Detection of glioblastoma response to temozolomide combined with bevacizumab based on μMRI and μPET imaging reveals [18F]-fluoro-l-thymidine as an early and robust predictive marker for treatment efficacy

The individualized care of glioma patients ought to benefit from imaging biomarkers as precocious predictors of therapeutic efficacy. Contrast enhanced MRI and [¹⁸F]-fluorodeoxyglucose (FDG)–PET are routinely used in clinical settings; their ability to forecast the therapeutic response is controversial. The objectives of our preclinical study were to analyze sensitive µMRI and/or µPET imaging biomarkers to predict the efficacy of anti-angiogenic and/or chemotherapeutic regimens. Human U87 and U251 orthotopic glioma models were implanted in nude rats. Temozolomide and/or bevacizumab were administered. µMRI (anatomical, diffusion, and microrheological parameters) and µPET ([¹⁸F]-FDG and [¹⁸F]-fluoro-l-thymidine [FLT]–PET) studies were undertaken soon (t₁) after treatment initiation compared with late anatomical µMRI evaluation of tumor volume (t₂) and overall survival. In both models, FDG and FLT uptakes were attenuated at t₁ in response to temozolomide alone or with bevacizumab. The distribution of FLT, reflecting intratumoral heterogeneity, was also modified. FDG was less predictive for treatment efficacy than was FLT (also highly correlated with outcome, P < .001 for both models). Cerebral blood volume was significantly decreased by temozolomide + bevacizumab and was correlated with survival for rats with U87 implants. While FLT was highly predictive of treatment efficacy, a combination of imaging biomarkers was superior to any one alone (P < .0001 in both tumors with outcome). Our results indicate that FLT is a sensitive predictor of treatment efficacy and that predictability is enhanced by a combination of imaging biomarkers. These findings may translate clinically in that individualized glioma treatments could be decided in given patients after PET/MRI examinations.     

Adaptive Methods: When and How Should They be Used in Clinical Trials?

Adaptive clinical trial designs are defined as designs that use data cumulated during trial to possibly modify certain aspects without compromising the validity and integrity of the said trial. Compared to more traditional trials, in theory, adaptive designs allow the same information to be generated but in a more efficient manner. The advantages and limits of this type of design together with the weight of the constraints, in particular of a logistic nature, that their use implies, differ depending on whether the trial is exploratory or confirmatory with a view to registration. One of the key elements ensuring trial integrity is the involvement of an independent committee to determine adaptations in terms of experimental design during the study. Adaptive methods for clinical trials are appealing and may be accepted by the relevant authorities. However, the constraints that they impose must be determined well in advance.     

A comparison of HIV‐1 drug susceptibility as provided by conventional phenotyping and by a phenotype prediction tool based on viral genotype

Concordance between the conventional HIV‐1 phenotypic drug resistance assay, PhenoSense? (PS), and virco®TYPE HIV‐1 (vT), a drug resistance assay based on prediction of the phenotype, was investigated in a data set from the Stanford HIV Resistance database (hivdb). Depending on the drug, between 287 and 902 genotype–phenotype data pairs were available for comparisons. Test results (fold‐change values) in the two assays were highly correlated, with an overall mean correlation coefficient of 0.90 using single PS measurements. This coefficient rose to 0.94 when the vT results were compared to the mean of repeat PS measurements. These results are comparable with the corresponding correlation coefficients of 0.87 and 0.95, calculated using single measurements, and the mean of repeat measurements, respectively, as obtained in the Antivirogram® assay, the conventional HIV‐1 phenotypic drug resistance test on which vT is based. The proportion of resistance calls resulting in a “major” discordance (fully susceptible or maximal response by one assay but fully resistant or minimal response by the other) ranged from 0% to 8.1% for drugs for which two clinical test cut‐offs were available in both assays (didanosine, abacavir, tenofovir, saquinavir/r, fosamprenavir/r, and lopinavir/r), from 2.4% to 8.1% for the drugs for which two clinical test cut‐offs were available in the vT assay and one clinical test cut‐off in the PS assay (lamivudine, stavudine, indinavir/r, and atazanavir/r) and from 3.1% to 10.3% for drugs for which biological test cut‐offs were used (zidovudine, nevirapine, delavirdine, efavirenz, indinavir, ritonavir, nelfinavir, saquinavir, and fosamprenavir). Our analyses suggest that these assays provide comparable resistance information, which will be of value to physicians who may be presented with either or both types of test report in their practice. J. Med. Virol. 81:1702–1709, 2009. © 2009 Wiley‐Liss, Inc.     

