Clinical Use of Quantitative Computed Tomography–Based Advanced Techniques in the Management of Osteoporosis in Adults: the 2015 ISCD Official Positions—Part III

The International Society for Clinical Densitometry (ISCD) has developed new official positions for the clinical use of computed tomography (CT) scans acquired without a calibration phantom, for example, CT scans obtained for other diagnosis such as colonography. This also addresses techniques suggested for opportunistic screening of osteoporosis. The ISCD task force for quantitative CT reviewed the evidence for clinical applications of these new techniques and presented a report with recommendations at the 2015 ISCD Position Development Conference. Here we discuss the agreed upon ISCD official positions with supporting medical evidence, rationale, controversy, and suggestions for further study. Advanced techniques summarized as statistical parameter mapping methods were also reviewed. Their future use is promising but the clinical application is premature. The clinical use of QCT of the hip is addressed in part I and of finite element analysis of the hip and spine in part II.

Smart Hybrid Polymers for Advanced Damascene Electroplating: Combination of Superfill and Leveling Properties

A successful bottom-up fill of single Damascene test features is achieved by using a two-component additive package consisting of bis-(sodium-sulfopropyl)-disulfide (SPS) and Imep polymers (polymerizates of imidazole and epichlorohydrin). In addition, a remarkable leveling effect is observed. Clearly, the Imep additive combines bottom-up fill capabilities with leveling characteristics in one single polymer component. These unique hybrid properties of the Imep are rationalized on the basis of an extended N-NDR (N-shaped negative differential resistance) being present in the linear-sweep voltammogram of the SPS/Imep additive system during Cu electrodeposition.

Impact of weight loss on survival after chemoradiation for locally advanced head and neck cancer: secondary results of a randomized phase III trial (SAKK 10/94).

BACKGROUND To analyze the impact of weight loss before and during chemoradiation on survival outcomes in patients with locally advanced head and neck cancer. METHODS From 07/1994-07/2000 a total of 224 patients with squamous cell carcinoma of the head and neck were randomized to either hyperfractionated radiation therapy alone or the same radiation therapy combined with two cycles of concomitant cisplatin. The primary endpoint was time to any treatment failure (TTF); secondary endpoints were locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS). Patient weight was measured 6 months before treatment, at treatment start and treatment end. RESULTS The proportion of patients with >5% weight loss was 32% before, and 51% during treatment, and the proportion of patients with >10% weight loss was 12% before, and 17% during treatment. After a median follow-up of 9.5 years (range, 0.1 - 15.4 years) weight loss before treatment was associated with decreased TTF, LRRFS, DMFS, cancer specific survival and OS in a multivariable analysis. However, weight loss during treatment was not associated with survival outcomes. CONCLUSIONS Weight loss before and during chemoradiation was commonly observed. Weight loss before but not during treatment was associated with worse survival.

Consensus and differences in primary radiotherapy for localized and locally advanced prostate cancer in Switzerland: A survey on patterns of practice

INTRODUCTION External beam radiotherapy (EBRT), with or without androgen deprivation therapy (ADT), is an established treatment option for nonmetastatic prostate cancer. Despite high-level evidence from several randomized trials, risk group stratification and treatment recommendations vary due to contradictory or inconclusive data, particularly with regard to EBRT dose prescription and ADT duration. Our aim was to investigate current patterns of practice in primary EBRT for prostate cancer in Switzerland. MATERIALS AND METHODS Treatment recommendations on EBRT and ADT for localized and locally advanced prostate cancer were collected from 23 Swiss radiation oncology centers. Written recommendations were converted into center-specific decision trees, and analyzed for consensus and differences using a dedicated software tool. Additionally, specific radiotherapy planning and delivery techniques from the participating centers were assessed. RESULTS The most commonly prescribed radiation dose was 78 Gy (range 70-80 Gy) across all risk groups. ADT was recommended for intermediate-risk patients for 6 months in over 80 % of the centers, and for high-risk patients for 2 or 3 years in over 90 % of centers. For recommendations on combined EBRT and ADT treatment, consensus levels did not exceed 39 % in any clinical scenario. Arc-based intensity-modulated radiotherapy (IMRT) is implemented for routine prostate cancer radiotherapy by 96 % of the centers. CONCLUSION Among Swiss radiation oncology centers, considerable ranges of radiotherapy dose and ADT duration are routinely offered for localized and locally advanced prostate cancer. In the vast majority of cases, doses and durations are within the range of those described in current evidence-based guidelines.

