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PURPOSE OF REVIEW: Gastroenteropancreatic NEN (GEP-NEN) are group of malignancies with significant clinical, anatomical and molecular heterogeneity. High-grade GEP-NEN in particular present unique management challenges. RECENT FINDINGS: In the current era, multidisciplinary management with access to a combination of functional imaging and targeted molecular profiling can provide important disease characterisation, guide individualised management and improve patient outcome. Multiple treatment options are now available, and combination and novel therapies are being explored in clinical trials. Precision medicine is highly relevant for a heterogenous disease like NEN. The integration of dual-tracer functional PET/CT imaging, molecular histopathology and genomic data has the potential to be used to gain a more comprehensive understanding of an individual patient's disease biology for precision diagnosis, prognostication and optimal treatment allocation.
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Neoplasias Gastrointestinais , Neoplasias Intestinais , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Neoplasias Gástricas , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias Gastrointestinais/diagnóstico por imagem , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/terapia , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Neoplasias Intestinais/diagnóstico por imagem , Neoplasias Intestinais/genética , Neoplasias Intestinais/terapia , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapiaRESUMO
There is now evidence that gene fusions activating the MAPK pathway are relatively common in pancreatic acinar cell carcinoma with potentially actionable BRAF or RET fusions being found in ~30%. We sought to investigate the incidence of RAF1 fusions in pancreatic malignancies with acinar cell differentiation. FISH testing for RAF1 was undertaken on 30 tumors comprising 25 'pure' acinar cell carcinomas, 2 mixed pancreatic acinar-neuroendocrine carcinomas, 1 mixed acinar cell-low grade neuroendocrine tumor and 2 pancreatoblastomas. RAF1 rearrangements were identified in 5 cases and confirmed by DNA and RNA sequencing to represent oncogenic fusions (GATM-RAF1, GOLGA4-RAF1, PDZRN3-RAF1, HERPUD1-RAF1 and TRIM33-RAF1) and to be mutually exclusive with BRAF and RET fusions, as well as KRAS mutations. Large genome-wide copy number changes were common and included 1q gain and/or 1p loss in all five RAF1 FISH-positive acinar cell carcinomas. RAF1 expression by immunohistochemistry was found in 3 of 5 (60%) of fusion-positive cases and no FISH-negative cases. Phospho-ERK1/2 expression was found in 4 of 5 RAF1-fusion-positive cases. Expression of both RAF1 and phospho-ERK1/2 was heterogeneous and often only detected at the tumor-stroma interface, thus limiting their clinical utility. We conclude that RAF1 gene rearrangements are relatively common in pancreatic acinar cell carcinomas (14.3% to 18.5% of cases) and can be effectively identified by FISH with follow up molecular testing. The combined results of several studies now indicate that BRAF, RET or RAF1 fusions occur in between one third and one-half of these tumors but are extremely rare in other pancreatic malignancies. As these fusions are potentially actionable with currently available therapies, a strong argument can be made to perform FISH or molecular testing on all pancreatic acinar cell carcinomas.
