RESUMO
BACKGROUND: The current study was conducted to examine the association between ipsilateral breast tumor recurrence (IBTR) and the timing of radiotherapy (RT) in women with ductal carcinoma in situ (DCIS) undergoing breast-conserving surgery (BCS). METHODS: Women with DCIS who were treated with BCS and RT from 1980 through 2010 were identified from a prospectively maintained database. IBTR rates, measured from the time of RT completion, were compared between those who initiated RT ≤8 weeks, >8 to 12 weeks, and >12 weeks after the completion of surgery. The association between RT timing and IBTR was evaluated by Kaplan-Meier and log-rank analyses; Cox modeling was used for multivariable analysis. RESULTS: A total of 1323 women met the inclusion criteria. The median follow-up was 6.6 years, with 311 patients followed for ≥10 years. A total of 126 IBTR events occurred. Patients were categorized by RT timing: 806 patients (61%) with timing of ≤8 weeks, 386 patients (29%) with timing of >8 to 12 weeks, and 131 patients (10%) with timing >12 weeks. The 5-year and 10-year IBTR rates were 5.8% and 13.0%, respectively, for RT starting ≤8 weeks after surgery; 3.8% and 7.6%, respectively, for RT starting >8 to 12 weeks after surgery; and 8.8% and 23.0%, respectively, for an RT delay >12 weeks after surgery (P = .004). On multivariable analysis, menopause (hazard ratio [HR], 0.54; P = .0009) and endocrine therapy (HR, 0.45; P = .002) were found to be protective against IBTR, whereas a delay in RT >12 weeks compared with ≤8 weeks was associated with a higher risk of IBTR (HR, 1.92; P = .014). There was no difference in IBTR noted between RT initiation at ≤8 weeks and initiation at >8 to 12 weeks after BCS (P = .3). CONCLUSIONS: A delay in RT >12 weeks is associated with a significantly higher risk of IBTR in women undergoing BCS for DCIS. Efforts should be made to avoid delays in starting RT to minimize the risk of disease recurrence. Cancer 2018;124:46-54. © 2017 American Cancer Society.
Assuntos
Neoplasias da Mama/radioterapia , Carcinoma Intraductal não Infiltrante/radioterapia , Mastectomia Segmentar , Recidiva Local de Neoplasia/epidemiologia , Radioterapia Adjuvante/métodos , Tempo para o Tratamento/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Intraductal não Infiltrante/tratamento farmacológico , Quimioterapia Adjuvante , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Humanos , Menopausa , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Fatores de Proteção , Fatores de RiscoRESUMO
BACKGROUND: Immunotherapy targeting cancer-testis antigen NY-ESO-1 shows promise for tumors with poor response to chemoradiation. Malignant peripheral nerve sheath tumors (MPNSTs) and liposarcomas (LPS) are chemoresistant and have few effective treatment options. Materials Methods: Using a comprehensive tissue microarray (TMA) of both benign and malignant tumors in primary, recurrent, and metastatic samples, we examined NY-ESO-1 expression in peripheral nerve sheath tumor (PNST) and adipocytic tumors. The PNST TMA included 42 MPNSTs (spontaneous n = 26, NF1-associated n = 16), 35 neurofibromas (spontaneous n = 22, NF-1 associated n = 13), 11 schwannomas, and 18 normal nerves. The LPS TMA included 48 well-differentiated/dedifferentiated (WD/DD) LPS, 13 myxoid/round cell LPS, 3 pleomorphic LPS, 8 lipomas, 1 myelolipoma, and 3 normal adipocytic tissue samples. Stained in triplicate, NY-ESO-1 intensity and density were scored. RESULTS: NY-ESO-1 expression was exclusive to malignant tumors. 100% of myxoid/round cell LPS demonstrated NY-ESO-1 expression, while only 6% of WD/DD LPS showed protein expression, one of which was WD LPS. Of MPNST, 4/26 (15%) spontaneous and 2/16 (12%) NF1-associated MPNSTs demonstrated NY-ESO-1 expression. Strong NY-ESO-1 expression was observed in myxoid/round cell and dedifferentiated LPS, and MPNST in primary, neoadjuvant, and metastatic settings. CONCLUSIONS: We found higher prevalence of NY-ESO-1 expression in MPNSTs than previously reported, highlighting a subset of MPNST patients who may benefit from immunotherapy. This study expands our understanding of NY-ESO-1 in WD/DD LPS and is the first demonstration of staining in a WD LPS and metastatic/recurrent myxoid/round cell LPS. These results suggest immunotherapy targeting NY-ESO-1 may benefit patients with aggressive tumors resistant to conventional therapy.
