ABSTRACT
OBJECTIVES: Investigation of the therapeutic effect of zoledronic acid (ZA) in a preclinical model of jaw osteosarcoma (JO). MATERIALS AND METHODS: The effect of 100 µg/kg ZA administered twice a week was assessed in a xenogenic mouse model of JO. The clinical (tumor growth, development of lung metastasis), radiological (bone microarchitecture by micro-CT analysis), and molecular and immunohistochemical (TRAP, RANK/RANKL, VEGF, and CD146) parameters were investigated. RESULTS: Animals receiving ZA exhibited an increased tumor volume compared with nontreated animals (71.3 ± 14.3 mm3 vs. 51.9 ± 19.9 mm3 at D14, respectively; p = 0.06) as well as increased numbers of lung metastases (mean 4.88 ± 4.45 vs. 0.50 ± 1.07 metastases, respectively; p = 0.02). ZA protected mandibular bone against tumor osteolysis (mean bone volume of 12.81 ± 0.53 mm3 in the ZA group vs. 11.55 ± 1.18 mm3 in the control group; p = 0.01). ZA induced a nonsignificant decrease in mRNA expression of the osteoclastic marker TRAP and an increase in RANK/RANKL bone remodeling markers. CONCLUSION: The use of bisphosphonates in the therapeutic strategy for JO should be further explored, as should the role of bone resorption in the pathophysiology of the disease.
ABSTRACT
Despite decades of effort in understanding pancreatic ductal adenocarcinoma (PDAC), there is still a lack of innovative targeted therapies for this devastating disease. Herein, we report the expression of apelin and its receptor, APJ, in human pancreatic adenocarcinoma and its protumoral function. Apelin and APJ protein expression in tumor tissues from patients with PDAC and their spatiotemporal pattern of expression in engineered mouse models of PDAC were investigated by immunohistochemistry. Apelin signaling function in tumor cells was characterized in pancreatic tumor cell lines by Western blot as well as proliferation, migration assays and in murine orthotopic xenograft experiments. In premalignant lesions, apelin was expressed in epithelial lesions whereas APJ was found in isolated cells tightly attached to premalignant lesions. However, in the invasive stage, apelin and APJ were co-expressed by tumor cells. In human tumor cells, apelin induced a long-lasting activation of PI3K/Akt, upregulated ß-catenin and the oncogenes c-myc and cyclin D1 and promoted proliferation, migration and glucose uptake. Apelin receptor blockades reduced cancer cell proliferation along with a reduction in pancreatic tumor burden. These findings identify the apelin signaling pathway as a new actor for PDAC development and a novel therapeutic target for this incurable disease.
Subject(s)
Adenocarcinoma , Apelin Receptors/metabolism , Apelin/metabolism , Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Adenocarcinoma/pathology , Animals , Carcinoma, Pancreatic Ductal/genetics , Cyclin D1/metabolism , Glucose , Humans , Mice , Oncogenes , Pancreatic Neoplasms/pathology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Signal Transduction , beta Catenin/metabolism , Pancreatic NeoplasmsABSTRACT
Bone tissue can be involved by primitive or metastatic tumors and requires a specific processing both at the department of pathology and during multidisciplinary meetings. The development of fine-needle percutaneous biopsies and of molecular techniques in bone tumor pathology requires a specific management. Moreover, decalcification of samples is crucial but can be deleterious if not controlled or not appropriate. The aim of this review is to provide recommendations for management and decalcification of bone tumor samples.
Subject(s)
Bone Neoplasms , Bone Neoplasms/secondary , Bone Neoplasms/therapy , Bone and Bones , Decalcification Technique/methods , Humans , ImmunohistochemistryABSTRACT
Diagnosis of osteocartilaginous pathologies depends on morphological examination and immunohistochemical and molecular biology analyses. Decalcification is required before tissue processing, but available protocols often lead to altered proteins and nucleic acids, and thus compromise the diagnosis. The objective of this study was to compare the effect of different methods of decalcification on histomolecular analyses required for diagnosis and to recommend an optimal protocol for processing these samples in routine practice. We prospectively submitted 35 tissue samples to different decalcification procedures with hydrochloric acid, formic acid, and EDTA, in short, overnight and long cycles for 1 to >10 cycles. Preservation of protein integrity was examined by immunohistochemistry, and quality of nucleic acids was estimated after extraction (DNA and RNA concentrations, 260/280 ratios, PCR cycle thresholds), analysis of DNA mutations (high-resolution melting) or amplifications (PCR, in situ hybridization), and detection of fusion transcripts (RT-PCR, in situ hybridization). Hydrochloric acid- and long-term formic acid-based decalcification induced false-negative results on immunohistochemistry and molecular analysis. EDTA and short-term formic acid-based decalcification (<5 cycles of 6 h each) did not alter antigenicity and allowed for detection of gene mutations, amplifications or even fusion transcripts. EDTA showed superiority for in situ hybridization techniques. According to these results and our institutional experience, we propose recommendations for decalcification of bone samples, from biopsies to surgical specimens.