Improved VMAT planning for head and neck tumors with an advanced optimization algorithm

OBJECTIVE In this study, the "Progressive Resolution Optimizer PRO3" (Varian Medical Systems) is compared to the previous version "PRO2" with respect to its potential to improve dose sparing to the organs at risk (OAR) and dose coverage of the PTV for head and neck cancer patients. MATERIALS AND METHODS For eight head and neck cancer patients, volumetric modulated arc therapy (VMAT) treatment plans were generated in this study. All cases have 2-3 phases and the total prescribed dose (PD) was 60-72Gy in the PTV. The study is mainly focused on the phase 1 plans, which all have an identical PD of 54Gy, and complex PTV structures with an overlap to the parotids. Optimization was performed based on planning objectives for the PTV according to ICRU83, and with minimal dose to spinal cord, and parotids outside PTV. In order to assess the quality of the optimization algorithms, an identical set of constraints was used for both, PRO2 and PRO3. The resulting treatment plans were investigated with respect to dose distribution based on the analysis of the dose volume histograms. RESULTS For the phase 1 plans (PD=54Gy) the near maximum dose D2% of the spinal cord, could be minimized to 22±5 Gy with PRO3, as compared to 32±12Gy with PRO2, averaged for all patients. The mean dose to the parotids was also lower in PRO3 plans compared to PRO2, but the differences were less pronounced. A PTV coverage of V95%=97±1% could be reached with PRO3, as compared to 86±5% with PRO2. In clinical routine, these PRO2 plans would require modifications to obtain better PTV coverage at the cost of higher OAR doses. CONCLUSION A comparison between PRO3 and PRO2 optimization algorithms was performed for eight head and neck cancer patients. In general, the quality of VMAT plans for head and neck patients are improved with PRO3 as compared to PRO2. The dose to OARs can be reduced significantly, especially for the spinal cord. These reductions are achieved with better PTV coverage as compared to PRO2. The improved spinal cord sparing offers new opportunities for all types of paraspinal tumors and for re-irradiation of recurrent tumors or second malignancies.

Outcomes in Advanced Head and Neck Cancer Treated with Up-front Neck Dissection prior to (Chemo)Radiotherapy.

OBJECTIVE Our aim was to compare outcomes with and without up-front neck dissection prior to (chemo)radiotherapy in head and neck squamous cell carcinoma. STUDY DESIGN Case series with chart review. SETTING Tertiary referral center. SUBJECTS AND METHODS Outcomes of oropharyngeal, laryngeal, and hypopharyngeal squamous cell carcinoma cases with neck lymph node metastases treated from January 2001 to March 2012 were analyzed. Due to imbalances in baseline characteristics between groups treated with (n = 129) and without (n = 95) up-front neck dissection, propensity score matching was performed. RESULTS Median follow-up was 48 months (range, 12-148). With up-front neck dissection, the hazard ratio for the primary end point, disease-free survival, was 0.63 (95% confidence interval: 0.37-1.06, P = .08). Up-front neck dissection reduced acute grade ≥3 toxicity significantly when xerostomia was excluded (odds ratio: 0.40, 95% confidence interval: 0.20-0.82, P = .012). CONCLUSION Our results indicate less acute treatment toxicity without any significant difference in terms of oncologic outcome with up-front neck dissection prior to (chemo)radiotherapy as compared with (chemo)radiotherapy alone. Well-designed randomized trials are required to verify this result and further investigate the impact of this strategy on late toxicity and oncologic outcome.

