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1.
Immunity ; 49(4): 764-779.e9, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30332632

RESUMO

The major types of non-small-cell lung cancer (NSCLC)-squamous cell carcinoma and adenocarcinoma-have distinct immune microenvironments. We developed a genetic model of squamous NSCLC on the basis of overexpression of the transcription factor Sox2, which specifies lung basal cell fate, and loss of the tumor suppressor Lkb1 (SL mice). SL tumors recapitulated gene-expression and immune-infiltrate features of human squamous NSCLC; such features included enrichment of tumor-associated neutrophils (TANs) and decreased expression of NKX2-1, a transcriptional regulator that specifies alveolar cell fate. In Kras-driven adenocarcinomas, mis-expression of Sox2 or loss of Nkx2-1 led to TAN recruitment. TAN recruitment involved SOX2-mediated production of the chemokine CXCL5. Deletion of Nkx2-1 in SL mice (SNL) revealed that NKX2-1 suppresses SOX2-driven squamous tumorigenesis by repressing adeno-to-squamous transdifferentiation. Depletion of TANs in SNL mice reduced squamous tumors, suggesting that TANs foster squamous cell fate. Thus, lineage-defining transcription factors determine the tumor immune microenvironment, which in turn might impact the nature of the tumor.


Assuntos
Diferenciação Celular/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Fatores de Transcrição SOXB1/imunologia , Microambiente Tumoral/imunologia , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Diferenciação Celular/genética , Linhagem Celular Tumoral , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Células Cultivadas , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Fator Nuclear 1 de Tireoide/genética , Fator Nuclear 1 de Tireoide/metabolismo , Microambiente Tumoral/genética
2.
J Behav Med ; 47(3): 405-421, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38418709

RESUMO

Loneliness may exacerbate poor health outcomes particularly among cancer survivors during the COVID-19 pandemic. Little is known about the risk factors of loneliness among cancer survivors. We evaluated the risk factors of loneliness in the context of COVID-19 pandemic-related prevention behaviors and lifestyle/psychosocial factors among cancer survivors. Cancer survivors (n = 1471) seen at Huntsman Cancer Institute completed a survey between August-September 2020 evaluating health behaviors, medical care, and psychosocial factors including loneliness during COVID-19 pandemic. Participants were classified into two groups: 'lonely' (sometimes, usually, or always felt lonely in past month) and 'non-lonely' (never or rarely felt lonely in past month). 33% of cancer survivors reported feeling lonely in the past month. Multivariable logistic regression showed female sex, not living with a spouse/partner, poor health status, COVID-19 pandemic-associated lifestyle factors including increased alcohol consumption and marijuana/CBD oil use, and psychosocial stressors such as disruptions in daily life, less social interaction, and higher perceived stress and financial stress were associated with feeling lonely as compared to being non-lonely (all p < 0.05). A significant proportion of participants reported loneliness, which is a serious health risk among vulnerable populations, particularly cancer survivors. Modifiable risk factors such as unhealthy lifestyle behaviors and psychosocial stress were associated with loneliness. These results highlight the need to screen for unhealthy lifestyle factors and psychosocial stressors to identify cancer survivors at increased risk of loneliness and to develop effective management strategies.


Assuntos
COVID-19 , Sobreviventes de Câncer , Neoplasias , Humanos , Feminino , Solidão/psicologia , Pandemias , Fatores de Risco , Comportamentos Relacionados com a Saúde
3.
Histopathology ; 82(4): 531-540, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36464647

RESUMO

BACKGROUND AND OBJECTIVES: Bone tumours are relatively rare and, as a consequence, treatment in a centre with expertise is required. Current treatment guidelines also recommend review by a specialised pathologist. Here we report on international consensus-based datasets for the pathology reporting of biopsy and resection specimens of bone sarcomas. The datasets were produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of major (inter-)national pathology and cancer organisations. METHODS AND RESULTS: According to the ICCR's process for dataset development, an international expert panel consisting of pathologists, an oncologic orthopaedic surgeon, a medical oncologist, and a radiologist produced a set of core and noncore data items for biopsy and resection specimens based on a critical review and discussion of current evidence. All professionals involved were bone tumour experts affiliated with tertiary referral centres. Commentary was provided for each data item to explain the rationale for selecting it as a core or noncore element, its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the documents were finalised and ratified, and the datasets, including a synoptic reporting guide, were published on the ICCR website. CONCLUSION: These first international datasets for bone sarcomas are intended to promote high-quality, standardised pathology reporting. Their widespread adoption will improve the consistency of reporting, facilitate multidisciplinary communication, and enhance comparability of data, all of which will help to improve management of bone sarcoma patients.


