Prevalence of obstructive sleep apnea after treatment for advanced T-stage head and neck cancer.

PURPOSE: Treatment of head and neck cancer (HNC) may lead to obstructive sleep apnea (OSA), but conclusive results on the prevalence of OSA are lacking. The objective of this study is to investigate the prevalence of OSA in a cohort of patients treated for advanced T-stage HNC. METHODS: A cross-sectional study was conducted in two tertiary cancer care centers including patients at least 1 year after treatment with curative intent with surgery and/or (chemo)radiotherapy ((C)RT) for advanced T-staged (T3-4) cancer of the oral cavity, oropharynx, hypopharynx, or larynx. A polysomnography (PSG) was performed in all participants. OSA was defined as an apnea-hypopnea index (AHI) of 15 events/h or higher or an AHI of 5 events/h and higher with OSA related symptoms, such as sleeping problems, daytime dysfunction and/or cardiac/metabolic comorbidities collected through file review and questionnaires. RESULTS: Of the 67 participants, 48 (72%, 95% CI 59-82%) were diagnosed with OSA. Possible risk factors are male gender, higher BMI, greater neck circumference, more nicotine pack years, cardiometabolic comorbidities, use of medication with sleepiness as side effect, present tonsils, lower T-stage (T3 vs. T4 stage), higher AJCC stage and a HPV-negative tumor. CONCLUSION: In this population of advanced T-stage HNC patients, the prevalence of OSA was 72%, which is considerably higher than in the general population (2-50%). Given the high prevalence, screening of this entire subgroup for OSA may be indicated. Future studies to identify high risk factors and develop an OSA screening protocol are needed.

Mind your head: two cases of mucosal metastasis of BRAF-mutated melanoma of the scalp.

Mucosal melanomas are rare and only a small portion bear BRAF mutations while cutaneous melanomas have a much higher prevalence and often harbor BRAF mutations. We present two cases in which, after a malignant melanocytic mucosal lesion with a BRAF mutation was found, the primary cutaneous source was identified and clonality confirmed between the lesions. In both cases, primary lesions occurred on the scalp, an often-overlooked site. Both lesions showed signs of regression implying that in due time these lesions could have been fully regressed and might never have been detected. In that case, the metastatic mucosal lesion would erroneously be identified as a BRAF-mutated mucosal melanoma. These cases give warrant; a careful dermatological inspection should be instigated when confronted with a BRAF-mutated mucosal melanoma. We hypothesize that some BRAF-mutated mucosal melanomas might actually represent metastases of regressed cutaneous melanomas.

The need to update NCRP 151 data for 10 MV linear accelerator bunker shielding based on new measurements and Monte Carlo simulations.

Linear accelerator bunker shielding protocols such as NCRP 151 have previously been tested against a large sample of measured data from real bunkers and machines but differences in per-energy concrete penetration (TVLs) for 10 MV has not yet been resolved. These differences are likely due to historical beam data and can potentially result in over-exposure of radiation workers and the public. This study examines a cohort of clinical linac bunker survey measurements and compares them to popular shielding protocols. Differences were investigated using contemporary beam data for both Monte Carlo simulation and in analytical equations. For primary barriers, NCRP 151 underestimates the dose rate through concrete by on average a factor of 2 with secondary barriers and maze entrance doses having much better agreement. Use of contemporary beam data in Monte Carlo simulation and an analytical equation yielded TVL values much closer to the measured values compared to NCRP 151. The TVL data in NCRP 151 is outdated and needs to be updated based upon the energy spectra of modern linear accelerators. Until then, physicists should use the TVL values shown in this study instead.

Management and outcome of middle ear adenomatous neuroendocrine tumours: A systematic review.

