Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 40
Filter
1.
JPRAS Open ; 33: 171-183, 2022 Sep.
Article in English | MEDLINE | ID: mdl-36051780

ABSTRACT

Background: Venous anatomy of the digits and the hand is poorly reported in the literature compared to arterial anatomy. While knowledge of the venous anatomy is crucial to ensure safe skin incisions, skin flap design, or blood return restoration for digital replantations, data in anatomical and clinical textbooks are rather limited. The purpose of this anatomical study was to describe the venous anatomy of the digits and the hand. Method: Our series reports descriptive results from 10 non-embalmed hand dissections from 5 different corpses. Hands were previously co-injected by arteries followed by veins with a different colored latex before being dissected under optical magnification (x4). Each anatomical specimen was photographed before being analyzed. Results: Each injection revealed both arterial and venous vascular systems. Latex injections were a useful technique to show the dorsal, volar superficial, and deep venous system. There was a constant and reliable topographic vascular anatomy of the superficial venous system of the digits and hand. However, we could not observe a high density of dorsal superficial venous valves as previously reported. Conclusion: The knowledge of the arrangement of the venous system of the digits and the hand should help the surgeon when performing surgical procedures in the hand. The surgeon should take into consideration this venous anatomy when performing skin incisions, skin flaps, or replantation procedures which would preserve the normal venous physiology as much as possible.

2.
Am J Transplant ; 21(9): 3088-3100, 2021 09.
Article in English | MEDLINE | ID: mdl-33445219

ABSTRACT

The 2007 Banff working classification of skin-containing Tissue Allograft Pathology addressed only acute T cell-mediated rejection in skin. We report the longitudinal long-term histological follow-up of six face transplant recipients, focusing on chronic and mucosal rejection. We identified three patterns suggestive of chronic rejection (lichen planus-like, vitiligo-like and scleroderma-like). Four patients presented lichen planus-like and vitiligo-like chronic rejection at 52 ± 17 months posttransplant with severe concomitant acute T cell-mediated rejection. After lichen planus-like rejection, two patients developed scleroderma-like alterations. Graft vasculopathy with C4d deposits and de novo DSA led to subsequent graft loss in one patient. Chronic active rejection was frequent and similar patterns were noted in mucosae. Concordance between 124 paired skin and mucosal biopsies acute rejection grades was low (κ = 0.2, p = .005) but most grade 0/I mucosal rejections were associated with grade 0/I skin rejections. We defined discordant (grade≥II mucosal rejection and grade 0/I skin rejection) (n = 55 [70%]) and concordant (grade≥II rejection in both biopsies) groups. Mucosal biopsies of the discordant group displayed lower intra-epithelial GranzymeB/FoxP3 ratios suggesting a less aggressive phenotype (p = .08). The grading system for acute rejection in mucosa may require phenotyping. Whether discordant infiltrates reflect a latent allo-immune reaction leading to chronic rejection remains an open question.


Subject(s)
Facial Transplantation , Kidney Transplantation , Biopsy , Follow-Up Studies , Graft Rejection/etiology , Humans , Mucous Membrane
3.
BMC Med Educ ; 19(1): 469, 2019 Dec 21.
Article in English | MEDLINE | ID: mdl-31864379

ABSTRACT

BACKGROUND: The national ranking examination (NRE) marks the end of the second cycle (6th university year) of French medical studies and ranks students allowing them to choose their specialty and city of residency. We studied the potential predictive factors of success at the 2015 NRE by students attending a French School of Medicine. METHODS: From March 2016 to March 2017, a retrospective study of factors associated with the 2015 NRE success was conducted and enrolled 242 students who attended their sixth year at the school of medicine of Reims. Demographic and academic data collected by a home-made survey was studied using univariate and then multivariate analysis by generalized linear regression with a threshold of p <  0.05 deemed significant. RESULTS: The factors independently associated with a better ranking at the NRE were the motivation for the preparation of the NRE (gain of 3327 ± 527 places, p <  0.0001); to have participated in the NRE white test organized by la Revue du Praticien in November 2014 (gain of 869 ± 426 places, p <  0.04), to have participated in the NRE white test organized by la conférence Hippocrate in March 2015 (+ 613 places ±297, p <  0.04). The factors independently associated with poor NRE ranking were repeating the first year (loss of 1410 places ±286, p <  0.0001), repeating a year during university course (loss of 1092 places ±385, p <  0.005), attendance of hospital internships in 6th year (loss of 706 places ±298, p <  0.02). CONCLUSIONS: The student motivation and their white tests completion were significantly associated with success at the NRE. Conversely, repeating a university year during their course and attendance of 6th year hospital internships were associated with a lower ranking.


