An interdisciplinary multimodal integrative healthcare program for chronic spinal pain and comorbid mental disorders.

OBJECTIVE: Previous studies evaluating interdisciplinary multimodal interventions for chronic spinal pain often excluded patients with comorbid mental disorders. This study aims to assess the effectiveness of an outpatient secondary care interdisciplinary multimodal integrative healthcare program for individuals experiencing co-occurring chronic spinal pain and mental disorders. METHODS: Participants were 944 patients with chronic spinal pain and comorbid mental disorders. Primary outcomes were Health-Related Quality of Life, assessed using the Research and Development-36 (RAND-36), and pain-related disability, assessed using the Quebec Back Pain Disability Scale (QBPDS). Secondary outcomes included pain intensity, pain catastrophizing, kinesiophobia, fatigue, lumbar mobility and isometric strength. Data was collected during the healthcare program at four time points: pre-treatment (T0), midway through 20-week treatment (T1), end of 20-week treatment (T2), and at completion of 12-month relapse prevention program (T3). Multilevel regression analyses were conducted to examine the effects of the healthcare program on primary outcomes over time. RESULTS: The 20-week treatment period yielded significant improvements in both mental (B = 0.44, t(943) = 19.42, p < 0.001) and physical component summary scores (B = 0.45, t(943) = 18.24, p < 0.001) of the RAND-36, as well as in QBPDS total score (B = -0.77, t(943) = -26.16 p < 0.001). Pre-treatment scores indicated the presence of problematic fatigue, kinesiophobia, and clinical levels of pain catastrophizing, all of which resolved by the end of the 12-month relapse prevention program. CONCLUSIONS: An interdisciplinary multimodal integrative healthcare program seems effective for patients with chronic spinal pain and comorbid mental disorders.

An interdisciplinary multimodal integrative healthcare program for somatic symptom disorder, with predominant (spinal) pain.

OBJECTIVE: Although multimodal interventions are generally recommended in patients with long-term somatic symptom disorders (SSD), available evidence is limited. The current study evaluates the effectiveness of an outpatient secondary care interdisciplinary multimodal integrative healthcare program for patients with SSD and predominant (spinal) pain. METHOD: The healthcare program consisted of two active treatment phases: main 20-week program and a 12-month relapse prevention program. Participants were 4453 patients diagnosed with SSD. The primary outcome was health-related quality of life (HRQoL) assessed using the RAND-36 (i.e., mental/physical component summary) and secondary outcomes included physical and psychological symptoms assessed using the Brief Symptom Inventory (BSI) and RAND-36 subscales. Mixed linear models were used to examine the effects of the multimodal healthcare program on primary/secondary outcomes over four time points: before start 20-week program (T0), halfway 20-week program (T1), end of 20-week program (T2) and end of relapse prevention program (T3). RESULTS: Significant improvements were found from T0 to T2 for all primary variables (i.e., mental/physical component summary) and secondary variables (i.e., BSI/RAND-36 subscales), which were maintained until the end of the relapse prevention program (T3). CONCLUSION: An interdisciplinary multimodal integrative treatment for SSD is effective for improving HRQoL and reducing physical and psychological symptoms.

Facilitating health care workers' self-determination: The impact of a self-leadership intervention on work engagement, health, and performance.

The present study aims to test the impact of a self-leadership intervention on the work engagement, performance, and health of health care workers. By integrating self-determination theory and self-leadership theory, we propose that when employees are trained how they can autonomously influence own cognitions and behaviour, this will impact their work engagement, perceived performance, and general health. To test the hypotheses, a longitudinal field experiment with three measurement waves was conducted (pre-intervention, immediately after the intervention, and 2 months after the intervention). Health care professionals (n = 195) from five different organizations participated on voluntary basis and were randomly assigned to the intervention or control group. Results show that a self-leadership training positively impacts work engagement and performance of health care workers. Furthermore, the improved work engagement also mediates the effects of the training on health and performance 2 months later. No direct effect was found on general health. Theoretical and practical implications are discussed. PRACTITIONERS POINTS: The self-leadership intervention facilitates healthcare workers to develop self-determination and autonomous motivation, which will positively impact their work engagement, health, and performanceParticipation in the self-leadership intervention needs to be based on volition as this will contribute to the intrinsic motivation for actual self-leadership development through training.

