[An original reconstruction technique for double upper white lip defect]. / Une technique originale de réparation d'une double perte de substance de l'hémilèvre supérieure blanche.

INTRODUCTION: Herein we report a case of a surgical repair of double substance loss along the nasolabial groove by means of a double superior advancement flap from the cheek to the upper lip that we have here called the "double jigsaw puzzle" flap. OBSERVATION: A 58-year-old man underwent surgery for 2 basal cell carcinomas located in the right white upper lip. The two lesions were first removed and the two defects were then carried over to the cheek symmetrically along the nasolabial groove. Two triangular "lugs" were excised on both sides to allow horizontal advancement of the cheek to the upper lip to fill the 2 gaps from the upper lip excisions like 2 pieces of a puzzle. The nasolabial groove was then recreated by deep anchoring stitches, with suturing comprising superficial stitches. DISCUSSION: This surgical flap can be created quickly and easily and yields good aesthetic results in the immediate postoperative period and in the longer term, and the scar is totally masked within the nasolabial fold. The only limitation to a good aesthetic outcome is the presence of a small area of hairless skin within what constitutes an area of hair growth in male subjects.

A pilot study of neuropsychological functions, APOE and amyloid imaging in patients with gliomas.

Brain tumor patients treated with radiotherapy (RT) often develop cognitive dysfunction, and recent studies suggest that the APOE ε-4 allele may influence cognitive outcome. The ε-4 allele is known to promote beta (ß) amyloid deposition in the cortex, and preliminary evidence suggests that RT may be associated with this process. However, it is unknown whether ß-amyloid accumulation contributes to treatment neurotoxicity. In this pilot study, we assessed neuropsychological functions and ß-amyloid retention using 18F-florbetaben (FBB) PET in a subset of brain tumor patients who participated in our study of APOE polymorphisms and cognitive functions. Twenty glioma patients treated with conformal RT ± chemotherapy participated in the study: 6 were APOE ε-4 carriers and 14 were non-ε-4 carriers. Patients completed a neuropsychological re-evaluation (mean time interval = 5 years, SD = 0.83) and brain MRI and FBB PET scans. Wilcoxon signed-rank test comparisons between prior and current neuropsychological assessments showed a significant decline in attention (Brief Test of Attention, p = 0.018), and a near significant decline in verbal learning (Hopkins Verbal learning Test-Learning, p = 0.07). Comparisons by APOE status showed significant differences over time in attention/working memory (WAIS-III digits forward, p = 0.028 and digits backward, p = 0.032), with a decline among APOE ε-4 carriers. There were no significant differences in any of the FBB PET analyses between APOE ε-4 carriers and non-ε-4 carriers. The findings suggest that glioma patients may experience worsening in attention and executive functions several years after treatment, and that the APOE ε-4 allele may modulate cognitive decline, but independent of increased ß-amyloid deposition.

Prognostic awareness and communication preferences among caregivers of patients with malignant glioma.

OBJECTIVE: Malignant glioma (MG) is a devastating neuro-oncologic disease with almost invariably poor prognosis, yet many families facing malignant glioma have poor prognostic awareness (PA), or the awareness of the patient's incurable disease and shortened life expectancy. Accurate PA is associated with favorable medical outcomes at end-of-life for patients and psychosocial outcomes for informal caregivers (ICs) through bereavement. To date, however, no study has specifically examined PA among MG ICs and the information they receive that shapes their awareness. METHODS: Thirty-two ICs of patients with malignant glioma completed a semi-structured assessment of their awareness of the incurability and life expectancy of their loved one's illness, and to understand their sources of prognostic information and preferences for communication of prognostic information. RESULTS: Twenty-two (69%) ICs had full PA-awareness of the incurability of malignant glioma and accurate estimates of their loved ones' life expectancy. Twenty-three (72%) felt that prognostic information was extremely or very important to possess, and 16 (50%) desired more prognostic information. The majority of ICs received prognostic information from physicians and the Internet. Qualitative analyses revealed that many ICs had difficulty navigating medical encounters in which they concurrently wanted to elicit prognostic information from physicians and protect patients from such information. CONCLUSIONS: Accurate and timely PA is necessary for ICs to serve as critical members of health care teams. Interventions are needed to foster ICs' skills in navigating prognostic communication with patients and health care providers and thereby improve their ability to advocate for their loved one's wishes.