Subject(s)
Artifacts , Bone Diseases/diagnosis , Decalcification Technique/methods , Nucleic Acids/agonists , Edetic Acid/pharmacology , Formates/pharmacology , Humans , Hydrochloric Acid/pharmacology , Immunohistochemistry , Nucleic Acids/analysis , Nucleic Acids/drug effectsABSTRACT
Acral soft tissue tumors are common neoplasms, a subset of which pose a diagnostic challenge. We report 10 cases of a previously unrecognized acral benign soft tissue tumor. These tumors arose on the fingers and toes and involved bone in half of cases. Histologically, the tumors were lobulated and displayed an abundant stroma made of variable fibrous, chondroid and myxoid material reminiscent of cartilaginous or myoepithelial differentiation. Tumor cells harbored small round to reniform nuclei with clear chromatin and inconspicuous nucleoli along with scant eosinophilic cytoplasm. The cells were mostly arranged haphazardly in the stroma but also in small clusters. No mitotic activity was detected. No specific feature was identified in recurrent cases. By immunohistochemistry, the cells consistently stained for CD34 (10/10), ERG (9/10), and SOX9 (7/10). Whole RNA sequencing identified a previously undescribed recurrent in frame THBS1-ADGRF5 gene fusion in all cases. The transcript was confirmed by RT-PCR and was not found in the control group of mimickers including soft tissue chondromas. We propose the name of Acral FibroChondroMyxoid Tumors for this new entity.
Subject(s)
Fingers/pathology , Neoplasms, Connective Tissue/genetics , Receptors, G-Protein-Coupled/genetics , Soft Tissue Neoplasms/genetics , Thrombospondin 1/genetics , Toes/pathology , Adult , Female , Humans , Male , Middle Aged , Oncogene Fusion/geneticsABSTRACT
Rhabdomyosarcomas with TFCP2 fusions represent an emerging subtype of tumors, initially discovered by RNA-sequencing. We report herein the clinicopathological, transcriptional, and genomic features of a series of 14 cases. Cases were retrospectively and prospectively recruited and studied by immunohistochemistry (MYF4, MYOD1, S100, AE1/E3, ALK), fluorescence in situ hybridization with TFCP2 break-apart probe (n = 10/14), array-comparative genomic hybridization (Agilent), whole RNA-sequencing (Truseq Exome, Illumina), or anchored multiplex PCR-based targeted next-generation sequencing (Archer® FusionPlex® Sarcoma kit). Patient's age ranged between 11 and 86 years, including 5 pediatric cases. Tumors were located in the bone (n = 12/14) and soft tissue (n = 2/14). Most bone tumors invaded surrounding soft tissue. Craniofacial bones were over-represented (n = 8/12). Median survival was 8 months and five patients are currently alive with a median follow-up of 20 months. Most tumors displayed a mixed spindle cell and epithelioid pattern with frequent vesicular nuclei. All tumors expressed keratins and showed a rhabdomyogenic phenotype (defined as expression of MYF4 and/or MYOD1). ALK was overexpressed in all but three cases without underlying ALK fusion on break-apart FISH (n = 5) nor next-generation sequencing (n = 14). ALK upregulation was frequently associated with an internal deletion at genomic level. TFCP2 was fused in 5' either to EWSR1 (n = 6) or FUS (n = 8). EWSR1 was involved in both soft tissue cases. FISH with TFCP2 break-apart probe was positive in all tested cases (n = 8), including one case with unbalanced signal. On array-CGH, all tested tumors displayed complex genetic profiles with genomic indexes ranging from 13 to 107.55 and recurrent CDKN2A deletions. FET-TFCP2 rhabdomyosarcomas clustered together and distinctly from other rhabdomyosarcomas subgroups. Altogether, our data confirm and expand the spectrum of the new family of FET-TFCP2 rhabdomyosarcomas, which are associated with a predilection for the craniofacial bones, an aggressive course, and recurrent pathological features. Their association with ALK overexpression might represent a therapeutic vulnerability.