Diagnostic Laparoscopy and Abdominal Cytology Reliably Detect Peritoneal Metastases in Patients with Urachal Adenocarcinoma.

BACKGROUND: Urachal adenocarcinoma (UrAC) is a rare malignancy that can cause peritoneal metastases (PM). Analogous to other enteric malignancies, selected patients with limited PM of UrAC can be treated by cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). OBJECTIVE: The aim of this study was to address the value of diagnostic laparoscopy (DLS) and abdominal cytology (ACyt) for the detection and evaluation of the extent of PM in patients with UrAC. METHODS: A consecutive series of cN0M0 patients with UrAC who underwent DLS with or without ACyt at a tertiary referral center between 2000 and 2018 was assessed. Patients were staged with computed tomography (CT) and/or positron emission tomography (PET)/CT or bone scan. DLS was performed to rule out PM and to evaluate the extent and resectability of PM if seen on imaging. Sensitivity and specificity values were calculated for imaging, DLS, ACyt, and the combination of DLS and ACyt. RESULTS: Thirty-two patients with UrAC underwent DLS. ACyt was obtained in 19 patients. Four patients had suspicion of PM on imaging. In the 28 patients who were PM-negative on imaging, DLS and ACyt revealed PM in 6 (21%) patients, of whom 5 had macroscopically visible PM; 1 patient had positive ACyt without visible PM. Sensitivity of combined DLS/ACyt for the detection of PM was 91%, with a specificity of 100%, whereas sensitivity of imaging was 36%. DLS correctly predicted resectability in all patients. CONCLUSION: Combined DLS/ACyt proved an effective tool to detect occult PM and to evaluate the extent of PM to select UrAC patients for possible treatment with CRS/HIPEC.

Histopathological Features of MRI-Invisible Regions of Prostate Cancer Lesions.

BACKGROUND: Previous studies have reported tumor volume underestimation with multiparametric (mp)MRI in prostate cancer diagnosis. PURPOSE: To investigate why some parts of lesions are not visible on mpMRI by comparing their histopathology features to those of visible regions. STUDY TYPE: Retrospective. POPULATION: Thirty-four patients with biopsy-proven prostate cancer scheduled for prostatectomy (median 68.7 years). FIELD STRENGTH/SEQUENCE: T2 -weighted, diffusion-weighted imaging, T2 mapping, and dynamic contrast-enhanced MRI on two 3T systems and one 1.5T system. ASSESSMENT: Two readers delineated suspicious lesions on mpMRI. A pathologist delineated the lesions on histopathology. A patient-customized mold enabled the registration of histopathology and MRI. On histopathology we identified mpMRI visible and invisible lesions. Subsequently, within the visible lesions we identified regions that were visible and regions that were invisible on mpMRI. For each lesion and region the following characteristics were determined: size, location, International Society of Urological Pathology (ISUP) grade, and Gleason subpatterns (density [dense/intermediate], tumor morphology [homogeneous/heterogeneous], cribriform growth [yes/no]). STATISTICAL TESTS: With generalized linear mixed-effect modeling we investigated which features explain why a lesion or a region was invisible on MRI. We compared imaging values (T2 , ADC, and Ktrans ) for these features with one-way analysis of variance (ANOVA). RESULTS: Small, anterior, and ISUP grade 1-2 lesions (n = 34) were missed more frequent than large, posterior, ISUP grade ≥ 3 lesions (n = 35). Invisible regions on mpMRI had lower tumor density, heterogeneous tumor morphology, and were located in the transition zone. Both T2 and ADC values were higher in "intermediate" compared with "dense" regions (P = 0.002 and < 0.001) and in regions with heterogeneous compared with homogeneous morphology (P < 0.001 and 0.03). Ktrans was not significantly different (P = 0.24 and 0.99). DATA CONCLUSION: Regions of prostate cancer lesions that are invisible on mpMRI have different histopathology features than visible regions. This may have implications for monitoring during active surveillance and focal treatment strategies. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:1235-1246.