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Carcinoma de Células Acinares/genética , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas c-raf/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Acinares/patologia , Bases de Dados Factuais , Feminino , Fusão Gênica , Rearranjo Gênico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Adulto JovemRESUMO
BACKGROUND: Postoperative chemoradiation and perioperative chemotherapy using epirubicin/cisplatin/5-fluorouracil (ECF) represent two standards of care for resectable gastric cancer. In the TOPGEAR (Trial Of Preoperative therapy for Gastric and Esophagogastric junction AdenocaRcinoma) trial, we hypothesized that adding preoperative chemoradiation to perioperative ECF will improve survival; however, the safety and feasibility of preoperative chemoradiation have yet to be determined. METHODS: TOPGEAR is an international phase III trial in which patients with adenocarcinoma of the stomach were randomized to perioperative ECF alone or with preoperative chemoradiation. The ECF-alone group received three preoperative cycles of ECF, while the chemoradiation group received two cycles of preoperative ECF followed by chemoradiation. Both groups received three postoperative cycles of ECF. A planned interim analysis of the first 120 patients was conducted, and was reviewed by the Independent Data Safety Monitoring Committee to assess treatment compliance, toxicity/safety, and response rates. RESULTS: The proportion of patients who received all cycles of preoperative chemotherapy was 93% (ECF group) and 98% (chemoradiation group), while 65 and 53%, respectively, received all cycles of postoperative chemotherapy. Overall, 92% of patients allocated to preoperative chemoradiation received this treatment. The proportion of patients proceeding to surgery was 90% (ECF group) and 85% (chemoradiation group). Grade 3 or higher surgical complications occurred in 22% of patients in both groups. Furthermore, grade 3 or higher gastrointestinal toxicity occurred in 32% (ECF group) and 30% (chemoradiation group) of patients, while hematologic toxicity occurred in 50 and 52% of patients. CONCLUSIONS: These results demonstrate that preoperative chemoradiation can be safely delivered to the vast majority of patients without a significant increase in treatment toxicity or surgical morbidity.
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Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Terapia Neoadjuvante , Neoplasias Gástricas/terapia , Adenocarcinoma/patologia , Idoso , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Terapia Combinada , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Assistência Perioperatória , Cuidados Pré-Operatórios , Prognóstico , Neoplasias Gástricas/patologia , Taxa de SobrevidaRESUMO
INTRODUCTION: A Cancer Council Australia multidisciplinary working group is currently revising and updating the 2008 evidence-based clinical practice guidelines for the management of cutaneous melanoma. While there have been many recent improvements in treatment options for metastatic melanoma, early diagnosis remains critical to reducing mortality from the disease. Improved awareness of the atypical presentations of this common malignancy is required to achieve this. A chapter of the new guidelines was therefore developed to aid recognition of atypical melanomas. Main recommendations: Because thick, life-threatening melanomas may lack the more classical ABCD (asymmetry, border irregularity, colour variegation, diameter > 6 mm) features of melanoma, a thorough history of the lesion with regard to change in morphology and growth over time is essential. Any lesion that is changing in morphology or growing over a period of more than one month should be excised or referred for prompt expert opinion. Changes in management as a result of the guidelines: These guidelines provide greater emphasis on improved recognition of the atypical presentations of melanoma, in particular nodular, desmoplastic and acral lentiginous subtypes, with particular awareness of hypomelanotic and amelanotic lesions.
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Detecção Precoce de Câncer , Melanoma/diagnóstico , Melanoma/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Austrália , Medicina Baseada em Evidências , HumanosRESUMO
BACKGROUND: Recently, there has been an increase in the availability of targeted molecular therapies for cancer treatment. The application of these approaches to esophageal cancer, however, has been hampered by the relative lack of appropriate models for preclinical testing. Patient-derived tumor xenograft (PDTX) models are gaining popularity for studying many cancers. Unfortunately, it has proven difficult to generate xenografts from esophageal cancer using these models. The purpose of this study was to improve the engraftment efficiency of esophageal PDTXs. METHODS: Fresh pieces of esophageal tumors obtained from endoscopic biopsies or resected specimens were collected from 23 patients. The tumors were then coated in Matrigel and transplanted in immunocompromised mice subcutaneously (n = 6) and/or using a novel implantation technique whereby the tumor is placed in a dorsal intramuscular pocket (n = 18). They are then monitored for engraftment. RESULTS: With the novel intramuscular technique, successful engraftment was achieved for all 18 patient tumors. Among these PDTXs, 13 recapitulated the original patient tumors with respect to degree of differentiation, molecular and genetic profiles, and chemotherapeutic response. Lymphomatous transformation was observed in the other five PDTXs. Successful engraftment was achieved for only one of six patient tumors using the classic subcutaneous approach. DISCUSSION: We achieved a much higher engraftment rate of PDTXs using our novel intramuscular transplant technique than has been reported in other published studies. It is hoped that this advancement will help expedite the development and testing of new therapies for esophageal cancer.