Assuntos
Patologia Clínica , Sarcoma , Humanos , Oncologia , Biópsia
4.
Cancer Causes Control ; 33(7): 939-950, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35554777

RESUMO

PURPOSE: There is limited information on how the COVID-19 pandemic has changed health behaviors among cancer patients. We examined changes in exercise behaviors since the pandemic and identified characteristics associated with these changes among cancer patients. METHODS: Cancer patients (n = 1,210) completed a survey from August to September 2020 to assess COVID-19 pandemic-related changes in health behaviors and psychosocial factors. Patients were categorized into three groups: exercising less, exercising did not change, and exercising more. Patient characteristics were compared by exercise groups. RESULTS: One-third of the patients reported a decreased amount of regular exercise, while 10% reported exercising more during the pandemic. Patients who exercised less were more likely to be unemployed/retired and have poor health status and psychosocial stressors such as disruptions in daily life while less likely to be former smokers (all p < 0.05). In contrast, patients who exercised more were younger, had stage IV diagnosis, and also reported disruptions in daily life (all p < 0.05). Patients who were living in rural areas were also more likely not to experience changes in exercise habits (all p < 0.05), although rural-urban status was not identified as a strong predictor. CONCLUSION: A significant proportion of cancer patients experienced changes in exercise habits, especially exercising less, during the first 6 months of the COVID-19 pandemic. Age, employment status, tumor stage, health status, smoking status, and psychosocial factors were associated with changes in exercise behaviors. Our results highlight the importance of promoting physical activity guidelines for cancer survivorship during the COVID-19 pandemic and may help improve the identification of cancer patients susceptible to exercising less.


Assuntos
COVID-19 , COVID-19/epidemiologia , Exercício Físico/psicologia , Comportamentos Relacionados com a Saúde , Humanos , Pandemias , Fumar/psicologia
5.
J Pathol ; 254(4): 474-493, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33428234

RESUMO

Sarcoma comprises a group of malignancies that includes over 100 individual disease entities. Type-specific genetic events initiate each tumor, occurring within a specific cellular context or circumstance. All sarcomas share a relationship with mesenchymal tissues of origin. Conceptual models for each specific route towards sarcomagenesis have developed over the years as clinical, cellular, and increasingly molecular observations have advanced hypotheses to be tested in the forward or reverse direction in experimental systems, often genetically engineered model organisms. This review considers the history of these discoveries in the context of technologies available at the time each was made and provides a comprehensive summary of the current knowledge of sarcoma genetics, including characteristic translocations, oncogene activation and loss of tumor suppressor gene events, and their putative cells of origin. Also considered are the interrelatedness of molecular clinical observations and genetic experiments in model systems to move this field of knowledge forward, as well as their implications for diagnostic and therapeutic paradigms for sarcoma. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Carcinogênese/genética , Sarcoma/genética , Sarcoma/patologia , Animais , Humanos
6.
Clin Orthop Relat Res ; 480(3): 539-548, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34559734

RESUMO

BACKGROUND: Endoprosthetic reconstruction after oncologic resection of bone tumors requires stable fixation between the prosthesis and residual host bone. Compressive osseointegration has been developed as an alternative to traditional stemmed implants to address the challenges and complications of achieving this fixation. Sufficient time has now passed from the advent of compressive implants to allow for an assessment of the intermediate-term and long-term results of this form of fixation. QUESTIONS/PURPOSES: At a minimum follow-up of 10 years after implantation of a compressive osseointegration device for oncologic reconstruction: (1) What is the risk of periprosthetic fracture, aseptic loosening, or implant breakage resulting in revision surgery for endoprosthesis removal? (2) What is the long-term cortical response at the host-endoprosthesis interface as visualized on plain radiographs? METHODS: A single-center, retrospective study was performed between 2002 and 2010, in which 110 patients with primary bone sarcoma of the proximal or distal femur were considered for oncologic resection and reconstruction. Patients were considered for a compressive osseointegration endoprosthesis if they were 50 years of age or younger, had not previously received femoral radiation, had no metabolic disease impairing bone healing, were not diagnosed with metastatic disease, and had life expectancy greater than six months. Of the 110 patients, 25 were treated with a compressive osseointegration implant of the proximal or distal femur, and 85 patients were treated with conventional stemmed implants or amputation because of older age, advanced disease, metabolic comorbidities, inability to tolerate a nonweightbearing postoperative period, or in the case of rotationplasty, patient preference. All patients who received this device during the period of study were considered eligible for inclusion in this review. The median (range) age was 18 years (7 to 50), and 13 of 25 patients were men. Five patients died of disease before the minimum follow-up duration of 10 years; two underwent amputation due to local recurrence and three died with the implant in situ, leaving 20 patients for complete analysis. Median follow-up was 144 months, and all 20 surviving patients had a minimum follow-up of 10 years (121 to 230 months). The primary endpoint was reoperation and implant removal for periprosthetic fracture, aseptic loosening, or mechanical breakage of any component of the compressive device in the endoprosthesis. In final analysis, death was considered a competing event to revision surgery, and cumulative incidence was reported after competing-event analysis. A secondary aim was radiographic evaluation of the host-implant interface to assess the long-term cortical response to compressive osseointegration. RESULTS: Spindle fracture or loosening was noted in three patients, and the remaining 17 patients maintained the compression device until the final follow-up. The risk of reoperation for aseptic loosening, periprosthetic fracture, or mechanical breakage of the implant using a competing risks estimator was 12% at 10 years (95% CI 0% to 26%). These complications occurred within 29 months of the index surgery; no patients had implant loosening or mechanical breakdown after this initial period. On radiographic assessment, 14 patients demonstrated cortical hypertrophy of the bone-implant interface, six patients had maintenance of the native cortical contour, and no patients had cortical atrophy or narrowing at the implant interface.Conclusion Long-term follow-up in patients with compressive osseointegrative endoprosthetic devices demonstrated no late revisions because of periprosthetic fracture, aseptic loosening, or implant breakage in this cohort with a minimum 10-year follow-up. There was no evidence of late-onset cortical atrophy or stress shielding at the host-implant interface. This study supports the long-term stability of the interface between host bone and the endoprosthesis in compressive osseointegration devices. LEVEL OF EVIDENCE: Level IV, therapeutic study.