Quantitative 3-T multi-parametric MRI and step-section pathology of recurrent prostate cancer patients after radiation therapy.

OBJECTIVES: Diagnosis of radio-recurrent prostate cancer using multi-parametric MRI (mp-MRI) can be challenging due to the presence of radiation effects. We aim to characterize imaging of prostate tissue after radiation therapy (RT), using histopathology as ground truth, and to investigate the visibility of tumor lesions on mp-MRI. METHODS: Tumor delineated histopathology slides from salvage radical prostatectomy patients, primarily treated with RT, were registered to MRI. Median T2-weighted, ADC, Ktrans, and kep values in tumor and other regions were calculated. Two radiologists independently performed mp-MRI-based tumor delineations which were compared with the true pathological extent. General linear mixed-effect modeling was used to establish the contribution of each imaging modality and combinations thereof in distinguishing tumor and benign voxels. RESULTS: Nineteen of the 21 included patients had tumor in the available histopathology slides. Recurrence was predominantly multifocal with large tumor foci seen after external beam radiotherapy, whereas these were small and sparse after low-dose-rate brachytherapy. MRI-based delineations missed small foci and slightly underestimated tumor extent. The combination of T2-weighted, ADC, Ktrans, and kep had the best performance in distinguishing tumor and benign voxels. CONCLUSIONS: Using high-resolution histopathology delineations, the real tumor extent and size were found to be underestimated on MRI. mp-MRI obtained the best performance in identifying tumor voxels. Appropriate margins around the visible tumor-suspected region should be included when designing focal salvage strategies. Recurrent tumor delineation guidelines are warranted. KEY POINTS: • Compared to the use of individual sequences, multi-parametric MRI obtained the best performance in distinguishing recurrent tumor from benign voxels. • Delineations based on mp-MRI miss smaller foci and slightly underestimate tumor volume of local recurrent prostate cancer. • Focal salvage strategies should include appropriate margins around the visible tumor.

Pathogenic and targetable genetic alterations in 70 urachal adenocarcinomas.

Urachal cancer (UrC) is a rare but aggressive malignancy often diagnosed in advanced stages requiring systemic treatment. Although cytotoxic chemotherapy is of limited effectiveness, prospective clinical studies can hardly be conducted. Targeted therapeutic treatment approaches and potentially immunotherapy based on a biological rationale may provide an alternative strategy. We therefore subjected 70 urachal adenocarcinomas to targeted next-generation sequencing, conducted in situ and immunohistochemical analyses (including PD-L1 and DNA mismatch repair proteins [MMR]) and evaluated the microsatellite instability (MSI) status. The analytical findings were correlated with clinicopathological and outcome data and Kaplan-Meier and univariable/multivariable Cox regression analyses were performed. The patients had a mean age of 50 years, 66% were male and a 5-year overall survival (OS) of 58% and recurrence-free survival (RFS) of 45% was detected. Sequence variations were observed in TP53 (66%), KRAS (21%), BRAF (4%), PIK3CA (4%), FGFR1 (1%), MET (1%), NRAS (1%), and PDGFRA (1%). Gene amplifications were found in EGFR (5%), ERBB2 (2%), and MET (2%). We detected no evidence of MMR-deficiency (MMR-d)/MSI-high (MSI-h), whereas 10 of 63 cases (16%) expressed PD-L1. Therefore, anti-PD-1/PD-L1 immunotherapy approaches might be tested in UrC. Importantly, we found aberrations in intracellular signal transduction pathways (RAS/RAF/PI3K) in 31% of UrCs with potential implications for anti-EGFR therapy. Less frequent potentially actionable genetic alterations were additionally detected in ERBB2 (HER2), MET, FGFR1, and PDGFRA. The molecular profile strengthens the notion that UrC is a distinct entity on the genomic level with closer resemblance to colorectal than to bladder cancer.

Lymphatic Drainage from Renal Tumors In Vivo: A Prospective Sentinel Node Study Using SPECT/CT Imaging.