Assuntos
Tecido Adiposo/metabolismo , Antígenos de Neoplasias/metabolismo , Proteínas de Membrana/metabolismo , Tecido Nervoso/metabolismo , Análise Serial de Tecidos , Adipogenia/genética , Antígenos de Neoplasias/genética , Biomarcadores , Humanos , Imuno-Histoquímica , Imunoterapia , Lipossarcoma/genética , Lipossarcoma/metabolismo , Lipossarcoma/patologia , Lipossarcoma/terapia , Proteínas de Membrana/genética , Metástase Neoplásica , Recidiva Local de Neoplasia , Neoplasias de Bainha Neural/genética , Neoplasias de Bainha Neural/metabolismo , Neoplasias de Bainha Neural/patologia , Neoplasias de Bainha Neural/terapia , Neurogênese , Análise Serial de Tecidos/métodosRESUMO
BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma with few treatment options. Tumor immune state has not been characterized in MPNST, and is important in determining response to immune checkpoint blockade. Our aim was to evaluate the expression of programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), and presence of CD8+ tumor infiltrating lymphocytes (TILs) in MPNST, and correlate these findings with clinical behavior and outcome. RESULTS: PD-L1 staining of at least 1% was seen in 0/20 nerves, 2/68 benign lesions and 9/53 MPNST. Two of 68 benign lesions and 7/53 (13%) MPNST had at least 5% PD-L1 staining. CD8 staining of at least 5% was seen in 1/20 (5%) nerves, 45/68 (66%) benign lesions and 30/53 (57%) MPNST. PD-L1 was statistically more prevalent in MPNST than both nerves and benign lesions (p=0.049 and p=0.008, respectively). Expression of PD-1 was absent in all tissue specimens. There was no correlation of PD-L1 or CD8 expression with disease state (primary versus metastatic) or patient survival. METHODS: A comprehensive PNST tissue microarray was created from 141 surgical specimens including primary, recurrent, and metastatic MPNST (n=53), neurofibromas (n=57), schwannoma (n=11), and normal nerve (n=20). Cores were stained in triplicate for PD-L1, PD-1, and CD8, and expression compared between tumor types. These data were then examined for survival correlates in 35 patients with primary MPNST. CONCLUSIONS: MPNST is characterized by low PD-L1 and absent PD-1 expression with significant CD8+ TIL presence. MPNST immune microenvironment does not correlate with patient outcome.
Assuntos
Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Linfócitos T CD8-Positivos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neurilemoma/imunologia , Neoplasias de Tecidos Moles/imunologia , Microambiente Tumoral , Progressão da Doença , Humanos , Imuno-Histoquímica , Metástase Neoplásica , Recidiva Local de Neoplasia , Neurilemoma/mortalidade , Neurilemoma/secundário , Neurilemoma/cirurgia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Neoplasias de Tecidos Moles/mortalidade , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/cirurgia , Fatores de Tempo , Análise Serial de Tecidos , Resultado do TratamentoRESUMO
Malignant peripheral nerve sheath tumor (MPNST) is the sixth most common type of soft tissue sarcoma. Most MPNSTs arise in association with a peripheral nerve or preexisting neurofibroma. Neurofibromatosis type is the most important risk factor for MPNST. Tumor size and fludeoxyglucose F 18 avidity are among the most helpful parameters to distinguish MPNST from a benign peripheral nerve sheath tumor. The histopathologic diagnosis is predominantly a diagnosis of light microscopy. Immunohistochemical stains are most helpful to distinguish high-grade MPNST from its histologic mimics. Current surgical management of high-grade MPNST is similar to that of other high-grade soft tissue sarcomas.