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Neoplasias Esofágicas/patologia , Sobrevivência de Enxerto , Transplante Heterólogo , Animais , Neoplasias Esofágicas/cirurgia , Humanos , Injeções Intramusculares , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Transplante de Neoplasias , Receptores de Interleucina-2/fisiologia , Células Tumorais CultivadasRESUMO
RATIONALE: Pediatric patients with refractory neuroblastoma have limited therapeutic options. Neuroblastoma may express somatostatin receptors (SSTRs) allowing imaging with 68Ga-DOTA-Octreotate (GaTATE) positron emission tomography/computed tomography (PET/CT) and peptide receptor radionuclide therapy (PRRT). We reviewed our experience with this theranostic combination. MATERIALS AND METHODS: GaTATE studies (8 patients; 2 to 9 years old) were reviewed and compared with 123I-MIBG or posttreatment 131I-MIBG studies. Immunohistochemistry (IHC) for SSTR subtype 2 was performed in 5 patients. Four patients received PRRT. RESULTS: GaTATE PET showed additional disease in 38% (3/8 patients), and upstaged 1 patient by detecting marrow involvement. IHC detected SSTR 2 in all patients assessed. Six patients were deemed suitable for PRRT on imaging. Four patients received 17 cycles of palliative PRRT (10 111In-DOTATATE; 5 177Lu-DOTATATE; 1 combined 111In and 177Lu-DOTATATE; 1 combined 177Lu and 90Y-DOTATATE) with no significant toxicity attributed to PRRT. All had objective responses. Two survivors are now 40 and 56 months from PRRT commencement. CONCLUSIONS: GaTATE PET was positive in a high proportion of patients with refractory neuroblastoma, correlating with SSTR 2 on IHC, with additional disease identified compared with MIBG imaging. PRRT seems safe, feasible, with responses observed in patients with progression despite multimodality treatment. These data support ongoing clinical trials in such patients.
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Antineoplásicos/uso terapêutico , Neuroblastoma/diagnóstico por imagem , Neuroblastoma/radioterapia , Octreotida/análogos & derivados , Compostos Organometálicos/uso terapêutico , 3-Iodobenzilguanidina , Criança , Pré-Escolar , Feminino , Humanos , Imuno-Histoquímica , Masculino , Imagem Multimodal , Octreotida/uso terapêutico , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/uso terapêutico , Receptores de Somatostatina/análise , Receptores de Somatostatina/biossíntese , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
Preclinical models that replicate patient tumours as closely as possible are crucial for translational cancer research. While in vitro cancer models have many advantages in assessing tumour response therapy, in vivo systems are essential to enable evaluation of the role of the tumour cell extrinsic factors, such as the tumour microenvironment and host immune system. The requirement for a functional immune system is particularly important given the current focus on immunotherapies. Therefore, we set out to generate an immunocompetent, transplantable model of colorectal cancer suitable for in vivo assessment of immune-based therapeutic approaches. Intestinal tumours from a genetically engineered mouse model, driven by expression of a Pik3ca mutation and loss of Apc, were transplanted into wild type C57BL/6 host mice and subsequently passaged to form a novel syngeneic transplant model of colorectal cancer. Our work confirms the potential to develop a panel of mouse syngeneic grafts, akin to human PDX panels, from different genetically engineered, or carcinogen-induced, mouse models. Such panels would allow the in vivo testing of new pharmaceutical and immunotherapeutic treatment approaches across a range of tumours with a variety of genetic driver mutations.