Subject(s)
Anaplastic Lymphoma Kinase/genetics , Biomarkers, Tumor/genetics , DNA-Binding Proteins/genetics , Epithelioid Cells/pathology , Gene Fusion , Rhabdomyosarcoma/genetics , Rhabdomyosarcoma/pathology , Transcription Factors/genetics , Adolescent , Adult , Aged, 80 and over , Biomarkers, Tumor/analysis , Child , Female , Genetic Predisposition to Disease , Humans , Immunohistochemistry , Male , Middle Aged , Molecular Diagnostic Techniques , Phenotype , Prognosis , Prospective Studies , Retrospective Studies , Rhabdomyosarcoma/chemistry , Rhabdomyosarcoma/mortality , Up-Regulation , Young AdultABSTRACT
BACKGROUND: The prognosis for pancreatic cancer remains poor despite diagnostic advances and treatments with new chemotherapeutic regimens. The five year survival rate remains below 3%. Consequently, there is an urgent need for new treatments to significantly improve the prognosis. In addition, there is a big gap in terms of the screening, early diagnosis and prevention of pancreatic cancer the incidence of which is increasing dramatically. METHODS: Design: the BACAP cohort is a prospective multicenter pancreatic cancer cohort (pancreatic ductal carcinoma) with clinical and multiple biological samples; Participating centers: 15 French academic and private hospitals; Study Population: any cytologically and/or histologically proven pancreatic carcinoma regardless of the stage (resectable, borderline, locally advanced or metastatic) or treatment (surgery, palliative chemotherapy, best supportive care). At least 1500 patients will be included. Clinical data collected include: disease presentation, epidemiological and social factors, baseline biology, radiology, endoscopic ultrasound, staging, pathology, treatments, follow-up (including biological and radiological), and survival. All these data are collected and stored through an e-observation system at a centralized data center. Biological samples and derived products (i.e. before any treatment): blood, saliva, endoscopic ultrasound-guided fine needle aspiration materials from the primary tumor, fine needle biopsy of metastases and surgically resected tissue. DNA and RNA are extracted from fine needle aspiration materials and are quantified and characterized for quality. Whole blood, plasma and serum are isolated from blood samples. Frozen tissues were specifically allocated to the cohort. All derived products and saliva are stored at - 80 °C. Main end-points: i) to centralize clinical data together with multiple biological samples that are harmonized in terms of sampling, the post sampling process and storage; ii) to identify new molecular markers for the diagnosis, prognosis and possibly the predictive response to pancreatic cancer surgery and or chemotherapy. DISCUSSION: The BACAP cohort is a unique prospective biological clinical database that provides the opportunity to identify correlations between the presence/expression of a broad panel of biomarkers (DNA, RNA, miRNA, proteins, etc.), epidemiological and social data, various clinical situations, various stages and the differentiation of the tumor, treatments and survival. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02818829 . Registration date: June 30, 2016.
Subject(s)
Carcinoma, Pancreatic Ductal , Databases as Topic , Pancreatic Neoplasms , Aged , Biomarkers, Tumor , Carcinoma, Pancreatic Ductal/epidemiology , Carcinoma, Pancreatic Ductal/etiology , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/therapy , Cohort Studies , Female , France , Humans , Male , Middle Aged , Pancreatic Neoplasms/epidemiology , Pancreatic Neoplasms/etiology , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/therapy , PrognosisABSTRACT
The infiltration by numerous osteoclastic giant cells is a frequent finding in bone tumors and pseudo-tumors. Pathologists must integrate clinical and radiological data to achieve a correct diagnosis in bone pathology. Benign giant-cell rich lesions of bone encompass giant cell tumor of bone, aneurysmal bone cyst, chondroblastoma, brown tumor and fibrous cortical defect/non-ossifying fibroma. Amongst malignant neoplasms, variants of conventional osteosarcoma, undifferentiated pleomorphic sarcoma, leiomyosarcoma and bone metastasis must be discussed. Recently, new diagnostic markers, antibodies for immuno-histochemistry and genetic markers, have been developed and are helpful to diagnose such lesions.