Assuntos
Neoplasias de Bainha Neural/diagnóstico por imagem , Neoplasias de Bainha Neural/patologia , Neurilemoma/complicações , Neurofibroma/complicações , Neurofibromatose 1/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Fluordesoxiglucose F18 , Humanos , Neurilemoma/patologia , Neurofibroma/patologia , Neurofibromatose 1/complicações , Neurofibromatose 1/patologia , SarcomaRESUMO
Tumor-targeting Salmonella enterica serovar Typhimurium A1-R (Salmonella A1-R) had strong efficacy on a melanoma patient-derived orthotopic xenograft (PDOX) nude-mouse model. GFP-expressing Salmonella A1-R highly and selectively colonized the PDOX melanoma and significantly suppressed tumor growth (p = 0.021). The combination of Salmonella A1-R and cisplatinum (CDDP), both at low-dose, also significantly suppressed the growth of the melanoma PDOX (P = 0.001). Salmonella A1-R has future clinical potential for combination chemotherapy with CDDP of melanoma, a highly-recalcitrant cancer.
Assuntos
Antineoplásicos/farmacologia , Modelos Animais de Doenças , Melanoma/terapia , Infecções por Salmonella/microbiologia , Salmonella typhimurium/crescimento & desenvolvimento , Animais , Terapia Combinada , Humanos , Melanoma/microbiologia , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Phyllodes tumors of the breast are rare fibroepithelial tumors that are characterized as benign, borderline, or malignant based on cellular characteristics such as stromal overgrowth and number of mitoses. Currently, there is a lack of consensus on risk factors and management of patients with phyllodes tumors, which has led to variation in treatment patterns as well as patient outcomes across many institutions. This study seeks to understand the clinicopathologic features, risk factors for local and metastatic recurrence, and clinical outcomes of patients with phyllodes tumors to better define optimal treatment patterns.
Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Gerenciamento Clínico , Tumor Filoide/patologia , Tumor Filoide/terapia , Adolescente , Adulto , Idoso , Neoplasias da Mama/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumor Filoide/etiologia , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Gender-based differences in disease onset in murine models of malignant peripheral nerve sheath tumor (MPNST) and in patients with Neurofibromatosis type-1-(NF-1)-associated or spontaneous MPNST has not been well studied. METHODS: Forty-three mGFAP-Cre+;Ptenloxp/+;LSL-K-rasG12D/+ mice were observed for tumor development and evaluated for gender disparity in age of MPNST onset. Patient data from the prospectively collected UCLA sarcoma database (1974-2011, n = 113 MPNST patients) and 39 published studies on MPNST patients (n = 916) were analyzed for age of onset differences between sexes and between NF-1 and spontaneous MPNST patients. RESULTS: Our murine model showed gender-based differences in MPNST onset, with males developing MPNST significantly earlier than females (142 vs. 162 days, p = 0.015). In the UCLA patient population, males also developed MPNST earlier than females (median age 35 vs. 39.5 years, p = 0.048). Patients with NF-1-associated MPNST had significantly earlier age of onset compared to spontaneous MPNST (median age 33 vs. 39 years, p = 0.007). However, expanded analysis of 916 published MPNST cases revealed no significant age difference in MPNST onset between males and females. Similar to the UCLA dataset, patients with NF-1 developed MPNST at a significantly younger age than spontaneous MPNST patients (p < 0.0001, median age 28 vs. 41 years) and this disparity was maintained across North American, European, and Asian populations. CONCLUSIONS: Although our preclinical model and single-institution patient cohort show gender dimorphism in MPNST onset, no significant gender disparity was detected in the larger MPNST patient meta-dataset. NF-1 patients develop MPNST 13 years earlier than patients with spontaneous MPNST, with little geographical variance.