Subject(s)
Educational Measurement , Educational Status , Schools, Medical , Adult , Female , Forecasting , France , Humans , Male , Retrospective Studies , Students, Medical , Young Adult
5.
Muscle Nerve ; 60(3): 328-335, 2019 09.
Article in English | MEDLINE | ID: mdl-31228273

ABSTRACT

INTRODUCTION: No etiologic therapy is available for Duchenne muscular dystrophy (DMD), but mesenchymal stem cells were shown to be effective in preclinical models of DMD. The objective of this study is to investigate the effect of microfragmented fat extracted on a murine model of DMD. METHODS: Fat tissue was extracted from healthy human participants and injected IM into DMD mice. Histological analysis, cytokines, and force measurement were performed up to 4 weeks after injection. RESULTS: Duchenne muscular dystrophy mice injected with microfragmented fat exhibited an improved muscle phenotype (decreased necrosis and fibrosis), a decrease of inflammatory cytokines, and increased strength. DISCUSSION: Administration of microfragmented fat in key muscles may improve muscular phenotype in patients with DMD. Muscle Nerve, 2019.


Subject(s)
Dystrophin/genetics , Mesenchymal Stem Cells/cytology , Muscle, Skeletal/pathology , Muscular Dystrophy, Duchenne/genetics , Adipose Tissue/pathology , Animals , Disease Models, Animal , Mice, Inbred C57BL , Muscle Strength/physiology
6.
J Invest Dermatol ; 139(9): 2004-2015.e13, 2019 09.
Article in English | MEDLINE | ID: mdl-31059696

ABSTRACT

The management of large congenital melanocytic nevi (lCMN) is based exclusively on iterative surgical procedures in the absence of validated medical therapy. The aim of our study was to develop an intra-lesional medical treatment for lCMN. Seventeen patients harboring NRAS-mutated lCMN were included. Nevocytes obtained from lCMN displayed an overactivation of mitogen-activated protein kinase and phosphoinositide 3-kinase (Akt) pathways. Mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) and Akt inhibitors reduced the nevosphere diameter in sphere-forming assays, as well as cell viability and proliferation in in vitro assays. Standardized lCMN explants were then cultured ex vivo with the same inhibitors, which induced a decrease in MelanA+ and Sox10+ cells in both epidermis and dermis. Finally, intradermal injections of these inhibitors were administered within standardized lCMN xenografts in Rag2-/- mice. They induced a dramatic decrease in nevocytes in treated xenografts, which persisted 30 days after the end of treatment. Using original nevus explant and xenograft preclinical models, we demonstrated that intradermal MEK/Akt inhibition might serve as neoadjuvant therapy for the treatment of NRAS-mutated congenital melanocytic nevi to avoid iterative surgeries.


Subject(s)
Antineoplastic Agents/administration & dosage , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Nevus, Pigmented/drug therapy , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Skin Neoplasms/drug therapy , Animals , Cell Proliferation/drug effects , Child , Child, Preschool , Female , GTP Phosphohydrolases/genetics , Humans , Infant , Injections, Intradermal , Injections, Intralesional , MART-1 Antigen/metabolism , Male , Melanocytes/drug effects , Melanocytes/pathology , Membrane Proteins/genetics , Mice , Mitogen-Activated Protein Kinase Kinases/metabolism , Nevus, Pigmented/congenital , Nevus, Pigmented/genetics , Nevus, Pigmented/pathology , Proto-Oncogene Proteins c-akt/metabolism , SOXE Transcription Factors/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Skin/cytology , Skin/pathology , Skin Neoplasms/congenital , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
7.
J Psychosom Res ; 119: 42-49, 2019 04.
Article in English | MEDLINE | ID: mdl-30947816

