Adaptive cone-beam CT planning improves long-term biochemical disease-free survival for 125I prostate brachytherapy.

PURPOSE: Determining the independent effect of additional intraoperative adaptive C-arm cone-beam CT (CBCT) planning vs. transrectal ultrasound (TRUS)-guided interactive planning alone in 125I brachytherapy for prostate cancer (PCa) on biochemical disease-free survival (BDFS). METHODS AND MATERIALS: T1/T2-stage PCa patients receiving TRUS-guided brachytherapy from 2000 to 2014 were analyzed. From October 2006, patients received additional intraoperative adaptive CBCT planning for dosimetric evaluation and subsequent remedial seed placement in underdosed areas. Patients were stratified according to the National Comprehensive Cancer Network (NCCN) risk classification. Kaplan-Meier analysis was used to estimate BDFS (primary outcome), overall survival, and PCa-specific survival (secondary outcomes). Cox regression was used to assess the relation between CBCT use and biochemical failure (BF) and overall mortality. RESULTS: In all, 1623 patients were included. Median followup was 99 months (interquartile range 70-115) for TRUS patients (n = 613) and 51 months (interquartile range 29-70) for CBCT patients (n = 1010). BF occurred 203 times and 206 patients died, 26 from PCa. For TRUS and CBCT patients, 7-year BDFS was 87.2% vs. 93.5% (log rank: p = 0.04) for low, 75.9% vs. 88.5% (p < 0.001) for intermediate, and 57.1% vs. 85.0% for high-risk patients (p < 0.001). For TRUS and CBCT patients, 7-year PCa-specific survival was 96.0% vs. 100% (p < 0.0001). After Cox regression, CBCT patients had lower hazard of BF: hazard ratio (HR) 0.25 (95% confidence interval [CI]: 0.18-0.33; p < 0.0001). Corrected for confounders, CBCT remained a predictor of BF: HR 0.51 (95% CI: 0.31-0.86; p = 0.01) but not for overall mortality: HR 0.66 (95% CI: 0.40-1.07; p = 0.09). CONCLUSIONS: Additional intraoperative adaptive CBCT planning in 125I prostate brachytherapy leads to a significant increase in BDFS in all NCCN risk groups.

Value of 18F-FDG PET/CT in diagnosing chronic Q fever in patients with central vascular disease.

BACKGROUND: The aim of this study is to describe the value of 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) in diagnosing chronic Q fever in patients with central vascular disease and the added value of 18F-FDG PET/CT in the diagnostic combination strategy as described in the Dutch consensus guideline for diagnosing chronic Q fever. METHODS: 18F-FDG PET/CT was performed in patients with an abdominal aortic aneurysm or aorto-iliac reconstruction and chronic Q fever, diagnosed by serology and positive PCR for Coxiella burnetii DNA in blood and/or tissue (PCR-positive study group). Patients with an abdominal aortic aneurysm or aorto-iliac reconstruction without clinical and serological findings indicating Q fever infection served as a control group. Patients with a serological profile of chronic Q fever and a negative PCR in blood were included in additional analyses (PCR-negative study group). RESULTS: Thirteen patients were evaluated in the PCR-positive study group and 22 patients in the control group. 18F-FDG PET/CT indicated vascular infection in 6/13 patients in the PCR-positive study group and 2/22 patients in the control group. 18F-FDG PET/CT demonstrated a sensitivity of 46% (95% CI: 23-71%), specificity of 91% (95% CI: 71-99%), positive predictive value of 75% (95% CI:41-93%) and negative predictive value of 74% (95% CI: 55-87%). In the PCR-negative study group, 18F-FDG PET/CT was positive in 10/20 patients (50%). CONCLUSION: The combination of 18F-FDG PET/CT, as an imaging tool for identifying a focus of infection, and Q fever serology is a valid diagnostic strategy for diagnosing chronic Q fever in patients with central vascular disease.

Development and internal validation of a multivariable prediction model for biochemical failure after whole-gland salvage iodine-125 prostate brachytherapy for recurrent prostate cancer.