Subject(s)
Bone Diseases/pathology , Bone Neoplasms/pathology , Giant Cells/pathology , Biomarkers, Tumor/analysis , Bone Cysts, Aneurysmal/chemistry , Bone Cysts, Aneurysmal/diagnosis , Bone Cysts, Aneurysmal/pathology , Bone Diseases/diagnosis , Bone Diseases/metabolism , Bone Neoplasms/chemistry , Bone Neoplasms/diagnosis , Bone Neoplasms/secondary , Chondroblastoma/chemistry , Chondroblastoma/diagnosis , Chondroblastoma/pathology , Diagnosis, Differential , Fibroma, Ossifying/chemistry , Fibroma, Ossifying/diagnosis , Fibroma, Ossifying/pathology , Genetic Markers , Giant Cell Tumor of Bone/chemistry , Giant Cell Tumor of Bone/diagnosis , Giant Cell Tumor of Bone/pathology , Humans , Immunohistochemistry/methods , Molecular Diagnostic Techniques , Sarcoma/chemistry , Sarcoma/diagnosis , Sarcoma/pathologyABSTRACT
Behjati et al recently described recurrent mutations of H3F3 genes in giant cell tumors of the bone and chondroblastomas. Both these entities belong to the spectrum of giant cell-rich bone lesions, often presenting a diagnostic challenge for the pathologist. Our aim was to investigate the value of searching for H3F3 mutations in the diagnosis of giant cell tumors of the bone and giant cell-rich chondroblastomas. Two hundred eighty-one bone lesion samples, including 170 giant cell tumors of the bone, 26 chondroblastomas and 85 other giant cell-rich and/or epiphyseal tumors, were analyzed. Mutation status was determined using first high resolution melting screening and then mutation profiling pyrosequencing. Mutational status was compared with clinical data and, for giant cell tumors of the bone, with p63 immunostaining status. As histone methylation changes have been reported in association with H3F3 mutations, the methylation status of lysine 37 was investigated. H3F3A and H3F3B were found in 85% of giant cell tumors of the bone and 88% of chondroblastomas. In addition to the major G35W mutation, we found two rare H3F3A mutations: one G35R and one G35V. Among the other tumors studied, we only found H3F3A gene mutations in two cases of 'dedifferentiated chondrosarcoma mimicking giant cell tumor of the bone'. A H3F3B mutation was also observed in one case of dedifferentiated chondroblastoma. P63 expression in giant cell tumors of the bone seems to be associated with H3F3 gene mutations (P=0.004). H3F3 mutations did not correlate with clinical data, outcome or methylation changes in Lysin 37. In conclusion, H3F3 mutations are sensitive and specific markers of giant cell tumors of the bone and chondroblastomas. High resolution melting and pyrosequencing procedures are high-performance tools in this context. Determination of H3F3 mutation will allow reclassification of some entities belonging to the spectrum of giant cell-rich lesions.
Subject(s)
Bone Neoplasms/genetics , Chondroblastoma/genetics , Giant Cell Tumor of Bone/genetics , Histones/genetics , Mutation , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Bone Neoplasms/diagnosis , Bone Neoplasms/pathology , Child , Chondroblastoma/diagnosis , Chondroblastoma/pathology , Chondrosarcoma/diagnosis , Chondrosarcoma/genetics , Chondrosarcoma/pathology , DNA Methylation , DNA Mutational Analysis , Diagnosis, Differential , Female , Giant Cell Tumor of Bone/diagnosis , Giant Cell Tumor of Bone/pathology , Humans , Male , Middle Aged , Young AdultSubject(s)
Bone Diseases , Fibroma, Ossifying , Fibroma, Ossifying/pathology , Gene Rearrangement , Genes, fos , HumansABSTRACT