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Adenocarcinoma , Classe I de Fosfatidilinositol 3-Quinases , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Animais , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Camundongos , Adenocarcinoma/genética , Adenocarcinoma/patologia , Neoplasias Intestinais/genética , Neoplasias Intestinais/patologia , Proteína da Polipose Adenomatosa do Colo/genética , Fosfatidilinositol 3-Quinases/metabolismo , Transplante Isogênico , Mutação , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologiaRESUMO
BACKGROUND: Epithelioid haemangioendothelioma (EHE) is an ultra-rare malignant vascular tumour with a prevalence of 1 per 1,000,000. It is typically molecularly characterised by a WWTR1::CAMTA1 gene fusion in approximately 90% of cases, or a YAP1::TFE3 gene fusion in approximately 10% of cases. EHE cases are typically refractory to therapies, and no anticancer agents are reimbursed for EHE in Australia. METHODS: We report a cohort of nine EHE cases with comprehensive histologic and molecular profiling from the Walter and Eliza Hall Institute of Medical Research Stafford Fox Rare Cancer Program (WEHI-SFRCP) collated via nation-wide referral to the Australian Rare Cancer (ARC) Portal. The diagnoses of EHE were confirmed by histopathological and immunohistochemical (IHC) examination. Molecular profiling was performed using the TruSight Oncology 500 assay, the TruSight RNA fusion panel, whole genome sequencing (WGS), or whole exome sequencing (WES). RESULTS: Molecular analysis of RNA, DNA or both was possible in seven of nine cases. The WWTR1::CAMTA1 fusion was identified in five cases. The YAP1::TFE3 fusion was identified in one case, demonstrating unique morphology compared to cases with the more common WWTR1::CAMTA1 fusion. All tumours expressed typical endothelial markers CD31, ERG, and CD34 and were negative for pan-cytokeratin. Cases with a WWTR1::CAMTA1 fusion displayed high expression of CAMTA1 and the single case with a YAP1::TFE3 fusion displayed high expression of TFE3. Survival was highly variable and unrelated to molecular profile. CONCLUSIONS: This cohort of EHE cases provides molecular and histopathological characterisation and matching clinical information that emphasises the molecular patterns and variable clinical outcomes and adds to our knowledge of this ultra-rare cancer. Such information from multiple studies will advance our understanding, potentially improving treatment options.
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In the present study, we have examined the effect of perforin (pfp) deficiency in 4 models of mouse B-cell lymphomagenesis. We have examined pfp loss on the background of either Mlh1 tumor suppressor allele loss or oncogene expression [Ig heavy chain (Emu)-v-Abl, Emu-myc, and vav-bcl2]. Pfp was shown to act as a suppressor of B-cell malignancies characteristically driven by v-Abl or bcl-2, whereas Mlh loss cooperated in accelerating spontaneous B-cell lymphomas characteristic of pfp loss. No protective role for pfp was observed in the more aggressive Emu-myc model of B-cell lymphoma. These transgenic models have allowed us to distinguish the role of pfp in surveillance of B-cell lymphomagenesis, as opposed to its loss simply driving the onset of a spontaneous lymphoma characteristic of pfp deficiency.
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Linfoma de Células B/genética , Perforina/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linfoma de Células B/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteína 1 Homóloga a MutL , Proteínas Nucleares/genética , Proteínas Oncogênicas v-abl/genética , Plasmocitoma/genética , Transplante Heterólogo , Proteína Supressora de Tumor p53/genéticaRESUMO
CD1d-restricted T cells are considered to play a host protective effect in tumor immunity, yet the evidence for a role of natural killer T (NKT) cells in tumor immune surveillance has been weak and data from several tumor models has suggested that some (type II) CD1d-restricted T cells may also suppress some types of antitumor immune response. To substantiate an important role for CD1d-restricted T cells in host response to cancer, we have evaluated tumor development in p53(+/-) mice lacking either type I NKT cells (TCR Jalpha18(-/-)) or all CD1d-restricted T cells (CD1d(-/-)). Our findings support a key role for type I NKT cells in suppressing the onset of sarcomas and hematopoietic cancers caused by p53 loss but do not suggest that other CD1d-restricted T cells are critical in regulating the same tumor development.