Effects of Prolyl Hydroxylase Inhibitor L-mimosine on Dental Pulp in the Presence of Advanced Glycation End Products

INTRODUCTION Proangiogenic prolyl hydroxylase (PHD) inhibitors represent a novel approach to stimulate tissue regeneration. Diabetes mellitus involves the accumulation of advanced glycation end products (AGEs). Here we evaluated the impact of AGEs on the response of human pulp tissue to the PHD inhibitor L-mimosine (L-MIM) in monolayer cultures of dental pulp-derived cells (DPCs) and tooth slice organ cultures. METHODS In monolayer cultures, DPCs were incubated with L-MIM and AGEs. Viability was assessed based on formazan formation, live-dead staining, annexin V/propidium iodide, and trypan blue exclusion assay. Vascular endothelial growth factor (VEGF), interleukin (IL)-6, and IL-8 production was evaluated by quantitative polymerase chain reaction and immunoassays. Furthermore, expression levels of odontoblast markers were assessed, and alizarin red staining was performed. Tooth slice organ cultures were performed, and VEGF, IL-6, and IL8 levels in their supernatants were measured by immunoassays. Pulp tissue vitality and morphology were assessed by MTT assay and histology. RESULTS In monolayer cultures of DPCs, L-MIM at nontoxic concentrations increased the production of VEGF and IL-8 in the presence of AGEs. Stimulation with L-MIM decreased alkaline phosphatase levels and matrix mineralization also in the presence of AGEs, whereas no significant changes in dentin matrix protein 1 and dentin sialophosphoprotein expression were observed. In tooth slice organ cultures, L-MIM increased VEGF but not IL-6 and IL-8 production in the presence of AGEs. The pulp tissue was vital, and no signs of apoptosis or necrosis were observed. CONCLUSIONS Overall, in the presence of AGEs, L-MIM increases the proangiogenic capacity, but decreases alkaline phosphatase expression and matrix mineralization.

Comparative release of growth factors from PRP, PRF, and advanced-PRF

OBJECTIVES The use of platelet concentrates has gained increasing awareness in recent years for regenerative procedures in modern dentistry. The aim of the present study was to compare growth factor release over time from platelet-rich plasma (PRP), platelet-rich fibrin (PRF), and a modernized protocol for PRF, advanced-PRF (A-PRF). MATERIALS AND METHODS Eighteen blood samples were collected from six donors (3 samples each for PRP, PRF, and A-PRF). Following preparation, samples were incubated in a plate shaker and assessed for growth factor release at 15 min, 60 min, 8 h, 1 day, 3 days, and 10 days. Thereafter, growth factor release of PDGF-AA, PDGF-AB, PDGF-BB, TGFB1, VEGF, EGF, and IGF was quantified using ELISA. RESULTS The highest reported growth factor released from platelet concentrates was PDGF-AA followed by PDGF-BB, TGFB1, VEGF, and PDGF-AB. In general, following 15-60 min incubation, PRP released significantly higher growth factors when compared to PRF and A-PRF. At later time points up to 10 days, it was routinely found that A-PRF released the highest total growth factors. Furthermore, A-PRF released significantly higher total protein accumulated over a 10-day period when compared to PRP or PRF. CONCLUSION The results from the present study indicate that the various platelet concentrates have quite different release kinetics. The advantage of PRP is the release of significantly higher proteins at earlier time points whereas PRF displayed a continual and steady release of growth factors over a 10-day period. Furthermore, in general, it was observed that the new formulation of PRF (A-PRF) released significantly higher total quantities of growth factors when compared to traditional PRF. CLINICAL RELEVANCE Based on these findings, PRP can be recommended for fast delivery of growth factors whereas A-PRF is better-suited for long-term release.

Serial [18F]-fluoromisonidazole PET during radiochemotherapy for locally advanced head and neck cancer and its correlation with outcome.