BACKGROUND: Based on preclinical data for the antitumour effect of zoledronate in osteosarcoma, we assessed whether zoledronate combined with chemotherapy and surgery improved event-free survival in children and adults with osteosarcoma. METHODS: In this randomised, multicentre, open-label, phase 3 trial (OS2006), patients aged between 5 years and 50 years with newly diagnosed high-grade osteosarcoma were randomly assigned to receive standard chemotherapy with or without ten zoledronate intravenous infusions (four preoperative and six postoperative). Adults older than 25 years received 4 mg zoledronate per infusion, patients aged 18-25 years received 0·05 mg/kg for the first two infusions and 4 mg for the remaining eight infusions, and younger patients received 0·05 mg/kg per infusion. Chemotherapy comprised high-dose methotrexate based chemotherapy in patients younger than 18 years, and doxorubicin, ifosfamide, and cisplatin in adults older than 25 years; patients aged 18-25 years were treated with either regime at the discretion of the treating centre. Balanced randomisation between the two groups was done centrally with online randomisation software, based on a minimisation algorithm taking into account centre, age, combined with chemotherapy regimen, and risk group (resectable primary and no metastasis vs other). Patients and investigators were not masked to treatment assignment, but the endpoint adjudication committee members who reviewed suspected early progressions were masked to group allocation. The primary endpoint was event-free survival, estimated from the randomisation to the time of first failure (local or distant relapse, progression, death) or to the last follow-up visit for the patients in first complete remission, analysed on a modified intention-to-treat population, which excluded patients found not to have a malignant tumour after central review. Three interim analyses were planned. This trial is registered with ClinicalTrials.gov, number NCT00470223. FINDINGS: Between April 23, 2007, and March 11, 2014, 318 patients, median age 15·5 years (range 5·8-50·9), were enrolled from 40 French centres; of whom 158 were assigned to the control group (chemotherapy alone) and 160 to the zoledronate group, including 55 (17%) patients with definite metastases. The trial was stopped for futility after the second interim analysis. With a median follow-up of 3·9 years (IQR 2·7-5·1), 125 events occurred (55 in the control group and 70 in the with zoledronate group). Event-free survival at 3 years for all 315 randomly assigned patients was 60·3% (95% CI 64·5-65·9); 3-year event-free survival was 63·4% (55·2-70·9) for the control group and 57·1% (48·8-65·0) for the zoledronate group. The risk of failure was not reduced and was even marginally higher in the zoledronate group than in the control group (hazard ratio [HR] 1·36 [95% CI 0·95-1·96]; p=0·094). No major increase in severe toxic effects of grade 3 or higher associated with zoledronate, barring expected hypocalcaemia (45 [29%] of 153 participants in the zoledronate group vs ten [6%] of 155 participants in the control group; p<0·0001) and hypophosphataemia (61 [40%] of 151 in the zoledronate group vs 26 [17%] of 156 in the control group; p<0·0001). No significant difference in orthopaedic complications was noted between the two groups (27 in the control group and 29 in the zoledronate group). Two treatment-related deaths were reported (one from cardiomyopathy in the control group and one from multiorgan failure in the zoledronate group before the first zoledronate infusion). INTERPRETATION: From the results observed in this study, we do not recommend zoledronate in osteosarcoma patients. Further biological studies are required to understand the discordance between the results of OS2006 trial and preclinical data. FUNDING: French National Cancer Institute (INCa), Novartis, Chugai, Ligue Nationale contre le Cancer, Fédération Enfants et Santé, Société Française des Cancers et Leucémies de l'Enfant.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Neoplasms/drug therapy , Bone Neoplasms/surgery , Osteosarcoma/drug therapy , Osteosarcoma/surgery , Adolescent , Adult , Bone Neoplasms/pathology , Case-Control Studies , Child , Child, Preschool , Cisplatin/administration & dosage , Combined Modality Therapy , Diphosphonates/administration & dosage , Doxorubicin/administration & dosage , Female , Follow-Up Studies , Humans , Ifosfamide/administration & dosage , Imidazoles/administration & dosage , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Staging , Osteosarcoma/secondary , Prognosis , Survival Rate , Young Adult , Zoledronic AcidABSTRACT