BACKGROUND: Localized recurrent prostate cancer after primary radiotherapy can be curatively treated using salvage iodine-125 ((125)I) brachytherapy. Selection is hampered by a lack of predictive factors for cancer control. This study aims to develop and internally validate a prognostic model for biochemical failure (BF) after salvage (125)I brachytherapy. METHODS AND MATERIALS: Whole-gland salvage (125)I brachytherapy patients were treated between 1993 and 2010 in two radiotherapy centers in the Netherlands. Multivariable Cox regression was performed to assess the predictive value of clinical parameters related to BF (Phoenix-definition [prostate-specific antigen [PSA]-nadir + 2.0 ng/mL]). Missing data were handled by multiple imputation. The model's discriminatory ability was assessed with Harrell's C-statistic. Internal validation was performed using bootstrap resampling (2000 data sets). Goodness-of-fit was evaluated with calibration plots. All analyses were performed using the recently published TRIPOD (Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis) statement. RESULTS: After median followup of 74 months (range 5-138), 43 of a total 62 patients developed BF. In multivariable analysis, disease-free survival interval (DFSI) after primary therapy and pre-salvage prostate-specific antigen doubling time (PSADT) were predictors of BF: corrected hazard ratio (HR) 0.99 (95% confidence interval 0.97-0.999; p = 0.04) and 0.94 (95% confidence interval 0.89-0.99; p = 0.03), both for a 1-month increase (optimism-adjusted C-statistic 0.70). Calibration was accurate up to 36 months. Of patients with PSADT >30 months and DFSI >60 months, 36-month biochemical disease-free survival was >75%. Every 12-month increase in DFSI will allow 3-month decrease in PSADT while maintaining the same biochemical recurrence-free rates. CONCLUSIONS: We have presented results from a cohort of patients undergoing salvage (125)I-brachytherapy. Our data show that better selection of patients is possible with the DFSI and PSADT.

Awake Flexible Fiberoptic Laryngoscopy to diagnose glossoptosis in Robin Sequence patients.

BACKGROUND: Robin Sequence (RS) is usually defined as the combination of micrognathia, glossoptosis and upper airway obstruction. No objective criteria to diagnose RS exist. To compare management strategy results, a single RS definition using objective criteria is needed. The most frequently used primary diagnostic tool for glossoptosis is awake Flexible Fiberoptic Laryngoscopy (aFFL). OBJECTIVES: To determine the reliability of the aFFL videos as an independent diagnostic tool itself, rather than on the complete evaluation of a patient. DESIGN, SETTING, PARTICIPANTS: All RS individuals from an existing cohort with an available aFFL video were included retrospectively. Thirty age-matched patients without pathologic findings on aFFL were used as controls. aFFL videos were scored by six otolaryngologists as: a. Marked glossoptosis, b. Mild glossoptosis, c. Severity unknown, d. No glossoptosis, e. Insufficient video quality. Videos were anonymised and rated twice, in altered sequences, after a washout period of minimally 2 weeks. MAIN OUTCOME MEASURES: Inter-rater and intrarater agreement. RESULTS: Twenty-six videos of 16 RS patients and 30 videos of controls were included. Inter-rater agreement was fair in the whole group (κ: 0.320) and RS group (κ: 0.226), and fair to moderate in determining presence of glossoptosis (total group κ: 0.430; RS κ: 0.302; controls κ: 0.212). The intrarater agreement for the presence of glossoptosis in RS was moderate (κ: 0.541). CONCLUSIONS: aFFL offers fair to moderate inter-rater agreement, with moderate intrarater agreement, in evaluating glossoptosis in RS. Using aFFL as the single tool in choosing management strategies in RS seems insufficient. There is need for a more reliable, patient friendly diagnostic tool or an internationally accepted aFFL scoring system, to diagnose glossoptosis in RS.

Brachytherapy after external beam radiotherapy and limited surgery preserves bladders for patients with solitary pT1-pT3 bladder tumors.

BACKGROUND: Several French, Belgian and Dutch radiation oncologists have reported good results with the combination of limited surgery after external beam radiotherapy (EBRT) followed by brachytherapy in early-stage muscle-invasive bladder cancer. PATIENTS AND METHODS: Data from 12 of 13 departments which are using this approach have been collected retrospectively, in a multicenter database, resulting in 1040 patients: 811 males and 229 females with a median age of 66 years, range 28-92 years. Results were analyzed according to tumor stage and diameter, histology grade, age and brachytherapy technique, continuous low-dose rate (CLDR) and pulsed dose rate (PDR). RESULTS: At 1, 3 and 5 years, the local recurrence-free probability was 91%, 80% and 75%, metastasis-free probability was 91%, 80% and 74%, disease-free probability was 85%, 68% and 61% and overall survival probability was 91%, 74% and 62%, respectively. The differences in the outcome between the contributing departments were small. After multivariate analysis, the only factor influencing the local control rate was the brachytherapy technique. Toxicity consisted mainly of 24 fistula, 144 ulcers/necroses and 93 other types. CONCLUSIONS: EBRT followed by brachytherapy, combined with limited surgery, offers excellent results in terms of bladder sparing for selected groups of patients suffering from bladder cancer.