Brain structure and function in patients with ovarian cancer treated with first-line chemotherapy: a pilot study.

Women with ovarian cancer often undergo chemotherapy involving multiple agents. However, little is known about treatment-related central neurotoxicity in this population. The goal of this cross-sectional study was to assess brain structure and function and neurocognitive abilities in patients with ovarian cancer following first-line chemotherapy. Eighteen patients with ovarian, peritoneal and fallopian tube cancer and eighteen healthy controls matched for gender, age and education participated in the study. The patients were evaluated 1-4 months following completion of first-line taxane/platinum chemotherapy. All participants underwent structural and functional magnetic resonance imaging (MRI), and completed neuropsychological tests of attention, memory and executive functions. Neuroimaging assessments included voxel-based morphometry (VBM) for measuring gray matter (GM) volume, and functional MRI (fMRI) during the N-back working memory task. The results of VBM showed that patients had significantly reduced GM volume compared to healthy controls in the right middle/superior frontal gyrus, and in the left supramarginal gyrus and left inferior parietal lobule. fMRI results indicated significantly decreased activation in patients relative to healthy controls in the left middle frontal gyrus and left inferior parietal lobule during the N-back task (1/2/3-back >0-back). There were no statistically significant differences between the two groups on the neuropsychological tests. This is the first study showing structural and functional alterations involving frontal and parietal regions in patients with ovarian cancer treated with first-line chemotherapy. These findings are congruent with studies involving women with breast cancer, and provide additional supporting evidence for central neurotoxicity associated with taxane/platinum chemotherapy.

NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy.

Mitophagy is critical for cell homeostasis. Externalization of the inner mitochondrial membrane phospholipid, cardiolipin (CL), to the surface of the outer mitochondrial membrane (OMM) was identified as a mitophageal signal recognized by the microtubule-associated protein 1 light chain 3. However, the CL-translocating machinery remains unknown. Here we demonstrate that a hexameric intermembrane space protein, NDPK-D (or NM23-H4), binds CL and facilitates its redistribution to the OMM. We found that mitophagy induced by a protonophoric uncoupler, carbonyl cyanide m-chlorophenylhydrazone (CCCP), caused externalization of CL to the surface of mitochondria in murine lung epithelial MLE-12 cells and human cervical adenocarcinoma HeLa cells. RNAi knockdown of endogenous NDPK-D decreased CCCP-induced CL externalization and mitochondrial degradation. A R90D NDPK-D mutant that does not bind CL was inactive in promoting mitophagy. Similarly, rotenone and 6-hydroxydopamine triggered mitophagy in SH-SY5Y cells was also suppressed by knocking down of NDPK-D. In situ proximity ligation assay (PLA) showed that mitophagy-inducing CL-transfer activity of NDPK-D is closely associated with the dynamin-like GTPase OPA1, implicating fission-fusion dynamics in mitophagy regulation.

[Prognostic value of the metabolically active tumour volume]. / Valeur pronostique du volume tumoral métabolique sur la TEP au ((18)F)-fluorodésoxyglucose préthérapeutique pour le cancer de l'œsophage localisé.