To evaluate the diagnostic value of MDM2 status in craniofacial fibro-osseous lesions, we investigated MDM2 expression by immunohistochemistry and analyzed MDM2 amplification by qPCR in 30 cases of ossifying fibroma (including 13 cases of the juvenile variant) and 17 cases of fibrous dysplasia. Two cases of uncommon extragnathic psammomatoid fibrous dysplasia and a mixed control group of 15 cases of low-grade osteosarcoma and 15 cases of well-differentiated/dedifferentiated liposarcoma were included. MDM2 amplification was found in 33% of ossifying fibromas (peak of 69% for the juvenile variant) and in 12% of fibrous dysplasia, in none of which was MDM2 overexpressed. All control cases exhibited MDM2 amplification and overexpression. To investigate possible polysomy of chromosome 12, we studied RASAL1 amplification, a gene telomeric to MDM2 on the long arm of chromosome 12. RASAL1 amplification was reported in all benign fibro-osseous lesions exhibiting MDM2 amplification but not in controls. Simultaneous amplification of these two genes was significantly higher in juvenile ossifying fibromas compared with fibrous dysplasia (P=0.004), non-juvenile ossifying fibromas (P=0.001), and all other benign craniofacial fibro-osseous lesions combined (P=0.0001). Of the nine cases of juvenile ossifying fibroma exhibiting amplification, three were locally invasive and four were recurrent, suggesting aggressive disease. The two cases of extragnathic psammomatoid fibrous dysplasia also showed MDM2 and RASAL1 amplification with no MDM2 overexpression. This large chromosome 12 rearrangement, spanning MDM2 and RASAL1, is the first recurrent molecular abnormality to be reported in juvenile ossifying fibroma. It may represent both a molecular diagnostic marker and a characteristic of more aggressive forms with a higher risk of recurrence. Finally, the presence of this rearrangement in extragnathic psammomatoid fibro-osseous lesions mimicking ossifying fibromas might reflect a common molecular pathway in their pathogenesis and calls into question the classification of such lesions within fibrous dysplasia.
Subject(s)
Bone Neoplasms/genetics , Chromosomes, Human, Pair 12/genetics , Fibroma, Ossifying/genetics , Fibrous Dysplasia of Bone/genetics , GTPase-Activating Proteins/genetics , Proto-Oncogene Proteins c-mdm2/genetics , Adolescent , Adult , Aged , Bone Neoplasms/diagnosis , Child , Child, Preschool , Facial Bones , Female , Fibroma, Ossifying/diagnosis , Fibrous Dysplasia of Bone/diagnosis , Gene Rearrangement , Humans , Immunohistochemistry , Infant , Male , Middle Aged , Polymerase Chain Reaction , Retrospective Studies , Skull , Skull Neoplasms/diagnosis , Skull Neoplasms/genetics , Young AdultABSTRACT
BACKGROUND: Diabetic neuropathy is one of the most common complications of diabetes and causes various problems in daily life. The aim of this study was to assess the effect of regional anaesthesia on post surgery opioid induced hyperalgesia in diabetic and non-diabetic mice. METHODS: Diabetic and non-diabetic mice underwent plantar surgery. Levobupivacaine and sufentanil were used before surgery, for sciatic nerve block (regional anaesthesia) and analgesia, respectively. Diabetic and non-diabetic groups were each randomly assigned to three subgroups: control, no sufentanil and no levobupivacaine; sufentanil and no levobupivacaine; sufentanil and levobupivacaine. Three tests were used to assess pain behaviour: mechanical nociception; thermal nociception and guarding behaviours using a pain scale. RESULTS: Sufentanil, alone or in combination with levobupivacaine, produced antinociceptive effects shortly after administration. Subsequently, sufentanil induced hyperalgesia in diabetic and non-diabetic mice. Opioid-induced hyperalgesia was enhanced in diabetic mice. Levobupivacaine associated to sufentanil completely prevented hyperalgesia in both groups of mice. CONCLUSION: The results suggest that regional anaesthesia can decrease opioid-induced hyperalgesia in diabetic as well as in non-diabetic mice. These observations may be clinically relevant for the management of diabetic patients.