ABSTRACT

Since 2005, at least 38 face transplantations have been performed worldwide. Available recommendations on psychological management are based on isolated cases or small case series, either not focused on mental health or with a short follow-up. We propose herein a clinical commentary on psychological and psychiatric outcomes from the follow-up of a prospective single-center cohort of six patients over a period of 3.5 to 9 years. Seven patients received a face transplant between January 2007 and April 2011: two patients with neurofibromatosis, four with self-inflicted ballistic trauma, one with self-immolation. One patient died at 63 days of cerebral sequelae from cardiac arrest in the setting of bacterial infection. The six other patients were routinely evaluated with unstructured psychological interviews up to May 2016 and with the Short Form 36-item health survey and the Mini-International Neuropsychiatric Interview at one year and at the end of the follow-up. Clinically meaningful observations were the following: a history of mental disorders before disfigurement was associated with poor physical and mental outcomes, including poor adherence and one suicide; untreated depression was associated with poor adherence; acceptance of the new face occurred rapidly and without significant distress in all of the patients; fear of transplant rejection was present to some degree in all of the patients and did not substantially differ from other transplantation settings; media exposure may be disturbing but may also have had positive psychological effects on some of the patients. Mental health issues related to chronic rejection and re-transplantation remain to be explored.


Subject(s)
Facial Transplantation/psychology , Adult , Cohort Studies , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prospective Studies
8.
Proc Natl Acad Sci U S A ; 116(13): 6075-6080, 2019 03 26.
Article in English | MEDLINE | ID: mdl-30867289

ABSTRACT

Genetic mutations affecting chromatin modifiers are widespread in cancers. In malignant peripheral nerve sheath tumors (MPNSTs), Polycomb repressive complex 2 (PRC2), which plays a crucial role in gene silencing, is inactivated through recurrent mutations in core subunits embryonic ectoderm development (EED) and suppressor of zeste 12 homolog (SUZ12), but mutations in PRC2's main catalytic subunit enhancer of zeste homolog 2 (EZH2) have never been found. This is in contrast to myeloid and lymphoid malignancies, which harbor frequent loss-of-function mutations in EZH2. Here, we investigated whether the absence of EZH2 mutations in MPNST is due to a PRC2-independent (i.e., noncanonical) function of the enzyme or to redundancy with EZH1. We show that, in the absence of SUZ12, EZH2 remains bound to EED but loses its interaction with all other core and accessory PRC2 subunits. Through genetic and pharmacological analyses, we unambiguously establish that EZH2 is functionally inert in this context, thereby excluding a PRC2-independent function. Instead, we show that EZH1 and EZH2 are functionally redundant in the slowly proliferating MPNST precursors. We provide evidence that the compensatory function of EZH1 is alleviated upon higher proliferation. This work reveals how context-dependent redundancies can shape tumor-type specific mutation patterns in chromatin regulators.


Subject(s)
Enhancer of Zeste Homolog 2 Protein/metabolism , Neoplasms/metabolism , Polycomb Repressive Complex 2/metabolism , Cell Line, Tumor , Cell Proliferation , Chromatin/metabolism , Enhancer of Zeste Homolog 2 Protein/genetics , Gene Expression Regulation, Neoplastic , Humans , Mutation/genetics , Neoplasm Proteins , Neoplasms/genetics , Neurofibroma/genetics , Neurofibroma/metabolism , Polycomb Repressive Complex 2/genetics , Transcription Factors
9.
J Reconstr Microsurg ; 35(1): 8-14, 2019 Jan.
Article in English | MEDLINE | ID: mdl-29859510