Abus sexuel et inaptitude à l’éducation physique et sportive

Context

In the course of a previous study on risky behaviors during adolescence, the first two authors uncovered a statistical link between a history of sexual abuse and medical exemptions from sports class. This association intrigued them, as it has not been described in the literature, although it is supported by the experience of several doctors employed by the National Education System, who are often confronted with revelations of sexual abuse during routine verifications of medical certificates for exemption from sports class. Cases of sexual abuse are frequently reported in the literature, with varying consequences, such as: feelings of degradation, difficulties inhabiting their bodies which they perceive to be dirty and/or damaged, associated with guilt that may incite the adolescent to injure his or her body or to put him/herself in danger. Frequently we see a drop in self-esteem and in feelings of well-being, a depressive symptomatology with more suicidal ideations and suicide attempts. During adolescence, the sexualization of the body obliges the adolescent to perform an intense narcissistic reshaping. Practicing a sport is one of the possible ways to appropriate this body in mutation. It appears to be a protective factor against anxious or depressive affects, encouraging identity building, high self-esteem, and a drop in suicidal ideations and contributes to better social integration. The emotional investment of hypermotricity may appear to oppose corporal inhibition, while they should both raise the issue of mastery over the sexual body. Exemptions from p.e. class thus take on a particular acuity given the stakes at his age. In France, the granting of an exemption from sports class is guided by legislation dating from 1988 and 1989, which was completed in 1994. For any medical exemption of three months or more (granted by the family doctor), the student (of primary school, junior high or high school) is re-examined by a school doctor who judges the legitimacy of the medical exemption certificate. In fact, a certain number of these situations can provide an opportunity to discover the mental suffering behind a physical complaint. The goal of this study is to confirm the link between a history of sexual abuse and a situation of exemption from sports class (long or partial exemption, single or repeated…) and the fact that this may be evidence of mental distress.

Methods

Population: we interviewed 361 adolescents in 10^th grade from 3 high schools in Tours (2 general high schools and a “professional” high school (high schools with a goal of preparing students for rapid insertion into the work force) in the “Centre” region of France): 43% boys, n = 151 and 57% girls, n = 204; with a median age of 16.58, SD = 0.87 years and range = 4.67 years. Students from the professional high school made up 18% of the total sample.

Material

Questions exploring the relationship between students’ previous experiences of sexual abuse, with or without penetration (having been touched in a sexual way (1) or forced to participate in sexual intercourse(2)), and exemptions from physical education activities at some time during their school years: (a) for an entire year, (b) for more than 3 months, (c) for short but repeated periods which add up to more than 3 months altogether or (d) having been absent from class with no valid reason. These questions were completed with evaluations of mental health (General Health Questionnaire, Goldberg 1972), self-esteem (Rosenberg’s Self-Esteem Scale, Rosenberg 1965) and the level of suicidal ideation (Suicidal Ideation Questionnaire, Reynolds 1987).

Procedure

In April 2004 in class (with guaranteed anonymity and volunteer participation (only 4 students refused to participate in the study).

Results

Analysis of the reliability of the scale. The adaptation of the questionnaires to our population was measured by the Cronbach alpha coefficient and proved to be satisfactory: coefficients of 0.78, 0.83 and 0.96 for mental health (GHQ), self-esteem (RSS) and suicidal ideations (SIQ). Sexual abuse and exemption from sports. The prevalence of sexual abuse measured (1) sexual violence (fondling) is 0.6% of boys (n = 1) and 13,9% of girls (n = 28) and (2) forced sexual intercourse for 1.3% of boys (n = 2) and 5.9% of girls (n = 12). But many students did not answer these questions. Concerning exemptions from sports, we can emphasize the fact that 3/4 (n = 260) of the high school students that we interviewed had at some time during their school attendance presented a certificate of medical exemption (of any length). Otherwise, we note that (a) 8% of boys (n = 12) and 10% of girls (n = 20) had presented a certificate for exemption of more than one year; (b) 18.7% of boys (n = 28) and 21.4% of girls (n = 43) for a period of more than three months; (c) 12.7% of boys (n = 19) et 21% of girls (n = 42) for short periods which add up to more than three months exemption from sports class and (d) finally that 16% of boys and 17% of girls had presented an unjustified absence. The prevalence of sexual abuse among those who had been exempted from p.e. activities is high: (1) 10.8% of girls excused from sports (a) (for the entire year) had experienced sexual abuse without penetration (n = 3); as had 32.1% (n = 9) of those exempted (b) for periods of more than 3 months and 50% (n = 28) for those who had obtained (c) exemptions for all the different periods of time considered together. The only boy concerned had never been exempted from sports; (2) the experience of sexual abuse with penetration concerned, respectively, (a) 16.7% (n = 2), (b) 41.7% (n = 5) and (c) 50% (n = 6) of the girls, while one of the concerned boys had been excused for all the different periods of time. A study into to the influence of a history of sexual abuse on the incidence of exemptions from sports is done by analysis of variance (anova). For adolescents, we do not find a significant effect on accumulated short-term exemptions (> 3 months absence): F (1,198) = 17.81; p < 0.001 for a history of sexual violence (fondling) and F (1,198) = 6.62; p < 0.05 for an antecedent of forced sexual intercourse. For boys, there is an influence of a history of forced sexual intercourse and exemptions for the entire year: F (1,148) = 4.95; p < 0.05. The other tendencies observed are not significant. We find a link between exemptions adding up to more than three months and a history of sexual abuse: coefficient of correlation r = 0.24, p < 0.001 for sexual fondling and 0.16, p < 0.05 for forced sexual intercourse. There is also a significant relationship between exemptions of more than three months and forced sexual intercourse (0.14, p < 0.05). Finally, there are links between absenteeism from sports classes and two situations of abuse, (respectively 0.15, p < 0.05 and 0.21, p < 0.001). For the other relationships, the correlations are not significant. Sexual abuse, mental health, self-esteem and suicidal ideations. As very few of the boys stated that they had been exposed to one of the forms of sexual abuse (n = 2) we only find insignificant tendencies concerning them (by correlation analysis). On the other hand, the girls presenting a history of sexual violence (fondling) have a diminished mental health (score above GHQ-12), lower self esteem and more suicidal ideations. Those who stated that they had been subject to forced sexual intercourse presented the same tendencies but only a rise in suicidal ideations is significant. Finally, the existence of meaningful links (> 0.50, p < 0.001) between a poor self-image, mental health (measured in the sense of psychic morbidity) and the rate of suicidal ideations shows that these 3 dimensions do indeed bear witness to suffering on the part of the subject.