Middle ear adenomatous neuroendocrine tumours (MEANTs) are rare, unpredictable tumours. Although most MEANTs are characterized by a benign biological behaviour and indolent growth pattern, some studies have reported locally invasive and metastastic disease. Currently, the optimal management strategy for MEANTs remains subject of debate. The aim of this study is to review the literature on MEANTs with focus on its clinical characteristics, treatment strategies and outcome. A systematic review was conducted using PubMed, Embase and Cochrane databases. A total of 111 studies comprising 198 patients with MEANT were included. Treatment modalities comprised surgery (90%), surgery with adjuvant radiotherapy (9%) and palliative (chemo)radiotherapy in (1%). Local recurrence was observed in 25% of the patients and 7% of the patients developed metastasis, over a median period of 5.7 years (range 7 months - 32 years). Twelve of 13 patients (92%) who developed metastases had a local recurrence. Four patients (2%) died of MEANT: three due to distant metastases and one due to extensive local recurrence. Reliable histopathologic predictors of outcome could not be identified. These findings indicate that the clinical presentations of MEANT vary substantially, the overall recurrence rate is considerable and initial local tumour control is paramount. Because of the unpredictable clinical course, prolonged follow-up is warranted.

Referrals for head and neck cancer in England and The Netherlands: an international qualitative study of the views of secondary-care surgical specialists.

One-year survival after head and neck cancer in England has been reported to be worse than that in Europe, despite five-year conditional survival being similar, which implies that patients present later in England. One country with better rates is The Netherlands. There are many possible causes, one of which may be the system of referral from primary to secondary care. We have compared the views of secondary care specialists in the two countries about their systems for referral, and identified aspects that might have an impact on outcomes. We organised semistructured qualitative interviews of surgical specialists in head and neck cancer in England and The Netherlands (n=12 in each). The most common theme was communication between primary care and specialists. Surgeons in England identified this as the aspect most lacking under the English "two-week" rule, while Dutch specialists felt that the good communication in their system was one of its best points. Other themes included the educational needs of primary care practitioners, criticism of "tick box" referrals in England, and too many patients referred who do not have cancer. Overall, specialists in both countries identified good aspects of their respective referral systems, but those in England felt strongly that the "two-week" rule/NICE guidance system could be improved with better direct communication between primary and secondary care, which might improve the speed and quality of referrals, reduce unnecessary ones, and assist in educating primary care physicians. It is not clear whether such improvements would improve survival, but further research and piloting of such a system should be considered in England.

Nationwide study of patients with head and neck paragangliomas carrying SDHB germline mutations.

BACKGROUND: Germline mutations in the succinate dehydrogenase B (SDHB) gene predispose to hereditary paraganglioma (PGL) syndrome type 4. The aim of this study was to evaluate the clinical characteristics and outcome of treatment strategies for patients with head and neck paraganglioma (HNPGL) carrying SDHB germline mutations. METHODS: This was a retrospective evaluation of patients with HNPGL carrying SDHB germline mutations in the Netherlands. RESULTS: In a Dutch nationwide cohort study of SDHB germline mutation carriers, 54 patients with a total of 62 HNPGLs were identified. Forty-one of 54 patients (76 per cent) visited the outpatient clinic because of associated complaints. Eight patients (15 per cent) had multiple PGLs. One patient (2 per cent) developed a phaeochromocytoma and three (6 per cent) developed a malignant PGL. Twenty-seven patients (50 per cent) had an operation for their HNPGL and 15 (28 per cent) received radiotherapy. Three patients with HNPGL (6 per cent) were diagnosed with additional non-paraganglionic tumours. CONCLUSION: If an SDHB germline mutation is identified in a patient with HNPGL, the clinician should be aware of the variable manifestations of the SDHB-linked tumour syndrome, the risk of catecholamine excess, concurrent phaeochromocytoma, and association with non-paraganglionic tumours.

A novel succinate dehydrogenase subunit B germline variant associated with head and neck paraganglioma in a Dutch kindred: A family-based study.

OBJECTIVE: In the Netherlands, the majority of hereditary head and neck paragangliomas (HNPGL) are caused by germline variants in the succinate dehydrogenase genes (SDHD, SDHB, SDHAF2). Here, we evaluate a four-generation family linked to a novel SDHB gene variant with the manifestation of a HNPGL. DESIGN: A family-based study. SETTING: The VU University Medical Center (VUmc) Amsterdam, a tertiary clinic for Otolaryngology and Head and Neck Surgery. PARTICIPANTS AND MAIN OUTCOME MEASURES: The index patients presented with an embryonic rhabdomyosarcoma and a non-Hodgkin lymphoma. Array-based comparative genomic hybridisation (aCGH) analysis and multiplex ligation-dependent probe amplification (MLPA) revealed a novel deletion of exon 1-3 in the SDHB gene, suspected to predispose to paraganglioma (PGL)/pheochromocytoma (PHEO) syndrome type 4. Subsequently, genetic counselling and DNA testing were offered to all family members at risk. Individuals that tested positive for this novel SDHB gene variant were counselled and additional clinical evaluation was offered for the identification of HNPGL and/or PHEO. RESULTS: The DNA of 18 family members was tested, resulting in the identification of 10 carriers of the exon 1-3 deletion in the SDHB gene. One carrier was diagnosed with a carotid body PGL and serum catecholamine excess, which was surgically excised. Negative SDHB immunostaining of the carotid body tumour confirmed that it was caused by the SDHB variant. The remaining 9 carriers showed no evidence of PGL/PHEO. CONCLUSION: Deletion of exon 1-3 in the SDHB gene is a novel germline variant associated with the formation of hereditary HNPGL.