ABSTRACT

BACKGROUND: The volume of the profunda femoris artery perforator (PAP) flap limits its indications to small- and medium-sized breast reconstructions after modified radical mastectomy for cancer. We report a modified PAP flap design, including not only a vertical extension that increases its volume but also the skin surface, which suits larger breasts requiring immediate or delayed breast reconstructions and compare the results with our horizontal skin paddle PAP flap experience. PATIENTS AND METHODS: In our center between November 2014 and November 2016, 51 consecutive patients underwent a PAP flap breast reconstruction following breast cancer. A retrospective analysis on the collected data was performed to compare 34 patients with a bra cup smaller than C who underwent 41 horizontal PAP flap procedures, with those (n = 17) of a bra cup greater than or equal to C who underwent 21 fleur-de-lys PAP flap procedures. Demographic, anthropometric, flap and surgical characteristics, postoperative complication rates, and hospital stay were compared between the two groups. RESULTS: The average flap weight was 480 g (range: 340-735 g) for the fleur-de-lys PAP flap group compared with 222 g (range: 187-325 g) for the horizontal PAP flap procedure (p < 0.001). The mean flap dimensions were 25 × 18 cm for the fleur-de-lys PAP flap group compared with 25 × 7 cm in the horizontal PAP flap group. No flap failure was observed in the fleur-de-lys PAP flap group compared with two flap failures secondary to venous thrombosis in the horizontal PAP flap group (NS). Three patients (14%) experienced delayed healing at the donor site compared with four patients (10%) in the horizontal PAP flap group (NS). CONCLUSION: The fleur-de-lys skin paddle design not only allows an increase of the horizontal PAP flap volume, but also increases the skin surface, with an acceptable donor site morbidity. For medium- or large-sized breasts, the fleur-de-lys PAP flap seems to be ideal when a DIEP flap-based reconstruction is contraindicated.


Subject(s)
Breast Neoplasms/surgery , Breast/anatomy & histology , Femoral Artery/transplantation , Mammaplasty/methods , Perforator Flap/blood supply , Thigh/surgery , Adult , Aged , Esthetics , Female , Humans , Mastectomy , Middle Aged , Organ Size , Patient Satisfaction/statistics & numerical data , Retrospective Studies , Treatment Outcome
10.
Surg Radiol Anat ; 41(4): 385-392, 2019 Apr.
Article in English | MEDLINE | ID: mdl-30547208

ABSTRACT

PURPOSE: While anatomical variations of the subscapular vessels are frequently encountered during axillary dissection, little is found in the literature. The aim of this cadaveric study was to define arterial and venous anatomical variations and frequencies of the subscapular vascular pedicle and its terminal/afferent vessels in women. METHODS: We performed 80 dissections of the axillary region on forty female formalin-embalmed cadavers. Each anatomical arrangement was photographed and recorded on a scheme before analysis. RESULTS: We propose a new classification of the subscapular pedicle variations. We observed three types of subscapular arterial variation. The type Ia was the most frequent arrangement (71% of our dissections), the type Ib was observed in 11% and the type II in 18% of cases. We observed four types of subscapular venous variation. The type Ia was observed in 63% of cases, the type Ib in 14%, the type II in 14% and the type III in 10% of cases. CONCLUSIONS: This knowledge of the anatomical variation arrangement and frequencies of the subscapular vascular pedicle will assist the surgeon when dissecting the axillary region for malignant or reconstructive procedures.


Subject(s)
Scapula/blood supply , Aged , Aged, 80 and over , Anatomic Variation , Axilla/blood supply , Breast Neoplasms/surgery , Cadaver , Female , Humans , Middle Aged , Prospective Studies
12.
Plast Reconstr Surg ; 141(1): 33-39, 2018 01.
Article in English | MEDLINE | ID: mdl-28915211