Discussion

The prevalence of sexual abuse in our population falls into the lower limits of those reported in the literature. The number of boys admitting to a history of abuse is too small to be exploited statistically. Their rate of non-response, higher than that of the girls, could lead us to believe that in reality their number is higher, especially as we know that boys express their suffering less directly than girls and have higher recourse to risky and antisocial behavior. This study allows us to confirm the relationship between exemption from sports class and a history of sexual abuse in the two forms we studied. (Fondling and forced sexual intercourse). A request for exemption from sports class may be the mark of an intense corporal malaise and represent indirect symptoms expressed by an adolescent who is the victim of sexual abuse. Reactional depression, defense mechanisms such as cleavage and dissociation may explain the increase in somatic complaints, which justify the request for exemption from sports. This flight from all physical activity or sports may also result more directly in an excessive pursuit of modesty, a denial or rejection of the body, feelings of shame or disgust towards the body. Physical activity and sports mobilize the adolescent in his physical, cognitive, emotional and social entirety. When a traumatism occurs, all of these aspects may be unsettled. The particularity of this work is its questioning of the relationship to sports and physical activity with a motricity of avoidance (socially adapted), which encourages putting separation of corporal trials and affects perceived as dangerous. These results complete the data described in the literature concerning the expression of suffering on the part of adolescents with a history of sexual abuse (suicide attempts, scarification, repeated accidents…) risky sexual behavior or the practice of intensive sports which tends to ensure mastery of the body. Any request for long-term exemption from sports class (for the entire year or more than three months) should attract. The attention of all professionals who may be concerned (school doctors, general practitioners, pediatricians, other specialists…, also indirectly sports teachers). Repeated short-term exemptions from sports (especially when they add up to significant periods of time) should be watched with increased attention, as they are not verified by school doctors. This also applies to absenteeism from sports class.

Conclusion

This study shows the existence of a link between exemption from sports class and a history of sexual abuse. The expression of mental suffering through the request for a medical exemption from sports class is more difficult to discern than “noisy” risky behaviors. Requests for medical exemption from sports class present a good opportunity to evaluate the mental health of adolescents, as well as the quality of social support system and family function. This research is a first look at these facts and should be completed by further research.     

Clinical cut-offs for HIV-1 phenotypic resistance estimates: Update based on recent pivotal clinical trial data and a revised approach to viral mixtures

