[(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.

High prevalence of severe vitamin D deficiency in combined antiretroviral therapy-naive and successfully treated Swiss HIV patients.

OBJECTIVES: To evaluate the prevalence of 25-hydroxyvitamin D [25(OH)D] deficiency in HIV-positive patients, a population at risk for osteoporosis. DESIGN: Retrospective assessment of vitamin D levels by season and initiation of combined antiretroviral therapy (cART). METHODS: 25(OH)D was measured in 211 HIV-positive patients: samples were taken before initiation of cART from February to April or from August to October as well as 12 (same season) and 18 months (alternate season) after starting cART. 1,25-Dihydroxyvitamin D [1,25(OH)2D] was measured in a subset of 74 patients. Multivariable analyses included season, sex, age, ethnicity, BMI, intravenous drug use (IDU), renal function, time since HIV diagnosis, previous AIDS, CD4 cell count and cART, in particular nonnucleoside reverse transcriptase inhibitor (NNRTI) and tenofovir (TDF) use. RESULTS: At baseline, median 25(OH)D levels were 37 (interquartile range 20-49) nmol/l in spring and 57 (39-74) nmol/l in the fall; 25(OH)D deficiency less than 30 nmol/l was more prevalent in spring (42%) than in fall (14%), but remained unchanged regardless of cART exposure. In multivariable analysis, 25(OH)D levels were higher in white patients and those with a longer time since HIV diagnosis and lower in springtime measurements and in those with active IDU and NNRTI use. 1-Hydroxylation rates were significantly higher in patients with low 25(OH)D. Hepatitis C seropositivity, previous AIDS and higher CD4 cell counts correlated with lower 1,25(OH)2D levels, whereas BMI and TDF use were associated with higher levels. In TDF-treated patients, higher 1,25(OH)2D correlated with increases in serum alkaline phosphatase. CONCLUSION: Based on the high rate of vitamin D deficiency in HIV-positive patients, systematic screening with consideration of seasonality is warranted. The impact of NNRTIs on 25(OH)D and TDF on 1,25(OH)2D needs further attention.

Tc-99m-MAA SPECT-derived tumor-to-normal liver ratios for partition model dosimetry in selective internal radiation therapy (SIRT)

Aim: When planning SIRT using 90Y microspheres, the partition model is used to refine the activity calculated by the body surface area (BSA) method to potentially improve the safety and efficacy of treatment. For this partition model dosimetry, accurate determination of mean tumor-to-normal liver ratio (TNR) is critical since it directly impacts absorbed dose estimates. This work aimed at developing and assessing a reliable methodology for the calculation of 99mTc-MAA SPECT/CT-derived TNR ratios based on phantom studies. Materials and methods: IQ NEMA (6 hot spheres) and Kyoto liver phantoms with different hot/background activity concentration ratios were imaged on a SPECT/CT (GE Infinia Hawkeye 4). For each reconstruction with the IQ phantom, TNR quantification was assessed in terms of relative recovery coefficients (RC) and image noise was evaluated in terms of coefficient of variation (COV) in the filled background. RCs were compared using OSEM with Hann, Butterworth and Gaussian filters, as well as FBP reconstruction algorithms. Regarding OSEM, RCs were assessed by varying different parameters independently, such as the number of iterations (i) and subsets (s) and the cut-off frequency of the filter (fc). The influence of the attenuation and diffusion corrections was also investigated. Furthermore, both 2D-ROIs and 3D-VOIs contouring were compared. For this purpose, dedicated Matlab© routines were developed in-house for automatic 2D-ROI/3D-VOI determination to reduce intra-user and intra-slice variability. Best reconstruction parameters and RCs obtained with the IQ phantom were used to recover corrected TNR in case of the Kyoto phantom for arbitrary hot-lesion size. In addition, we computed TNR volume histograms to better assess uptake heterogeneityResults: The highest RCs were obtained with OSEM (i=2, s=10) coupled with the Butterworth filter (fc=0.8). Indeed, we observed a global 20% RC improvement over other OSEM settings and a 50% increase as compared to the best FBP reconstruction. In any case, both attenuation and diffusion corrections must be applied, thus improving RC while preserving good image noise (COV<10%). Both 2D-ROI and 3D-VOI analysis lead to similar results. Nevertheless, we recommend using 3D-VOI since tumor uptake regions are intrinsically 3D. RC-corrected TNR values lie within 17% around the true value, substantially improving the evaluation of small volume (<15 mL) regions. Conclusions: This study reports the multi-parameter optimization of 99mTc MAA SPECT/CT images reconstruction in planning 90Y dosimetry for SIRT. In phantoms, accurate quantification of TNR was obtained using OSEM coupled with Butterworth and RC correction.