ABSTRACT

The deep inferior epigastric perforator (DIEP) flap is a workhorse of breast reconstruction. Risks of herniation derive from violation of the rectus abdominis muscle anterior rectus sheath and might be reduced by minimally invasive laparoscopic dissection ("MILD") of the deep inferior epigastric vessels. The authors performed a feasibility study on five anatomical subjects and performed a secondary right breast reconstruction on a 67-year-old woman. A 30-degree laparoscope was used with laparoscopy ports inset to preserve the flap. Blunt preperitoneal dissection followed by carbon dioxide insufflation allowed the deep inferior epigastric pedicle to be dissected and clip-sectioned. The anterior rectus sheath was opened around the perforating vessels, and the flap was anastomosed on the internal mammary vessels. The length of incision in the anterior rectus sheath was compared between laparoscopic and conventional approaches. The mean incision length in the anterior rectus sheath was 3 cm versus 12 cm in the classic approach. Average duration of laparoscopic flap harvest was 50 minutes, including a mean of 30 minutes for deep inferior epigastric dissection. Adhesions led to a 1-cm peritoneal laceration in our first anatomical subject. There were no preoperative or postoperative complications in the clinical case. The clinical procedure duration was 8 hours 15 minutes, with the anterior rectus sheath incision reduced from the conventional 12 cm to 5 cm. Flap ischemia lasted 50 minutes. The patient was discharged on postoperative day 5. This anatomical study and first successful laparoscope-assisted DIEP flap harvest prove that reduced trauma to the anterior rectus sheath is feasible and promising.


Subject(s)
Dissection/methods , Epigastric Arteries/surgery , Laparoscopy/methods , Mammaplasty/methods , Perforator Flap/surgery , Aged , Feasibility Studies , Female , Humans
13.
Case Rep Obstet Gynecol ; 2017: 8963013, 2017.
Article in English | MEDLINE | ID: mdl-29158931

ABSTRACT

Malignant phyllodes tumors (MPT) are rare breast neoplasms. Preoperative diagnosis is often challenging due to the unspecific clinical, radiological, and histological characteristics of the tumor. Dissemination pathways are local with chest wall invasion, regional with lymph nodes metastasis, and distant, hematogenous, mostly to the lungs, bones, and brain. Distant metastasis (DM) can be synchronous or appear months to years after the diagnosis and initial management. The current report describes the case of a 57-year-old woman presenting with a giant/neglected MPT of the breast, with no DM at initial staging, treated by radical modified mastectomy. Motor disorders due to medullar compression by a paravertebral mass appeared at short follow-up, also treated surgically. The patient died from several DM of rapid evolution. To our knowledge, this is the only case described of MPT with metastases to soft tissue causing medullar compression. We present a literature review on unusual metastatic localizations of MPT.

15.
J Plast Reconstr Aesthet Surg ; 70(6): 781-791, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28259642

ABSTRACT

INTRODUCTION: The deep inferior epigastric perforator (DIEP) flap is a reliable and reproducible technique for autologous microsurgical breast reconstruction. Several recipient vessels sites for microvascular anastomosis have been described such as the internal thoracic vessels, the thoracodorsal vessels, and the circumflex scapular vessels. Nonetheless, the choice of the recipient site depends mainly on individual operator's experience and preferences, and currently the best recipient vessel site is under debate. This anatomical observational study aimed to determine whether anatomy could address this dilemma by determining the best vessel diameter to match the donor with these three recipient sites. METHODS: Our series reports 80 dissections of the three anatomical regions of interest. Forty formalin-preserved female cadavers were dissected bilaterally. Internal vessels diameter measurements were recorded with a vascular gauge ranging from 1.0 to 5.0 mm with successive half-millimeter graduations. RESULTS: The median diameter of the deep inferior epigastric (DIEA), internal thoracic (ITA), circumflex scapular (CSA), and thoracodorsal arteries (TDA) were: 2.0, 2.5, 2.5, and 1.5 mm, respectively. The median diameter of the deep inferior epigastric, internal thoracic, circumflex scapular, and thoracodorsal veins were: 3.0, 3.0, 3.0, and 2.5 mm, respectively. At the individual level, the perfect match between DIEA and ITA was significantly more frequent than between DIEA and TDA (p = 0.002), and it was more frequent between DIEA and CSA than between DIEA and TDA (p = 0.009). CONCLUSIONS: This study supports the use of the internal thoracic pedicle as the first recipient vessel choice, which should be considered, at least anatomically, as the best one with the closest diameter matching with the donor pedicle.