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Deleção de Genes , Genes p53 , Vigilância Imunológica , Células T Matadoras Naturais/imunologia , Neoplasias Experimentais/imunologia , Síndromes Neoplásicas Hereditárias/imunologia , Subpopulações de Linfócitos T/imunologia , Envelhecimento/imunologia , Animais , Antígenos CD1d/genética , Cruzamentos Genéticos , Feminino , Genes Codificadores da Cadeia alfa de Receptores de Linfócitos T , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/classificação , Neoplasias Experimentais/genética , Síndromes Neoplásicas Hereditárias/genética , Organismos Livres de Patógenos Específicos , Subpopulações de Linfócitos T/classificação , Carga TumoralRESUMO
BACKGROUND AND PURPOSE: The chemotherapy exposure during chemoradiotherapy for rectal cancer is adequate for radiosensitization but suboptimal for treatment of distant micrometastasis. This study aimed to determine tolerability, dose intensity, response, and toxicity of a novel intensified neoadjuvant treatment approach. MATERIALS AND METHODS: Eligible patients were MRI-staged T3-4NxM0 rectal adenocarcinoma. Treatment consisted of FOLFOX chemotherapy given in weeks 1, 6, and 11 with pelvic radiotherapy (25.2 Gy in 3 weeks in 1.8 Gy/fraction with oxaliplatin and 5-FU continuous infusion) given in weeks 3-5, and weeks 8-10. Surgery was performed 4-6 weeks later. The primary endpoint was tolerability defined as the percentage of patients who were able to complete the planned treatment course. Survival rates were estimated using the Kaplan-Meier method. RESULTS: Median age of the 40 patients was 61.5 years. Rectal MRI-stage was T3 in 88%. Overall, 95% completed the regimen. All patients received 50.4 Gy. Relative dose intensity (≥75%) was 92% and 98% for oxaliplatin and 5-FU, respectively. High grade toxicities included neutropenia (25% grade 3; 7.5% grade 4) and diarrhoea (10%). Pathologic CR rate was 20%. Median follow-up was 54 months. The 5-year overall survival, freedom from relapse, locoregional control, and freedom from distant metastasis of the cohort was 82%, 72%, 97% and 72%. CONCLUSIONS: Delivery of intensified neoadjuvant treatment with interdigitating chemotherapy and radiotherapy is feasible with no increase in acute perioperative complications. A larger prospective study is required to further evaluate the potential survival benefit of this design.
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Terapia Neoadjuvante , Neoplasias Retais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Leucovorina/efeitos adversos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Oxaliplatina , Estudos Prospectivos , Neoplasias Retais/patologia , Resultado do TratamentoRESUMO
BACKGROUND: The use of neoadjuvant therapy, in particular chemoradiotherapy (CRT), in the treatment of esophageal cancer (EC) remains controversial. The ability to predict treatment response in an individual EC patient would greatly aid therapeutic planning. Gene expression profiles of EC were measured and relationship to therapeutic response assessed. METHODS: Tumor biopsy samples taken from 46 EC patients before neoadjuvant CRT were analyzed on 10.5K cDNA microarrays. Response to treatment was assessed and correlated to gene expression patterns by using a support vector machine learning algorithm. RESULTS: Complete clinical response at conclusion of CRT was achieved in 6 of 21 squamous cell carcinoma (SCC) and 11 of 25 adenocarcinoma (AC) patients. CRT response was an independent prognostic factor for survival (P < .001). A range of support vector machine models incorporating 10 to 1000 genes produced a predictive performance of tumor response to CRT peaking at 87% in SCC, but a distinct positive prediction profile was unobtainable for AC. A 32-gene classifier was produced, and by means of this classifier, 10 of 21 SCC patients could be accurately identified as having disease with an incomplete response to therapy, and thus unlikely to benefit from neoadjuvant CRT. CONCLUSIONS: Our study identifies a 32-gene classifier that can be used to predict response to neoadjuvant CRT in SCC. However, because of the molecular diversity between the two histological subtypes of EC, when considering the AC and SCC samples as a single cohort, a predictive profile could not be resolved, and a negative predictive profile was observed for AC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/terapia , Terapia Neoadjuvante , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Adenocarcinoma/terapia , Idoso , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundário , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/radioterapia , Esofagectomia , Feminino , Perfilação da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Taxa de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVES: To investigate the spectrum of growth rates in melanomas and to identify clinical