The clinical utility of HIV-1 resistance testing is dependent upon accurate interpretation and application of results. The development of clinical cut-offs (CCOs) for most HIV antiretroviral drugs assessed by the vircoTYPE^® HIV-1 resistance test has been described previously. Updated CCOs based on new methodology and new data from clinical cohorts and pivotal clinical studies are presented in this communication. Data for analysis included the original records for CCO derivation from eight clinical trials and two cohort studies plus new records from the clinical cohorts and from the TITAN, POWER, and DUET clinical studies. Drug-specific linear regression models were developed to describe the relationship between baseline characteristics (phenotypic resistance as estimated by virtualPhenotype™-LM using methods revised recently for handling mixed viral sequences; viral load; and treatment history), new treatment regimen, and 8-week virologic outcome. The clinical cut-offs were defined as the estimated phenotypic resistance levels (fold change, FC) associated with a 20% and 80% loss of drug activity. The development dataset included 6550 records with an additional 2299 reserved for validation. The updated, v.4.2 CCOs were generally close to the v4.1 values, with a trend observed toward marginally higher cut-offs for the NRTIs. These results suggest that the updated CCOs provide a relevant tool for estimating the contribution to virological response of individual antiviral drugs in antiretroviral drug combinations as used currently in clinical practice.     

The murine homolog of human Nectin1delta serves as a species nonspecific mediator for entry of human and animal alpha herpesviruses in a pathway independent of a detectable binding to gD

The full-length cDNA of the murine homolog of human nectin1delta (mNectin1delta), also known as human poliovirus receptor related 1 (PRR1) or herpesvirus entry mediator C, was cloned and showed a >90% identity with its human counterpart. mNectin1delta is expressed in some murine cell lines, exemplified by NIH 3T3 and L cells, and in murine tissues. It mediates entry of an extended range of herpes simplex virus (HSV) strains, porcine pseudorabies virus (PrV), and bovine herpesvirus 1. A soluble form of the mediator blocked infectivity in mNectin1delta and human nectin1delta (hNectin1delta)-expressing cells, suggesting a physical interaction of the mediator with virions. The higher concentrations of soluble mNectin1 required to block infectivity relative to soluble hNectin1 suggest that the target of the two molecules is not identical. Entry of HSV, but not PrV, was blocked by soluble mNectin1delta in NIH 3T3 and L cells. Two features were unexpected. First, soluble mNectin1delta failed to physically interact with HSV glycoprotein D (gD) at a detectable level, although it interacted physically with virions. Second, coexpression of mNectin1delta and HSV gD did not restrict HSV or PrV infection, whereas coexpression of hNectin and gD did restrict infection, suggesting that mNectin1delta fails to be sequestered by HSV gD. We conclude that mNectin1delta serves as a species-nonspecific mediator for entry of the human and animal alphaherpesviruses. This activity, at least for HSV, is independent of a detectable binding to gD.     

Cell-mediated immune proliferative responses to HIV-1 of chimpanzees vaccinated with different vaccinia recombinant viruses

The only animal that can be reproducibly infected with HIV, and that thus provides an experimental system for testing the effectiveness of prototype vaccines, is the chimpanzee. We compared proliferative responses to HIV and to vaccinia virus (VV) antigens of lymphocytes taken at various times from chimpanzees vaccinated with recombinant VV expressing different HIV genes. Animals were immunized with the original VV strain, as control, or with constructs expressing gp160 (VV160) given exclusively or in combination with one or two other constructs producing p25 (VV25), F/3'-orf (VVF), or the human interleukin-2 (IL-2) gene, which was included in an attempt to amplify immune responses. Irrespective of the HIV gene utilized, lymphocyte proliferation to HIV was usually weak and rapidly decreased after each inoculation, contrasting with strong and sustained responses to VV. Lack of adequate recall reactivity after challenge with fixed autologous lymphocytes expressing VV-produced HIV antigens indicated that vaccination resulted only in low levels of HIV-specific memory cell priming. The use of IL-2-producing VV did not lead to increased responsiveness. Reactivity to soluble purified gp160, but not to p25, could be detected in PBL from animals that had received both VV160 and VV25, while immunization with VVF resulted in a significant response to this protein in one of two animals. The transient nature of T cell reactivity to HIV might explain why, in similar studies, chimpanzees were not protected from infection with live HIV.     

Sacral bedsore: an evaluation of 10 years' treatment with the gluteus maximus muscle]

The authors review the notes of 40 patients who underwent surgery for large sacral pressure sore over the last 10 years. In most cases a gluteus maximus flap with skin graft has been employed to cover sacral sore, as originally described by Ger in 1971. The results of this series are then compared with those published by other authors using different techniques, with particular attention to gluteus maximus musculo-cutaneous island flaps and purely cutaneous flaps. All procedures carry a small mortality rate because of the advanced age and frail conditions of most patients. In our series 2 patients died in the postoperative period; in all the others we eventually achieved a sound healing of the sacral sore. We conclude that the gluteus maximus rotation flap is a safe and effective for the treatment of this condition. Its only major drawback is represented by the prolonged period required for the epithelisation by secondary intention of some fairly frequent areas of failure on the skin graft. The importance of a multidisciplinary team approach in the management of these patients cannot be overemphasised.