Subject(s)
Mammaplasty/methods , Microsurgery/methods , Perforator Flap/blood supply , Thoracic Arteries/anatomy & histology , Thorax/blood supply , Veins/anatomy & histology , Aged , Aged, 80 and over , Cadaver , Epigastric Arteries/anatomy & histology , Female , Humans , Middle Aged
16.
Lancet ; 388(10052): 1398-1407, 2016 Oct 01.
Article in English | MEDLINE | ID: mdl-27567680

ABSTRACT

BACKGROUND: More than 30 face transplantations have been done worldwide since 2005 but no documented long-term follow-up has been reported in the literature. We aimed to answer remaining question about the long-term risks and benefits of face transplant. METHODS: In this single-centre, prospective, open study, we assessed 20 patients presenting with facial defects. Ten patients were selected, and, after three were secondarily excluded, seven were transplanted: two with neurofibromatosis 1, one with a burn, and four with self-inflicted facial gunshot injuries. We report the long-term outcomes of six face allotransplant recipients at an average of 6 years (range 3·4-9 years) after the transplantation. All admissions to hospital except for planned revisions and immunosuppressive follow-up therapy were reported as adverse events (safety endpoint). Predefined immunological, metabolic, surgical, and social integration endpoints were collected prospectively. Patients underwent quantitative health-related quality of life assessments through Short Form 36 health questionnaires. This study was registered with ClinicalTrials.gov, number NCT00527280. FINDINGS: Two of seven patients died: one at 65 days due to transplant destruction with concomitant pseudomonas infection and the second at 3·4 years after transplantation by suicide. The six patients alive at long-term follow-up presented with functional transplants. Safety endpoints were related to infection in the first month, acute rejection from 1 day to 7 years after transplantation, or side-effects of immunosuppressive therapy. Recurrent rejection episodes justified maintenance therapy with high-dose steroids at high levels in all patients at last follow-up, yet none of the patients developed diabetes. Three patients were found to have hypertension with one requiring therapy. All patients had a noticeable reduction in glomerular filtration rate. All recipients and their families accepted their transplant. Improvements in social integration and quality of life were highly variable among the patients and depended on baseline levels and psychiatric comorbidities. INTERPRETATION: These long-term results show the crucial effect of patients' social support and pre-existing psychiatric conditions on the risk-benefit ratio of facial transplantation. Careful preoperative patient selection and long-term postoperative follow-up programmes under strict institutional review board controls should be used for any future grafts of this type. FUNDING: Protocole Hospitalier de Recherche Clinique (PHRC) National.

17.
Plast Reconstr Surg ; 137(4): 700e-711e, 2016 Apr.
Article in English | MEDLINE | ID: mdl-27018698

ABSTRACT

BACKGROUND: Neurofibromas in neurofibromatosis type 1 induce aesthetic and functional morbidity. Perioperative bleeding has been reported as an obstacle to neurofibroma resections. The authors studied the requirement for blood transfusion during surgical treatment of neurofibromatosis type 1. METHODS: Six hundred twenty-two procedures performed on 390 neurofibromatosis type 1 patients at the national referral center from 1995 to 2011 were analyzed in two chronologic sets of patients: set 1 (February of 1995 to September of 2007), in which only one surgeon operated; and set 2 (October of 2007 to January of 2011), in which two additional surgeons were involved. Malignant peripheral nerve sheath tumors, reconstructive procedures, and spontaneous hemorrhages were excluded from the analysis. Age, sex, preoperative hemoglobin concentration, location, length, estimated volume and histologic features of the largest neurofibroma (cumulative values for multiple neurofibromas), and procedure duration were studied as potential predictors of blood transfusion that were measured in terms of units of packed red blood cells. RESULTS: Seventy reconstructive procedures, two cases of spontaneous hemorrhage, and 32 malignant peripheral nerve sheath tumor resections were excluded. Among 516 procedures (318 and 198 in sets 1 and 2, respectively), 17 (2.7 percent) required blood transfusions. The requirement for transfusion was associated with neurofibroma length in both sets, with an optimal cutoff value of 13 cm in both sets. CONCLUSIONS: Contrary to the literature, the requirement for blood transfusion was found to be low (2.7 percent of the cases) during elective resection of neurofibromas in neurofibromatosis type 1. Elective resections of benign neurofibromas less than 13 cm in length were not associated with a requirement for blood transfusion. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.


