three times more common among Cases compared with Controls. CONCLUSIONS: Cisplatin causes high-frequency hearing loss, but speech perception tests performed both in quiet and in background noise 30 years post-treatment indicate that the clinical relevance is limited for most patients. Few patients develop severe hearing loss that requires rehabilitation but it is important to identify these patients. Self-reported hearing loss and tinnitus were more common among Cases compared with Controls.

Non-allergic, mastocytosis-associated rhinitis.

BACKGROUND: Systemic mastocytosis (SM) is a clonal proliferative disorder of mast cells (MC) that causes pathological accumulation of mast cells in various tissues, which results in clinical symptoms (e.g. diarrhoea, urticaria) due to MC mediator release. Previous studies have shown that up to fifty percent of rhinitis symptoms in SM patients are non-allergic and it has been assumed that these nasal complaints in SM patients are due an increased nasal mast cell burden. Nevertheless, to date there are no data supporting this hypothesis. OBJECTIVE: The study aims to investigate if the presence of allergy-suggesting nasal complaints in non-allergic SM patients is correlated with objective measure of nasal mast cell burden. PATIENTS AND METHODS: Eleven adult patients with systemic mastocytosis underwent a comprehensive rhinologic work-up. All patients fulfilled the clinical ARIA criteria for rhinitis. The allergologic work-up included serological allergy testing, determination of tryptase levels (serum and nasal secretion), skin prick testing, and nasal provocation testing. RESULTS: Ten out of eleven SM patients with clinical persistent allergic rhinitis were found to be non-allergic. In these patients, the most predominant symptoms were rhinorrhea, sneezing, and itching. All three symptoms were strongly correlated with the nasal tryptase level but not to the level of serum tryptase. CONCLUSION AND CLINICAL RELEVANCE: Non-allergic persistent nasal complaints in systemic mastocytosis were significantly correlated with elevated nasal tryptase level as a measure of local MC burden. Furthermore, elevated nasal tryptase correlated with persistent rhinorrhea, sneezing, and itching as predominant symptoms, which seems to characterize a non-allergic mastocytosis-associated rhinitis (NAMAR) in systemic mastocytosis.

Associations between patient-reported late effects and systemic cytokines in long-term survivors of head and neck cancer treated with radiotherapy.

PURPOSE: Head and neck cancer (HNC) treatment may lead to late effects and impaired health-related quality of life of survivors. Knowledge on long-term late effects after radiotherapy (RT) and potential underlying biological mechanisms is lacking. We assessed the prevalence of xerostomia, dysphagia, and chronic fatigue (CF) in HNC survivors ≥ 5 years post-RT, and examined associations between pro-inflammatory cytokines and late effects. METHODS: In a cross-sectional study, 263 HNC survivors treated between 2007 and 2013 were enrolled. They completed validated questionnaires assessing xerostomia and dysphagia (the EORTC QLQ-H&N35), and CF (the Fatigue Questionnaire), and underwent blood sampling and clinical examination. Pro-inflammatory cytokines were analyzed in 262 survivors and 100 healthy age- and gender-matched controls. RESULTS: Median time since treatment was 8.5 years. The proportions of survivors reporting xerostomia, dysphagia, and CF were 58%, 31%, and 33%, respectively, with a preponderance of females. We found no significant associations between IL-6, IL-8, IP-10, TARC, TNF, or ENA-78 and the three late effects. The odds of having elevated levels of IL-6 and IP-10 were significantly higher in the survivors compared to the controls. CONCLUSIONS: More than one-third of long-term HNC survivors experienced xerostomia, dysphagia, and CF. Persistent inflammation, with elevated systemic cytokines, was not associated with these late effects, although HNC survivors had higher levels of some cytokines than the controls. IMPLICATIONS FOR CANCER SURVIVORS: This study provides new knowledge on late effects that can serve as grounds for informing patients with HNC about risk of late effects more than 5 years after RT.