Assuntos
Prótese Ancorada no Osso , Neoplasias Femorais/cirurgia , Desenho de Prótese , Falha de Prótese , Adolescente , Adulto , Criança , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fraturas Periprotéticas , Reoperação , Estudos Retrospectivos , Adulto Jovem
7.
Cancer ; 127(16): 2934-2942, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-33910263

RESUMO

BACKGROUND: Among sarcomas, which are rare cancers, many types are exceedingly rare; however, a definition of ultra-rare cancers has not been established. The problem of ultra-rare sarcomas is particularly relevant because they represent unique diseases, and their rarity poses major challenges for diagnosis, understanding disease biology, generating clinical evidence to support new drug development, and achieving formal authorization for novel therapies. METHODS: The Connective Tissue Oncology Society promoted a consensus effort in November 2019 to establish how to define ultra-rare sarcomas through expert consensus and epidemiologic data and to work out a comprehensive list of these diseases. The list of ultra-rare sarcomas was based on the 2020 World Health Organization classification, The incidence rates were estimated using the Information Network on Rare Cancers (RARECARENet) database and NETSARC (the French Sarcoma Network's clinical-pathologic registry). Incidence rates were further validated in collaboration with the Asian cancer registries of Japan, Korea, and Taiwan. RESULTS: It was agreed that the best criterion for a definition of ultra-rare sarcomas would be incidence. Ultra-rare sarcomas were defined as those with an incidence of approximately ≤1 per 1,000,000, to include those entities whose rarity renders them extremely difficult to conduct well powered, prospective clinical studies. On the basis of this threshold, a list of ultra-rare sarcomas was defined, which comprised 56 soft tissue sarcoma types and 21 bone sarcoma types. CONCLUSIONS: Altogether, the incidence of ultra-rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas. This confirms that the challenges inherent in ultra-rare sarcomas affect large numbers of patients.


Assuntos
Sarcoma , Neoplasias de Tecidos Moles , Tecido Conjuntivo/patologia , Consenso , Humanos , Incidência , Estudos Prospectivos , Sarcoma/diagnóstico , Sarcoma/epidemiologia , Sarcoma/terapia , Neoplasias de Tecidos Moles/epidemiologia
8.
J Shoulder Elbow Surg ; 30(9): 2134-2145, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33482370

RESUMO

BACKGROUND: The purpose of the study was to identify genetic variants associated with rotator cuff disease by performing a genome-wide association study (GWAS) for shoulder impingement using the UK Biobank (UKB) cohort and then combining the GWAS data with a prior GWAS for rotator cuff tears. The loci identified by the GWAS and meta-analysis were examined for changes in expression following rotator cuff tearing using RNA sequencing. METHODS: A GWAS was performed using data from UKB with 3864 cases of shoulder impingement. The summary statistics from shoulder impingement and a prior study on rotator cuff tears were combined in a meta-analysis. Also, the previous association of 2 single-nucleotide polymorphisms (SNPs) with shoulder impingement from a published GWAS using the UKB was tested. Rotator cuff tendon biopsies were obtained from 24 patients with full-thickness rotator cuff tears who underwent arthroscopic rotator cuff repair (cases) and 9 patients who underwent open reduction internal fixation for a proximal humeral fracture (controls). Total RNA was extracted and differential gene expression was measured by RNA sequencing for genes with variants associated with rotator cuff tearing. RESULTS: The shoulder impingement GWAS identified 4 new loci: LOC100506457, LSP1P3, LOC100506207, and MIS18BP1/LINC00871. Combining data with a prior GWAS for rotator cuff tears in a meta-analysis resulted in the identification of an additional 7 loci: SLC39A8/UBE2D3, C5orf63, ASTN2, STK24, FRMPD4, ACOT9/SAT1, and LINC00890/ALG13. Many of the identified loci have known biologic functions or prior associations with diseases, suggesting possible biologic pathways leading to rotator cuff disease. RNA sequencing experiments show that expression of STK24 increases whereas expression of SAT1 and UBE2D3 decreases following rotator cuff tearing. Two SNPs previously reported to show an association with shoulder impingement from a prior UKB GWAS were not validated in our study. CONCLUSION: This is the first GWAS for shoulder impingement in which new data from UKB enabled the identification of 4 loci showing a genetic association. A meta-analysis with a prior GWAS for rotator cuff tearing identified an additional 7 loci. The known biologic roles of many of the 11 loci suggest plausible biologic mechanisms underlying the etiology of rotator cuff disease. The risk alleles from each of the genetic loci can be used to assess the risk for rotator cuff disease in individual patients, enabling preventative or restorative actions via personalized medicine.


