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1.
Biomacromolecules ; 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39189480

RESUMO

Mass cytometry (MC), a powerful single-cell analysis technique, has limitations in detecting low-abundance biomarkers. Nanoparticle (NP) reagents offer the potential for enhancing sensitivity by carrying large numbers of heavy metal isotopes. Here, we report NP reporters for imaging mass cytometry (IMC) based on NaYF4:Yb3+/Er3+ NPs. A two-step ligand exchange was used to coat NP surfaces with either methoxy-PEG2K-neridronate (PEG-Ner) and/or poly(sulfobetaine methacrylate)-neridronate (PSBMA-Ner). Both modifications provided long-term colloidal stability in PBS buffer. IMC measurements on tonsil tissue showed that PSBMA-Ner or a 1:1 mixture of PSBMA-Ner + PEG-Ner effectively suppressed nonspecific binding (NSB) at 2 × 1010 NPs/mL, unlike PEG-Ner alone. However, breast cancer tissue samples showed increased NSB at titers above 2 × 1010 NPs/mL. Reduced NSB with mixed PEG-Ner and PSBMA-Ner coatings opens the door for using heterobifunctional PEGs for the development of NP conjugates with bioaffinity agents, enabling more sensitive and specific MC analyses.

2.
Mol Pharm ; 20(1): 582-592, 2023 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-36516432

RESUMO

In this study, we investigated convection-enhanced delivery (CED) of 23 ± 3 nm gold nanoparticles (AuNPs) labeled with the ß-particle-emitting radionuclide 177Lu (177Lu-AuNPs) for treatment of orthotopic U251-Luc human glioblastoma multiforme (GBM) tumors in NRG mice. The cytotoxicity in vitro of 177Lu-AuNPs (0.0-2.0 MBq, 4 × 1011 AuNPs) on U251-Luc cells was also studied by a clonogenic survival assay, and DNA double-strand breaks (DSBs) caused by ß-particle emissions of 177Lu were measured by confocal immunofluorescence microscopy for γH2AX. NRG mice with U251-Luc tumors in the right cerebral hemisphere of the brain were treated by CED of 1.1 ± 0.2 MBq of 177Lu-AuNPs (4 × 1011 AuNPs). Control mice received unlabeled AuNPs or normal saline. Tumor retention of 177Lu-AuNPs was assessed by single-photon emission computed tomography/computed tomography (SPECT/CT) imaging and biodistribution studies. Radiation doses were estimated for the tumor, brain, and other organs. The effectiveness for treating GBM tumors was determined by bioluminescence imaging (BLI) and T2-weighted magnetic resonance imaging (MRI) and by Kaplan-Meier median survival. Normal tissue toxicity was assessed by monitoring body weight and hematology and blood biochemistry analyses at 14 d post-treatment. 177Lu-AuNPs (2.0 MBq, 4 × 1011 AuNPs) decreased the clonogenic survival of U251-Luc cells to 0.005 ± 0.002 and increased DNA DSBs by 14.3-fold compared to cells treated with unlabeled AuNPs or normal saline. A high proportion of 177Lu-AuNPs was retained in the U251-Luc tumor in NRG mice up to 21 d with minimal re-distribution to the brain or other organs. The radiation dose in the tumor was high (599 Gy). The dose in the normal right cerebral hemisphere of the brain excluding the tumor was 93-fold lower (6.4 Gy), and 2000-3000-fold lower doses were calculated for the contralateral left cerebral hemisphere (0.3 Gy) or cerebellum (0.2 Gy). The doses in peripheral organs were <0.1 Gy. BLI revealed almost complete tumor growth arrest in mice treated with 177Lu-AuNPs, while tumors grew rapidly in control mice. MRI at 28 d post-treatment and histological staining showed no visible tumor in mice treated with 177Lu-AuNPs but large GBM tumors in control mice. All control mice reached a humane endpoint requiring sacrifice within 39 d (normal saline) or 45 d post-treatment (unlabeled AuNPs), while 5/8 mice treated with 177Lu-AuNPs survived up to 150 d. No normal tissue toxicity was observed in mice treated with 177Lu-AuNPs. We conclude that CED of 177Lu-AuNPs was highly effective for treating U251-Luc human GBM tumors in the brain in NRG mice at amounts that were non-toxic to normal tissues. These 177Lu-AuNPs administered by CED hold promise for treating patients with GBM to prevent recurrence and improve long-term outcome.