FDG-PET has no definite role in preoperative imaging in gastric cancer.

BACKGROUND: Gastric cancer is fourth on the incidence list of cancers worldwide with a high disease-related mortality rate. Curation can only be achieved by a radical resection including an adequate lymphadenectomy. However, prognosis remains poor and cancer recurrence rates are high, also due to lymph node metastases. To improve outcome, (neo)adjuvant treatment strategies with chemo- and/or radiotherapy regimes are employed. AIMS: Accurate staging of gastric cancer at primary diagnosis is essential for adequate treatment. In this non-systematic review the role 18-F-Fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) in preoperative staging is investigated. Furthermore, the results of neoadjuvant chemotherapy-induced tumour response monitoring by FDG-PET are discussed. RESULTS AND CONCLUSION: It is concluded that currently FDG-PET has no role in the primary detection of gastric cancer due to its low sensitivity. FDG-PET shows, however, slightly better results in the evaluation of lymph node metastases in gastric cancer compared to CT and could have therefore a role in the preoperative staging. Improvement in accuracy could be achieved by using PET/CT or other PET tracers than FDG, but these modalities need further investigation. FDG-PET, however, adequately detects therapy responders at an early stage following neoadjuvant chemotherapy.

Long-term prognosis of patients with local recurrence after conservative surgery and radiotherapy for early breast cancer.

We have studied the long-term prognosis of 266 patients considered to have isolated local recurrence in the breast following conservative surgery and radiotherapy for early breast cancer. The median follow-up of the patients still alive after diagnosis of local relapse was 11.2 years. At 10 years from the date of salvage treatment, the overall survival rate for the 226 patients with invasive local recurrence was 39% (95% CI, 32-46), the distant recurrence-free survival rate was 36% (95% CI, 29-42), and the local control rate (i.e., survival without subsequent local recurrence or local progression) was 68% (95% CI, 62-75). Among patients with a local recurrence at or near the original tumour site a better distant disease-free survival was observed for patients with recurrences measuring 1cm or less, compared to those with larger recurrences. This suggests, though does not prove, that early detection of local recurrence can improve the treatment outcome but might as well point towards a different biologic behaviour, facilitating early detection.

The value of [18F]fluoro-2-deoxy-D-glucose positron emission tomography in the selection of patients with stage IIIA-N2 non-small cell lung cancer for combined modality treatment.

Combined modality treatment (CMT) for patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) is at present studied extensively. To select patients with truly stage IIIA-N2 disease, however, proves to be difficult with current diagnostic tests. Distant metastases may become clinically overt during induction chemotherapy (IC) or shortly after, revealing the inaccuracies of current staging algorithms. A prospective study with [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) in IIIA-N2 NSCLC patients was performed to assess its value in the selection of this patient group. Fifty-seven patients received a whole body FDG PET scan as part of an ongoing response monitoring trial. Results were compared with conventional staging. In 32/57 (56%) PET suggested upstaging, which was confirmed in 17/57 (30%) with a median follow-up of 16 (range 2-49) months. These results show that using the conventional staging algorithm a substantial group of patients was understaged. FDG PET improves the selection of patients suitable for CMT.

Failure patterns of combined modality treatment in lung cancer: the impact of staging.

BACKGROUND: Patients with locally advanced non-small cell lung cancer (NSCLC) may be treated with induction chemotherapy (IC) followed by surgery with curative intent. The impact of staging inaccuracies on the failure rate of this intensive combined modality treatment approach, i.e. non-curative chemotherapy and thoracotomy, requires further investigation. METHODS: The records of a cohort of 38 consecutive NSCLC IIIA-N2 patients treated with IC followed by surgery were reviewed. RESULTS: The clinical course strongly suggested that the standard diagnostic algorithm failed to demonstrate stage IV disease in 34% of the cases. Surgery instigated by CT-based response criteria at restaging after chemotherapy proved to be irradical in 70% of cases. CONCLUSION: Our data confirm the limitations of the current work-up of patients with apparently locally advanced NSCLC. This applies to the selection of patients to be assigned to combined modality treatment as well as to the post-chemotherapy assessment of resectability. Improved (re)staging of these patients will enhance the efficiency of intervention trials and prevent patients from being exposed to intensive and toxic therapy from which they derive no benefit.

Auditory performance of young children with hearing aids: the Nijmegen experience.