PURPOSE The aim was to assess changes of tumour hypoxia during primary radiochemotherapy (RCT) for head and neck cancer (HNC) and to evaluate their relationship with treatment outcome. MATERIAL AND METHODS Hypoxia was assessed by FMISO-PET in weeks 0, 2 and 5 of RCT. The tumour volume (TV) was determined using FDG-PET/MRI/CT co-registered images. The level of hypoxia was quantified on FMISO-PET as TBRmax (SUVmaxTV/SUVmean background). The hypoxic subvolume (HSV) was defined as TV that showed FMISO uptake ⩾1.4 times blood pool activity. RESULTS Sixteen consecutive patients (T3-4, N+, M0) were included (mean follow-up 31, median 44months). Mean TBRmax decreased significantly (p<0.05) from 1.94 to 1.57 (week 2) and 1.27 (week 5). Mean HSV in week 2 and week 5 (HSV2=5.8ml, HSV3=0.3ml) were significantly (p<0.05) smaller than at baseline (HSV1=15.8ml). Kaplan-Meier plots of local recurrence free survival stratified at the median TBRmax showed superior local control for less hypoxic tumours, the difference being significant at baseline and after 2weeks (p=0.031, p=0.016). CONCLUSIONS FMISO-PET documented that in most HNC reoxygenation starts early during RCT and is correlated with better outcome.

Sleep-Wake Cycle Dysfunction in the TgCRND8 Mouse Model of Alzheimer's Disease: From Early to Advanced Pathological Stages.

In addition to cognitive decline, individuals affected by Alzheimer's disease (AD) can experience important neuropsychiatric symptoms including sleep disturbances. We characterized the sleep-wake cycle in the TgCRND8 mouse model of AD, which overexpresses a mutant human form of amyloid precursor protein resulting in high levels of β-amyloid and plaque formation by 3 months of age. Polysomnographic recordings in freely-moving mice were conducted to study sleep-wake cycle architecture at 3, 7 and 11 months of age and corresponding levels of β-amyloid in brain regions regulating sleep-wake states were measured. At all ages, TgCRND8 mice showed increased wakefulness and reduced non-rapid eye movement (NREM) sleep during the resting and active phases. Increased wakefulness in TgCRND8 mice was accompanied by a shift in the waking power spectrum towards fast frequency oscillations in the beta (14-20 Hz) and low gamma range (20-50 Hz). Given the phenotype of hyperarousal observed in TgCRND8 mice, the role of noradrenergic transmission in the promotion of arousal, and previous work reporting an early disruption of the noradrenergic system in TgCRND8, we tested the effects of the alpha-1-adrenoreceptor antagonist, prazosin, on sleep-wake patterns in TgCRND8 and non-transgenic (NTg) mice. We found that a lower dose (2 mg/kg) of prazosin increased NREM sleep in NTg but not in TgCRND8 mice, whereas a higher dose (5 mg/kg) increased NREM sleep in both genotypes, suggesting altered sensitivity to noradrenergic blockade in TgCRND8 mice. Collectively our results demonstrate that amyloidosis in TgCRND8 mice is associated with sleep-wake cycle dysfunction, characterized by hyperarousal, validating this model as a tool towards understanding the relationship between β-amyloid overproduction and disrupted sleep-wake patterns in AD.

Advanced Noncontrast MR Imaging in Musculoskeletal Radiology

Multiple nonmorphologic magnetic resonance sequences are available in musculoskeletal imaging that can provide additional information to better characterize and diagnose musculoskeletal disorders and diseases. These sequences include blood-oxygen-level-dependent (BOLD), arterial spin labeling (ASL), diffusion-weighted imaging (DWI), and diffusion-tensor imaging (DTI). BOLD and ASL provide different methods to evaluate skeletal muscle microperfusion. The BOLD signal reflects the ratio between oxyhemoglobin and deoxyhemoglobin. ASL uses selective tagging of inflowing blood spins in a specific region for calculating local perfusion. DWI and DTI provide information about the structural integrity of soft tissue including muscles and fibers as well as pathologies.

