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1.  Pseudoprogression after high-dose busulfan-thiotepa with autologous stem cell transplantation and radiation therapy in children with brain tumors: Impact on survival 
Neuro-Oncology  2012;14(11):1413-1421.
Children with a brain tumor treated with high-dose busulfan-thiotepa with autologous stem cell transplantation (ASCT) and radiation therapy (RT) often experience radiographic changes during follow-up. The purpose of the study was to identify the incidence, time course, risk factors, and clinical outcome of this complication. From May 1988 through May 2007, 110 patients (median age, 3.6 years; range, 1 month to 15.3 years) with a brain tumor had received 1 course of high-dose busulfan-thiotepa with stem cell rescue, followed or preceded by RT as part of their treatment. All MRI follow-up examinations were systematically reviewed. Twenty-three patients (21%) developed neuroradiological abnormalities at a median time of 9.2 months (range, 5.6–17.3 months) after ASCT. All contrast-enhancing lesions appeared in patients who had received RT after ASCT and were localized inside the 50–55Gy isodoses. They disappeared in 14 of 23 patients after a median time of 8 months (range, 3–17 months), leaving microcalcifications in some cases. The presence of MRI abnormalities was an independent prognostic factor for overall survival in the multivariate analysis (hazard ratio, 0.12; 95% confidence interval [CI], 0.04–0.33), with a 5-year overall survival rate of 84% among patients with MRI abnormalities (95% CI, 62–94), compared with 27% (95% CI, 19–37) among those without lesions. MRI-detectable pseudoprogression is a common early finding in children treated with high-dose busulfan-thiotepa followed by radiation therapy and is correlated with a better outcome.
PMCID: PMC3480264  PMID: 23042716
brain tumor; busulfan; child; pseudoprogression; radiation therapy
2.  Prognostic significance of anti-p53 and anti-KRas circulating antibodies in esophageal cancer patients treated with chemoradiotherapy 
BMC Cancer  2012;12:119.
P53 mutations are an adverse prognostic factor in esophageal cancer. P53 and KRas mutations are involved in chemo-radioresistance. Circulating anti-p53 or anti-KRas antibodies are associated with gene mutations. We studied whether anti-p53 or anti-KRas auto-antibodies were prognostic factors for response to chemoradiotherapy (CRT) or survival in esophageal carcinoma.
Serum p53 and KRas antibodies (abs) were measured using an ELISA method in 97 consecutive patients treated at Saint Louis University Hospital between 1999 and 2002 with CRT for esophageal carcinoma (squamous cell carcinoma (SCCE) 57 patients, adenocarcinoma (ACE) 27 patients). Patient and tumor characteristics, response to treatment and the follow-up status of 84 patients were retrospectively collected. The association between antibodies and patient characteristics was studied. Univariate and multivariate survival analyses were conducted.
Twenty-four patients (28%) had anti-p53 abs. Abs were found predominantly in SCCE (p = 0.003). Anti-p53 abs were associated with a shorter overall survival in the univariate analysis (HR 1.8 [1.03-2.9], p = 0.04). In the multivariate analysis, independent prognostic factors for overall and progression-free survival were an objective response to CRT, the CRT strategy (alone or combined with surgery [preoperative]) and anti-p53 abs. None of the long-term survivors had p53 abs. KRas abs were found in 19 patients (23%, no difference according to the histological type). There was no significant association between anti-KRas abs and survival neither in the univariate nor in the multivariate analysis. Neither anti-p53 nor anti-KRas abs were associated with response to CRT.
Anti-p53 abs are an independent prognostic factor for esophageal cancer patients treated with CRT. Individualized therapeutic approaches should be evaluated in this population.
PMCID: PMC3338390  PMID: 22448886
Esophageal cancer; Radiotherapy; Chemotherapy; p53; Ras
3.  Low-Dose-Rate Definitive Brachytherapy for High-Grade Vaginal Intraepithelial Neoplasia 
The Oncologist  2011;16(2):182-188.
The efficacy and safety results of treatment with low-dose-rate vaginal brachytherapy for grade 3 vaginal intraepithelial neoplasia over a 25-year period at Gustave Roussy Institute are presented. This treatment was found to be both safe and effective.
Learning Objectives
After completing this course, the reader will be able to: Utilize data supporting the efficacy of low-dose definitive brachytherapy to inform clinical decisions about treating women with high-grade vaginal intraepithelial neoplasia.Implement methods for delivering low-dose definitive brachytherapy that minimize toxicity.Communicate to patients the type and incidence of toxic events associated with low-dose definitive brachytherapy.
