[(18)F]FDG-PET Standard Uptake Value as a Metabolic Predictor of Bone Marrow Response to Radiation: Impact on Acute and Late Hematological Toxicity in Cervical Cancer Patients Treated With Chemoradiation Therapy.

PURPOSE: To quantify the relationship between bone marrow (BM) response to radiation and radiation dose by using (18)F-labeled fluorodeoxyglucose positron emission tomography [(18)F]FDG-PET standard uptake values (SUV) and to correlate these findings with hematological toxicity (HT) in cervical cancer (CC) patients treated with chemoradiation therapy (CRT). METHODS AND MATERIALS: Seventeen women with a diagnosis of CC were treated with standard doses of CRT. All patients underwent pre- and post-therapy [(18)F]FDG-PET/computed tomography (CT). Hemograms were obtained before and during treatment and 3 months after treatment and at last follow-up. Pelvic bone was autosegmented as total bone marrow (BMTOT). Active bone marrow (BMACT) was contoured based on SUV greater than the mean SUV of BMTOT. The volumes (V) of each region receiving 10, 20, 30, and 40 Gy (V10, V20, V30, and V40, respectively) were calculated. Metabolic volume histograms and voxel SUV map response graphs were created. Relative changes in SUV before and after therapy were calculated by separating SUV voxels into radiation therapy dose ranges of 5 Gy. The relationships among SUV decrease, radiation dose, and HT were investigated using multiple regression models. RESULTS: Mean relative pre-post-therapy SUV reductions in BMTOT and BMACT were 27% and 38%, respectively. BMACT volume was significantly reduced after treatment (from 651.5 to 231.6 cm(3), respectively; P<.0001). BMACT V30 was significantly correlated with a reduction in BMACT SUV (R(2), 0.14; P<.001). The reduction in BMACT SUV significantly correlated with reduction in white blood cells (WBCs) at 3 months post-treatment (R(2), 0.27; P=.04) and at last follow-up (R(2), 0.25; P=.04). Different dosimetric parameters of BMTOT and BMACT correlated with long-term hematological outcome. CONCLUSIONS: The volumes of BMTOT and BMACT that are exposed to even relatively low doses of radiation are associated with a decrease in WBC counts following CRT. The loss in proliferative BM SUV uptake translates into low WBC nadirs after treatment. These results suggest the potential of intensity modulated radiation therapy to spare BMTOT to reduce long-term hematological toxicity.

Ultra-High Field (7 Tesla) MRI for Gamma Knife Surgery Targeting of the Ventro-Intermediate Nucleus: A Pilot in Vivo Study

Aim: Gamma Knife surgery (GKS) is a non-invasive neurosurgical stereotactic procedure, increasingly used as an alternative to open functional procedures. This includes the targeting of the ventro-intermediate (Vim) nucleus of the thalamus for tremor. We currently perform an indirect targeting, using the "quadrilatere of Guyot," as the Vim nucleus is not visible on current 3 Tesla (T) MRI acquisitions. The primary objective of the current study was to enhance anatomic imaging for Vim GKS using high-field (7 T) MRI, with the aim of refining the visualization and precision of anatomical targeting. Method: Five young healthy subjects (mean age 23 years) were scanned both on 3 and 7 T MRI in Lausanne University Hospital (CHUV) and Center for Biomedical Imaging (CIBM). Classical T1-weighted MPRAGE, T2 CISS sequences (replacing former ventriculography) and diffusion tensor imaging were acquired at 3T. We obtained high-resolution susceptibility weighted images (SWI) at 7T for the visualization of thalamic subparts. SWI was further integrated for the first time into Leksell Gamma Plan® (LGP) software and co-registered with the 3T images. A simulation of targeting of the Vim was done using the "quadrilatere of Guyot" methodology on the 3T images. Furthermore, a correlation with the position of the found target on SWI was performed. The atlas of Morel et al. was used to confirm the findings on a detailed computer analysis outside LGP. Also, 3T and 7T MRI of one patient undergoing GKS Vim thalamotomy, were obtained before and 2 years after the procedure, and studied similarly. Results: The use of SWI provided a superior resolution and improved image contrast within the central gray matter. This allowed visualization and direct delineation of groups of thalamic nuclei in vivo, including the Vim. The position of the target, as assessed with the "quadrilatere of Guyot" method on 3 T, perfectly matched with the supposed one of the Vim on the SWI. Furthermore, a 3-dimensional model of the Vim target area was created on the basis of 3T and 7T images. Conclusion: This is the first report of the integration of SWI high-field MRI into the LGP in healthy subjects and in one patient treated GKS Vim thalamotomy. This approach aims at the improvement of targeting validation and further direct targeting of the Vim in tremor. The anatomical correlation between the direct visualization on 7T and the current targeting methods on 3T seems to show a very good anatomical matching.