PURPOSE: Lymphatic drainage from renal tumors is unpredictable. In vivo drainage studies of primary lymphatic landing sites may reveal the variability and dynamics of lymphatic connections. The purpose of this study was to investigate the lymphatic drainage pattern of renal tumors in vivo with single photon emission/computerized tomography after intratumor radiotracer injection. MATERIALS AND METHODS: We performed a phase II, prospective, single arm study to investigate the distribution of sentinel nodes from renal tumors on single photon emission/computerized tomography. Patients with cT1-3 (less than 10 cm) cN0M0 renal tumors of any subtype were enrolled in analysis. After intratumor ultrasound guided injection of 0.4 ml 99mTc-nanocolloid we performed preoperative imaging of sentinel nodes with lymphoscintigraphy and single photon emission/computerized tomography. Sentinel and locoregional nonsentinel nodes were resected with a γ probe combined with a mobile γ camera. The primary study end point was the location of sentinel nodes outside the locoregional retroperitoneal templates on single photon emission/computerized tomography. Using a Simon minimax 2-stage design to detect a 25% extralocoregional retroperitoneal template location of sentinel nodes on imaging at α = 0.05 and 80% power at least 40 patients with sentinel node imaging on single photon emission/computerized tomography were needed. RESULTS: Of the 68 patients 40 underwent preoperative single photon emission/computerized tomography of sentinel nodes and were included in primary end point analysis. Lymphatic drainage outside the locoregional retroperitoneal templates was observed in 14 patients (35%). Eight patients (20%) had supradiaphragmatic sentinel nodes. CONCLUSIONS: Sentinel nodes from renal tumors were mainly located in the respective locoregional retroperitoneal templates. Simultaneous sentinel nodes were located outside the suggested lymph node dissection templates, including supradiaphragmatic sentinel nodes in more than a third of the patients.

EXPOSURE IN VIVO VERSUS PAIN-CONTINGENT PHYSICAL THERAPY IN COMPLEX REGIONAL PAIN SYNDROME TYPE I: A COST-EFFECTIVENESS ANALYSIS.

OBJECTIVES: The aim of this study was to evaluate the cost-effectiveness of exposure in vivo (EXP, a cognitive-behavioral treatment targeting pain-related fear) in Complex Regional Pain Syndrome Type I (CRPS-I), as compared to pain-contingent physical therapy (PPT). METHODS: Data from a randomized controlled trial were used to compare the cost-effectiveness of EXP versus PPT from a societal perspective. Intervention costs, other healthcare costs, costs to patient and family, and productivity losses were included. The main outcomes were changes in the SF-36 physical component scale and quality-adjusted life-years. Changes were followed until 6 months after treatment. Uncertainty was estimated using nonparametric bootstrap analysis, cost-effectiveness acceptability curves and cost-effectiveness planes. Sensitivity analyses were performed to check robustness of findings. RESULTS: Forty-six patients were randomized and thirty-eight completed the study. Over 6 months, EXP resulted in greater improvement in physical health-related quality of life and quality-adjusted life-years than PPT. Despite higher initial treatment costs, EXP showed a tendency to reduce all costs compared with PPT; healthcare costs were significantly reduced. Furthermore, the cost-effectiveness planes were in favor of EXP. Sensitivity analyses, for different program costs and complete cases only, confirmed robustness of these findings. CONCLUSIONS: EXP, a cognitive-behavioral treatment, seems more cost-effective than PPT in CRPS patients with pain-related fear. The initial higher costs for EXP are offset by a long-term reduction of costs for healthcare use, and a tendency to lower work absenteeism and reduced societal costs. Due to low sample sizes, replication of findings is required to confirm results.

Expression of Programmed Death Ligand 1 in Penile Cancer is of Prognostic Value and Associated with HPV Status.