associations of rapidly growing melanomas. DESIGN: Clinical interview, skin examination, and pathology review. SETTING: Three tertiary melanoma referral centers and 2 private dermatology practices. PATIENTS: A total of 404 consecutive patients with invasive primary cutaneous melanomas. MAIN OUTCOME MEASURE: A surrogate for rate of growth in primary invasive melanoma was calculated as the ratio of Breslow thickness to time to melanoma development based on a previously reported assessment tool. RESULTS: One third of the melanomas grew 0.5 mm per month or more. The median monthly growth rate was 0.12 mm for superficial spreading melanomas, 0.13 mm for lentigo maligna melanomas, and 0.49 mm for nodular melanomas. Rapid tumor growth was associated with tumor thickness (
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Melanoma/patologia , Neoplasias Cutâneas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Inquéritos e QuestionáriosRESUMO
UNLABELLED: Standard pretreatment staging for gastric cancer includes CT of the chest, abdomen, and pelvis; gastroscopy; and laparoscopy. Although (18)F-PET combined with CT has proven to be a useful staging tool in many cancers, some gastric cancers are not (18)F-FDG-avid and its clinical value is still debatable. METHODS: Gastric cancer patients who underwent staging (18)F-FDG PET scans from 2002 to 2013 at the Peter MacCallum Cancer Center were retrospectively analyzed, and a systematic review was also conducted using PubMed between 2000 to March 2014 to investigate clinicopathologic parameters associated with (18)F-FDG avidity. A pretreatment PET scoring system was developed from predictors of (18)F-FDG avidity. RESULTS: Both the retrospective analysis of the patients and the systematic literature review showed similar significant predictors of (18)F-FDG avidity, including large tumor size, non-signet ring cell carcinoma type, and glucose transporter 1-positive expression on immunohistochemistry. A PET scoring system was developed from these clinicopathologic parameters that allowed (18)F-FDG-avid tumors to be detected with a sensitivity of 85% and a specificity of 71%. CONCLUSION: A pretreatment PET scoring system can assist in the selection of patients with gastric adenocarcinoma when staging (18)F-FDG PET is being considered.
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Fluordesoxiglucose F18 , Estadiamento de Neoplasias/métodos , Seleção de Pacientes , Tomografia por Emissão de Pósitrons/métodos , Neoplasias Gástricas/diagnóstico por imagem , Adenocarcinoma/diagnóstico , Adenocarcinoma/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/diagnóstico , Carcinoma/diagnóstico por imagem , Carcinoma de Células em Anel de Sinete/diagnóstico , Carcinoma de Células em Anel de Sinete/diagnóstico por imagem , Feminino , Transportador de Glucose Tipo 1/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Estudos Prospectivos , Estudos Retrospectivos , Sensibilidade e Especificidade , Neoplasias Gástricas/diagnósticoRESUMO
PURPOSE: Patients presenting with locally advanced rectal cancer currently receive preoperative radiotherapy with or without chemotherapy. Although pathologic complete response is achieved for approximately 10% to 30% of patients, a proportion of patients derive no benefit from this therapy while being exposed to toxic side effects of treatment. Therefore, there is a strong need to identify patients who are unlikely to benefit from neoadjuvant therapy to help direct them toward alternate and ultimately more successful treatment options. EXPERIMENTAL DESIGN: In this study, we obtained expression profiles from pretreatment biopsies for 51 rectal cancer patients. All patients underwent preoperative chemoradiotherapy, followed by resection of the tumor 6 to 8 weeks posttreatment. Gene expression and response to treatment were correlated, and a supervised learning algorithm was used to generate an original predictive classifier and validate previously published classifiers. RESULTS: Novel predictive classifiers based on Mandard's tumor regression grade, metabolic response, TNM (tumor node metastasis) downstaging, and normal tissue expression profiles were generated. Because there were only 7 patients who had minimal treatment response (>80% residual tumor), expression profiles were used to predict good tumor response and outcome. These classifiers peaked at 82% sensitivity and 89% specificity; however, classifiers with the highest sensitivity had poor specificity, and vice versa. Validation of predictive classifiers from previously published reports was attempted using this cohort; however, sensitivity and specificity ranged from 21% to 70%. CONCLUSIONS: These results show that the clinical utility of microarrays in predictive medicine is not yet within reach for rectal cancer and alternatives to microarrays should be considered for predictive studies in rectal adenocarcinoma.