Assuntos
Glioblastoma , Nanopartículas Metálicas , Humanos , Animais , Camundongos , Ouro , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Distribuição Tecidual , Convecção , Solução Salina , Radioisótopos/uso terapêutico , Linhagem Celular Tumoral , DNA
3.
Arch Pathol Lab Med ; 147(7): 797-807, 2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-36191342

RESUMO

CONTEXT.­: Although several neuroendocrine cell types constitute gastroenteropancreatic neuroendocrine tumors (NETs), the clinical and prognostic implications of the expression of multiple peptide hormones have not been comprehensively evaluated in rectal NETs. OBJECTIVE.­: To identify the clinicopathologic characteristics and prognostic impact of peptide hormone expression. DESIGN.­: We evaluated the expression of peptide YY (PYY), glucagon, somatostatin, serotonin, insulin, and gastrin using immunolabeling in 446 endoscopically or surgically resected rectal NETs. RESULTS.­: PYY, glucagon, serotonin, somatostatin, insulin, and gastrin were expressed in 261 of 389 (67.1%), 205 of 446 (46.0%), 36 of 446 (8.1%), 33 of 446 (7.4%), 2 of 446 (0.4%), and 1 of 446 cases (0.2%), respectively. Immunoreactivity to any peptide hormone was present in 345 of 446 cases (77.4%). Tumors expressing serotonin or somatostatin were associated with lymphovascular invasion, chromogranin A expression, and shorter disease-free survival (DFS). Rectal NETs were classified as L-cell, enterochromaffin-cell, D-cell, null-expression, or mixed-expression type based on peptide hormonal expression status. Patients with D-cell NET had the shortest DFS (10-year DFS, 54.5%), followed by those with enterochromaffin-cell NET (89.5%), null expression (97.0%), L-cell NET (99.6%), and mixed-expression NET (100%; P < .001). Multivariable analyses revealed that somatostatin expression was an independent indicator of poor prognosis with respect to DFS in rectal NETs (P = .001). CONCLUSIONS.­: Somatostatin expression is a poor prognostic indicator in patients with rectal NETs. Therefore, additional peptide hormonal immunolabeling, including somatostatin, serotonin, and PYY, in rectal NETs can provide more information regarding DFS.


Assuntos
Tumores Neuroendócrinos , Neoplasias Retais , Humanos , Tumores Neuroendócrinos/patologia , Glucagon , Gastrinas , Serotonina , Somatostatina/metabolismo , Insulina
4.
Pancreatology ; 22(3): 427-434, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35292233

RESUMO

BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) are frequently detected on endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) specimens. The conventional methods for evaluating the Ki-67 labeling index (Ki67LI) in EUS-FNAB specimens are laborious, and their results are difficult to interpret. More practical and easy methods for evaluating the Ki67LI in PanNETs from EUS-FNAB specimens is increasing in need. METHODS: We used double Ki-67 and synaptophysin (double Ki-Syn) antibody cocktail; Ki67LI, total Ki-67 positive cells, and total tumor cells were counted and compared with those detected on conventional single Ki-67 immunostaining (single Ki-67) of 96 PanNETs [Grade 1 (G1), 68 cases (71%); G2, 26 (27%); G3, 2 (2%)] from EUS-FNAB specimens. RESULTS: The tumor grading between double Ki-Syn and single Ki-67 immunolabeling was highly concordant (correlation, 0.95; Fisher's exact test, P < 0.001). Seven EUS-FNAB specimens (7%) had discrepant results, of which 2 were removed through surgical resection and showed the same tumor grade as that detected on double Ki-Syn immunolabeling. Fifty-four specimens (56%) had higher Ki-67 positive tumor cell counts on single Ki-67 immunolabeling. Sixty-two specimens (65%) had higher total tumor cell counts on double Ki-Syn immunolabeling. The number of specimens with less than 500 total counted tumor cells were significantly reduced when double Ki-Syn immunolabeling was applied [P = 0.046; single Ki-67, 17 specimens (18%); double Ki-Syn, 9 specimens (9%)]. CONCLUSION: Double Ki-Syn immunolabeling enables the accurate counting of the number of proliferating tumor cells without including inflammatory and contaminant epithelial cells compared with single Ki-67 immunolabeling in PanNETs from EUS-FNAB specimens.


Assuntos
Tumores Neuroendócrinos , Neoplasias Pancreáticas , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Humanos , Antígeno Ki-67 , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Sinaptofisina
5.
Pancreatology ; 20(7): 1486-1494, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32948429