This article is available for continuing medical education credit at
Treatment of high-grade vaginal intraepithelial neoplasia (VAIN) is controversial and could include surgical excision, topical medication, brachytherapy, or other treatments. We report the results of low-dose-rate (LDR) vaginal brachytherapy for grade 3 VAIN (VAIN-3) over a 25-year period at Gustave Roussy Institute.
Patients and Methods.
We retrospectively reviewed the files of all patients treated at Gustave Roussy Institute for VAIN-3 since 1985. The treatment consisted of LDR brachytherapy using a personalized vaginal mold and delivered 60 Gy to 5 mm below the vaginal mucosa. All patients had at least an annual gynecological examination, including a vaginal smear.
Twenty-eight patients were eligible. The median follow-up was 41 months. Seven patients had a follow-up <2 years, and the median follow-up for the remaining 21 patients was 79 months. The median age at brachytherapy was 63 years (range, 38–80 years). Twenty-six patients had a history of VAIN recurring after cervical intraepithelial neoplasia and 24 had a previous hysterectomy. The median brachytherapy duration was 4.5 days. Median doses to the International Commission of Radiation Units and Measurements rectum and bladder points were 68 Gy and 45 Gy, respectively. The median prescription volume (60 Gy) was 74 cm3. Only one “in field” recurrence occurred, corresponding to a 5- and 10-year local control rate of 93% (95% confidence interval, 70%–99%). The treatment was well tolerated, with no grade 3 or 4 late toxicity and only one grade 2 digestive toxicity. No second cancers were reported.
LDR brachytherapy is an effective and safe treatment for vaginal intraepithelial neoplasia.
PMCID: PMC3228085  PMID: 21262875
Vaginal neoplasms; Carcinoma in situ; Cervical intraepithelial neoplasia; Brachytherapy
4.  Delineation in thoracic oncology: a prospective study of the effect of training on contour variability and dosimetric consequences 
As part of French residents' radiotherapy training, delineation workstations were available at a national teaching course. We report a prospective comparative study of a non small cell lung cancer (NSCLC) case delineated by 120 residents before and after a radioanatomy/radiotherapy lecture.
Materials and methods
The case of a patient with right upper lobe non small cell lung cancer (NSCLC) was provided for delineation to 32 groups of residents before and after a radiation therapy lecture about thoracic delineation. GTV, CTV and PTV was asked to each group. In a second step, the GTV, CTV and PTV were compared with those of 9 groups of senior physicians. Finally the consequences for treatment planning between each group before and after the course were explored.
The expert's average GTV, CTV and PTV were 89.1 cm3, 242.3 cm3 and 293.9 cm3 respectively. For residents, those volumes were 103.4 cm3, 242.3 cm3 and 457.9 cm3 before teaching, compared to 99.5 cm3, 224.2 cm3 and 412.5 cm3 after teaching. The overlap (OV) and kappa (KI) indices before and after education were respectively 0.58 and 0.73. Compared to senior physicians, OV and KI indices were lower in the residents group (p = 0.039 and p = 0.043). An increased dose to the lung is noted for the residents' dosimetry compared to the experts' (V20: 23.2% versus 36.5%) due to the larger PTV delineated. No significant difference was observed for other organs at risk.
There were no significant differences for the delineation of the GTV and CTV before and after the course, although the differences tended to decrease after the course. The good initial quality of the contours could explain the lack of difference. V20 for lung was higher in the residents group compared to the experts group (23.2% vs 36.5%). No other treatment planning consequences were observed for other critical organs.
PMCID: PMC3195101  PMID: 21929770
Lung cancer; volume delineation; education; conformal radiotherapy; inter-observer variability
5.  Chronic Rapamycin Treatment Causes Glucose Intolerance and Hyperlipidemia by Upregulating Hepatic Gluconeogenesis and Impairing Lipid Deposition in Adipose Tissue 
Diabetes  2010;59(6):1338-1348.
The mammalian target of rapamycin (mTOR)/p70 S6 kinase 1 (S6K1) pathway is a critical signaling component in the development of obesity-linked insulin resistance and operates a nutrient-sensing negative feedback loop toward the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway. Whereas acute treatment of insulin target cells with the mTOR complex 1 (mTORC1) inhibitor rapamycin prevents nutrient-induced insulin resistance, the chronic effect of rapamycin on insulin sensitivity and glucose metabolism in vivo remains elusive.