Body mass index less than 28 kg/m2 is a predictor of subjective improvement after laser-assisted uvulopalatoplasty for snoring.

OBJECTIVE/HYPOTHESIS: To investigate whether body mass index (BMI) can be used to predict subjective improvement of snoring after laser-assisted uvulopalatoplasty (LAUP). STUDY DESIGN: One hundred nineteen consecutive adult patients who had LAUP performed for socially disruptive snoring were contacted by mail 3 months after surgery and asked to complete a questionnaire with the following alternatives as to the effect of surgery on their snoring: no improvement (1); some improvement (2); moderate improvement (3); substantial improvement (4) and abolished snoring (5). Patients reporting to categories 3, 4, or 5 were referred to as responders and to categories 1 or 2 as nonresponders. Seventy patients (59%) completed the questionnaire. METHODS: A one-stage LAUP was performed with local anesthesia in an outpatient ear, nose, and throat clinic with a CO2 laser. Patients were divided into two categories with BMI above and below 28 kg/m2 at the time of surgery. RESULTS: BMI correlated significantly with subjective postoperative improvement. (R = 0.29; P < .02; Pearson's correlation test). Odds ratio (OR) for success by BMI less than 28 kg/m2 compared to patients with BMI greater than 28 kg/m2 was 4.8 (95% confidence interval [CI]: 1.48-15.53). CONCLUSIONS: BMI is a simple, yet important predictor of subjective reduction of snoring after LAUP and should be considered before performing such surgery.

Treatment of esthesioneuroblastomas.

OBJECTIVE: To analyze the clinical features, treatment outcomes, pattern of failures, and course of the disease of a cohort of patients treated for esthesioneuroblastoma (ENB) with craniofacial resection (CFR) at a single institution during a 12-year period. MATERIAL AND METHODS: Retrospective analysis of 11 patients with ENB treated with CFR in a tertiary care academic medical center from 1998 to 2009. RESULTS: Median age at diagnosis was 51 years (range 41-67 years). The most common presenting symptom was nasal obstruction (91%). Four patients (36%) presented with Kadish stage B, six patients (55%) with Kadish stage C, and one patient (9%) with Kadish stage D. The initial treatment was craniofacial resection (CFR) alone for three patients (23%), CFR followed by postoperative radiation therapy (RT) in seven patients (64%), while one patient (9%) received both neoadjuvant and adjuvant RT in addition to surgery. The mean and median follow-up times were 66 and 58 months, respectively (range 23-158 months). Seven patients are currently alive with no evidence of disease (64%), while two patients are alive with disease (18%). Overall survival was 100% at one year postoperatively and 80% five years after the primary treatment. The progression free survival was calculated to 73% at one year and 64% at five years. CONCLUSIONS: ENB is an uncommon diagnosis with an incidence of 0.037/100,000 persons/year in the catchment area of our institution. Treatment can be challenging, especially with advanced disease. CFR with RT offers good oncologic disease control with minimal morbidity.

The distribution of hypopnoeic events in relation to apnoeic events in patients with sleep-induced upper airway narrowing.

The purpose of this study was to investigate patients with sleep-induced upper airay narrowing to see if: (1) apnoeic and hypopnoeic events regularly coexist; (2) if sleep-induced upper airway narrowing usually involves more than one level; and (3) whether the distribution of hypopnoeic events reflects that of apnoeic events. A retrospective review of 50 patients with sleep-induced upper airway narrowing was conducted. Recordings were made with a solid-state microtransducer pressure-catheter and an external thermistor for assessment of the distribution and number of obstructive events. Ninety-four per cent of the patients had a mixture of apnoeic and hypopnoeic events. Both transpalatal and subpalatal obstructions were identified in 84% of patients. In 80% of the patients the level of apnoeic events, classified as either mainly (> 50% of total) transpalatal (upper) or subpalatal (lower) reflected that of hypopnoeic events. The percentage upper to total amount of hypopnoeic events correlated significantly with that of apnoeic events (R = 0.77, P < 0.001; Spearman rank correlation).