PURPOSE: PD-L1 (programmed death ligand 1) inhibits T-cell function and prevents tumor eradication. This is facilitated by PD-L1 positive tumor cells and PD-L1 positive immune cells, and can be prevented by anti-PD-1 (programmed death 1)/PD-L1 immunotherapy. In advanced penile cancer there is a need for new therapeutic strategies. We investigated PD-L1 expression in penile cancers and compared PD-L1 expression with disease specific survival, lymph node metastases at diagnosis and high risk HPV status in a large patient cohort. MATERIALS AND METHODS: A total of 213 primary tumors were immunohistochemically stained for PD-L1 and scored for tumor (percentage), stroma (binary) and PD-L1 positive tumor infiltrating macrophages. Additionally, PD-L1 positive tumors were scored for expression pattern, that is diffuse or predominantly present at the tumor-stroma margin. RESULTS: Staining was successful in 200 tumors, of which 75% were high risk HPV negative. Median followup was 62 months. Of 200 tumors 96 (48%) were PD-L1 positive (scored 1% or greater), of which 59 (62%) had a marginal expression pattern and 79 (82%) were high risk HPV negative (p = 0.03). Compared to PD-L1 negative tumors, the PD-L1 expression patterns had different prognostic values in the whole cohort as well as in the high risk HPV negative subgroup. On multivariable analyses a marginal expression pattern was associated with absent lymph node metastases (OR 0.4) while diffuse expression was associated with poor survival (HR 2.58). These results were more prominent in the high risk HPV negative subgroup (OR 0.25, HR 3.92). CONCLUSIONS: PD-L1 was expressed in 48% of penile carcinomas and mainly in high risk HPV negative tumors. The pattern of expression was a prognostic factor as marginal expression was associated with absent lymph node metastases and diffuse expression was associated with poor survival.

Clinical Relevance of Incidental Prostatic Lesions on FDG-Positron Emission Tomography/Computerized Tomography-Should Patients Receive Further Evaluation?

PURPOSE: FDG ((18)F-fluoro-2-deoxy-D-glucose)-PET/CT (positron emission tomography)/(computerized tomography) is a widely used diagnostic tool for whole body imaging. Incidental prostatic uptake is often found on FDG-PET/CT. The objective of this study was to determine the clinical relevance of incidental prostatic uptake on FDG-PET/CT. MATERIALS AND METHODS: We analyzed 108 consecutive male patients with bladder cancer who underwent FDG-PET/CT and subsequently radical cystoprostatectomy between May 2009 and November 2014. PET/CT scans were blindly reviewed by a dedicated nuclear medicine physician for incidental prostatic FDG uptake. If present, the maximum standardized uptake value was determined. Subsequently incidental prostatic uptake was categorized as suspect, indeterminate or nonsuspect for prostate cancer. RESULTS: Incidental prostatic uptake was present in 43 of 108 patients (40%). Of these 43 patients 13 (30%) had occult prostate cancer in cystoprostatectomy specimens. Overall prostate cancer was found in 25 of 108 specimens (23%). If all incidental prostatic uptake was regarded as prostate cancer, the sensitivity and specificity of FDG-PET/CT for prostate cancer detection were 52% and 64%, respectively. Positive and negative predictive values were 30% and 82%, respectively. If only lesions labeled suspect or indeterminate were regarded as prostate cancer, sensitivity, specificity, and positive and negative predictive values were 32%, 76%, 29% and 79%, respectively. Categorizing indeterminate lesions as nonprostate cancer did not improve diagnostic accuracy. Gleason score did not correlate with maximum standardized uptake value or serum prostate specific antigen. CONCLUSIONS: Incidental prostatic uptake on FDG-PET/CT has a low positive predictive value for prostate cancer. An attempt to classify lesions as suspect or nonsuspect did not increase diagnostic accuracy. Based on these results physicians should be cautious about applying invasive diagnostic methods to detect prostate cancer in case of incidental prostatic uptake on FDG-PET/CT.

Multimodal hybrid imaging agents for sentinel node mapping as a means to (re)connect nuclear medicine to advances made in robot-assisted surgery.