PURPOSE: The purpose of this study was to assess the prognostic value of different parameters on pretreatment fluorodeoxyglucose [((18)F)-FDG] positron emission tomography-computed tomography (PET-CT) in patients with localized oesophageal cancer. PATIENTS AND METHOD: We retrospectively reviewed 83 cases of localised oesophageal cancer treated in our institution. Patients were treated with curative intent and have received chemoradiotherapy alone or followed by surgery. Different prognostic parameters were correlated to survival: cancer-related factors, patient-related factors and parameters derived from PET-CT (maximum standardized uptake value [SUV max], metabolically active tumor volume either measured with an automatic segmentation software ["fuzzy locally adaptive bayesian": MATVFLAB] or with an adaptive threshold method [MATVseuil] and total lesion glycolysis [TLGFLAB and TLGseuil]). RESULTS: The median follow-up was 21.8 months (range: 0.16-104). The median overall survival was 22 months (95% confidence interval [95%CI]: 15.2-28.9). There were 67 deaths: 49 associated with cancer and 18 from intercurrent causes. None of the tested factors was significant on overall survival. In univariate analysis, the following three factors affected the specific survival: MATVFLAB (P=0.025), TLGFLAB (P=0.04) and TLGseuil (P=0.04). In multivariate analysis, only MATVFLAB had a significant impact on specific survival (P=0.049): MATVFLAB<18 cm(3): 31.2 months (95%CI: 21.7-not reached) and MATVFLAB>18 cm(3): 20 months (95%CI: 11.1-228.9). CONCLUSION: The metabolically active tumour volume measured with the automatic segmentation software FLAB on baseline PET-CT was a significant prognostic factor, which should be tested on a larger cohort.

18F-FDG PET/CT for the assessment of gastrointestinal GVHD: results of a pilot study.

This prospective pilot study aimed to evaluate the predictive value of (18)F-FDG PET/CT for early diagnosis of acute gastrointestinal GVHD (GI-GVHD). In all, 42 consecutive patients who received allo-SCT were included. (18)F-FDG PET/CT was systematically performed at a median of 28 (range, 24-38) days after allo-SCT. (18)F-FDG PET/CT data review was positive in 15 cases (36%) (9 true positive (TP) cases and 6 false positive (FP) cases) and negative in 27 cases (64%; 26 true negative (TN) cases and 1 false negative (FN) case) at visual analysis. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of (18)F-FDG PET/CT for the diagnosis of acute GI-GVHD were, respectively, 81%, 90%, 60%, 96% and 83%. There were no significant differences of SUVmax values between grade 1-2 GI-GVHD and severe grade 3-4 GI-GVHD. Overall, these preliminary findings suggested that the inflammatory activity of the gastrointestinal tract associated with acute GI-GVHD could be assessed by (18)F-FDG PET/CT suggesting that noninvasive (18)F-FDG PET/CT could become a valuable examination to be performed shortly before endoscopy to map acute GI-GVHD lesions, guide the biopsy sites and choose the appropriate endoscopic procedure, especially in those asymptomatic patients with a positive (18)F-FDG PET/CT.

Head and neck presentations of B-NHL and B-AL in children/adolescents: experience of the LMB89 study.

PURPOSE: Describe the epidemiology, clinical profiles and outcomes associated with head and neck (H&N) involvement in children/adolescents with B-cell non-Hodgkin lymphoma (B-NHL). METHODS: Analysis of children/adolescents with H&N B-NHL prospectively enrolled in the SFOP LMB-89 trial (July 1989-June 1996). RESULTS: One hundred and twelve of 561 patients (20%) had H&N involvement. The mean age of the patients was 8.4 years. Murphy staging differed between the H&N patients and the others (P < 0.0001): 9% versus 5% of the patients presented with stage I disease, 36% versus 11% presented with stage II disease, 12% versus 59% presented with stage III disease, 17% versus 10% with stage IV disease and 27% versus 16% with B-AL. Twenty-nine H&N patients (26%) had CNS involvement at diagnosis versus 8.5% in the group without H&N involvement (P < 0.0001). Patients were treated according to the LMB89 protocol: 3 H&N patients were allocated to group A, 70 to group B and 39 to group C. Ninety-seven percent of H&N patients achieved CR and event-free and overall survival at 4 years was 95.5% (5 deaths in patients with CNS disease). On multivariate analysis, EFS was significantly better in H&N patients than in non-H&N patients (P = 0.021), but not OS (P = 0.11). CONCLUSION: The H&N site is the second most common location for B-NHL at diagnosis and is more frequently associated with disseminated disease and CNS involvement than other sites. However, outcomes are no worse for these patients than for the rest of the population.

FDG-PET in the evaluation of myeloma in 2012.