D-glucaric acid in common duct bile and relation to choledocholithiasis.

BACKGROUND: The aim was to investigate a possible association between D-glucaric acid (DGA), biliary bilirubin glucuronidation and brown pigment stones in the common bile duct. METHODS: A high performance liquid chromatography method with a strong cation resin (HPX-87H) was developed for measuring biliary DGA. Bile was obtained during ERCP by deep cannulation of the common bile duct in 100 patients with suspected biliary disease. RESULTS: The concentration of DGA in common bile duct bile was 60 (1.1-633) micromol l(-1) (median, range). The values were lower than previously reported. There were no differences in DGA concentrations in patients with common bile duct stones compared to patients without common bile duct stones, irrespective of stone type, cholesterol or brown pigment stones. Bilirubin conjugates in common duct bile did not vary with DGA concentrations. CONCLUSION: DGA is probably insignificant in the pathogenesis of common bile duct stones.

The relationship between obstructive sleep apnoea and body mass index.

Obese patients have a high prevalence of obstructive sleep apnoea (OSA), but a low response rate and high frequency of relapse after uvulopalatopharyngoplasty (UVPP). In this study we have determined the level of obstruction during sleep in 31 men with OSA, using a catheter with multiple micropressure transducers and a portable digital recorder. The proportion of apnoeic episodes with obstruction at lower levels correlated with increasing body mass index (BMI) (P < 0.05). Thus, with increasing obesity, there seems to be a shift to a lower level of obstruction. All patients with BMI > 30 and apnoea index (AI) > 5 had predominantly lower obstructions (P < 0.05). This may explain why many obese patients fail to respond, or have relapses after UVPP.

The sites of obstruction in OSA, identified by continuous measurements of airway pressure and flow during sleep: ambulatory versus in-hospital recordings.

Polysomnography provides information about the severity of obstructive sleep apnoea (OSA), but is less satisfactory in predicting the effect of uvulopalatopharyngoplasty (UVPP). Another possible investigation in patients with suspected OSA is to determine the sites of pharyngeal obstruction or collapse by an overnight recording of airflow and upper airway pressures at several levels during sleep. Before these measurements can be established as a routine investigation, reproducibility studies have to be carried out. In 11 men with suspected OSA, we recorded airway pressure and airflow during sleep for 2 nights, the first in hospital and the second at home (ambulatory). The recording conditions were deliberately different in order to set up a 'worst case' comparison. Transpalatal (upper) or subpalatal (lower) obstructive predominance remained constant in 9 patients despite considerable changes in the absolute number of obstructive events. Only one patient had exclusively upper or lower obstructive events during the initial recording and this suggests that the level diagnosis after an overnight study using pressure and airflow may be more accurately described as percentage upper obstructive events of total. We conclude that the relationship between upper and lower obstructive events is reproducible between ambulatory and hospital recording, but recommend that level diagnosis should be interpreted with caution in patients with low recorded apnoea hypopnoea index (AHI).

Urinary D-glucaric acid, a marker substance for microsomal enzyme induction. Methodological aspects, responses to alcohol and findings in workers exposed to toluene.

D-glucaric acid, an end product of glucuronic acid metabolism, has been used as a marker substance for microsomal enzyme induction. In this study a convenient microtitre-plate based method for the quantification of urinary D-glucaric acid has been developed and validated. Mean urinary D-glucaric acid excretion in 20 health humans as measured by this method was 3.2 mumol glucaric acid mmol-1 creatinine, 95% confidence interval 3.0-3.4. Moderate alcohol consumption in 18 healthy volunteers did not significantly augment the urinary D-glucaric acid excretion. Occupational exposition to toluene in a printing plant was investigated. In spite of considerable intra- and inter-individual variability, a significant difference between exposed (3.5, 3.1-3.9) and non-exposed (2.6, 2.2-3.0) workers was observed, p < 0.025. We conclude that the measurement of D-glucaric acid can be utilized for biological screening of enzyme induction on a group basis.