Subject(s)
Analgesics, Opioid/adverse effects , Anesthesia, Conduction , Bupivacaine/analogs & derivatives , Diabetes Mellitus, Experimental/complications , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Postoperative Complications/drug therapy , Animals , Bupivacaine/pharmacology , Bupivacaine/therapeutic use , Diabetes Mellitus, Experimental/pathology , Hyperalgesia/pathology , Inflammation/pathology , Levobupivacaine , Male , Mice, Inbred C57BL , Nerve Block , Sciatic Nerve/drug effects , Sciatic Nerve/pathology , Skin/pathology , Wound Healing/drug effectsSubject(s)
Anaplastic Lymphoma Kinase/antagonists & inhibitors , Bone Neoplasms/therapy , Carbazoles/administration & dosage , Chemoradiotherapy , Lactams, Macrocyclic/administration & dosage , Piperidines/administration & dosage , Rhabdomyosarcoma , Adolescent , Aminopyridines , Anaplastic Lymphoma Kinase/metabolism , Bone Neoplasms/diagnostic imaging , Bone Neoplasms/metabolism , Bone Neoplasms/pathology , DNA-Binding Proteins/metabolism , Female , Humans , Lactams , Oncogene Proteins, Fusion/metabolism , Pyrazoles , RNA-Binding Protein FUS/metabolism , Rhabdomyosarcoma/diagnostic imaging , Rhabdomyosarcoma/metabolism , Rhabdomyosarcoma/pathology , Rhabdomyosarcoma/therapy , Transcription Factors/metabolismABSTRACT
BACKGROUND: The aim of the study was to evaluate the relationship between bone microvascularization of the footprint and tendon integrity after rotator cuff repair of the shoulder. METHODS: Forty-eight patients (mean age, 59 years; ±7.9) with a chronic rotator cuff tear underwent a tendon repair with a single-row technique and were studied prospectively. A core obtained from the footprint during the procedure allowed determination of the bone's microvascularization with an immunohistochemistry technique using anti-CD34 antibodies. Clinical evaluation was performed at a minimum of 12-month follow-up, and rotator cuff integrity was assessed with ultrasound according to Sugaya's classification. RESULTS: At a mean follow-up of 13 months, the Constant score improved from 40 to 75 points; American Shoulder and Elbow Surgeons score, from 59 to 89 points; and subjective shoulder value, from 38% to 83% (P < .001). Ultrasound identified 18 patients with Sugaya type I healing, 27 patients with type II, and 3 patients with type IV. No patients showed Sugaya type III or V repairs. The rate of microvascularization of the footprint was 15.6%, 13.9%, and 4.2% for type I, II, and IV tendon integrity, respectively (I vs. II, P = .22; II vs. IV, P = .02; I vs. IV, P = .0022). Patients with a history of corticosteroid injection had a lower rate of microvascularization than the others (10.3% vs. 16.2%; P = .03). CONCLUSIONS: Even if overall satisfactory clinical outcomes are achieved after a rotator cuff repair, bone microvascularization of the footprint plays a role in rotator cuff healing. A lower rate of microvessels decreases the tendon integrity and healing potential after repair.
Subject(s)
Arthroscopy/methods , Plastic Surgery Procedures/methods , Rotator Cuff/surgery , Shoulder Injuries , Wound Healing , Adult , Aged , Female , Follow-Up Studies , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Prospective Studies , Rotator Cuff/pathology , Rotator Cuff Injuries , Rupture/surgery , Shoulder Joint/surgery , Treatment OutcomeABSTRACT
PURPOSE: The aim of the study was to analyse greater tuberosity's (GT) micro-vascularization in the context of rotator cuff tear and to identify factors that could affect the rate and distribution of micro-vessels. METHODS: Eighty-seven patients with supraspinatus and/or infraspinatus tendon tears were included in a prospective study. Mean age at surgery was 58 years (41-78) and clinical symptoms were lasting from an average of 20 months before surgery. A bone core of 1-cm depth was obtained from the GT during rotator cuff repair at two localizations, medial and lateral within tuberosity. Micro-vascularization was then analysed with an immunohistochemistry technique based on CD34 antigen tracking endothelial cells at two levels of depth for each sample (more and less than 5 mm). Epidemiologic and pathologic data were correlated with the rate of micro-vascularization measured. RESULTS: Median rate of GT's micro-vascularization was 9.8 %, which ranged from 0.13 % to 33.4 %. This rate decreased with preoperative steroid injection (7.4 % vs 11.2) and with localization close to the cartilage of the humeral head (8.7 % vs 11.9 %). However, it remains almost homogenous along the depth's core. Moreover, no significant correlation was found regarding age at surgery, gender, context of previous trauma, smoking habits, duration of symptoms, and specific data regarding the tendon tear. CONCLUSIONS: This study highlighted the variability of GT's micro-vascularization in case of rotator cuff tear. A greater rate was observed at the lateral part of the footprint, whereas medical history of steroid injection has a negative influence on micro-vascularization.