Radiation therapy duration influences overall survival in patients with cervical carcinoma.

OBJECTIVE: This article analyses the influence of treatment duration on survival in patients with invasive carcinoma of the cervix treated by radical radiation therapy. METHOD: Three hundred and sixty patients with FIGO stage IB-IIIB carcinoma of the cervix were treated in Lausanne (Switzerland) with external radiation and brachytherapy as first line therapy. Median therapy duration was 45 days. Patients were classified according to the duration of the therapies, taking 60 days (the 75th percentile) as an arbitrary cut-off. RESULTS: The 5-year survival was 61% (S.E. = 3%) for the therapy duration group of less than 60 days and 53% (S.E. = 7%) for the group of more than 60 days. In terms of univariate hazard ratio (HR), the relative difference between the two groups corresponds to a 50% increase of deaths (HR = 1.53, 95% CI = 1.03-2.28) for the longer therapy duration group (P = 0.044). In a multivariate analysis, the magnitude of estimated relative hazards for the longer therapies are confirmed though significance was reduced (HR = 1.52, 95% CI = 0.94-2.45, P = 0.084). CONCLUSION: These findings suggest that short treatment duration is a factor associated with longer survival in carcinoma of the cervix.

Randomized controlled trial of interventions for young people at ultra-high risk of psychosis: study design and baseline characteristics.

OBJECTIVE: Intervention during the pre-psychotic period of illness holds the potential of delaying or even preventing the onset of a full-threshold disorder, or at least of reducing the impact of such a disorder if it does develop. The first step in realizing this aim was achieved more than 10 years ago with the development and validation of criteria for the identification of young people at ultra-high risk (UHR) of psychosis. Results of three clinical trials have been published that provide mixed support for the effectiveness of psychological and pharmacological interventions in preventing the onset of psychotic disorder. METHOD: The present paper describes a fourth study that has now been undertaken in which young people who met UHR criteria were randomized to one of three treatment groups: cognitive therapy plus risperidone (CogTher + Risp: n = 43); cognitive therapy plus placebo (CogTher + Placebo: n = 44); and supportive counselling + placebo (Supp + Placebo; n = 28). A fourth group of young people who did not agree to randomization were also followed up (monitoring: n = 78). Baseline characteristics of participants are provided. RESULTS AND CONCLUSION: The present study improves on the previous studies because treatment was provided for 12 months and the independent contributions of psychological and pharmacological treatments in preventing transition to psychosis in the UHR cohort and on levels of psychopathology and functioning can be directly compared. Issues associated with recruitment and randomization are discussed.

The role of PET/CT in cervical cancer.

In locally advanced cervical cancer, (18)F-fluorodeoxyglucose (FDG) positron emission tomography - computed tomography (PET/CT) has become important in the initial evaluation of disease extent. It is superior to other imaging modalities for lymph node status and distant metastasis. PET-defined cervical tumor volume predicts progression-free and overall survival. Higher FDG uptake in both primary and regional lymph nodes is strongly predictive of worse outcome. FDG-PET is useful for assessing treatment response 3 months after completing concurrent chemo-radiotherapy (CRT) and predicting long-term survival, and in suspected disease recurrence. In the era of image-guided adaptive radiotherapy, accurately defining disease areas is critical to avoid irradiating normal tissue. Based on additional information provided by FDG-PET, radiation treatment volumes can be modified and higher doses to FDG-positive lymph nodes safely delivered. FDG-PET/CT has been used for image-guided brachytherapy of FDG-avid tumor volume, while respecting low doses to bladder and rectum. Despite survival improvements due to CRT in cervical cancer, disease recurrences continue to be a major problem. Biological rationale exists for combining novel non-cytotoxic agents with CRT, and drugs targeting specific molecular pathways are under clinical development. The integration of these targeted therapies in clinical trials, and the need for accurate predictors of radio-curability is essential. New molecular imaging tracers may help identifying more aggressive tumors. (64)Cu-labeled diacetyl-di(N(4)-methylthiosemicarbazone) is taken up by hypoxic tissues, which may be valuable for prognostication and radiation treatment planning. PET/CT imaging with novel radiopharmaceuticals could further impact cervical cancer treatment as surrogate markers of drug activity at the tumor microenvironment level. The present article reviews the current and emerging role of PET/CT in the management of cervical cancer.