beta-Glucuronidase in common duct bile, methodological aspects, variation of pH optima and relation to gallstones.

beta-Glucuronidase of human or bacterial origin may deconjugate bilirubin diglucuronide, causing pigment gallstones. Intrinsic interference by biliary compounds must be minimized for accurate assay of beta-glucuronidase. We report a modified ion-pair extraction of interfering substances by tetrahexylammonium chloride (THAC) in ethyl acetate in the presence of albumin, and a microtitre plate assay for biliary beta-glucuronidase activity in bile with the substrate p-nitrophenol-glucuronide. Adding albumin improved the recovery of beta-glucuronidase activity to 99.8% (CV 1.9%), and 92.2% of the bilirubin in bile samples was extracted in one step. Competitive inhibition was overcome by increasing the substrate concentration. In endoscopically obtained common duct bile from 44 patients, five different beta-glucuronidase activity peaks were identified, at pH 3.9, 4.8, 5.3, 5.8 and 7.2. The pH profiles were classified into one bacterial pattern and five patterns for presumed human beta-glucuronidase. Of the latter patterns, four displayed dual activity peaks. In a second sample, obtained at follow up in four patients, their original pH profile was maintained. In conclusion, using the modified purification and assay system, we found functionally diverse subcategories of human beta-glucuronidase with respect to activity at variable pH. Our results indicate that several pH optima have to be taken into consideration in order to clarify the role of human biliary beta-glucuronidase in the pathogenesis of pigment gallstones. Bacterial beta-glucuronidase activity was associated with duodenal diverticula (p < 0.05) and common duct stones (p < 0.05).

Lipopolysaccharides and beta-glucuronidase activity in choledochal bile in relation to choledocholithiasis.

Common duct gallstones are mainly of the brown pigment type, which are usually attributed to bacterial factors. Bacterial beta-glucuronidase most probably plays a role in the pathogenesis in many but not all patients. The role of other bacterial factors is more undecided. The aims of this study were to investigate a possible association between lipopolysaccharides (LPS) and choledocholithiasis, and to examine the interrelationship to beta-glucuronidase. Common duct bile obtained at endoscopic retrograde cholangiography in 86 patients was assayed for LPS by a limulus amebocyte lysate test, and beta-glucuronidase activity at pH 7.0 was measured. We found that both elevated concentration of LPS and the presence of juxtapapillary duodenal diverticula were associated with common duct stones (p < 0.01, both). Patients who had their common duct stones removed recently had a lower LPS concentration and a lower activity of beta-glucuronidase than those who had a stone in situ (p < 0.01, both), but still higher LPS concentration than those without choledocholithiasis at all (p < 0.01). In multiple logistic regression analysis, elevated LPS was the significant predictor of common duct stones (p < 0.01), and not confounding with neither beta-glucuronidase nor juxtapapillary diverticula. We conclude that gram-negative bacteria convey bacterial factors associated with choledocholithiasis, by mechanisms independent of, and additional to beta-glucuronidase.

Repeatability of sites of sleep-induced upper airway obstruction. A 2-night study based on recordings of airway pressure and flow.