Monitoring drug therapy.

Drug development has improved over recent decades, with refinements in analytical techniques, population pharmacokinetic-pharmacodynamic (PK-PD) modelling and simulation, and new biomarkers of efficacy and tolerability. Yet this progress has not yielded improvements in individualization of treatment and monitoring, owing to various obstacles: monitoring is complex and demanding, many monitoring procedures have been instituted without critical assessment of the underlying evidence and rationale, controlled clinical trials are sparse, monitoring procedures are poorly validated and both drug manufacturers and regulatory authorities take insufficient account of the importance of monitoring. Drug concentration and effect data should be increasingly collected, analyzed, aggregated and disseminated in forms suitable for prescribers, along with efficient monitoring tools and evidence-based recommendations regarding their best use. PK-PD observations should be collected for both novel and established critical drugs and applied to observational data, in order to establish whether monitoring would be suitable. Methods for aggregating PK-PD data in systematic reviews should be devised. Observational and intervention studies to evaluate monitoring procedures are needed. Miniaturized monitoring tests for delivery at the point of care should be developed and harnessed to closed-loop regulated drug delivery systems. Intelligent devices would enable unprecedented precision in the application of critical treatments, i.e. those with life-saving efficacy, narrow therapeutic margins and high interpatient variability. Pharmaceutical companies, regulatory agencies and academic clinical pharmacologists share the responsibility of leading such developments, in order to ensure that patients obtain the greatest benefit and suffer the least harm from their medicines.

Monitoring tumor antigen specific T-cell responses in cancer patients and phase I clinical trials of peptide-based vaccination.

Numerous phase I and II clinical trials testing the safety and immunogenicity of various peptide vaccine formulations based on CTL-defined tumor antigens in cancer patients have been reported during the last 7 years. While specific T-cell responses can be detected in a variable fraction of immunized patients, an even smaller but significant fraction of these patients have objective tumor responses. Efficient therapeutic vaccination should aim at boosting naturally occurring antitumor T- and B-cell responses and at sustaining a large number of tumor antigen specific and fully functional effector T cells at tumor sites. Recent progress in our ability to quantitatively and qualitatively monitor tumor antigen specific CD8 T-cell responses will greatly help in making rapid progress in this field.

Pédiatrie 4. Comment traiter la fièvre de l'enfant en 2013 avec un peu d'évidence [How to treat pediatric fever in 2013 with little evidence-based?].

Treatment of pediatric fever is based on two main molecules, paracetamol and ibuprofen. Fever should be treated when associated with discomfort. The two molecules have almost similar efficacy and safety. Monotherapy should be preferred to a combined or alternating treatment. Antipyretics do not seem to prevent febrile seizures.

Ocular biocompatibility of novel Cyclosporin A formulations based on methoxy poly(ethylene glycol)-hexylsubstituted poly(lactide) micelle carriers.