CD34+ selected versus unselected autologous stem cell transplantation in patients with advanced-stage mantle cell and diffuse large B-cell lymphoma

Novel strategies aiming to increase survival rates in patients with advanced-stage mantle cell lymphoma (MCL) and relapsing diffuse large B-cell lymphoma (DLBCL) are a clinical need. High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) has improved progression-free (PFS) and overall survival (OS) in MCL and relapsed DLBCL. However, the role of CD34+ cell selection before ASCT in MCL and DLBCL is unclear. We retrospectively analyzed the outcome of 62 consecutive patients with advanced-stage MCL or relapsed DLBCL undergoing ASCT with (n=31) or without (n=31) prior CD34+ selection. All patients had stage III or IV disease, with 47% having DLBCL and 53% MCL. The median duration for neutrophil and platelet recovery was 12 and 16 days in CD34+ selected patients, and 11 (P<.001) and 14 days (P=.012) in the group without selection, respectively. No differences in toxicities were observed. The 5-year PFS for CD34+ selected versus not selected patients was 67% and 39% (P=.016), and the 5-year OS was 86% and 54% (P=.007). Our data suggest that using CD34+ selected autografts for ASCT in advanced stage MCL and DLBCL is associated with longer PFS and OS without increased toxicity.

Improvement of platelets after SVR among patients with chronic HCV infection and advanced hepatic fibrosis.

BACKGROUND & AIMS Patients with chronic hepatitis C virus (HCV) infection may develop cirrhosis with portal hypertension, reflected by decreased platelet count and splenomegaly. This retrospective cohort study aimed to assess changes in platelet counts after antiviral therapy among chronic HCV-infected patients with advanced fibrosis. METHODS Platelet counts and spleen sizes were recorded in an international cohort of patients with Ishak 4-6 fibrosis who started antiviral therapy between 1990 and 2003. Last measured platelet counts and spleen sizes were compared to their pre-treatment values (within 6 six months prior to the start of therapy). All registered platelet count measurements from 24 week following cessation of antiviral therapy were included in repeated measurement analyses. RESULTS This study included 464 patients; 353 (76%) had cirrhosis and 187 (40%) attained sustained virological response (SVR). Among patients with SVR, median platelet count, increased by 35 x10(9) /L (IQR 7-62, p<0.001). In comparison, patients without SVR showed a median decline of 17 x10(9) /L (IQR -5-47, p<0.001). In a subgroup of 209 patients, median decrease in spleen size was 1.0 cm (IQR 0.3-2.0) for patients with SVR, while median spleen size increased with 0.6 cm (IQR -0.1-2.0, p<0.001) among those without SVR. The changes in spleen size and platelet count were significantly correlated (R=-0.41, p<0.001). CONCLUSIONS Among chronic HCV-infected patients with advanced hepatic fibrosis the platelet counts improved following SVR and the change in platelets correlated with the change in spleen size following antiviral therapy. These results suggest that HCV eradication leads to reduced portal pressure. This article is protected by copyright. All rights reserved.

Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial

BACKGROUND VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. METHODS In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01140347. FINDINGS Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0-10·6) versus 7·6 months (6·0-9·3) for the placebo group (HR 0·87 [95% CI 0·72-1·05]; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated with placebo), hypertension (34 [12%] vs ten [4%]), asthenia (14 [5%] vs five [2%]), malignant neoplasm progression (18 [6%] vs 11 [4%]), increased aspartate aminotransferase concentration (15 [5%] vs 23 [8%]), thrombocytopenia (13 [5%] vs one [<1%]), hyperbilirubinaemia (three [1%] vs 13 [5%]), and increased blood bilirubin (five [2%] vs 14 [5%]). The most frequently reported (≥1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression. INTERPRETATION Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable. FUNDING Eli Lilly and Co.