Multiple myeloma (MM) is a malignant haematological disease characterised by clonal proliferation of malignant plasma cells in the bone marrow. MM is expressed by diffuse infiltration of the bone marrow, focal bone lesions and extra-medullary lesions. Conventional staging follows the Salmon and Durie classification, which was recently revised (Salmon and Durie plus) to include MRI and FDG-PET examinations. FDG-PET is being evaluated for initial staging and therapeutic monitoring and its place still needs to be validated, particularly in comparison with MRI of the pelvis and spine, the reference examination for diagnosis, which is systematically combined with X-rays of the skeleton. Certain recent data in the literature suggest that FDG-PET provides better staging of the disease at the time of diagnosis than MRI, and that the examination has considerable prognostic value when it normalises after the initial courses of chemotherapy and at the end of treatment. As for the evaluation of lymphomas, the interpretation criteria should be standardised.

Imatinib-ULS-lysozyme: a proximal tubular cell-targeted conjugate of imatinib for the treatment of renal diseases.

The anticancer drug imatinib is an inhibitor of the platelet-derived growth factor receptor (PDGFR) kinases, which are involved in the pathogenesis of fibrotic diseases. In the current study we investigated the delivery of imatinib to the proximal tubular cells of the kidneys and evaluated the potential antifibrotic effects of imatinib in tubulointerstitial fibrosis. Coupling of imatinib to the low molecular weight protein lysozyme via the platinum (II)-based linker ULS yielded a 0.8:1 drug-carrier conjugate that rapidly accumulated in the proximal tubular cells upon intravenous and intraperitoneal administration. The bioavailability of intraperitoneally administered imatinib-ULS-lysozyme was 100%. Renal imatinib levels persisted for up to 3 days after a single injection of imatinib-ULS-lysozyme. Compared with an equal dose imatinib mesylate, imatinib-ULS-lysozyme resulted in a 30- and 15-fold higher renal exposure of imatinib, for intravenous and intraperitoneal administration respectively. Imatinib-ULS-lysozyme could not be detected in the heart, which is the organ at risk for side-effects of prolonged treatment with imatinib. The efficacy of imatinib-ULS-lysozyme in the treatment of tubulointerstitial fibrosis was evaluated in the unilateral ureteral obstruction (UUO) model in mice. Three days UUO resulted in all signs of early fibrosis, i.e. an increased deposition of matrix and production of profibrotic factors. Although a moderately increased activity of PDGFR-ß was observed, the profibrotic phenotype could not be inhibited with imatinib mesylate or with imatinib-ULS-lysozyme. Further evaluation of imatinib mesylate and imatinib-ULS-lysozyme is therefore warranted in an animal model of renal disease in which the activation of PDGFR-ß is more pronounced.

Reduction of fibrogenesis by selective delivery of a Rho kinase inhibitor to hepatic stellate cells in mice.

One of the pathways activated during liver fibrosis is the Rho kinase pathway, which regulates activation, migration, and contraction of hepatic stellate cells (HSC). Inhibition of this kinase by the Rho kinase inhibitor Y27632 [(+)-(R)-trans- 4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride] has been shown to reduce fibrosis in animal models. However, kinase expression is ubiquitous, so any inhibitor may affect many cell types. We hypothesize that cell-specific delivery of a kinase inhibitor will be beneficial. Therefore, we conjugated Y27632 to the carrier mannose-6-phosphate (M6P) human serum albumin (HSA), which is taken up specifically in activated HSC through the M6P/insulin-like growth factor II receptor. This conjugate decreased protein expression of phosphorylated myosin light chain 2 (pMLC2) and vinculin, downstream of Rho kinase, in activated primary HSC and decreased the migration and contraction of HSC. In an ex vivo model, free Y27632 decreased contractility of rat aortas, whereas the Y27-conjugate did not, showing that the Y27-conjugate does not affect nontarget tissue. In chronic CCl(4)-induced liver fibrosis, both free drug and conjugate reduced HSC activation; however, only the Y27-conjugate significantly reduced collagen deposition. Treatment with the Y27-conjugate, but not with free drug, reduced pMLC2 expression in livers 24 h after injection, demonstrating prolonged inhibition of the Rho kinase pathway. The Rho kinase inhibitor Y27632 can be specifically targeted to HSC using M6PHSA, decreasing its effects in nontarget tissues. The targeted drug effectively reduced fibrotic parameters in vivo via the inhibition of the Rho kinase pathway.