Topical ocular drug delivery has always been a challenge for pharmaceutical technology scientists. In the last two decades, many nano-systems have been studied to find ways to overcome the typical problems of topical ocular therapy, such as difficult corneal penetration and poor drug availability. In this study, methoxy poly(ethylene glycol)-hexylsubstituted poly(lactides) (MPEG-hexPLA) micelle formulations, which are promising nanocarriers for poorly water soluble drugs, were investigated for the delivery of Cyclosporin A (CsA) to the eye. As a new possible pharmaceutical excipient, the ocular compatibility of MPEG-hexPLA micelle formulations was evaluated. An in vitro biocompatibility assessment on human corneal epithelial cells was carried out using different tests. Cytotoxicity was studied by using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT), and clonogenic tests and revealed that the CsA formulations and copolymer solutions were not toxic. After incubation with MPEG-hexPLA micelle formulations, the activation of caspase-dependent and -independent apoptosis as well as autophagy was evaluated using immunohistochemistry by analyzing the localization of four antibodies: (1) anti-caspase 3; (2) anti-apoptotic inducing factor (AIF); (3) anti-IL-Dnase II and (4) anti-microtubule-associated protein 1 light chain 3 (LC3). No apoptosis was induced when the cells were treated with the micelle solutions that were either unloaded or loaded with CsA. The ocular tolerance was assessed in vivo on rabbit eyes by Confocal Laser Scanning Ophthalmoscopy (CLSO), and very good tolerability was seen. The observed corneal surface was comparable to a control surface that was treated with a 0.9% NaCl solution. In conclusion, these results demonstrate that MPEG-hexPLA micelles are promising drug carriers for ocular diseases involving the activation of cytokines, such as dry eye syndrome and autoimmune uveitis, or for the prevention of corneal graft rejection.

A colorectal cancer classification system that associates cellular phenotype and responses to therapy.

Colorectal cancer (CRC) is a major cause of cancer mortality. Whereas some patients respond well to therapy, others do not, and thus more precise, individualized treatment strategies are needed. To that end, we analyzed gene expression profiles from 1,290 CRC tumors using consensus-based unsupervised clustering. The resultant clusters were then associated with therapeutic response data to the epidermal growth factor receptor-targeted drug cetuximab in 80 patients. The results of these studies define six clinically relevant CRC subtypes. Each subtype shares similarities to distinct cell types within the normal colon crypt and shows differing degrees of 'stemness' and Wnt signaling. Subtype-specific gene signatures are proposed to identify these subtypes. Three subtypes have markedly better disease-free survival (DFS) after surgical resection, suggesting these patients might be spared from the adverse effects of chemotherapy when they have localized disease. One of these three subtypes, identified by filamin A expression, does not respond to cetuximab but may respond to cMET receptor tyrosine kinase inhibitors in the metastatic setting. Two other subtypes, with poor and intermediate DFS, associate with improved response to the chemotherapy regimen FOLFIRI in adjuvant or metastatic settings. Development of clinically deployable assays for these subtypes and of subtype-specific therapies may contribute to more effective management of this challenging disease.

The novel ss469415590 variant predicts virological response to therapy in patients with chronic hepatitis C virus type 1 infection.

BACKGROUND: A novel dinucleotide variant TT/∆G (ss469415590) has been associated with hepatitis C virus clearance. AIM: To assess the role of the ss469415590 variant, compared with the known IL28B polymorphisms (rs8099917, rs12979860 and rs12980275) for predicting virological response to therapy in chronic hepatitis C, and its association with the CXCL10 chemokine serum levels - a surrogate marker of interferon-stimulated genes activation. METHODS: Multivariate analysis of factors predicting rapid and sustained virological response in 280 consecutive, treatment-naïve, nondiabetic, Caucasian patients with chronic hepatitis C treated with peginterferon alpha and ribavirin. RESULTS: In hepatitis C virus genotype 1, the OR (95% CI) for rapid and sustained virological response for the wild-type ss469415590 TT was 9.88 (1.99-48.99) and 7.25 (1.91-27.51), respectively, similar to those found for rs12979860 CC [9.55 (1.93-47.37) and 6.30 (1.71-23.13)] and for rs12980275 AA [9.62 (1.94-47.77] and 7.83 (2.02-30.34)], but higher than for rs8099917 TT [4.8 (1.73-13.33) and 4.75 (2.05-10.98)]. In hepatitis C virus genotype 1, mean (SD) CXCL10 levels in patients with the TT/TT, TT/∆G and ∆G/∆G variants were, respectively, 355.1 (240.6), 434.4 (247.4) and 569.9 (333.3) (P = 0.04). In patients with genotypes 2 and 3 no significant association was found for TT/∆G with viral response. The predictive value of ss469415590 was stronger in patients with advanced fibrosis. CONCLUSIONS: The novel IL28B variants at marker ss469415590 predict response to IFN alpha in chronic hepatitis C patients, especially in those with advanced fibrosis. Their determination may be superior to that of known IL28B variants for patient management using IFN-based regimens.