RESUMO

OBJECTIVES: Venous invasion is a poor prognostic factor for pancreatic ductal adenocarcinoma (PDAC). However, our understanding of various features of venous invasion is limited. Our aim is to comprehensively evaluate various histopathologic features of venous invasion, including status, type (lymphatic or venous), number of invasion foci, and histologic pattern (pancreatic intraepithelial neoplasia [PanIN]-like, conventional) in PDACs. METHODS: Various features of venous invasion, including status, number of invasion foci, histologic patterns [pancreatic intraepithelial neoplasia (PanIN)-like, conventional], and size of involved vessels in 471 surgically resected PDACs were evaluated with all available hematoxylin and eosin (H&E)-stained slides. RESULTS: Venous invasion was observed in 319 cases (67.7%) and was more frequently associated with increased tumor size, extrapancreatic extension, resection margin involvement, diffuse tumor distribution, lymph node metastasis, and perineural invasion (all Ps < .05). High frequency (≥3 foci) of venous invasion was associated with shorter overall survival both in the entire group and in the early stage subgroup (stage I; all Ps < .05). Multivariate analysis indicated that a high frequency (≥3 foci) of venous invasion, large tumor size (>4 cm), higher histologic grade, and lymph node metastasis, were independent prognostic factors of worse overall survival (all Ps < .05). CONCLUSION: Precise evaluation of venous invasion status, including foci number of invasion, can provide additional prognostic information for patients undergoing surgical resection of PDAC, especially for those with early disease stage.


Assuntos
Carcinoma Ductal Pancreático/irrigação sanguínea , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/cirurgia , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática/patologia , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias Pancreáticas/cirurgia , Prognóstico , Fluxo Sanguíneo Regional , Análise de Sobrevida , Veias/patologia
6.
J Pathol Transl Med ; 54(5): 387-395, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32683855

RESUMO

BACKGROUND: Although lymph node metastasis is a poor prognostic factor in patients with pancreatic ductal adenocarcinoma (PDAC), our understanding of lymph node size in association with PDAC is limited. Increased nodal size in preoperative imaging has been used to detect node metastasis. We evaluated whether lymph node size can be used as a surrogate preoperative marker of lymph node metastasis. METHODS: We assessed nodal size and compared it to the nodal metastatic status of 200 patients with surgically resected PDAC. The size of all lymph nodes and metastatic nodal foci were measured along the long and short axis, and the relationships between nodal size and metastatic status were compared at six cutoff points. RESULTS: A total of 4,525 lymph nodes were examined, 9.1% of which were metastatic. The mean size of the metastatic nodes (long axis, 6.9±5.0 mm; short axis, 4.3±3.1 mm) was significantly larger than that of the non-metastatic nodes (long axis, 5.0±4.0 mm; short axis, 3.0±2.0 mm; all p<.001). Using a 10 mm cutoff, the sensitivity, specificity, positive predictive value, overall accuracy, and area under curve was 24.8%, 88.0%, 17.1%, 82.3%, and 0.60 for the long axis and 7.0%, 99.0%, 40.3%, 90.6%, and 0.61 for the short axis, respectively. CONCLUSIONS: The metastatic nodes are larger than the non-metastatic nodes in PDAC patients. However, the difference in nodal size was too small to be identified with preoperative imaging. The performance of preoperative radiologic imaging to predict lymph nodal metastasis was not good. Therefore, nodal size cannot be used a surrogate preoperative marker of lymph node metastasis.