PURPOSE: Radical prostatectomy and complementary extended pelvic lymph node dissection (ePLND) of sentinel lymph nodes (SNs) and non-sentinel lymph nodes (LNs) at risk of containing metastases are increasingly being performed using high-tech robot-assisted approaches. Although this technological evolution has clear advantages, the physical nature of robotic systems limits the integrated use of routine radioguided surgery technologies. Hence, engineering effort in robotics are focused on the integration of fluorescence guidance technologies. Using the hybrid SN tracer indocyanine green-(99m)Tc-nanocolloid (radioactive and fluorescent), for the first time in combination with a robot-integrated laparoscope, we investigated whether the robot-assisted approach affects the accuracy of fluorescence detection of SNs identified preoperatively using nuclear medicine. METHODS: The study included 55 patients (Briganti nomogram-based risk >5 % on LN metastases) scheduled for robot-assisted radical prostatectomy, SN biopsy and ePLND. Following indocyanine green-(99m)Tc-nanocolloid injection, preoperative nuclear imaging (lymphoscintigraphy and SPECT/CT) was used to locate the SN(s). The fluorescence laparoscope was used intraoperatively to identify the SN(s) with standard fluorescence settings (in 50 patients) and with customized settings (in 5 patients). The number and location of the SNs, the radioactive, fluorescence (both in vivo and ex vivo) and tumour status of the resected SNs/LNs, and postoperative complications were recorded and analysed. RESULTS: Combined, preoperative lymphoscintigraphy and SPECT/CT imaging identified 212 SNs (median 4 per patient). Intraoperative fluorescence imaging using standard fluorescence settings visualized 80.4 % (148/184 SNs; 50 patients; ex vivo 97.8 %). This increased to 85.7 % (12/14 SNs; 5 patients; ex vivo 100 %) with customized fluorescence settings. SPECT/CT images provided guidance towards the residual SNs. Ex vivo all removed SNs were radioactive. SNs were tumour-positive in 25.4 % of patients (14/55; false-negative rate 7 %, 1/14 patients). In ten patients, the SN was the only tumour-positive LN. Surgical complications were minimal. CONCLUSION: Directly linking 3D preoperative nuclear imaging information on SNs to a robot-integrated fluorescence laparoscope improved the surgeon's use of the technology and did not influence the sensitivity or morbidity of the procedure. To our surprise, however, the detection rates with the current fluorescence camera did not improve.

Classic and nonclassic HLA class I expression in penile cancer and relation to HPV status and clinical outcome.

PURPOSE: Loss of expression of HLA class I is a mechanism of immune evasion in various cancers that is often associated with a worse patient outcome. We analyzed HLA expression in a large cohort with penile cancer in relation to clinical outcome. MATERIALS AND METHODS: We used penile cancer tissue blocks from 168 patients who underwent surgical resection between 2000 and 2009 to construct tissue microarrays. Immunohistochemical staining was done with antibodies directed against classic and nonclassic HLA molecules. HLA expression was scored semiquantitatively, divided into 3 expression groups and correlated with clinicopathological variables, including HPV and survival. Survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards models. RESULTS: Complete and partial loss of total classic HLA class I was observed in 32% and 50% of cases, and up-regulation of HLA-E and G in 16% and 13%, respectively. When corrected for relevant clinical parameters, partial HLA-A loss was significantly associated with decreased survival overall (HR 2.3, 95% CI 1.1-4.6) and in HPV negative patients alone (HR 3.4, 95% CI 1.4-8.4). Abnormal HLA-B/C, E or G expression levels were not associated with survival. CONCLUSIONS: To our knowledge this is the first study to describe a link between HLA expression and the clinical outcome of penile cancer. HLA down-regulation occurs frequently and partial loss of HLA-A is an independent predictor of poor survival in HPV negative patients. Complete understanding of the mechanisms and relevance of HLA down-regulation and immune evasion in regard to the clinical outcome will contribute to the future design of immunotherapy interventions.

Human papillomavirus prevalence in invasive penile cancer and association with clinical outcome.