The penetrance of paraganglioma and pheochromocytoma in SDHB germline mutation carriers.

Germline mutations in succinate dehydrogenase B (SDHB) predispose to hereditary paraganglioma (PGL) syndrome type 4. The risk of developing PGL or pheochromocytoma (PHEO) in SDHB mutation carriers is subject of recent debate. In the present nationwide cohort study of SDHB mutation carriers identified by the clinical genetics centers of the Netherlands, we have calculated the penetrance of SDHB associated tumors using a novel maximum likelihood estimator. This estimator addresses ascertainment bias and missing data on pedigree size and structure. A total of 195 SDHB mutation carriers were included, carrying 27 different SDHB mutations. The 2 most prevalent SDHB mutations were Dutch founder mutations: a deletion in exon 3 (31% of mutation carriers) and the c.423+1G>A mutation (24% of mutation carriers). One hundred and twelve carriers (57%) displayed no physical, radiological or biochemical evidence of PGL or PHEO. Fifty-four patients had a head and neck PGL (28%), 4 patients had a PHEO (2%), 26 patients an extra-adrenal PGL (13%). The overall penetrance of SDHB mutations is estimated to be 21% at age 50 and 42% at age 70 when adequately corrected for ascertainment. These estimates are lower than previously reported penetrance estimates of SDHB-linked cohorts. Similar disease risks are found for different SDHB germline mutations as well as for male and female SDHB mutation carriers.

Low penetrance of paraganglioma and pheochromocytoma in an extended kindred with a germline SDHB exon 3 deletion.

In the Netherlands, the majority of hereditary paragangliomas (PGL) is caused by SDHD, SDHB and SDHAF2 mutations. Founder mutations in SDHD are particularly prevalent, but several SDHB founder mutations have also been described. Here, we describe an extended PGL family with a Dutch founder mutation in SDHB, c.201-4429_287-933del. The proband presented with apparently sporadic head and neck paraganglioma at advanced age. Subsequently, evaluation of the family identified several unaffected mutation carriers, asymptomatic and symptomatic PGL patients, and patients presenting with early-onset malignant pheochromocytoma. The calculated penetrance of the SDHB mutation in this kindred is lower than the risk suggested for SDHB mutations in the literature. This may represent a characteristic of this particular SDHB mutation, but may also be a reflection of the inclusion of relatively large numbers of asymptomatic mutation carriers in this family and adequate statistical correction for ascertainment bias. The low penetrance of SDHB mutations may obscure the hereditary nature of SDHB-linked disease and is important in the counseling of SDHB-linked patients. Risk estimates should preferably be based on the specific mutation involved.

Calculation of the TLD700:LiF energy response from Ir-192 using novel Monte Carlo and empirical methods.

Lithium fluoride thermoluminescent dosimeters (TLDs) exhibit a dependence on the energy of the radiation beam of interest so need to be carefully calibrated for different energy spectra if used for clinical radiation oncology beam dosimetry and quality assurance. TLD energy response was investigated for a specific set of TLD700:LiF(Mg,Ti) chips for a high dose rate (192)Ir brachytherapy source. A novel method of energy response calculation for (192)Ir was developed where dose was determined through Monte Carlo modelling in Geant4. The TLD response was then measured experimentally. Results showed that TLD700 has a depth dependent response in water ranging from 1.170 ± 0.125 at 20 mm to 0.976 ± 0.043 at 50 mm (normalised to a nominal 6 MV beam response). The method of calibration and Monte Carlo data developed through this study could be easily applied by other Medical Physics departments seeking to use TLDs for (192)Ir patient dosimetry or treatment planning system experimental verification.