7.
Nucl Med Biol ; 84-85: 11-19, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31931305

RESUMO

INTRODUCTION: Desferrioxamine (DFO) is conjugated to antibodies to chelate 89Zr for PET, but DFO forms a hexadentate complex with Zr4+ that exhibits instability contributing to bone uptake of 89Zr, while the cationic charge of the Zr4+-DFO complex may promote normal tissue uptake of the radioimmunoconjugates (RICs). DFO* is a novel chelator that forms a more stable octadentate and neutral complex with 89Zr. Our aim was to compare the in vitro stability of [89Zr]Zr-DFO*-human IgG (hIgG) and [89Zr]Zr-DFO-hIgG RICs, and the in vivo PET imaging properties of the antibody-drug conjugate (ADC), trastuzumab-DM1 (T-DM1), labeled with 89Zr by conjugation to DFO or DFO*. METHODS: SCN-pPhe-DFO and SCN-pPhe-DFO* were reacted with hIgG at a 14.6-fold excess or with T-DM1 at a 4.1-fold or 10-fold excess, respectively, purified and labeled with 89Zr. The number of DFO* introduced was determined by measuring the absorbance at 245/252 nm and the protein concentration was measured at 280 nm. The stability of [89Zr]Zr-DFO*-hIgG was studied in vitro in human plasma, and by challenge with a 385-fold excess (0.1 mM) of DFO or EDTA. An inverse stability study was performed with [89Zr]Zr-DFO-hIgG challenged with 0.1 mM DFO*. The HER2 binding affinity of [89Zr]Zr-DFO*-T-DM1 was measured in a direct (saturation) binding assay using SK-BR-3 human breast cancer cells or SK-OV-3 human ovarian cancer cells. The biodistribution of [89Zr]Zr-DFO*-T-DM1 and [89Zr]Zr-DFO-T-DM1 were compared in non-tumor bearing Balb/c mice and in NOD/SCID mice with s.c. SK-OV-3 xenografts at 96 h post-intravenous injection (p.i.). MicroPET/CT images were obtained at 96 h p.i. of the RICs. RESULTS: hIgG and T-DM1 were conjugated to 4.5-5.3 and 3.1 chelators (DFO or DFO*), respectively, and labeled with 89Zr to a final radiochemical purity of 91-99%. [89Zr]Zr-DFO*-hIgG was stable in vitro in human plasma or to challenge with 0.1 mM EDTA, but incubation with 0.1 mM DFO caused 26.0 ± 2.1% loss of 89Zr after 5 days. In contrast, incubation of [89Zr]Zr-DFO-hIgG with 0.1 mM DFO* resulted in 77.0 ± 3.9% loss of 89Zr after 5 days. [89Zr]Zr-DFO*-T-DM1 retained high affinity binding to HER2 on SK-BR-3 and SK-OV-3 cells with a Kd = 2.2 ± 0.3 nM and 1.9 ± 0.3 nM, respectively, and Bmax = 3.4 ± 0.1 × 105 and 1.1 ± 0.04 × 105 receptors/cell, respectively. Biodistribution studies of [89Zr]Zr-DFO-T-DM1 and [89Zr]Zr-DFO*-T-DM1 in Balb/c and NOD/SCID mice revealed significantly lower uptake in bone, liver, kidneys, and spleen for [89Zr]Zr-DFO*-T-DM1 than [89Zr]Zr-DFO-T-DM1. Uptake of [89Zr]Zr-DFO*-T-DM1 and [89Zr]Zr-DFO-T-DM1 in SK-OV-3 tumors was moderate [5.0 ± 1.8% injected dose/g (%ID/g) and 6.3 ± 0.6%ID/g, respectively; P = 0.18]. Tumors were imaged with both RICs. CONCLUSION: We conclude that DFO* conjugated to T-DM1 provides more stable complexation of 89Zr and therefore, [89Zr]Zr-DFO*-T-DM1 would be more useful than [89Zr]Zr-DFO-T-DM1 to probe the delivery of T-DM1 to tumors by PET, which we previously found is correlated with response to treatment with T-DM1 in mouse tumor xenograft models. ADVANCES IN KNOWLEDGE AND IMPLICATION FOR PATIENT CARE: This study is the first to directly compare the PET imaging properties of [89Zr]Zr-DFO*-T-DM1 and [89Zr]Zr-DFO-T-DM1 in a HER2-overexpressing tumor xenograft mouse model. Our results indicate that [89Zr]Zr-DFO*-T-DM1 provides superior imaging properties due to the greater stability of the [89Zr]Zr-DFO* than [89Zr]Zr-DFO complex.


Assuntos
Ado-Trastuzumab Emtansina/química , Desferroxamina/química , Imunoconjugados/química , Neoplasias Ovarianas/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Receptor ErbB-2/metabolismo , Animais , Transporte Biológico , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Feminino , Humanos , Imunoconjugados/farmacocinética , Camundongos , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/metabolismo , Radioquímica , Radioisótopos/química , Distribuição Tecidual , Zircônio/química
8.
Angle Orthod ; 89(5): 768-774, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30896249

RESUMO

OBJECTIVES: To identify the most characteristic variables out of a large number of anatomic landmark variables on three-dimensional computed tomography (CT) images. A modified principal component analysis (PCA) was used to identify which anatomic structures would demonstrate the major variabilities that would most characterize the patient. MATERIALS AND METHODS: Data were collected from 217 patients with severe skeletal Class III malocclusions who had undergone orthognathic surgery. The input variables were composed of a total of 740 variables consisting of three-dimensional Cartesian coordinates and their Euclidean distances of 104 soft tissue and 81 hard tissue landmarks identified on the CT images. A statistical method, a modified PCA based on the penalized matrix decomposition, was performed to extract the principal components. RESULTS: The first 10 (8 soft tissue, 2 hard tissue) principal components from the 740 input variables explained 63% of the total variance. The most conspicuous principal components indicated that groups of soft tissue variables on the nose, lips, and eyes explained more variability than skeletal variables did. In other words, these soft tissue components were most representative of the differences among the Class III patients. CONCLUSIONS: On three-dimensional images, soft tissues had more variability than the skeletal anatomic structures. In the assessment of three-dimensional facial variability, a limited number of anatomic landmarks being used today did not seem sufficient. Nevertheless, this modified PCA may be used to analyze orthodontic three-dimensional images in the future, but it may not fully express the variability of the patients.