Single cell gene expression profiling reveals qualitatively distinct CD8 T cells elicited by different gene-based vaccines

The CD8 T cell response generatedby gene-based vaccines is importantfor protective immunity againstmany infectious diseases but its complexityis incompletely understood.Here, we report that different vaccinesencoding HIV Env elicit qualitativelydistinct CD8 T cells that wereidentified by patterns of gene expressionin individual cells. Three alternativeprime-boost vector combinationsstimulated antigen-specific CD8 Tcell populations of similar magnitudeand function by intracellular cytokinestaining; however, single cell geneexpression profiling enabled the discriminationof distinct CM and EMCD8 cells elicited by the three vaccines.Two previously unrecognizedCD8 T cell subsets have been definedby their coexpression of Eomes,Cxcr3 and Ccr7; or Klrk1, Klrg1 andCcr5 in CM and EM cells respectively.

Three-dimensional radiobiological dosimetry of kidneys for treatment planning in peptide receptor radionuclide therapy.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) delivers high absorbed doses to kidneys and may lead to permanent nephropathy. Reliable dosimetry of kidneys is thus critical for safe and effective PRRT. The aim of this work was to assess the feasibility of planning PRRT based on 3D radiobiological dosimetry (3D-RD) in order to optimize both the amount of activity to administer and the fractionation scheme, while limiting the absorbed dose and the biological effective dose (BED) to the renal cortex. METHODS: Planar and SPECT data were available for a patient examined with (111)In-DTPA-octreotide at 0.5 (planar only), 4, 24, and 48 h post-injection. Absorbed dose and BED distributions were calculated for common therapeutic radionuclides, i.e., (111)In, (90)Y and (177)Lu, using the 3D-RD methodology. Dose-volume histograms were computed and mean absorbed doses to kidneys, renal cortices, and medullae were compared with results obtained using the MIRD schema (S-values) with the multiregion kidney dosimetry model. Two different treatment planning approaches based on (1) the fixed absorbed dose to the cortex and (2) the fixed BED to the cortex were then considered to optimize the activity to administer by varying the number of fractions. RESULTS: Mean absorbed doses calculated with 3D-RD were in good agreement with those obtained with S-value-based SPECT dosimetry for (90)Y and (177)Lu. Nevertheless, for (111)In, differences of 14% and 22% were found for the whole kidneys and the cortex, respectively. Moreover, the authors found that planar-based dosimetry systematically underestimates the absorbed dose in comparison with SPECT-based methods, up to 32%. Regarding the 3D-RD-based treatment planning using a fixed BED constraint to the renal cortex, the optimal number of fractions was found to be 3 or 4, depending on the radionuclide administered and the value of the fixed BED. Cumulative activities obtained using the proposed simulated treatment planning are compatible with real activities administered to patients in PRRT. CONCLUSIONS: The 3D-RD treatment planning approach based on the fixed BED was found to be the method of choice for clinical implementation in PRRT by providing realistic activity to administer and number of cycles. While dividing the activity in several cycles is important to reduce renal toxicity, the clinical outcome of fractionated PRRT should be investigated in the future.

Economics of dialysis dependence following renal replacement therapy for critically ill acute kidney injury patients.