Assuntos
Lesões do Manguito Rotador , Síndrome de Colisão do Ombro , Artroscopia , Estudo de Associação Genômica Ampla , Humanos , Manguito Rotador , Lesões do Manguito Rotador/genética , Lesões do Manguito Rotador/cirurgia , Síndrome de Colisão do Ombro/genética , Síndrome de Colisão do Ombro/cirurgia
9.
J Shoulder Elbow Surg ; 30(3): 520-531, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32663566

RESUMO

BACKGROUND: The etiology of rotator cuff tearing is likely multifactorial, including a potential genetic predisposition. The purpose of the study was to identify genetic variants associated with rotator cuff tearing utilizing the UK Biobank (UKB) cohort, confirm variants using a separate genetic database, and evaluate tissue expression of genes with associated variants following rotator cuff tearing using RNA sequencing. METHODS: Genome-wide association study (GWAS): A GWAS was performed using data from UKB with 5701 cases of rotator cuff injury. RNA sequencing analyses: rotator cuff biopsies were obtained from 24 patients with full-thickness rotator cuff tears who underwent arthroscopic rotator cuff repair (cases) and 9 patients who underwent open reduction internal fixation for a proximal humerus fracture (controls). Total RNA was extracted and differential gene expression was measured by RNAseq for genes with variants associated with rotator cuff tearing. RESULTS: The results of the UKB GWAS identified 3 loci that reached genome-wide statistical significance: 2 loci on chromosome 7 in GLCCI1 (rs4725069; P = 5.0E-09) and THSD7A (rs575224171; P = 5.3E-09), and 1 locus on chromosome 2 in ZNF804A (rs775583810; P = 3.9E-09). The association with rotator cuff injury of the GLCCI1 single-nucleotide polymorphism (SNP; rs4725069) was confirmed in the Kaiser Permanente Research Bank cohort (P = .008). Twenty previously reported SNPs in 12 genes were evaluated using summary statistics from the UKB GWAS, which confirmed 3 SNPs in TNC with rotator cuff injury (rs1138545, rs72758637, and rs7021589; all P < .0024). Of 17 genes with variants associated with rotator cuff injury (14 previously from literature plus 3 new genes from current UKB GWAS), TIMP2, Col5A1, TGFBR1, and TNC were upregulated (P < .001 for all) and THSD7A was downregulated (P = .005) in tears vs. controls in the RNA sequencing data set. CONCLUSION: The UKB GWAS has identified 3 novel loci associated with rotator cuff tearing (ZNF804A, GLCCI1, THSD7A). Expression of the THSD7A gene was significantly downregulated in rotator cuff tears vs. controls supporting a potential functional role. Three previously reported SNPs in the TNC gene were validated in the UKB GWAS, supporting a role for this gene in rotator cuff tearing. Finally, TIMP2, Col5A1, TGFBR1, and TNC genes were found to have significantly upregulated tissue expression in cases vs. controls supporting a biologic role in tearing for these genes.


Assuntos
Lesões do Manguito Rotador , Manguito Rotador , Artroscopia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fatores de Transcrição Kruppel-Like , Polimorfismo de Nucleotídeo Único , Lesões do Manguito Rotador/genética
10.
PLoS Genet ; 13(4): e1006742, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28445472

RESUMO

Hereditary Multiple Exostoses (HME) is a rare pediatric disorder caused by loss-of-function mutations in the genes encoding the heparan sulfate (HS)-synthesizing enzymes EXT1 or EXT2. HME is characterized by formation of cartilaginous outgrowths-called osteochondromas- next to the growth plates of many axial and appendicular skeletal elements. Surprisingly, it is not known whether such tumors also form in endochondral elements of the craniofacial skeleton. Here, we carried out a retrospective analysis of cervical spine MRI and CT scans from 50 consecutive HME patients that included cranial skeletal images. Interestingly, nearly half of the patients displayed moderate defects or osteochondroma-like outgrowths in the cranial base and specifically in the clivus. In good correlation, osteochondromas developed in the cranial base of mutant Ext1f/f;Col2-CreER or Ext1f/f;Aggrecan-CreER mouse models of HME along the synchondrosis growth plates. Osteochondroma formation was preceded by phenotypic alteration of cells at the chondro-perichondrial boundary and was accompanied by ectopic expression of major cartilage matrix genes -collagen 2 and collagen X- within the growing ectopic masses. Because chondrogenesis requires bone morphogenetic protein (BMP) signaling, we asked whether osteochondroma formation could be blocked by a BMP signaling antagonist. Systemic administration with LDN-193189 effectively inhibited osteochondroma growth in conditional Ext1-mutant mice. In vitro studies with mouse embryo chondrogenic cells clarified the mechanisms of LDN-193189 action that turned out to include decreases in canonical BMP signaling pSMAD1/5/8 effectors but interestingly, concurrent increases in such anti-chondrogenic mechanisms as pERK1/2 and Chordin, Fgf9 and Fgf18 expression. Our study is the first to reveal that the cranial base can be affected in patients with HME and that osteochondroma formation is amenable to therapeutic drug intervention.