PURPOSE: The incidence of penile cancer is increasing, and is suggested to be explained by changes in sexual practice and increased exposure of men to sexually transmitted high risk human papillomavirus infection. In penile cancers from a Dutch population treated in 1963 to 2001 we found a high risk human papillomavirus prevalence of about 30%. In this study we assessed the prevalence of high risk human papillomavirus-DNA in a more recent, contemporary penile cancer cohort and its association with patient survival. MATERIALS AND METHODS: High risk human papillomavirus-DNA presence was assessed by GP5+6+ polymerase chain reaction in 212 formalin fixed, paraffin embedded invasive penile tumor specimens of patients treated between 2001 and 2009. The 5-year disease specific survival was calculated using the Kaplan-Meier method with the log rank test and Cox regression. RESULTS: High risk human papillomavirus-DNA was detected in a subset of penile cancer cases (25%, 95% CI 19-31). HPV16 was the predominant type, representing 79% (42 of 53) of all high risk human papillomavirus infections. The 5-year disease specific survival in the high risk human papillomavirus negative group and the high risk human papillomavirus positive group was 82% and 96%, respectively (log rank test p=0.016). Adjusted for stage, grade, lymphovascular invasion and age, human papillomavirus status was still prognostic for disease specific survival (p=0.030) with a hazard ratio of 0.2 (95% CI 0.1-0.9). CONCLUSIONS: High risk human papillomavirus-DNA was observed in a quarter of penile cancer cases. No relevant increase in high risk human papillomavirus prevalence in recent decades was observed. The presence of high risk human papillomavirus-DNA in penile cancer confers a survival advantage.

Calcined bone provides a reliable substrate for strontium isotope ratios as shown by an enrichment experiment.

RATIONALE: Strontium isotopes ((87) Sr/(86) Sr) are used in archaeological and forensic science as markers of residence or mobility because they reflect the local geological substrate. Currently, tooth enamel is considered to be the most reliable tissue, but it rarely survives heating so that in cremations only calcined bone fragments survive. We set out to test the proposition that calcined bone might prove resistant to diagenesis, given its relatively high crystallinity, as the ability to measure in vivo (87) Sr/(86) Sr from calcined bone would greatly extend application to places and periods in which cremation was the dominant mortuary practice, or where unburned bone and enamel do not survive. METHODS: Tooth enamel and calcined bone samples were exposed to a (87) Sr-spiked solution for up to 1 year. Samples were removed after various intervals, and attempts were made to remove the contamination using acetic acid washes and ultrasonication. (87) Sr/(86) Sr was measured before and after pre-treatment on a Nu Plasma multi-collector induced coupled plasma mass spectrometer using NBS987 as a standard. RESULTS: The strontium isotopic ratios of all samples immersed in the spiked solution were strongly modified showing that significant amounts of strontium had been adsorbed or incorporated. After pre-treatment the enamel samples still contained significant amounts of (87) Sr-enriched contamination while the calcined bone fragments did not. CONCLUSIONS: The results of the artificial enrichment experiment demonstrate that calcined bone is more resistant to post-mortem exchange than tooth enamel, and that in vivo strontium isotopic ratios are retained in calcined bone.

Is exposure in vivo cost-effective for chronic low back pain? A trial-based economic evaluation.

BACKGROUND: Back pain is one of the most expensive health complaints. Comparing the economic aspects of back pain interventions may therefore contribute to a more efficient use of available resources. This study reports on a long-term cost-effectiveness analysis (CEA) and cost-utility analysis (CUA) of two treatments as viewed from a societal perspective: 1) exposure in vivo treatment (EXP), a recently developed cognitive behavioral treatment for patients with chronic low back pain who have elevated pain-related fear and 2) the more commonly used graded activity (GA) treatment. METHODS: Sixty-two patients with non-specific chronic low back pain received either EXP or GA. Primary data were collected at four participating treatment centers in the Netherlands. Primary outcomes were self-reported disability (for the CEA) and quality-adjusted life years (for the CUA). Program costs, health care utilization, patient and family costs, and production losses were measured by analyzing therapy records and cost diaries. Data was gathered before, during, and after treatment, and at 6 and 12 months after treatment. Non-parametric bootstrap analyses were used to quantify the uncertainty concerning the cost-effectiveness ratio. In addition, cost-effectiveness planes and cost-effectiveness acceptability curves were performed. RESULTS: EXP showed a tendency to reduce disability, increase quality adjusted life years and decrease costs compared to GA. The incremental cost-effectiveness ratios of both the CEA and CUA are in favor of EXP. CONCLUSIONS: Based on these results, implementing EXP for this group of patients seems to be the best decision. TRIAL REGISTRATION: ISRCTN88087718.