OBJECTIVES: To evaluate repeatability of overnight continuous airway pressure and flow recordings for assessment of obstructive sites and their distribution in patients with obstructive sleep apnea (OSA). STUDY DESIGN: Open, prospective study of 30 men with sleep-induced obstructive events (apnea and hypopnea). METHODS: Repeated ambulatory sleep recordings of airway pressure and flow to assess the localization of sites of obstructive events were compared. Obstructive sites were divided into upper (transpalatal) or lower (subpalatal). The exact distribution of obstructive sites was expressed as percentage upper obstructive events. A cut-off at apnea index (AI) = 5 was used for comparison between frequent and infrequent obstructers. RESULTS: Eighty-two percent (14/17) of patients with frequent, and 58% of those with infrequent apneic events maintained their predominant site of obstructive events classified as upper (transpalatal) or lower (subpalatal) [72% (21/29) in the entire group]. We found a significant correlation between recordings for the percentage upper apneic (R = 0.54, P = 0.024, n = 17) and hypopneic (R = 0.59, P = 0.012, n = 17) events in patients with frequent, but not in those with infrequent apneic events. Patients who had the vast majority of obstructive events located at a single site were more stable than those with more evenly distributed obstructive events. CONCLUSION: Repeatability of sites of obstructive events is influenced by the severity of illness and the degree of upper or lower obstructive predominance. The distribution of sites of obstructive events (classified as mainly "upper"/"lower" or as percent upper obstructive events of all) can be identified with relative confidence in patients who have frequent apneic events (AI > or = 5) or a high degree of upper or lower obstructive predominance and especially in those who have a combination of these two criteria.

Total protein in common duct bile measured by acetonitrile precipitation and a micro bicinchoninic acid (BCA) method.

Bile protein assays are complicated due to interference by other bile substances. In the present study we describe a microtiter plate method for the purification and quantification of bile proteins. The method is based on addition of acetonitrile in three steps to reconstituted freeze-dried bile, followed by ethanol washing of the precipitated proteins. Finally, protein in the precipitate is quantitated by two-point colour development using micro BCA reagents. Overall recoveries of protein in reconstituted bile spiked with exogenous protein (Seronorm) ranged from 91.0% (coefficient of variation; CV = 7.0%) to 97.1% (CV = 2.4%) by recoveries of 125I-Fibrinogen and 125I-Albumin. Bile pigments were largely removed during precipitation and washing, as verified by high pressure liquid chromatography (HPLC). Preferably the samples should be freeze-dried initially, as this lowered the blank readings. Two-point colour development with the BCA reagents were identical for standards assayed directly and standards added to protein depleted bile, and processed through all steps. Hence, no interference by either residual bile constituents nor the reagents upon the BCA protein assay could be detected. Standard curves ranged from 0.05 to 5.0 gl-1 (r > 0.98). Within day reproducibility (n = 15) was 7.8% (CV) and day to day (n = 10) was 12.1% (CV). Mean protein concentration in common duct bile from 30 patients was 1.20 gl-1 (range 0.34-3.87 gl-1). The method appears suitable for assay of bile protein, requires only limited sample volumes and allows processing of many samples within a short time.

Quantification of lipopolysaccharides in human bile with or without gram-negative bacteria.

Lipopolysaccharide (LPS) was assayed in 78 samples of human common-duct bile, obtained at endoscopic retrograde cholangiography. The LPS was assayed by a chromogenic limulus amebocyte lysate (LAL) test, after dilution of bile samples in heparinized plasma and inactivation of inhibitors. The assay was not influenced by other biliary constituents, as demonstrated by the recovery of standards. Bile pigments did not influence the results. The LAL test was positive in 60 of the samples, 59 of which had a positive culture for gram-negative bacteria or Candida sp. The levels of LPS were significantly correlated to the total number of bacteria (n = 16, R = 0.55, p less than 0.05). The median LPS level was 35,250 ng/l and showed a very large variation (140 ng/l to 27.8 mg/l). In four of the samples gram-negative bacteria were present, but no LPS could be detected. The study demonstrates the presence of LPS in great quantities in human bile and supports the feasibility of using the LAL test on bile samples. The presence of LPS (within the detection limit) appears to be associated with local microbial colonization.

Structure and composition of common bile duct stones in relation to duodenal diverticula, gastric resection, cholecystectomy and infection.