Assuntos
Má Oclusão Classe III de Angle , Cirurgia Ortognática , Procedimentos Cirúrgicos Ortognáticos , Pontos de Referência Anatômicos , Cefalometria , Humanos , Imageamento Tridimensional , Mandíbula , Análise de Componente Principal
9.
Pancreas ; 48(3): 400-411, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30747828

RESUMO

OBJECTIVE: Although complete surgical resection is the only curative method for pancreatic cancer, the radial resection margins of pylorus-preserving pancreaticoduodenectomy specimens might be underevaluated. METHODS: KRAS mutation was assessed with droplet digital polymerase chain reaction on cells collected from the radial resection margins of 81 patients, and the results were compared with those of conventional pathologic resection margin (pRM) evaluation. RESULTS: KRAS mutation was detected in 76 patients (94%), and molecular resection margin (mRM) positivity defined by a KRAS mutation rate of 4.19% or greater was observed in 18 patients (22%). Patients with mRM-positive had significantly worse recurrence-free survival (RFS) than those with mRM-negative in entire groups (P = 0.008) and in subgroups without chemotherapy or radiation therapy (all, P < 0.001). When combined pRMs-mRMs were evaluated, patients with combined pRM-mRM-positive (either pRM- or mRM-positive) had significantly worse RFS than those with combined resection margin-negative (both pRM and mRM negative) by univariate (P = 0.002) and multivariate (P = 0.03) analyses. CONCLUSIONS: KRAS mutational analysis with ultrasensitive droplet digital polymerase chain reaction of the radial resection margin in pancreatic cancer patients who underwent pylorus-preserving pancreaticoduodenectomy can provide more accurate information on RFS by using alone or in combination with conventional pRM evaluation, especially in patients without chemotherapy or radiation therapy.


Assuntos
Carcinoma Ductal Pancreático/cirurgia , Margens de Excisão , Mutação , Neoplasias Pancreáticas/cirurgia , Reação em Cadeia da Polimerase/métodos , Proteínas Proto-Oncogênicas p21(ras)/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/terapia , Quimiorradioterapia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Pancreaticoduodenectomia/métodos , Estudos Retrospectivos
10.
Surgery ; 163(5): 1071-1079, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29452703

RESUMO

BACKGROUND: The American Joint Committee on Cancer recently proposed the eighth edition of cancer staging system. Validation studies are required to evaluate the prognostic stratification of ampulla of Vater cancer patients. METHODS: In the study, 369 operatively resected patients with ampullary cancers were grouped based on the eighth T (T1a, limited to sphincter of Oddi; T1b, invasion to duodenal submucosa; T2, invasion to duodenal proper muscle; T3a, invasion to pancreas ≤0.5 cm; T3b, invasion to pancreas >0.5 cm; and T4, involvement of celiac axis or superior mesenteric artery) and N (N0, no nodal metastasis; N1, 1-3 nodal metastasis; and N2, ≥4 nodal metastasis) category of ampullary cancer staging. RESULTS: Overall 5-year survival rates for T and N categories were as followed: T1a, 83%; T1b, 71%; T2, 46%; T3a, 48%; T3b, 28.5%, T4, 7% (P< .001); N0, 44.8%; N1, 20%; N2, 4% (P < .001). Pair-wise comparisons demonstrated significant differences between T1a-b (P = .005), T3a-T3b (P = .03), N0-N1 (P < .001), and N1-N2 (P = .007) tumors, but not between T1b-T2 (P = .20), T2-T3a (P = .84), and T3b-T4 (P = .17) lesions. CONCLUSION: The eighth edition T category for ampullary cancer does not stratify patients accurately with regard to prognosis. Modification of the current T category with eliminating subcategories (T1, invasion to duodenal submucosa; T2, invasion to duodenal proper muscle; T3, invasion to pancreas or duodenal subserosa) is a better way for determining prognosis of ampullary cancer. The current N category segregates patient survival well.


Assuntos
Ampola Hepatopancreática/patologia , Carcinoma/patologia , Neoplasias do Ducto Colédoco/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/mortalidade , Neoplasias do Ducto Colédoco/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , República da Coreia/epidemiologia , Estudos Retrospectivos
11.
Lifetime Data Anal ; 22(1): 100-21, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25511333

RESUMO

Regarding survival data analysis in regression modeling, multiple conditional quantiles are useful summary statistics to assess covariate effects on survival times. In this study, we consider an estimation problem of multiple nonlinear quantile functions with right censored survival data. To account for censoring in estimating a nonlinear quantile function, weighted kernel quantile regression (WKQR) has been developed by using the kernel trick and inverse-censoring-probability weights. However, the individually estimated quantile functions based on the WKQR often cross each other and consequently violate the basic properties of quantiles. To avoid this problem of quantile crossing, we propose the non-crossing weighted kernel quantile regression (NWKQR), which estimates multiple nonlinear conditional quantile functions simultaneously by enforcing the non-crossing constraints on kernel coefficients. The numerical results are presented to demonstrate the competitive performance of the proposed NWKQR over the WKQR.