Malaria in pregnancy: the difficulties in measuring birthweight.

Recommendations for interventions to control malaria in pregnancy are often based on studies using birthweight as the primary endpoint. Differences in birthweight may be attributable partly to methodological difficulties. We performed a structured search of the literature using 'malaria', 'pregnancy' and 'birth weight' as search terms. Of the clinical trials reporting birthweight, only 33% (14/43) gave information about the timing of the measurement and details on the scales used. Seventy seven per cent explained how gestational age was estimated. We propose a standardised method for the measurement and reporting of birthweight in future studies.

Platelet factor 4 and beta-thromboglobulin in inflammatory bowel disease and giant cell arteritis.

BACKGROUND: As platelet factors are important in the inflammatory response, we examined the course of platelet factor 4 and beta-thromboglobulin in relation to disease activity in inflammatory bowel disease and in giant cell arteritis. PATIENTS AND METHODS: In a prospective study, the platelet count, platelet factor 4 and beta-thromboglobulin were measured in 20 patients with Crohn's disease, 18 with ulcerative colitis and 19 with giant cell arteritis, during active and inactive disease, as well as in 51 controls without inflammation. RESULTS: Platelet counts were significantly higher in active vs. inactive Crohn's disease, ulcerative colitis and giant cell arteritis. Levels of platelet factor 4 and beta-thromboglobulin were significantly higher in active inflammatory bowel disease and giant cell arteritis, as well as in inactive inflammatory bowel disease and giant cell arteritis, than in the non-inflammatory controls. A positive correlation was found between the Crohn's disease activity index and the platelet count, platelet factor 4 and beta-thromboglobulin. Also, a positive correlation was found between the ulcerative colitis activity index and beta-thromboglobulin. However, even after 12 months of follow-up, in Crohn's disease and ulcerative colitis the mean levels of platelet factor 4 and beta-thromboglobulin were significantly higher than the levels of the controls. CONCLUSION: Platelet factors were correlated with inflammatory bowel disease activity. Levels of platelet factor 4 and beta-thromboglobulin, however, were markedly raised for a long time in clinically inactive inflammatory bowel disease, which might point to a pre-thrombotic state of disease.

Differential behavior of coagulation factor XIII in patients with inflammatory bowel disease and in patients with giant cell arteritis.

The aim of this prospective study was to examine the role of coagulation factor XIII (FXIII) in relation to disease activity in inflammatory bowel disease (IBD) and in giant cell arteritis. Plasma FXIII activity was studied during active and inactive disease in newly diagnosed patients with Crohn's disease (CD; n = 20), ulcerative colitis (UC; n = 18) and giant cell arteritis (GCA; n = 19), in 3-month intervals (median follow-up 12 months). FXIII was also measured in two noninflammatory control groups, age and sex matched for IBD (n = 25) and GCA (n = 26). FXIII activity was significantly lower in active CD or UC than in active GCA or the noninflammatory controls. Both in CD and UC, FXIII activity correlated inversely with indices of clinical disease activity, the erythrocyte sedimentation rate, fibrinogen and C-reactive protein levels. Low FXIII activity is a characteristic feature of active IBD, and serial measurements may be useful to assess IBD activity.

Duodenal diverticulitis.

The case history of a 56-year-old woman with an acute abdomen is presented. Laboratory data, a plain abdominal X-ray and ultrasound examination provided no clues for a definite diagnosis. Surprisingly, a duodenal diverticulitis was found at operation. Some aspects and complications of duodenal diverticula are discussed.

Validation of the Dutch translation of the Inflammatory Bowel Disease Questionnaire (IBDQ): a health-related quality of life questionnaire in inflammatory bowel disease.

Health-related quality of life assessment can benefit several groups involved with health care. The aim of our study was to assess construct validity, reliability, discriminant ability and sensitivity to change of the Dutch translation of the Inflammatory Bowel Disease Questionnaire (IBDQ), a disease-specific quality-of-life questionnaire. A group of 120 IBD patients completed the IBDQ and two Visual Analogue Scales concerning general well-being and bowel function twice. Fifty-two patients also completed the Short-Form 36 twice. Disease activity was assessed once. Correlations between the IBDQ scores and the global assessments were reasonably high and the IBDQ was shown to be discriminative. High intraclass correlation coefficients between both measurements of the IBDQ were observed in patients who reported no change in bowel complaints. In contrast, significant differences were found between both moments in patients who reported change. The Dutch IBDQ proved to be valid, discriminative and reliable.