To assess the metabolic effects of chronic inhibition of the mTORC1/S6K1 pathway, rats were treated with rapamycin (2 mg/kg/day) or vehicle for 15 days before metabolic phenotyping.
Chronic rapamycin treatment reduced adiposity and fat cell number, which was associated with a coordinated downregulation of genes involved in both lipid uptake and output. Rapamycin treatment also promoted insulin resistance, severe glucose intolerance, and increased gluconeogenesis. The latter was associated with elevated expression of hepatic gluconeogenic master genes, PEPCK and G6Pase, and increased expression of the transcriptional coactivator peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α) as well as enhanced nuclear recruitment of FoxO1, CRTC2, and CREB. These changes were observed despite normal activation of the insulin receptor substrate/PI 3-kinase/Akt axis in liver of rapamycin-treated rats, as expected from the blockade of the mTORC1/S6K1 negative feedback loop.
These findings unravel a novel mechanism by which mTORC1/S6K1 controls gluconeogenesis through modulation of several key transcriptional factors. The robust induction of the gluconeogenic program in liver of rapamycin-treated rats underlies the development of severe glucose intolerance even in the face of preserved hepatic insulin signaling to Akt and despite a modest reduction in adiposity.
PMCID: PMC2874694  PMID: 20299475
6.  Control of Brown Adipose Tissue Glucose and Lipid Metabolism by PPARγ 
Brown adipose tissue (BAT) non-shivering thermogenesis impacts energy homeostasis in rodents and humans. Mitochondrial uncoupling protein 1 in brown fat cells produces heat by dissipating the energy generated by fatty acid and glucose oxidation. In addition to thermogenesis and despite its small relative size, sympathetically activated BAT constitutes an important glucose, fatty acid, and triacylglycerol-clearing organ, and such function could potentially be used to alleviate dyslipidemias, hyperglycemia, and insulin resistance. To date, chronic sympathetic innervation and peroxisome proliferator-activated receptor (PPAR) γ activation are the only recognized inducers of BAT recruitment. Here, we review the major differences between these two BAT inducers in the regulation of lipolysis, fatty acid oxidation, lipid uptake and triacylglycerol synthesis, glucose uptake, and de novo lipogenesis. Whereas BAT recruitment through sympathetic drive translates into functional thermogenic activity, PPARγ-mediated recruitment is associated with a reduction in sympathetic activity leading to increased lipid storage in brown adipocytes. The promising therapeutic role of BAT in the treatment of hypertriglyceridemic and hyperglycemic conditions is also discussed.
PMCID: PMC3356105  PMID: 22654830
rosiglitazone; PPARγ; brown adipose tissue; sympathetic nervous system; glucose metabolism; lipid metabolism; obesity
7.  Current Status of Adjuvant Therapy for Colon Cancer 
Due to its frequency and persistently high mortality, colorectal cancer represents a major public health problem. The use of adjuvant chemotherapy has improved prognosis in stage III disease, but much work remains to be done in optimizing adjuvant treatment, including refinement of ability to predict disease course and response to chemotherapy. The FOLFOX4 regimen is now considered standard treatment for stage III disease. Combinations of irinotecan and 5-fluorouracil (5-FU) have not proven to be more effective than 5-FU/folinic acid (FA). Oral fluoropyrimidines (eg, capecitabine, UFT + FA) now offer an alternative to intravenous 5-FU. Adjuvant chemotherapy for stage II colorectal cancer is more controversial. Use of adjuvant chemotherapy does not appear to be justified in patients with no particular risk factors (T3N0 with no poor prognosis factor). In contrast, the risk:benefit ratio in patients with one or more poor prognostic factors (T4 tumor, occlusion or perforation, poorly differentiated tumor, vascular invasion, or < 10 lymph nodes examined) appears to favor adjuvant treatment with FOLFOX4. Ongoing adjuvant trials are evaluating bevacizumab and cetuximab combined with 5-FU and oxaliplatin, and are examining the utility of such potential predictive markers as tumor microsatellite instability and loss of heterozygosity. Duration of therapy and prevention of oxaliplatin neurotoxicity are other critical areas for future research.
PMCID: PMC2632821  PMID: 19262714

Results 1-7 (7)