Assuntos
Exostose Múltipla Hereditária/genética , N-Acetilglucosaminiltransferases/genética , Osteocondroma/genética , Proteína Smad1/genética , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Medula Cervical/metabolismo , Medula Cervical/patologia , Condrogênese/genética , Modelos Animais de Doenças , Desenvolvimento Embrionário/genética , Exostose Múltipla Hereditária/diagnóstico por imagem , Exostose Múltipla Hereditária/tratamento farmacológico , Exostose Múltipla Hereditária/patologia , Lâmina de Crescimento/metabolismo , Lâmina de Crescimento/patologia , Heparitina Sulfato/biossíntese , Humanos , Imageamento por Ressonância Magnética , Camundongos , Camundongos Knockout , Mutação , Osteocondroma/diagnóstico por imagem , Osteocondroma/patologia , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Tomografia Computadorizada de Emissão
11.
Int J Mol Sci ; 21(7)2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32290096

RESUMO

Synovial sarcoma, an uncommon cancer, typically affects young adults. Survival rates range from 36% to 76%, decreasing significantly when metastases are present. Synovial sarcomas form in soft tissues, often near bones, with about 10% demonstrating ossification in the tumor. The literature is inconclusive on whether the presence of ossification portends a worse prognosis. To this end, we analyzed our genetic mouse models of synovial sarcoma to determine the extent of ossification in the tumors and its relationship with morbidity. We noted higher ossification within our metastatic mouse model of synovial sarcoma. Not only did we observe ossification within the tumors at a frequency of 7%, but an even higher frequency, 72%, of bone reactivity was detected by radiography. An enrichment of bone development genes was associated with primary tumors, even in the absence of an ossification phenotype. In spite of the ossification being intricately linked with the metastatic model, the presence of ossification was not associated with a faster or worse morbidity in the mice. Our conclusion is that both metastasis and ossification are dependent on time, but that they are independent of one another.


Assuntos
Ossificação Heterotópica , Fenótipo , Sarcoma Sinovial/patologia , Animais , Biomarcadores Tumorais , Biópsia , Osso e Ossos/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Fusão Gênica , Genótipo , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Camundongos , Metástase Neoplásica , Prognóstico , Sarcoma Sinovial/etiologia , Sarcoma Sinovial/metabolismo , Sarcoma Sinovial/mortalidade
12.
J Surg Oncol ; 118(3): 532-535, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30114336

RESUMO

BACKGROUND: The prevalence of metastatic bone disease (MBD) grows each year as treatments improve. Little has been published about functional and pain outcomes in this group after surgery. Patient-Reported Outcomes Measurement Information System (PROMIS® ) can collect information, in just minutes, about patient's physical, mental, and social health. This study evaluated PROMIS® pain and functional scores in surgically treated patients with MBD. METHODS: Basic demographics and PROMIS® scores were recorded from a total of 13 patients at 9 periods of time over 6 months. RESULTS: The average change in physical function at week 1 was -2.5 (standard deviation [SD] = 5.4), at 2 weeks 1.7 (SD = 7.6), after 4 weeks 6.9 (SD = 10), after 6 weeks 6.4 (SD = 10.9), after 10 weeks 15.3 (SD = 3.1), and after 3 months 8.6 (SD = 7.6). The average change in pain inference at week 1 was -1.2 (SD = 7.3), at 2 weeks -2.1 (SD = 9.5), after 4 weeks -12.6 (SD = 4.5), after 6 weeks -8.3 (SD = 10.2), after 10 weeks -16.6 (SD = 4.3), and after 3 months -11.4 (SD = 8.2). CONCLUSIONS: PROMIS® provides a feasible means to collect data in this population. Trends of improved function and decreased pain were seen after surgery. Continuing this study will hopefully elucidate more insight into the surgical treatment of MBD.


Assuntos
Neoplasias Ósseas/cirurgia , Medição da Dor/normas , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Neoplasias Ósseas/complicações , Neoplasias Ósseas/secundário , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Inquéritos e Questionários
13.
J Pathol ; 236(2): 210-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25644707

RESUMO

Peripheral chondrosarcoma (PCS) develops as malignant transformation of an osteochondroma, a benign cartilaginous outgrowth at the bone surface. Its invasive, lobular growth despite low-grade histology suggests a loss of chondrocyte polarity. The known genetics of osteochondromagenesis include mosaic loss of EXT1 or EXT2 in both hereditary and non-hereditary cases. The most frequent genetic aberrations in human PCS also include disruptions of CDKN2A or TP53. In order to test the sufficiency of either of these to drive progression of an osteochondroma to PCS, we added conditional loss of Trp53 or Ink4a/Arf in an Ext1-driven mouse model of osteochondromagenesis. Each additional tumour suppressor silencing efficiently drove the development of growths that mimic human PCS. As in humans, lobules developed from both Ext1-null and Ext1-functional clones within osteochondromas. Assessment of their orientation revealed an absence of primary cilia in the majority of mouse PCS chondrocytes, which was corroborated in human PCSs. Loss of primary cilia may be responsible for the lost polarity phenotype ascribed to PCS. Cilia deficiency blocks proliferation in physeal chondrocytes, but cell cycle deregulation is sufficient to rescue chondrocyte proliferation following deciliation. This provides a basis of selective pressure for the frequent cell-cycle regulator silencing observed in peripheral chondrosarcomagenesis. Mosaic loss of Ext1 combined with loss of cell cycle regulators promotes peripheral chondrosarcomagenesis in the mouse and reveals deficient ciliogenesis in both the model and the human disease, explaining biological behaviour including lobular and invasive growth.