Surgical treatment of renovascular hypertension in children.

OBJECTIVES: The aim of this retrospective study was to report the author's experience of the surgical treatment of renovascular hypertension in children and to define the role of surgery in its treatment. MATERIAL AND METHODS: This series includes 85 patients (50 girls, 35 boys), 28 months to 18 years of age (mean: 10.3) operated on from 1970 to 2005. All patients had arterial hypertension and underwent the investigations usually performed in hypertensive patients. Renal artery lesions were bilateral in 26 cases. Due to bilateral procedures and to secondary or late reoperations, the number of surgical procedures was 114 (15 nephrectomies and 99 arterial repairs). RESULTS: Fibrodysplasia of the renal artery was the prevailing pathologic factor (71%). Associated vascular lesions were observed in 61% of the patients. There was no postoperative death in this series. Seven postoperative thromboses occurred (7% of the repairs). The complete cure of arterial hypertension was obtained in 82% of the patients. In young children, growth of the repairs was normal when age increased. CONCLUSION: Surgery still holds a prominent place in the treatment of renovascular hypertension in children. Its prognosis is favourable since atheroma or organ lesions are usually lacking.

Renal targeting of kinase inhibitors.

Activation of proximal tubular cells by fibrotic and inflammatory mediators is an important hallmark of chronic kidney disease. We have developed a novel strategy to intervene in renal fibrosis, by means of locally delivered kinase inhibitors. Such compounds will display enhanced activity within tubular cells and reduced unwanted systemic effects. In our approach kinase inhibitors are linked to the renal carrier lysozyme using a platinum-based linker that binds drugs via a coordinative linkage. Many kinase inhibitors contain aromatic nitrogen atoms able to bind to this linker without the need of prior derivatization. The resulting drug-lysozyme conjugates are rapidly filtered in the glomerulus into the tubular lumen and subsequently reabsorbed via the endocytic pathway for clearance of low-molecular weight proteins. An important property of the formed conjugates is their in vivo stability and the sustained drug release profile within target cells. This review summarizes the state-of-the-art of drug targeting to the kidney. Furthermore, we will highlight recent results obtained with kinase inhibitor-lysozyme conjugates targeted to different kinases, i.e. the transforming growth factor (TGF)-beta-receptor kinase, p38 MAPkinase and Rho-associated kinase. Both in vitro and in vivo results demonstrated their efficient tubular uptake and beneficial therapeutic effects, superior to treatment with free kinase inhibitors. These proof-of-concept studies clearly indicate the feasibility of drug targeting for improving the renal specificity of kinase inhibitors.

[Vascular complications of lumbar disk surgery]. / Les complications vasculaires de la chirurgie discale lombaire.

Vascular complications of lumbar disc surgery are rare (about 0,04% of discectomies) but very severe. Great variations of the anatomical lesions and of their clinical aspects may be observed. These lesions are often unrecognised during the operation and they are sometimes identified several years after the injury. The treatment is mainly surgical but percutaneous endovascular treatment has been recently performed successfully in several patients.

[Panniculectomy as first part of colorectal resection for cancer in a morbidly obese patient]. / La panniculectomie première comme voie d'abord dans la résection colorectale pour cancer chez le grand obèse.

We reported the case of a patient presenting a rectal cancer of the upper part with a BMI at 59 which was previously considered as a contraindication to surgery. To perform the operation we had to make as first step of the procedure a panniculectomy. The technique made possible the rectal resection under good conditions, without blood transfusion. The post-operative course was uneventful except a pulmonary embolism controlled with medical treatment. This procedure is feasible in colorectal surgery.

[The history of intermittent claudication due to arterial disease]. / Histoire de la claudication intermittente d'origine artérielle.

The clinical description of intermittent claudication due to arterial occlusive disease was made by two French precursors: a veterinary surgeon, Jean-François Bouley, and a neurologist, Jean-Martin Charcot. The subsequent works clarified the aetiology, the investigations and the treatment of this trouble but did not add anything to the initial description.