During recent years, significant progress has been made in the development of methods for screening hearing sensitivity in toddlers. Nowadays, in several countries, nationwide screening programmes are carried out. Much less attention has been paid to the next step, namely treatment of very young hearing-impaired children with hearing devices. A review of published data indicate that the DSL (Desired Sensation Level) hearing aid prescription method, developed especially for young children, is at least a good point to begin hearing aid fitting. DSL target values for gain and output seems to be adequate for young children. Documenting the benefit for hearing aid use in young children is still cumbersome. One option is to measure the development of basal auditory functions. A review of available data showed that for this purpose, speech material can only be used in children of 3 years and older. For children of 1 year and older, tests with environmental sounds can be applied. It is concluded that, although growing, there is a lack of tests and limited knowledge on how to optimize hearing aid fittings and how to document hearing aid benefit in toddlers.

HDR brachytherapy applied to cervical carcinoma with moderate lateral expansion: modified principles of treatment.

BACKGROUND AND PURPOSE: In order to meet the deficiencies of endocavitary applications, a combined technique was introduced with the aim of achieving better target coverage for improvement of loco-regional tumour control. In high dose rate (HDR) endocavitary applications with tandem and ovoids, enlargement of the distance between the ovoids, shifting of dwell times and also optimization often fail to achieve sufficient expansion of the cervical parametrial area encompassed by the reference isodose. MATERIALS AND METHODS: The Deventer method, whereby HDR endocavitary and HDR interstitial brachytherapy are applied in the same session, was applied for tumours with a lateral expansion of 25 mm or more from the axis of the cervical canal. For the addition of HDR interstitial brachytherapy, each ovoid was provided with a channel which allowed insertion of an afterloading needle into the cervix up to a fixed depth. The dose specifications and dosimetry in neighbouring organs are presented in detail. RESULTS: Seventy-six combined applications were given to 41 patients. The follow-up averaged at 23 months, with a maximum of 59 months. No severe early or persistent late complications were observed. In stage IIB tumours, the most important evaluation of the merits of this technique, the disease-free 3-year survival determined with the Kaplan-Meier method was 75% (n=20). CONCLUSIONS: The Deventer method of HDR endocavitary and HDR interstitial brachytherapy applied in the same session is a feasible method for enlargement of the reference isodose envelope in the cervical parametrial area. The 3-year disease-free survival in stage IIB patients and the low complication rates in all stages together, justify its continuation.

Monitoring response to therapy in cancer using [18F]-2-fluoro-2-deoxy-D-glucose and positron emission tomography: an overview of different analytical methods.

[18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) is considered a valuable tool in the diagnosis and staging of cancer. In addition, it seems promising as a technique to monitor response to therapy. Progress is hampered, however, by the fact that various methods for the analysis of uptake of FDG in tumours have been described and that it is by no means clear whether these methods have the same sensitivity for monitoring response to treatment. As interest in monitoring response using FDG PET is growing, the danger exists that non-optimal methods will be used for evaluation. Hence an overview of the various analytical methods is given, highlighting both advantages and shortcomings of each of the methods. The ideal analytical method for response monitoring should represent an optimal trade-off between accuracy and simplicity (clinical applicability). At present, that trade-off still needs to be defined. Studies relating response, as measured with any of the available analytical methods, to outcome are urgently needed. Until then response monitoring studies should be conducted in such a way that all analytical methods can be compared with the most quantitative one, which at present is full compartmental modelling of the data.

On the use of image-derived input functions in oncological fluorine-18 fluorodeoxyglucose positron emission tomography studies.

There is growing interest in monitoring response to therapy in oncology patients using positron emission tomography and fluorine-18 fluorodeoxyglucose (FDG). Quantification is required, and various methods have been described. Arterial sampling, which provides the most accurate input function, often is not feasible in patients undergoing chemotherapy. In the thorax an image-derived input function can be obtained from the large vascular structures. In many studies the left ventricle (LV) is used, but the obtained data are rarely validated. In this study a simple quality control procedure for the image-derived input function was developed and compared with a standard LV curve. Twenty dynamic FDG scans were obtained in nine patients with non-small cell lung cancer stage IIIA-N2. Three venous blood samples were taken as a quality control for the image-derived input function. Regions of interest (ROIs) were defined for aorta, LV and left atrium. Input curves were generated according the the standard use of the LV curve and by applying the quality control method to all vascular ROIs. Tumour ROIs were defined and both input functions were used to calculate tumour glucose metabolism (MRglu), using both standard non-linear regression and Patlak analyses. Mean differences in MRglu using "standard" LV and "quality control approved" input functions were 16.2% and 17.5% for non-linear regression and Patlak analyses, respectively, indicating that the use of "standard" LV curve might lead to significant errors. It is concluded that care should be taken in using image derived input functions without appropriate quality control. The proposed procedure is simple and results in significantly more accurate MRglu data.