Assuntos
Neoplasias Ósseas/genética , Condrossarcoma/genética , N-Acetilglucosaminiltransferases/genética , Osteocondroma/genética , Animais , Carcinogênese/genética , Ciclo Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Condrócitos/fisiologia , Cílios/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Modelos Animais de Doenças , Integrases/genética , Camundongos Transgênicos , Mosaicismo , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética
14.
Ann Surg Oncol ; 22(12): 3921-8, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25777096

RESUMO

BACKGROUND: Metastatic disease to the acetabulum presents a difficult technical and philosophical challenge: complicated surgeries in patients with often short life expectancies force us to examine both the outcome and cost of these operations. Therefore, we studied the durability of a cement-screw rebar reconstruction technique and risk factors for failure, and we compare the results to other reconstruction options. METHODS: This is a retrospective review of 52 acetabular reconstructions in 50 patients for nonprimary disease using a retrograde screw-rebar-cement all-polyethylene technique. Mean age was 57 years (range 25-81 years). Twenty-four lesions were classified as Harrington class II; 28 were Harrington class III. Mean follow-up was 17.7 months (range 1-92 months). Outcomes included patient survival, prosthesis survival, and complications. RESULTS: Forty-eight of 50 (96 %) patients ambulated after surgery. Five of 52 (9.6 %) of prostheses failed, three from loosening due to tumor progression, one from aseptic loosening, and one from soft tissue instability (dislocation). The three cases of tumor progression failure occurred in patients with massive preoperative ischial tumor burden. Mean surgical time was 198 min, and hospital stay was 5.2 days. DISCUSSION: The screw-cement-rebar all-polyethylene cup reconstruction technique is a comparatively successful and inexpensive reconstruction option for treating nonprimary oncologic disease in the acetabulum. All cases of loosening occurred beyond the median patient survival. Surgeons should be wary of massive ischial tumor burden in patients with projected longevity, as it may be associated with implant failure. Surgical time and hospital stay are consistent with historical data for alternative implants, and implant cost is lower.


Assuntos
Acetábulo/cirurgia , Artroplastia de Quadril/métodos , Neoplasias Ósseas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Artroplastia de Quadril/efeitos adversos , Cimentos Ósseos/uso terapêutico , Neoplasias Ósseas/secundário , Parafusos Ósseos , Feminino , Seguimentos , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Polietileno , Falha de Prótese , Estudos Retrospectivos , Taxa de Sobrevida , Caminhada , Adulto Jovem
15.
Clin Orthop Relat Res ; 473(3): 877-82, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25057117

RESUMO

BACKGROUND: There are several options for proximal humerus reconstruction in young children after resection of a malignant tumor and no one technique has been definitively shown to be superior to others, leaving the decision to surgeon and patient choice. Claviculo pro humeri (CPH) is a biologic reconstruction of the proximal humerus using the patient's ipsilateral clavicle as a rotational osseous flap. CPH represents a potential option for this complicated clinical problem in very young children, but little is known about it because the indications for its use are so uncommon. QUESTIONS/PURPOSES: The purposes of this study were to (1) assess the oncologic outcomes of CPH at a minimum of 2 years in a small series of patients; (2) elicit the complications associated with this procedure; and (3) show the Musculoskeletal Tumor Society (MSTS) functional score of these patients. METHODS: Four patients (average age, 5 years 11 months; range, 4 years 5 months to 8 years 9 months at the time of surgery) were treated with CPH for reconstruction after resection of a proximal humerus sarcoma; this represented all of the patients treated with this approach for this problem between January 2008 and April 2011 at one institution. During this period, the general indications for using CPH were the need to reconstruct a proximal humerus defect in a child younger than 10 years of age. During this time, CPH was used for all patients treated for proximal humerus sarcomas meeting these criteria. Patient demographics, diagnosis, tumor size and extent, operative details, radiographs and MRIs, complications, and functional outcomes were assessed. RESULTS: All are alive with no evidence of disease at a minimum followup of 31 months (average, 43 months; range, 31-58 months). Two patients developed nonunion and underwent revision surgery. Osseous union and a stable neoshoulder articulation were ultimately obtained in all patients. Limited shoulder motion was the only functional deficit noted with forward elevation ranging between 30° and 90°. MSTS functional scores were excellent with a range of 87% to 90%. CONCLUSIONS: This is a rarely used procedure in North America but we achieved functional limb salvage in all four patients. Consistent with prior literature, nonunion was the major complication in this series. The two nonunions were successfully treated without interruption of chemotherapy or significant bone graft donor site morbidity. Based on these results, the authors suggest that this procedure is a reasonable reconstruction option to consider after proximal humerus resection in patients younger than 10 years of age. Further followup will be required to assess long-term results and to determine how this procedure compares with the alternatives. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.