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Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Farmacológicos/análise , Biomarcadores Farmacológicos/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Terapia Combinada , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Terapia Neoadjuvante , Prognóstico , Neoplasias Retais/diagnóstico , Neoplasias Retais/genética , Fatores de TempoRESUMO
Parathyroid hormone-related protein (PTHrP) is required for mammary gland development and promotes the growth of breast cancer metastases within bone. However, there are conflicting reports of the prognostic significance of its expression in primary breast cancers. To study the role of PTHrP in early breast cancer, the effect of conditional deletion of PTHrP was examined in the context of neu-induced mammary tumorigenesis. Loss of PTHrP resulted in a higher tumor incidence. Transcriptional profiling of the tumors revealed that PTHrP influenced genes relevant to heterotypic cell signaling, including regulators of monocyte recruitment. Immunohistochemical analysis of human breast cancers revealed that PTHrP expression was associated with both HER-2/neu expression and macrophage infiltration in preinvasive ductal carcinoma in situ. The gene expression signature associated with loss of PTHrP expression in vivo correlated with poorer outcome in human breast cancer. Together, these data indicate that loss of PTHrP accelerates mammary tumorigenesis possibly by a non-cell-autonomous tumor suppressor pathway.
Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Intraductal não Infiltrante/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Monócitos/imunologia , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Animais , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/genética , Carcinoma Intraductal não Infiltrante/imunologia , Carcinoma Intraductal não Infiltrante/patologia , Feminino , Deleção de Genes , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Masculino , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Vírus do Tumor Mamário do Camundongo/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Monócitos/patologia , Proteína Relacionada ao Hormônio Paratireóideo/deficiência , Proteína Relacionada ao Hormônio Paratireóideo/genética , Receptor ErbB-2/biossínteseRESUMO
In this study we aimed to determine the suitability of the Lewis-Y carbohydrate antigen as a target for immunotherapy using genetically redirected T cells. Using the 3S193 monoclonal antibody and immunohistochemistry, Lewis-Y was found to be expressed on a range of tumors including 42% squamous cell lung carcinoma, 80% lung adenocarcinoma, 25% ovarian carcinoma, and 25% colorectal adenocarcinoma. Expression levels varied from low to intense on between 1% and 90% of tumor cells. Lewis- was also found in soluble form in sera from both normal donors and cancer patients using a newly developed enzyme-linked immunosorbent assay. Serum levels in patients was often less than 1 ng/mL, similar to normal donors, but approximately 30% of patients had soluble Lewis-Y levels exceeding 1 ng/mL and up to 9 ng/mL. Lewis-Y-specific human T cells were generated by genetic modification with a chimeric receptor encoding a single-chain humanized antibody linked to the T-cell signaling molecules, T-cell receptor-zeta, and CD28. T cells responded against the Lewis-Y antigen by cytokine secretion and cytolysis in response to tumor cells. Importantly, the T-cell response was not inhibited by patient serum containing soluble Lewis-Y. This study demonstrates that Lewis-Y is expressed on a large number of tumors and Lewis-Y-specific T cells can retain antitumor function in the presence of patient serum, indicating that this antigen is a suitable target for this form of therapy.