Oral language acquisition in children assessed with the Reynell Developmental Language Scales.

Oral language development of ten children, prelingually deafened by meningitis, was assessed with a Dutch version of the Reynell Developmental Language Scales. The test was administered pre-operatively and at regular intervals after implantation. The average rate of language development between two consecutive evaluations was computed. This rate was defined as the quotient of the increase of the language age and the increase of the chronological age between the evaluations. A normal language development has a rate of 1; this means 12 months language development in 12 months time. In case of language retardation the rate of language development is less than 1. The rate of receptive language development showed a gradual increase. In the interval between 12 and 24 months of implant use the ratio was 0.9. This implies a language development that is quite similar with the development in normal hearing children. The rate of expressive language development showed a fast improvement in the period between 6 and 12 months after implantation, up to 1.4. If this rate of development continues the children with C.I. will catch up with their normal hearing peers.

Auditory training in severely and profoundly hearing impaired toddlers: the development of auditory skills and verbal communication.

Three different tests are applied to evaluate the performance of very young hearing impaired children. Three subgroups were formed according to hearing loss. The sound identification test as well as the Reynell Developmental Scales proved to be useful but Early Scales of Communication did not differentiate well enough between the three subgroups.

Histological determinants for different types of local recurrence after breast-conserving therapy of invasive breast cancer. Dutch Study Group on local Recurrence after Breast Conservation (BORST)

The purpose of this study was to determine which histological factors are associated with an increased risk for local recurrence in the breast after breast-conserving therapy for early breast cancer (TNM stage I and II) and whether risk patterns vary according to menopausal status and type of local recurrence. Through complete follow-up of the patients of eight regional radiation oncology departments, two cancer institutes and one surgical clinic in The Netherlands, 360 patients were identified with local recurrence in the breast after having received breast-conserving therapy (local tumour excision, axillary dissection and irradiation of the whole breast and a boost to the tumour bed) during the 1980s. For each case, two controls with a follow-up of similar duration without local recurrence were randomly selected. Histological slides of the primary tumour were reviewed. Among premenopausal patients the risk of recurrence for those younger than 35 years was significantly higher than that for premenopausal patients of 45 years or older (relative risk (RR) 2.9; 95% confidence interval (95% CI) 1.3-6.6, P < 0.05). The risk of recurrence at or near the site of the primary tumour was most significantly increased for patients with high grade extensive intraductal component (EIC) adjacent to the primary tumour (RR 4.1; 95% CI 1.7-9.8, P < 0.01). Microscopic margin involvement was an important risk indicator for diffuse recurrence and recurrence in the skin of the breast, especially in the presence of vascular invasion (RR 25; 95% CI 4.0-150, P < 0.001). To prevent local recurrence at or near the site of the primary tumour, local excision with a 1-2 cm margin of healthy tissue and a 15 Gy boost seemed adequate local treatment for patients with well differentiated EIC. In contrast, a wider surgical margin, a higher boost dose or mastectomy should be considered for patients with poorly differentiated EIC. Microscopic margin involvement in the presence of vascular invasion significantly increases the risk of diffuse recurrence or recurrence in the skin.

Assessment of basal sound identification skills and communication abilities in profoundly deaf children fitted with hearing aids or a cochlear implant.

Basal auditory functions and early verbal communication skills were examined in young, profoundly deaf children with hearing aids or a cochlear implant. The hearing aid users (n = 23) were subdivided on the basis of their (unaided) hearing thresholds into: group A (pure tone average (PTA) at 0.5, 1 and 2 kHz: 90-100 dB HL); group B (PTA: 100-110 dB HL); and group C (PTA > 110 dB HL). All the children with a cochlear implant (n = 20) had a profound sensorineural hearing loss with a PTA that exceeded 120 dB HL. Functional hearing was evaluated by means of basal sound identification. The child's communication abilities with hearing aids or a cochlear implant were assessed using structured observations on the Scales of Early Communication Skills for Hearing Impaired Children. The basal auditory functions on a sound identification level improved over time in the cochlear implant users and groups A and B. Hardly any improvement was seen in group C. The performance of all the groups (either hearing aid or cochlear implant) on the Scales of Early Communication Skills for Hearing Impaired Children at 6 months after fitting the device and at later evaluations, was close to the average level for their age.