Assuntos
Neoplasias Ósseas/cirurgia , Úmero/cirurgia , Salvamento de Membro/métodos , Procedimentos de Cirurgia Plástica/métodos , Sarcoma/cirurgia , Transplante Ósseo , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Resultado do Tratamento
16.
Clin Orthop Relat Res ; 473(3): 883-90, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24942962

RESUMO

BACKGROUND: Aseptic complications such as stress shielding leading to bone loss are major problems associated with revision of cemented and uncemented long-stem tumor endoprostheses. Endoprosthetic reconstruction using compressive osseointegration fixation is a relatively new limb salvage technology designed to enhance osseointegration, prevent stress shielding, and provide fixation for short end-segments. QUESTIONS/PURPOSES: (1) What is the survivorship of this technique at minimum 5-year followup? (2) Were patient factors (age, sex, body mass index), oncological factors, or anatomic locations associated with implant failure? (3) Were there any prosthesis-related variables associated with failure? METHODS: A single-center, retrospective review of patients with a minimum 5-year followup (mean, 8 years; range, 5-12 years) treated with an osseointegration compressive device for endoprosthetic fixation of proximal and distal femoral limb salvage reconstructions was performed. We have previously published the implant survivorship of this patient cohort with a minimum 2-year followup and are now reporting on the 5-year survivorship data. From 2002 to 2008, we performed 22 such procedures in 22 patients. Four patients died of their disease within 5 years of surgery and all surviving patients (n = 18) had complete followup data at a minimum of 5 years. General indications for this device during that time were pediatric and adult patients requiring primary endoprosthetic reconstructions of the proximal or distal femur for benign and malignant bone lesions. The primary outcome was reoperations for mechanical (aseptic) failures. Secondary outcomes included implant removal for nonmechanical failures and any patient-, oncological-, or implant-related variables associated with implant removal. RESULTS: At a minimum of 5 years followup, overall mechanical (aseptic) implant survivorship was 16 of 18. Survivorship for all modes of failure (oncological failure, infection, arthrofibrosis, and mechanical failure) was 12 of 18. All mechanical failures occurred early, within the first 30 months. We identified no patient-, oncological-, or implant-related features predictive of failure. CONCLUSIONS: Our intermediate-term experience with compressive osseointegration fixation for endoprosthetic limb reconstructions demonstrates with longer clinical followup, no additional mechanical failures were observed as compared with our early analysis. Our experience with this fixation at a minimum of 5-years followup adds to a very limited but increasing body of literature demonstrating that after a transient period of increased risk for implant failures, survivorship stabilizes. Assessment of this fixation strategy beyond 10 years of clinical followup is needed. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.


Assuntos
Neoplasias Femorais/cirurgia , Fêmur/cirurgia , Salvamento de Membro/métodos , Osseointegração , Implantação de Prótese/métodos , Sarcoma/cirurgia , Adolescente , Adulto , Criança , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Próteses e Implantes , Desenho de Prótese , Falha de Prótese , Procedimentos de Cirurgia Plástica/métodos , Reoperação , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
17.
J Natl Compr Canc Netw ; 12(2): 214-20, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24586083

RESUMO

Neoplastic transformation is a consequence of maladaptive alterations in the cellular processes normally involved in cell growth, proliferation, differentiation, and survival. Despite the relative infrequent nature of skeletal neoplasms, current understanding of the pathobiology underlying these conditions is becoming increasingly characterized. This article highlights some of the established molecular abnormalities identified in various benign and malignant skeletal neoplasms and how they pertain to tumor biology, diagnosis, and prognosis. Most of the commonly accepted cellular aberrancies in skeletal neoplasms pertain to mutations, copy number changes, and/or chromosomal rearrangements. However, it is becoming increasingly understood that the complexity of tumorigenic pathways necessary for neoplastic growth are manipulated by numerous overlapping alterations in the genetic code and are further influenced by higher-order molecular programs, such as pretranscriptional and posttranscriptional regulation and chromatin reorganization. Over time, identification and quantification of these increasingly recognized neoplastic processes will gradually translate into valuable clinical applications, enhancing the current diagnostic and prognostic capabilities.


Assuntos
Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/genética , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/terapia , Humanos , Prognóstico
18.
Connect Tissue Res ; 55(2): 80-8, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24409815

RESUMO

Abstract An interdisciplinary and international group of clinicians and scientists gathered in Philadelphia, PA, to attend the fourth International Research Conference on Multiple Hereditary Exostoses (MHE), a rare and severe skeletal disorder. MHE is largely caused by autosomal dominant mutations in EXT1 or EXT2, genes encoding Golgi-associated glycosyltransferases responsible for heparan sulfate (HS) synthesis. HS chains are key constituents of cell surface- and extracellular matrix-associated proteoglycans, which are known regulators of skeletal development. MHE affected individuals are HS-deficient, can display skeletal growth retardation and deformities, and consistently develop benign, cartilage-capped bony outgrowths (termed exostoses or osteochondromas) near the growth plates of many skeletal elements. Nearly 2% of patients will have their exostoses progress to malignancy, becoming peripheral chondrosarcomas. Current treatments are limited to the surgical removal of symptomatic exostoses. No definitive treatments have been established to inhibit further formation and growth of exostoses, prevent transition to malignancy, or address other medical problems experienced by MHE patients, including chronic pain. Thus, the goals of the Conference were to assess our current understanding of MHE pathogenesis, identify key gaps in information, envision future therapeutic strategies and discuss ways to test and implement them. This report provides an assessment of the exciting and promising findings in MHE and related fields presented at the Conference and a discussion of the future MHE research directions. The Conference underlined the critical usefulness of gathering experts in several research fields to forge new alliances and identify cross-fertilization areas to benefit both basic and translational biomedical research on the skeleton.