Subject(s)
Blood Loss, Surgical/statistics & numerical data , Blood Transfusion/statistics & numerical data , Elective Surgical Procedures , Neurofibromatosis 1/surgery , Adolescent , Adult , Aged , Aged, 80 and over , Child , Databases, Factual , Female , Follow-Up Studies , Humans , Logistic Models , Male , Middle Aged , Neurofibromatosis 1/pathology , Plastic Surgery Procedures , Risk Factors , Tumor Burden , Young Adult
18.
Oncotarget ; 7(24): 35753-35767, 2016 Jun 14.
Article in English | MEDLINE | ID: mdl-26840085

ABSTRACT

Approximately 30-50% of individuals with Neurofibromatosis type 1 develop benign peripheral nerve sheath tumors, called plexiform neurofibromas (PNFs). PNFs can undergo malignant transformation to highly metastatic malignant peripheral nerve sheath tumors (MPNSTs) in 5-10% of NF1 patients, with poor prognosis. No effective systemic therapy is currently available for unresectable tumors. In tumors, the NF1 gene deficiency leads to Ras hyperactivation causing the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways and inducing multiple cellular responses including cell proliferation. In this study, three NF1-null MPNST-derived cell lines (90-8, 88-14 and 96-2), STS26T sporadic MPNST cell line and PNF-derived primary Schwann cells were used to test responses to AZD8055, an ATP-competitive "active-site" mTOR inhibitor. In contrast to rapamycin treatment which only partially affected mTORC1 signaling, AZD8055 induced a strong inhibition of mTORC1 and mTORC2 signaling in MPNST-derived cell lines and PNF-derived Schwann cells. AZD8055 induced full blockade of mTORC1 leading to an efficient decrease of global protein synthesis. A higher cytotoxic effect was observed with AZD8055 compared to rapamycin in the NF1-null MPNST-derived cell lines with IC50 ranging from 70 to 140 nM and antiproliferative effect was confirmed in PNF-derived Schwann cells. Cell migration was impaired by AZD8055 treatment and cell cycle analysis showed a G0/G1 arrest. Combined effects of AZD8055 and PD0325901 MEK inhibitor as well as BRD4 (BromoDomain-containing protein 4) inhibitors showed a synergistic antiproliferative effect. These data suggest that NF1-associated peripheral nerve sheath tumors are an ideal target for AZD8055 as a single molecule or in combined therapies.


Subject(s)
Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors , Mechanistic Target of Rapamycin Complex 2/antagonists & inhibitors , Morpholines/pharmacology , Nerve Sheath Neoplasms/drug therapy , Neurofibroma, Plexiform/drug therapy , Protein Kinase Inhibitors/pharmacology , Antineoplastic Agents/therapeutic use , Benzamides/pharmacology , Cell Cycle Proteins , Cell Line, Tumor , Cell Movement/drug effects , Diphenylamine/analogs & derivatives , Diphenylamine/pharmacology , Drug Synergism , G1 Phase Cell Cycle Checkpoints/drug effects , Humans , Inhibitory Concentration 50 , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 1/metabolism , MAP Kinase Kinase 2/antagonists & inhibitors , MAP Kinase Kinase 2/metabolism , Morpholines/therapeutic use , Nerve Sheath Neoplasms/etiology , Nerve Sheath Neoplasms/genetics , Neurofibroma, Plexiform/etiology , Neurofibroma, Plexiform/genetics , Neurofibromatosis 1/complications , Neurofibromatosis 1/genetics , Neurofibromin 1/genetics , Nuclear Proteins/metabolism , Primary Cell Culture , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-akt/metabolism , Schwann Cells , Signal Transduction/drug effects , Sirolimus/pharmacology , Sirolimus/therapeutic use , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Transcription Factors/metabolism , ras Proteins/metabolism
19.
Plast Reconstr Surg ; 137(5): 1361-1371, 2016 May.
Article in English | MEDLINE | ID: mdl-26796375