Assuntos
Antígenos de Neoplasias/imunologia , Imunoterapia Adotiva , Antígenos do Grupo Sanguíneo de Lewis/imunologia , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/transplante , Antígenos de Neoplasias/sangue , Antígenos de Neoplasias/genética , Linhagem Celular Tumoral , Citotoxicidade Imunológica/imunologia , Humanos , Interferon gama/biossíntese , Interferon gama/imunologia , Antígenos do Grupo Sanguíneo de Lewis/sangue , Antígenos do Grupo Sanguíneo de Lewis/genética , Neoplasias/patologia , Linfócitos T/imunologia , Transdução GenéticaRESUMO
Esophageal cancer is a particularly aggressive tumor with poor prognosis, however, our current knowledge of the genes and pathways involved in tumorigenesis of the esophagus are limited. To obtain insight into the molecular processes underlying tumorigenesis of the esophagus, we have used cDNA microarrays to compare the gene expression profiles of 128 tissue samples representing the major histological subtypes of esophageal cancer (squamous cell carcinoma and adenocarcinoma (ADC)) as well as Barrett's esophagus (BE), the precursor lesion to ADC, and normal esophageal epithelium. Linear discriminant analysis and unsupervised hierarchical clustering show the separation of samples into 4 distinct groups consistent with their histological subtype. Differentially expressed genes were identified between each of the tissue types. Comparison of gene ontologies and gene expression profiles identified gene profiles specific to esophageal cancer, as well as BE. "Esophageal cancer clusters," representing proliferation, immune response, and extracellular matrix genes were identified, as well as digestion, hydrolase, and transcription factor clusters specific to the columnar phenotype observed during BE and esophageal ADC. These clusters provide valuable insight into the molecular and functional differences between normal esophageal epithelium, BE, and the 2 histologically distinct forms of esophageal cancers. Our thorough, unbiased analysis provides a rich source of data for further studies into the molecular basis of tumorigenesis of the esophagus, as well as identification of potential biomarkers for early detection of progression.
Assuntos
Adenocarcinoma/genética , Esôfago de Barrett/genética , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Análise por Conglomerados , Humanos , Análise de Sequência com Séries de OligonucleotídeosRESUMO
The BRAF(T1799A) mutation encodes BRAF(V600E) that leads to activation of the mitogen-activated protein kinase pathway. This study aimed to assess the clinico-pathological features of primary invasive melanomas containing the BRAF(T1799A) mutation. Patients (n=251) with invasive primary melanomas from Australia were interviewed and examined with respect to their melanoma characteristics and risk factors. Independent review of pathology, allele-specific PCR for the BRAF(T1799A) mutation, immunohistochemical staining with Ki67, and phospho-histone-H3 (PH3) were performed. The BRAF(T1799A) mutation was found in 112 (45%) of the primary melanomas. Associations with the BRAF(T1799A) mutation (P<0.05) were as follows: low tumor thickness (odds ratio (OR)=3.3); low mitotic rate (OR=2.0); low Ki67 score (OR=5.0); low PH3 score (OR=3.3); superficial spreading melanoma (OR=10.0); pigmented melanoma (OR=3.7); a lack of history of solar keratoses (OR=2.7); a location on the trunk (OR=3.4) or extremity (OR=2.0); a high level of self-reported childhood sun exposure (OR=2.0); < or =50 years of age (OR=2.5); and fewer freckles (OR=2.5). We conclude that the BRAF(T1799A) mutation has associations with host phenotype, tumor location, and pigmentation. Although implicated in the control of the cell cycle, the BRAF(T1799A) mutation is associated with a lower rate of tumor proliferation.