Assuntos
Pesquisa Biomédica , Neoplasias Ósseas , Condrossarcoma , Exostose Múltipla Hereditária , Animais , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Neoplasias Ósseas/fisiopatologia , Condrossarcoma/genética , Condrossarcoma/metabolismo , Condrossarcoma/patologia , Condrossarcoma/fisiopatologia , Congressos como Assunto , Exostose Múltipla Hereditária/genética , Exostose Múltipla Hereditária/metabolismo , Exostose Múltipla Hereditária/patologia , Exostose Múltipla Hereditária/fisiopatologia , Transtornos do Crescimento/genética , Transtornos do Crescimento/metabolismo , Transtornos do Crescimento/patologia , Transtornos do Crescimento/fisiopatologia , Humanos , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Philadelphia
19.
J Surg Oncol ; 110(7): 813-6, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25111615

RESUMO

BACKGROUND AND OBJECTIVES: While convention defines atypical neurofibroma as benign and low-grade malignant peripheral nerve sheath tumors (MPNSTs) as malignant, sparse outcomes data exist for these tumors. This study reviews clinical outcomes of surgically resected low-grade MPNST and atypical neurofibroma, focusing on the effect of surgical margins on outcome. METHODS: This study is a retrospective review of 23 patients who underwent surgical resection of a low-grade MPNST or atypical neurofibroma. Treatment characteristics of adjuvant therapy and surgical margin were noted. Endpoints of local recurrence, presence of metastatic disease, disease-specific survival, and overall survival were reviewed. RESULTS: Eighteen of 23 patients (78%) had microscopically positive margins on the resection. Disease-specific survival was 100% for both atypical neurofibroma patients and those with low-grade MPNST, regardless of surgical margin. Local recurrence in terms of recurrence of measureable disease occurred in 2/12 (16.7%) of LGMPNST patients and 1/11 (9.1%) of atypical NF patients, all of whom had microscopically positive surgical margins. CONCLUSIONS: In a study dedicated exclusively to "intermediate" nerve sheath tumors, no patients developed metastatic disease nor died of disease despite a high rate of microscopically positive surgical margins (78%). While positive margins did lead to increased rates of local recurrence, these data suggest that surgeons potentially can temper their zeal for negative surgical margins in the setting of low-grade MPNST and atypical neurofibroma, as surgical morbidity may be more important than a presumed survival benefit of wide resection.


Assuntos
Recidiva Local de Neoplasia/diagnóstico , Neurilemoma/cirurgia , Neurofibroma/cirurgia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Gradação de Tumores , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/cirurgia , Neurilemoma/mortalidade , Neurilemoma/patologia , Neurofibroma/mortalidade , Neurofibroma/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
20.
BMC Med Imaging ; 14: 8, 2014 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-24548622

RESUMO

BACKGROUND: Coccidioidomycosis is an endemic fungal infection in the southwestern of United States. Most infections are asymptomatic or manifest with mild respiratory complaints. Rare cases may cause extrapulmonary or disseminated disease. We report two cases of knee involvement that presented as isolated lytic lesions of the patella mimicking neoplasms. CASE PRESENTATION: The first case, a 27 year-old immunocompetent male had progressive left anterior knee pain for four months. The second case was a 78 year-old male had left anterior knee pain for three months. Both of them had visited general physicians without conclusive diagnosis. A low attenuation lytic lesion in the patella was demonstrated on their image studies, and the initial radiologist's interpretation was suggestive of a primary bony neoplasm. The patients were referred for orthopaedic oncology consultation. The first case had a past episode of pulmonary coccioidomycosis 2 years prior, while the second case had no previous coccioidal infection history but lived in an endemic area, the central valley of California. Surgical biopsy was performed in both cases due to diagnostic uncertainty. Final pathologic examination revealed large thick walled spherules filled with endospores establishing the final diagnosis of extrapulmonary coccidioidomycosis. CONCLUSIONS: Though history and laboratory findings are supportive, definitive diagnosis still depends on growth in culture or endospores identified on histology. We suggest that orthopaedic surgeons and radiologists keep in mind that chronic fungal infections can mimic osseous neoplasm by imaging.


Assuntos
Coccidioidomicose/diagnóstico , Coccidioidomicose/cirurgia , Neoplasias Femorais/diagnóstico , Patela/patologia , Adulto , Idoso , Coccidioidomicose/patologia , Diagnóstico Diferencial , Humanos , Imageamento por Ressonância Magnética , Masculino , Patela/diagnóstico por imagem , Tomografia Computadorizada por Raios X
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