ABSTRACT

BACKGROUND: Sequelae resulting from breast cancer negatively impact patients' quality of life. Although the deep inferior epigastric perforator (DIEP) flap has become a standard for autologous breast reconstruction, there are limited data regarding long-term quality of life. The authors studied patients' quality of life more than 5 years after DIEP flap breast reconstruction and compare it with two French reference samples. METHODS: A cross-sectional study of quality of life was performed in women who underwent DIEP flap breast reconstruction between 1995 and 2007 using the Medical Outcomes Study 36-Item Health Survey (Short Form-36). The first reference sample included subjects from the French general population (n = 3308), and the second included cancer survivors who underwent mastectomy with (n = 70) or without (n = 135) breast reconstruction. RESULTS: One hundred eleven respondents were analyzed among 186 eligible women. The mean follow-up period after reconstruction was 8.6 years (range, 5 to 15 years). There were no statistically significant differences in the quality of life between women from 45 to 64 years old who underwent DIEP flap breast reconstruction and from the French general population. Five of the eight Short Form-36 dimensions were significantly better in the DIEP flap breast reconstruction group in the 65- to 74-year-old cohort. In addition, quality of life of our study population was significantly higher than that of women who underwent mastectomy with or without any type of breast reconstruction. CONCLUSION: These results indicate that DIEP flap breast reconstruction allows patients with breast cancer to maintain a good postoperative quality of life comparable to that of the general population. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.


Subject(s)
Mammaplasty/methods , Perforator Flap/surgery , Aged , Aged, 80 and over , Breast Neoplasms/surgery , Female , Follow-Up Studies , France , Humans , Mammaplasty/psychology , Mastectomy , Middle Aged , Patient Satisfaction , Postoperative Complications/epidemiology , Postoperative Complications/psychology , Quality of Life , Surveys and Questionnaires , Survivors/psychology
20.
Arch Immunol Ther Exp (Warsz) ; 64(4): 299-310, 2016 Aug.
Article in English | MEDLINE | ID: mdl-26708158

ABSTRACT

Many more patients would benefit from vascularized composite allotransplantation if less toxic and safer immunosuppressive protocols will become available. Tolerance induction protocols with donor cells co-transplantation are one of the promising pathways to reduce maintenance immunosupressive regimens. We investigated the role of donor bone marrow cells (BMC), mesenchymal stromal cells (MSC) and in vivo created chimeric cells (CC) used as supportive therapies in a fully MHC-mismatched rat face transplantation model. Twenty-four fully MHC-mismatched hemiface transplantations were performed between ACI (RT1(a)) donors and Lewis (RT1(l)) recipients under combined seven-day immunosuppressive regimen of anti-αß-T-cell receptor (TCR) monoclonal antibody and cyclosporin A. We studied four experimental groups-group 1: no cellular therapy; group 2: supportive therapy with BMC; group 3: supportive therapy with MSC; group 4: supportive therapy with CC generated in a primary chimera. We evaluated clinical and histological rejection grades, transplanted cells migration, donor-specific chimerism in the peripheral blood and bone marrow compartments, and CD4(+)/CD25(+) T-cell levels. Face allograft rejection was observed at 26.8 ± 0.6 days post-transplant (PT) in the absence of cellular therapy, at 34.5 ± 1.1 days for group 2, 29.3 ± 0.8 days for group 3, and 30.3 ± 1.38 PT for group 4. The longest survival was observed in allografts supported by co-transplantation of BMC. All support in cellular therapies delayed face allograft rejection by chimerism induction and/or immunomodulatory properties of co-transplanted cells. Survival time was comparable between groups, however, further studies, with different cell dosages, delivery routes and delivery times are required.


Subject(s)
Bone Marrow Cells/cytology , Bone Marrow Cells/immunology , Chimerism , Facial Transplantation/methods , Major Histocompatibility Complex , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/immunology , Animals , Biopsy , Bone Marrow/metabolism , Cell Movement , Cell Survival , Face , Flow Cytometry , Graft Rejection , Graft Survival , Immunosuppression Therapy , Immunosuppressive Agents/therapeutic use , Phenotype , Rats , Rats, Inbred ACI , Rats, Inbred Lew , Receptors, Antigen, T-Cell/immunology , Transplantation, Homologous
SELECTION OF CITATIONS
SEARCH DETAIL
...