Assuntos
Análise de Regressão , Análise de Sobrevida , Algoritmos , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Simulação por Computador , Transplante de Coração/mortalidade , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Modelos Estatísticos , Método de Monte Carlo , Dinâmica não Linear
12.
Hum Pathol ; 45(11): 2341-6, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25248573

RESUMO

The T classification for pancreatic cancer of the American Joint Committee on Cancer may be inaccurate owing to lack of consideration of tumor size in cases of extension beyond the pancreas. To examine the accuracy of American Joint Committee on Cancer staging and to determine the prognostic implication of combined tumor size and extrapancreatic extension, 6145 cases of pancreatic ductal adenocarcinomas from the Surveillance, Epidemiology, and End Results database were categorized according to tumor size and extension as follows: group 1 (G1, ≤2 cm and limited to the pancreas), G2 (>2 cm and limited to the pancreas), G3 (≤2 cm with extrapancreatic extension), and G4 (>2 cm with extrapancreatic extension). The median survival of G1, G2, G3, and G4 were 23, 15, 19, and 14 months, respectively (P < .001), and the survival time in G3 was closer to that of G2 than G4. To test the classification system for accuracy of prognosis, G3 was merged with G2. The survival discrimination of this new grouping was greater (overall comparison, P < .001; G1 versus G2 + G3, P < .001; G2 + G3 versus G4, P < .001; χ(2) = 92.043) than that of the current T-classification scheme (overall comparison, P < .001; G1 versus G2, P < .001; G2 versus G3 + G4, P = .048; χ(2) = 60.424). To better discriminate survival, patients with a tumor less than or equal to 2 cm extending beyond the pancreas should be downstaged from the current class T3 to class T2.


Assuntos
Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/patologia , Idoso , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/cirurgia , Prognóstico , Taxa de Sobrevida
13.
Proteome Sci ; 12: 27, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24883046

RESUMO

BACKGROUND: Vascular endothelial growth factor (VEGF) is a critical pro-angiogenic factor, found in a number of cancers, and a target of therapy. It is typically assessed by immunohistochemistry (IHC) in clinical research. However, IHC is not a quantitative assay and is rarely reproducible. We compared VEGF levels in colon cancer by IHC and a quantitative immunoassay on proteins isolated from formalin fixed, paraffin embedded tissues. RESULTS: VEGF expression was studied by means of a well-based reverse phase protein array (RPPA) and immunohistochemistry in 69 colon cancer cases, and compared with various clinicopathologic factors. Protein lysates derived from formalin fixed, paraffin embedded tissue contained measurable immunoreactive VEGF molecules. The VEGF expression level of well differentiated colon cancer was significantly higher than those with moderately and poorly differentiated carcinomas by immunohistochemistry (P = 0.04) and well-based RPPA (P = 0.04). VEGF quantification by well-based RPPA also demonstrated an association with nodal metastasis status (P = 0.05). In addition, the normalized VEGF value by well-based RPPA correlated (r = 0.283, P = 0.018). Furthermore, subgroup analysis by histologic type revealed that adenocarcinoma cases showed significant correlation (r = 0.315, P = 0.031) between well-based RPPA and IHC. CONCLUSIONS: The well-based RPPA method is a high throughput and sensitive approach, is an excellent tool for quantification of marker proteins. Notably, this method may be helpful for more objective evaluation of protein expression in cancer patients.

14.
J Clin Pathol ; 67(3): 216-21, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24062356

RESUMO

AIMS: Due to the rarity of small intestine adenocarcinoma (SIAC), estimating the prognosis for patients with surgically resected SIAC is difficult. Overexpression of S100A4 has been linked to worse patient survival in several malignant neoplasms, but its significance in SIAC has not been determined. METHODS: S100A4 protein expression was assessed in 197 surgically resected SIAC cases and compared with clinicopathological factors, including patient survival. RESULTS: A progressive increase in S100A4 labelling was observed in normal intestinal epithelium, adenoma and adenocarcinoma (p<0.001), and 50 SIAC cases (26.2%) showed strong S100A4 expression. Patients with SIAC with strong S100A4 expression had a higher pT classification (p=0.05), as well as increased lymph node metastasis (p=0.009) and perineural invasion (p=0.002). Patients with SIAC with strong S100A4 expression had significantly worse survival (median survival, 21 months) than those with weak/no S100A4 expression (42.5 months) by univariable (p=0.04) and multivariable (p=0.01) analyses. CONCLUSIONS: S100A4 overexpression is observed in a subset of SIACs, is associated with advanced disease and can be used as a prognostic indicator of poor prognosis in patients with SIAC.