BACKGROUND: Common bile duct stones represent a clinical problem often involving severe infection, cholangitis and cholestasis. Stasis and infection are thought to play a part in the pathogenesis of choledocholithiasis. Investigations on the etiology of common bile duct stones are, however, scarce because of the difficult access to common bile duct stones and bile. In a clinical series of common bile duct stones, we studied the gross appearance of stones extracted endoscopically from the common bile duct and measured the cholesterol and bilirubinate content in order to elucidate factors of importance to etiology. METHODS: In 135 patients treated endoscopically for bile duct stones, the stones or parts of the stones were collected. Appearances of the cut surface of the stones were studied and described. Cholesterol and bilirubinate content were analyzed enzymatically and with infrared spectroscopy. The growth in bile of gas-producing bacteria previously shown to be correlated with enterobacteriacea was investigated. RESULTS: Seventy-five percent of the stones were pigment stones, the majority with concentric pigmented layering. There was good agreement between cholesterol measurements. With a cutoff at 50% for the infrared measurements and 25% for the enzymatic assay only 3 stones were discordant between cholesterol measurements and visual inspection. Twenty-one of 23 patients with a previous Billroth-II gastric resection had pigment stones (p < 0.05). Gas-producing bacteria were significantly more prevalent in the bile from patients with layered pigment stones. CONCLUSION: Pigment stones with concentric layering highly suggestive of a cyclic process of crystallization were recovered from the common bile duct in 70% of the patients in our series.

Brown pigment stones in the common bile duct: reduced bilirubinate diconjugate in bile.

BACKGROUND: Bilirubin is the main component of most common bile duct stones. Normally, almost all bilirubin in bile is conjugated to glucuronic acid or some other sugar moiety. These conjugates are unstable and liable to deconjugation. Unconjugated bilirubin is insoluble and may precipitate as the calcium salt found in brown pigment stones. The pattern of bilirubin conjugates in common duct bile of patients with choledocholithiasis has been unknown. METHODS: In a clinical series of 55 patients with choledocholithiasis common-duct bile was aspirated, and the bilirubin conjugates analyzed with high-performance liquid chromatography. One stone from each patient was analyzed for cholesterol and bilirubin content to determine stone type. RESULTS: Sixteen patients had cholesterol stones, 38 patients had brown pigment stones, and 1 patient had a black stone. Patients with pigment stones had a lower percentage of bilirubin diglucuronide (median, 60.3%; interquartile range, 49.7%-67.3%) than patients with cholesterol stones (64.0%; 60.2%-73.3%) (Mann-Whitney, P=0.015). No significant difference was found for the other bilirubin conjugates, total bilirubin, or biliary pH when pigment and cholesterol stone patients were compared. The time of bile sampling in relation to papillotomy and treatment of cholestasis was not associated with the low percentage of bilirubin diglucuronide. The observation of reduced values for bilirubin diglucuronide could not be ascribed to duodenal diverticula or Billroth-II gastric resection. CONCLUSION: The percentage of the main bilirubinate conjugate, bilirubin diglucuronide, is decreased in the common duct bile of patients with pigmented compared with cholesterol stones.

Common bile duct stones are mainly brown and associated with duodenal diverticula.

This study investigated the composition of common duct gall stones from 61 patients, aged 49-94. The stones were collected endoscopically with a dormia basket after endoscopic papillotomy. The cholesterol content was measured both by infrared spectroscopy (mean 29%, range 0-99%) and enzymatically (mean 23%, range 0-96%). The results of the two measurements showed good correlation (r2 = 0.92), indicating that cholesterol can be adequately measured enzymatically. Most of the stones were pigment stones. When examined by infrared spectroscopy, 44 stones (72%) contained less than 50% cholesterol (mean 4%, range 0-23%). The bilirubinate content in these stones was 56%, range 12-100%. Forty two of these stones were brown stones, and only two were black stones. Pigment stones were associated with juxtapapillary diverticula (p < 0.01). It was found that brown pigment stones were the commonest symptomatic bile duct calculi in the patients studied, who are representative of a Western population.