BACKGROUND: The obective of this study was to perform a cost-effectiveness analysis comparing intermittent with continuous renal replacement therapy (IRRT versus CRRT) as initial therapy for acute kidney injury (AKI) in the intensive care unit (ICU). METHODS: Assuming some patients would potentially be eligible for either modality, we modeled life year gained, the quality-adjusted life years (QALYs) and healthcare costs for a cohort of 1000 IRRT patients and a cohort of 1000 CRRT patients. We used a 1-year, 5-year and a lifetime horizon. A Markov model with two health states for AKI survivors was designed: dialysis dependence and dialysis independence. We applied Weibull regression from published estimates to fit survival curves for CRRT and IRRT patients and to fit the proportion of dialysis dependence among CRRT and IRRT survivors. We then applied a risk ratio reported in a large retrospective cohort study to the fitted CRRT estimates in order to determine the proportion of dialysis dependence for IRRT survivors. We conducted sensitivity analyses based on a range of differences for daily implementation cost between CRRT and IRRT (base case: CRRT day $632 more expensive than IRRT day; range from $200 to $1000) and a range of risk ratios for dialysis dependence for CRRT as compared with IRRT (from 0.65 to 0.95; base case: 0.80). RESULTS: Continuous renal replacement therapy was associated with a marginally greater gain in QALY as compared with IRRT (1.093 versus 1.078). Despite higher upfront costs for CRRT in the ICU ($4046 for CRRT versus $1423 for IRRT in average), the 5-year total cost including the cost of dialysis dependence was lower for CRRT ($37 780 for CRRT versus $39 448 for IRRT on average). The base case incremental cost-effectiveness analysis showed that CRRT dominated IRRT. This dominance was confirmed by extensive sensitivity analysis. CONCLUSIONS: Initial CRRT is cost-effective compared with initial IRRT by reducing the rate of long-term dialysis dependence among critically ill AKI survivors.

Empirical antifungal therapy in neutropaenic cancer patients with persistent fever

Invasive fungal infections are frequent and severe complications in leukaemic patients with prolonged neutropaenia. Empirical antifungal therapy has become the standard of care in patients with persistent fever despite treatment with broad-spectrum antibiotics. For decades amphotericin B deoxycholate has been the sole option for empirical antifungal therapy. Recently, several new antifungal agents became available. The choice of the most appropriate drug should be guided by efficacy and safety criteria. The recommendations from the First European Conference on Infections in Leukaemia (ECIL-1) on empirical antifungal therapy in neutropaenic cancer patients with persistent fever have been developed by an expert panel after assessment of clinical practices in Europe and evidence-based review of the literature. Many antifungal regimens can now be recommended for empirical therapy in neutropaenic cancer patients. However, persistent fever lacks specificity for initiation of therapy. Development of empirical and pre-emptive strategies using new clinical parameters, laboratory markers and imaging techniques for early diagnosis of invasive mycoses are needed.

The switch from conventional to atypical antipsychotic treatment should not be based exclusively on the presence of cognitive deficits. A pilot study in individuals with schizophrenia.

Background: Atypical antipsychotics provide better control of the negative and affective symptoms of schizophrenia when compared with conventional neuroleptics; nevertheless, their heightened ability to improve cognitive dysfunction remains a matter of debate. This study aimed to examine the changes in cognition associated with long-term antipsychotic treatment and to evaluate the effect of the type of antipsychotic (conventional versus novel antipsychotic drugs) on cognitive performance over time. Methods: In this naturalistic study, we used a comprehensive neuropsychological battery of tests to assess a sample of schizophrenia patients taking either conventional (n = 13) or novel antipsychotics (n = 26) at baseline and at two years after. Results: Continuous antipsychotic treatment regardless of class was associated with improvement on verbal fluency, executive functions, and visual and verbal memory. Patients taking atypical antipsychotics did not show greater cognitive enhancement over two years than patients taking conventional antipsychotics. Conclusions Although long-term antipsychotic treatment slightly improved cognitive function, the switch from conventional to atypical antipsychotic treatment should not be based exclusively on the presence of these cognitive deficits.