Assuntos
Adenocarcinoma/química , Biomarcadores Tumorais/análise , Neoplasias Intestinais/química , Intestino Delgado/química , Proteínas S100/análise , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Intestinais/mortalidade , Neoplasias Intestinais/patologia , Neoplasias Intestinais/cirurgia , Intestino Delgado/patologia , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Fatores de Risco , Proteína A4 de Ligação a Cálcio da Família S100 , Fatores de Tempo , Análise Serial de Tecidos , Resultado do Tratamento , Regulação para Cima , Adulto Jovem
15.
Surgery ; 155(1): 74-84, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24238122

RESUMO

BACKGROUND: Although the number of metastatic lymph nodes in most gastrointestinal carcinomas is correlated inversely with prognosis, the prognostic value of the number of metastatic lymph nodes in ampullary adenocarcinoma has not been well characterized. METHODS: Lymph node metastasis was assessed in the Surveillance, Epidemiology and End Results database in 1,057 ampullary adenocarcinomas that were operatively resected and for which at least 12 lymph nodes were examined. A complex pattern of survival versus extent of lymph node metastasis was captured by censored local regression. The impact of the extent of lymph nodes metastasis on survival was investigated by use of the K-adaptive partitioning algorithm to identify the most significant cut-off points of metastatic lymph nodes affecting survival. RESULTS: Two significant cut-off points (0 and 2) for the metastatic lymph node segregated patients into 3 groups with clinically important differences in median survival: patients with no metastatic lymph node (477 cases) had a median survival of 91 months, patients with 1-2 metastatic lymph nodes (279 cases) had a median survival of 29 months, whereas patients with ≥3 metastatic Lymph nodes (301 cases) had a median survival of 19 months (P < .0001). These results were validated with additional single institution dataset (318 cases, P < .0001). CONCLUSION: The present results suggest that the nodal classification of ampullary adenocarcinoma should be categorized N0 (no metastatic lymph node), N1 (1-2 metastatic lymph nodes), and N2 (≥3 metastatic lymph nodes).


Assuntos
Adenocarcinoma/patologia , Ampola Hepatopancreática , Neoplasias do Ducto Colédoco/patologia , Linfonodos/patologia , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Ampola Hepatopancreática/patologia , Neoplasias do Ducto Colédoco/mortalidade , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , República da Coreia/epidemiologia , Estudos Retrospectivos , Adulto Jovem
16.
Korean J Orthod ; 43(4): 160-7, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24015385

RESUMO

OBJECTIVE: To evaluate the shapes and sizes of nasopharyngeal airways by using cone-beam computed tomography and to assess the relationship between nasopharyngeal airway shape and adenoid hypertrophy in children. METHODS: Linear and cross-sectional measurements on frontal and sagittal cross-sections containing the most enlarged adenoids and nasopharyngeal airway volumes were obtained from cone-beam computed tomography scans of 64 healthy children (11.0 ± 1.8 years), and the interrelationships of these measurements were evaluated. RESULTS: On the basis of frontal section images, the subjects' nasopharyngeal airways were divided into the following 2 types: the broad and long type and the narrow and flat type. The nasopharyngeal airway sizes and volumes were smaller in subjects with narrow and flat airways than in those with broad and long airways (p < 0.01). Children who showed high adenoid-nasopharyngeal ratios on sagittal imaging, indicating moderate to severe adenoid hypertrophy, had the narrow and flat type nasopharyngeal airway (p < 0.01). CONCLUSIONS: Cone-beam computed tomography is a clinically simple, reliable, and noninvasive tool that can simultaneously visualize the entire structure and a cross section of the nasopharyngeal airway and help in measurement of adenoid size as well as airway volume in children with adenoid hypertrophy.