An ultra-sensitive impedimetric immunosensor for detection of the serum oncomarker CA-125 in ovarian cancer patients.

Effective treatment of ovarian cancer depends upon the early detection of the malignancy. Here, we report on the development of a new nanostructured immunosensor for early detection of cancer antigen 125 (CA-125). A gold electrode was modified with mercaptopropionic acid (MPA), and then consecutively conjugated with silica coated gold nanoparticles (AuNP@SiO2), CdSe quantum dots (QDs) and anti-CA-125 monoclonal antibody (mAb). The engineered MPA|AuNP@SiO2|QD|mAb immunosensor was characterised using transmission electron microscopy (TEM), atomic force microscopy (AFM), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Successive conjugation of AuNP@SiO2, CdSe QD and anti-CA-125 mAb onto the gold electrode resulted in sensitive detection of CA-125 with a limit of detection (LOD) of 0.0016 U mL(-1) and a linear detection range (LDR) of 0-0.1 U mL(-1). Based on the high sensitivity and specificity of the immunosensor, we propose this highly stable and reproducible biosensor for the early detection of CA-125.

Retrospective feasibility study of simultaneous integrated boost in cervical cancer using Tomotherapy: the impact of organ motion and tumor regression.

BACKGROUND: Whole pelvis intensity modulated radiotherapy (IMRT) is increasingly being used to treat cervical cancer aiming to reduce side effects. Encouraged by this, some groups have proposed the use of simultaneous integrated boost (SIB) to target the tumor, either to get a higher tumoricidal effect or to replace brachytherapy. Nevertheless, physiological organ movement and rapid tumor regression throughout treatment might substantially reduce any benefit of this approach. PURPOSE: To evaluate the clinical target volume - simultaneous integrated boost (CTV-SIB) regression and motion during chemo-radiotherapy (CRT) for cervical cancer, and to monitor treatment progress dosimetrically and volumetrically to ensure treatment goals are met. METHODS AND MATERIALS: Ten patients treated with standard doses of CRT and brachytherapy were retrospectively re-planned using a helical Tomotherapy - SIB technique for the hypothetical scenario of this feasibility study. Target and organs at risk (OAR) were contoured on deformable fused planning-computed tomography and megavoltage computed tomography images. The CTV-SIB volume regression was determined. The center of mass (CM) was used to evaluate the degree of motion. The Dice's similarity coefficient (DSC) was used to assess the spatial overlap of CTV-SIBs between scans. A cumulative dose-volume histogram modeled estimated delivered doses. RESULTS: The CTV-SIB relative reduction was between 31 and 70%. The mean maximum CM change was 12.5, 9, and 3 mm in the superior-inferior, antero-posterior, and right-left dimensions, respectively. The CTV-SIB-DSC approached 1 in the first week of treatment, indicating almost perfect overlap. CTV-SIB-DSC regressed linearly during therapy, and by the end of treatment was 0.5, indicating 50% discordance. Two patients received less than 95% of the prescribed dose. Much higher doses to the OAR were observed. A multiple regression analysis showed a significant interaction between CTV-SIB reduction and OAR dose increase. CONCLUSIONS: The CTV-SIB had important regression and motion during CRT, receiving lower therapeutic doses than expected. The OAR had unpredictable shifts and received higher doses. The use of SIB without frequent adaptation of the treatment plan exposes cervical cancer patients to an unpredictable risk of under-dosing the target and/or overdosing adjacent critical structures. In that scenario, brachytherapy continues to be the gold standard approach.