Assuntos
Neoplasias de Bainha Neural/epidemiologia , Neurofibromatose 1/epidemiologia , Neoplasias do Sistema Nervoso Periférico/epidemiologia , Caracteres Sexuais , Adolescente , Adulto , Fatores Etários , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Animais , Modelos Animais de Doenças , Feminino , Engenharia Genética , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Neoplasias de Bainha Neural/genética , Neoplasias do Sistema Nervoso Periférico/genética , Fatores Sexuais , Adulto JovemRESUMO
PURPOSE: Integration of numerous prognostic variables not included in the conventional staging of retroperitoneal soft tissue sarcomas (RPS) is essential in providing effective treatment. The purpose of this study was to build a specific nomogram for predicting postoperative overall survival (OS) and disease-free survival (DFS) in patients with primary RPS. PATIENTS AND METHODS: Data registered in three institutional prospective sarcoma databases were used. We included patients with primary localized RPS resected between 1999 and 2009. Univariate (Kaplan and Meier plots) and multivariate (Cox model) analyses were carried out. The a priori chosen prognostic covariates were age, tumor size, grade, histologic subtype, multifocality, quality of surgery, and radiation therapy. External validation was performed by applying the nomograms to the patients of an external cohort. The model's discriminative ability was estimated by means of the bootstrap-corrected Harrell C statistic. RESULTS: In all, 523 patients were identified at the three institutions (developing set). At a median follow-up of 45 months (interquartile range, 22 to 72 months), 171 deaths were recorded. Five- and 7-year OS rates were 56.8% (95% CI, 51.4% to 62.6%) and 46.7% (95% CI, 39.9% to 54.6%. Two hundred twenty-one patients had disease recurrence. Five- and 7-year DFS rates were 39.4% (95% CI, 34.5% to 45.0%) and 35.7% (95% CI, 30.3% to 42.1%). The validation set consisted of 135 patients who were identified at the fourth institution for external validation. The bootstrap-corrected Harrell C statistics for OS and DFS were 0.74 and 0.71 in the developing set and 0.68 and 0.69 in the validating set. CONCLUSION: These nomograms accurately predict OS and DFS. They should be used for patient counseling in clinical practice and stratification in clinical trials.
Assuntos
Neoplasias Retroperitoneais/mortalidade , Sarcoma/mortalidade , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nomogramas , Estudos Prospectivos , Neoplasias Retroperitoneais/patologia , Neoplasias Retroperitoneais/cirurgia , Sarcoma/patologia , Sarcoma/cirurgia , Análise de Sobrevida , Resultado do TratamentoRESUMO
Liposarcoma is a type of soft tissue sarcoma that exhibits poor survival and a high recurrence rate. Treatment is generally limited to surgery and radiation, which emphasizes the need for better understanding of this disease. Because very few in vivo and in vitro models can reproducibly recapitulate the human disease, we generated several xenograft models from surgically resected human dedifferentiated liposarcoma. All xenografts recapitulated morphological and gene expression characteristics of the patient tumors after continuous in vivo passages. Importantly, xenograftability was directly correlated with disease-specific survival of liposarcoma patients. Thus, the ability for the tumor of a patient to engraft may help identify those patients who will benefit from more aggressive treatment regimens. Gene expression analyses highlighted the association between xenograftability and a unique gene expression signature, including down-regulated PTEN tumor-suppressor gene expression and a progenitor-like phenotype. When treated with the PI3K/AKT/mTOR pathway inhibitor rapamycin alone or in combination with the multikinase inhibitor sorafenib, all xenografts responded with increased lipid content and a more differentiated gene expression profile. These human xenograft models may facilitate liposarcoma research and accelerate the generation of readily translatable preclinical data that could ultimately influence patient care.