Identification of recurrent FGFR3 fusion genes in lung cancer through kinome-centred RNA sequencing.

Oncogenic fusion genes that involve kinases have proven to be effective targets for therapy in a wide range of cancers. Unfortunately, the diagnostic approaches required to identify these events are struggling to keep pace with the diverse array of genetic alterations that occur in cancer. Diagnostic screening in solid tumours is particularly challenging, as many fusion genes occur with a low frequency. To overcome these limitations, we developed a capture enrichment strategy to enable high-throughput transcript sequencing of the human kinome. This approach provides a global overview of kinase fusion events, irrespective of the identity of the fusion partner. To demonstrate the utility of this system, we profiled 100 non-small cell lung cancers and identified numerous genetic alterations impacting fibroblast growth factor receptor 3 (FGFR3) in lung squamous cell carcinoma and a novel ALK fusion partner in lung adenocarcinoma.

Comparison of two gallium purification procedures for isotopic measurements by MC-ICP-MS in a set of silicate reference materials.

Gallium is a moderately volatile, moderately siderophile element with two stable isotopes: 69Ga and 71Ga. A general interest in Ga isotopes arose over the last few years, as its moderately volatile behavior potentially marks it as a useful tracer of various processes such as condensation and evaporation. Nevertheless, there is a lack of agreement between laboratories for consistent δ71Ga values in geological reference materials. In this work, we have developed and evaluated two methods for purification protocols leading to precise analysis of gallium (Ga) isotopic composition in silicate rock materials. The first method is a three-step column chemistry using the resins AG1-X8, HDEHP, and AG50W-X12 whereas the second method uses only two columns, AG1-X8 and AG50W-X8. The two methods were applied to a range of both synthetic (multi-element) solutions and geological samples. Both methods show comparable results with no isotope fractionation occurring during purification chemistry, allowing us to define the δ71Ga of selected USGS reference materials (BHVO-2, BCR-2, RGM-2). Similar to previously reported results, we also observe no Ga fractionation between distinct igneous terrestrial materials.

How to bridge the nurse innovation-diffusion gap? An in-depth case study of Create4Care.

Introduction: Nurses frequently innovate in response to operational failures, regulations, procedures, and/or other workflow barriers that prevent them from delivering high-quality patient care. Unfortunately, most nurse innovations do not diffuse to a broader audience, depriving other nurses from taking advantage of solutions that have already been developed elsewhere. This under-diffusion is problematic from a societal and welfare point of view. The goal of this paper is to understand how diffusion shortage of nurse innovations can be reduced. Methods: We develop a qualitative case study of a medical makerspace at the largest academic hospital in the Netherlands. This medical makerspace reported unusually high rates of nurse innovation diffusion. Our data collection includes on-site observations, archival data, secondary data, and fifteen in-depth interviews with key informants. Qualitative coding procedures and a combination of deductive and inductive reasoning are used to analyze the data. Results: Our data show that personal, organizational, regulatory, and market barriers prevent nurses from further developing and diffusion their innovations in an anticipatory manner. That is, because nurses expect that transforming an initial solution into an innovation that can be shared with others will be too time consuming and difficult they do not proceed with the further development. The medical makerspace that we investigated adequately addresses this problem by developing an innovation ecosystem that largely takes over the innovation and diffusion process. Discussion: We provide a concrete example of how a medical makerspace, and innovation support systems in a broader sense, can be designed to more adequately address the nurse innovation-diffusion gap. The two main elements of the practical solution that we identified are: (1) Support systems should facilitate that others may lead the development and diffusion of innovations and (2) The support system should promote that actors integrate their functional specializations within an innovation ecosystem. We make two theoretical contributions. First, we contribute to understanding barriers in the nurse innovation-diffusion process from a psychological point. Second, we identified that an ecosystem perspective is beneficial to develop innovation support systems in which diffusion occurs more often.