Le sevrage ultra-rapide sous anesthésie générale: l'expérience de l'Hôpital de St-Loup [Ultrafast opiate detoxification under general anesthesia: the St. Loup Hospital experience]

Rapid antagonist induction under anesthesia is a method that has been increasingly used to detoxify opiate addicts. These procedures are useful to reduce the duration and the discomfort of withdrawal. However, the high risk and the cost of these methods require randomized clinical trial to evaluate safety and clinical effectiveness. The University Substance Abuse Division of Lausanne and the Intensive Care Unit of the St-Loup Hospital work on a randomized clinical trial comparing anesthesia-assisted versus traditional clonidine detoxification combined with an additional psychosocial week. This paper describes the technique of anesthesia used in our study. Our clinical experience suggests that, integrating this technique in a multidisciplinary network, with a strong emphasis on post-anesthetic follow-up, is a viable and safe option in the treatment of opiate dependence.

International periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome cohort: description of distinct phenotypes in 301 patients.

OBJECTIVES: The aims of this study were to describe the clinical features of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) and identify distinct phenotypes in a large cohort of patients from different countries. METHODS: We established a web-based multicentre cohort through an international collaboration within the periodic fevers working party of the Pediatric Rheumatology European Society (PReS). The inclusion criterion was a diagnosis of PFAPA given by an experienced paediatric rheumatologist participating in an international working group on periodic fever syndromes. RESULTS: Of the 301 patients included from the 15 centres, 271 had pharyngitis, 236 cervical adenitis, 171 oral aphthosis and 132 with all three clinical features. A total of 228 patients presented with additional symptoms (131 gastrointestinal symptoms, 86 arthralgias and/or myalgias, 36 skin rashes, 8 neurological symptoms). Thirty-one patients had disease onset after 5 years and they reported more additional symptoms. A positive family history for recurrent fever or recurrent tonsillitis was found in 81 patients (26.9%). Genetic testing for monogenic periodic fever syndromes was performed on 111 patients, who reported fewer occurrences of oral aphthosis or additional symptoms. Twenty-four patients reported symptoms (oral aphthosis and malaise) outside the flares. The CRP was >50 mg/l in the majority (131/190) of the patients tested during the fever. CONCLUSION: We describe the largest cohort of PFAPA patients presented so far. We confirm that PFAPA may present with varied clinical manifestations and we show the limitations of the commonly used diagnostic criteria. Based on detailed analysis of this cohort, a consensus definition of PFAPA with better-defined criteria should be proposed.

Endoscopic extraction of a prevertebral migrated guidewire after posterior cervical instrumentation.

Images of Spine Care

Alterations of Neuromuscular Function after the World's Most Challenging Mountain Ultra-Marathon

We investigated the physiological consequences of the most challenging mountain ultra-marathon (MUM) in the world: a 330-km trail run with 24000 m of positive and negative elevation change. Neuromuscular fatigue (NMF) was assessed before (Pre-), during (Mid-) and after (Post-) the MUM in experienced ultra-marathon runners (n = 15; finish time = 122.43 hours +/-17.21 hours) and in Pre- and Post- in a control group with a similar level of sleep deprivation (n = 8). Blood markers of muscle inflammation and damage were analyzed at Pre- and Post-. Mean +/- SD maximal voluntary contraction force declined significantly at Mid- (-13+/-17% and -10+/-16%, P<0.05 for knee extensor, KE, and plantar flexor muscles, PF, respectively), and further decreased at Post- (-24+/-13% and -26+/-19%, P<0.01) with alteration of the central activation ratio (-24+/-24% and -28+/-34% between Pre- and Post-, P<0.05) in runners whereas these parameters did not change in the control group. Peripheral NMF markers such as 100 Hz doublet (KE: -18+/-18% and PF: -20+/-15%, P<0.01) and peak twitch (KE: -33+/-12%, P<0.001 and PF: -19+/-14%, P<0.01) were also altered in runners but not in controls. Post-MUM blood concentrations of creatine kinase (3719+/-3045 Ul.1), lactate dehydrogenase (1145+/-511 UI.L-1), C-Reactive Protein (13.1+/-7.5 mg.L-1) and myoglobin (449.3+/-338.2 microg.L-1) were higher (P<0.001) than at Pre- in runners but not in controls. Our findings revealed less neuromuscular fatigue, muscle damage and inflammation than in shorter MUMs. In conclusion, paradoxically, such extreme exercise seems to induce a relative muscle preservation process due likely to a protective anticipatory pacing strategy during the first half of MUM and sleep deprivation in the second half.