Subject(s)
Rotator Cuff Injuries , Rotator Cuff/surgery , Tendons/blood supply , Adult , Aged , Antigens, CD34/metabolism , Female , Humans , Humeral Head/injuries , Immunohistochemistry , Male , Middle Aged , Neovascularization, Pathologic , Prospective Studies , Rotator Cuff/pathology , RuptureABSTRACT
INTRODUCTION: Laryngeal chondrosarcoma (LCS) is a rare tumor of slow evolution whose treatment is poorly codified. For a long time, a radical treatment by total laryngectomy (TL) was proposed. More recent studies tend to propose a conservative surgical approach of the larynx. The objective of this study was to compare the overall survival (OS) of total laryngectomized patients (TL+) versus non-laryngectomized patients (TL-). The secondary objectives were to analyse the reoperation free survival (RFS), the total laryngectomy free survival (TLFS) and to identify the preoperative factors leading surgeons to propose TL. MATERIALS AND METHODS: A retrospective analysis of prospectively collected incident cases from the REFCOR and NetSarc-ResOs multicenter databases between March 1997 and June 2021 was conducted. A propensity score matching analysis was performed to compare the OS of TL+ and TL-patients. RESULTS: 74 patients were included. After propensity score, the 5-year OS of TL+ and TL-patients was comparable (100 %, p = 1). The 5-year RFS rate was 69.2 % (95 % CI [57.5-83.4]) and the 5-year TLFS was 61.7 % (95 % CI [50.4-75.5]). Cricoid involvement greater than 50 % (HR 3.58; IC 95 % [1.61-7.92] p < 0.001), an ASA score of 3 or 4 (HR 5.07; IC 95 % [1.64-15.67] p = 0.009) and involvement of several cartilages (HR 5.26; IC 95 % [1.17-23.6] p = 0.04) are prognostic factors for TL. Dyspnea caused by the tumour is a prognostic factor for reoperation (HR 2.59; IC 95 % [1.04-6.45] p = 0.03). CONCLUSION: These results demonstrate that conservative treatment should be considered as first-line treatment for laryngeal chondrosarcoma.
Subject(s)
Chondrosarcoma , Laryngeal Neoplasms , Larynx , Humans , Prognosis , Retrospective Studies , Larynx/surgery , Larynx/pathology , Laryngectomy/methods , Chondrosarcoma/surgery , Chondrosarcoma/pathologyABSTRACT
GNAS (guanine nucleotide-binding protein/α-subunit) mutations that induce the activation of G-protein α-subunit participate in the pathogenesis of fibrous dysplasia. The aim of this study was to evaluate the sensitivity and specificity of GNAS mutations in fibrous dysplasia and other fibro-osseous lesions, to assess the value of investigating this mutation in the diagnosis of fibro-osseous lesions. We studied 91 cases of fibrous dysplasia. The quality and/or quantity of genomic DNA were suitable for molecular analysis for 51 cases of fibrous dysplasia. GNAS mutations were investigated by three techniques: high-resolution melting (exon 8), allele-specific PCR (exons 8 and 9) and/or direct DNA sequencing (exons 8 and 9). Fibrous dysplasia samples were classified blind to the GNAS mutation status into six histological subtypes as conventional, fibro-involutive, osteosclerosing, cementifying, osteocartilaginous and with prominent aneurysmal cystic changes. We also studied 14 cases of low-grade osteosarcoma, 21 cases of ossifying fibroma, 3 cases of osteofibrous dysplasia, 1 case of osseous dysplasia of the jawbone and 1 post-traumatic lesion of the ribs. Twenty-three cases of fibrous dysplasia (45%) showed mutations of codon 201 (exon 8, p.R201H or p.R201C). No mutation was found on codon 227 (exon 9). GNAS mutations in conventional fibrous dysplasia were detected in the same proportion (47%) as in the other histological subtypes (47%, P=0.96), regardless of sex (P=0.44), age (P=0.90) and location (P=1). GNAS mutations were not detected in any other fibro-osseous lesions. The GNAS mutation was thus specific to fibrous dysplasia in the context of fibro-osseous lesions. The particular mosaicism of mutant and non-mutant cells within the lesion or the existence of other mutations not already described could explain the lack of GNAS mutation in cases of fibrous dysplasia. Investigating this mutation may constitute a valuable complementary diagnostic tool, despite its low sensitivity, particularly in unconventional morphologically different subtypes of fibrous dysplasia.