A single session of intraluminal brachytherapy in palliation of oesophageal cancer.

Between September 1987 and September 1993, 88 patients with oesophageal cancer were treated by a single session of intraluminal brachytherapy of 15 Gy prescribed at 1 cm distance from the central axis, using MDR137Cs (n = 51) during the first part of the study and HDR192Ir (n = 37) during the second part of the study. All patients were regarded as inoperable. Improvement of dysphagia, assessed 4-6 weeks after treatment, was noted in 50 of 75 (67%) evaluable patients, whereas swallowing ability was completely restored in 47% of them. Relapse of dysphagia occurred in 28 (37%) patients during follow-up. Additional palliative treatment consisted of endoprosthesis in 14 (19%), a second course of brachytherapy in 13 (17%), one or more dilatations only in 11 (15%) and laser treatment in four (5%) patients. One non-fatal haemorrhage and five fistulae occurred, all in the presence of tumour. Two severe ulcerations without evidence of tumour were noted, both managed by combined curative treatment. The median survival of the group investigated was 5.5 months. An exophytic, non-circular growth pattern was associated with a better response. In a multivariate analysis the presence of distant metastases (p = 0.0028), weight loss (p = 0.0051) and an exophytic growth pattern (p = 0.0199) were associated with a worse survival. The present data indicate that a single session of ILB is appropriate in the palliation of dysphagia in patients with inoperable oesophagal cancer showing bad prognostic signs. Up to now there has been no clear evidence for benefit of addition of ERT.

[Postinfectious tropical malabsorption and the differences from non-tropical sprue (celiac disease)]. / Postinfectieuze tropische malabsorptie en de verschillen met niet-tropische spruw (coeliakie).

The clinical course is described of a 69-year-old patient with a malabsorption syndrome since her stay in Indonesia. Besides chronic diarrhoea and weight loss she suffered from malnutrition and had partial villous atrophy. Coeliac disease was considered in the differential diagnosis but considering the endemic appearance of postinfectious tropical sprue (PTS) in Indonesia and the extreme vitamin B12 deficiency our patient experienced, PTS appeared more likely. A good response to the therapy prescribed for PTS confirmed the diagnosis.

Palliation in esophageal cancer with a single session of intraluminal irradiation.

From September 1987 to December 1989, 36 patients with advanced esophageal cancer entered a study in order to determine the efficacy of palliation by a single session of intraluminal irradiation. A dose of 15 Gy was administered at 1 cm distance from the central axis of the applicator. In 22 of 32 patients alive at least 6 weeks after treatment dysphagia improved, in 14 this relief was complete. Re-obstruction occurred in 8 of the 22 responders, but a second treatment with intraluminal irradiation gave improvement in six. Intraesophageal prostheses were needed in only 6 of the 36 patients. Intraluminal irradiation is easy to administer and safe, it forms a useful addition to the therapeutic possibilities for the palliation of esophageal cancer.

Platelet count, platelet function, coagulation activity and fibrinolysis in the acute phase of inflammatory bowel disease.

Twenty two patients with exacerbation of inflammatory bowel disease (19 with Crohn's disease, 3 with ulcerative colitis) and thrombocytosis were tested for possible activation of the coagulation and platelet system. Fifteen patients had abnormal platelet function i.e. unphysiologically high sensitivity in vitro towards ADP 2 mumol/l aggregation induction. In 81.8% of the patients we found enhanced fibrinogen concentrations. In 22.7% of the patients thrombin-antithrombin III values exceeded the upper limit of the reference range, and in 68.2% of the patients the D-Dimer concentration exceeded the upper reference limit as a result of reactive fibrinolysis. The altered platelet count and function, and the increased levels of fibrinogen and thrombin-antithrombin III with reactive fibrinolysis activation indicate the presence of prethrombotic factors in patients with exacerbation of inflammatory bowel disease. The presence of enhanced fibrinolysis in these patients might have consequences for the therapeutic treatment.