17.
Mod Pathol ; 24(2): 256-66, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20871595

RESUMO

Telomeres protect against chromosomal breakage, fusion, and interchromosome bridges during cell division. Shortened telomeres have been observed in the lowest grade of pancreatic intraepithelial neoplasia (PanIN). Genetically engineered mouse models of pancreatic neoplasia develop acinar-to-ductal metaplasia prior to the development of PanIN, suggesting that acinar-to-ductal metaplasias can be an early precursor lesion to pancreatic cancer. Some human PanINs are associated with acinar-to-ductal metaplasias, and it has been suggested that these acinar-to-ductal metaplasias arise as a consequence of growth of adjacent PanINs. As the earliest known genetic lesions of PanINs is shortened telomeres, we compared the telomere lengths of acinar-to-ductal metaplasia lesions, PanINs, and adjacent normal cells of human pancreata to determine whether acinar-to-ductal metaplasias could be precursors to PanIN. We used quantitative fluorescent in situ hybridization to measure the telomere length of cells from pancreatic lesions and adjacent normal pancreata from 22 patients, including 20 isolated acinar-to-ductal metaplasias, 13 PanINs associated with acinar-to-ductal metaplasias, and 12 PanINs. Normalized mean telomere fluorescence was significantly different among the cell types analyzed; 12.6 ± 10.2 units in normal acinar cells, 10.2 ± 6.4 in ductal cells, 8.4 ± 5.9 in fibroblasts, 9.4 ± 7.3 in isolated acinar-to-ductal metaplasias, 4.1 ± 2.9 in PanIN-associated acinar-to-ductal metaplasias, and 1.6 ± 1.9 in PanINs, respectively (P<0.001, ANOVA with randomized block design). Telomeres were significantly shorter in PanIN-associated acinar-to-ductal metaplasias (P<0.05, post hoc Duncan test) and in PanINs (P<0.05), than in normal cells, or isolated acinar-to-ductal metaplasias. Thus, shortened telomeres are found in PanIN-associated acinar-to-ductal metaplasias, but not in isolated acinar-to-ductal metaplasia lesions. These results indicate that isolated acinar-to-ductal metaplasias are not a precursor to PanIN, and support the hypothesis that PanIN-associated acinar-to-ductal metaplasias arise secondary to PanIN lesions.


Assuntos
Carcinoma in Situ/genética , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Telômero/patologia , Análise de Variância , Carcinoma in Situ/patologia , Humanos , Hibridização in Situ Fluorescente , Metaplasia/genética , Metaplasia/patologia , Neoplasias Pancreáticas/patologia
18.
Biom J ; 52(2): 201-8, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20394082

RESUMO

Quantile regression methods have been used to estimate upper and lower quantile reference curves as the function of several covariates. Especially, in survival analysis, median regression models to the right-censored data are suggested with several assumptions. In this article, we consider a median regression model for interval-censored data and construct an estimating equation based on weights derived from interval-censored data. In a simulation study, the performances of the proposed method are evaluated for both symmetric and right-skewed distributed failure times. A well-known breast cancer data are analyzed to illustrate the proposed method.


Assuntos
Biometria/métodos , Neoplasias da Mama/patologia , Censos , Intervalos de Confiança , Interpretação Estatística de Dados , Modelos de Riscos Proporcionais , Análise de Sobrevida , Feminino , Humanos , Método de Monte Carlo , Taxa de Sobrevida
19.
Neoplasia ; 11(11): 1185-93, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19881954

RESUMO

Chemotherapy for metastatic bladder cancer is rarely curative. The recently developed small molecule, lapatinib, a dual epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor-2 receptor tyrosine kinase inhibitor, might improve this situation. Recent findings suggest that identifying which patients are likely to benefit from targeted therapies is beneficial, although controversy remains regarding what types of evaluation might yield optimal candidate biomarkers of sensitivity. Here, we address this issue by developing and comparing lapatinib sensitivity prediction models for human bladder cancer cells. After empirically determining in vitro sensitivities (drug concentration necessary to cause a 50% growth inhibition) of a panel of 39 such lines to lapatinib treatment, we developed prediction models based on profiling the baseline transcriptome, the phosphorylation status of EGFR pathway signaling targets, or a combination of both data sets. We observed that models derived from microarray gene expression data showed better prediction performance (93%-98% accuracy) compared with models derived from EGFR pathway profiling of 23 selected phosphoproteins known to be involved in EGFR-driven signaling (54%-61% accuracy) or from a subset of the microarray data for transcripts in the EGFR pathway (86% accuracy). Combining microarray data and phosphoprotein profiling provided a combination model with 98% accuracy. Our findings suggest that transcriptome-wide profiling for biomarkers of lapatinib sensitivity in cancer cells provides models with excellent predictive performance and may be effectively combined with EGFR pathway phosphoprotein profiling data. These results have significant implications for the use of such tools in personalizing the approach to cancers treated with EGFR-directed targeted therapies.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica/métodos , Modelos Moleculares , Quinazolinas/uso terapêutico , Neoplasias da Bexiga Urinária/genética , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Receptores ErbB/efeitos dos fármacos , Receptores ErbB/metabolismo , Expressão Gênica , Humanos , Lapatinib , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Sensibilidade e Especificidade , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico
20.
Surgery ; 146(2): 250-7, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19628081

RESUMO

BACKGROUND: The American Joint Committee on Cancer (AJCC) T classification system for cholangiocarcinoma does not take into account the unique pathologic features of the bile duct. As such, the current AJCC T classification for distal cholangiocarcinoma may be inaccurate. METHODS: A total of 147 patients with distal cholangiocarcinoma were identified from a single institution database. The prognostic importance of depth of tumor invasion relative to the AJCC T classification system was assessed. RESULTS: The AJCC T classification was T1 (n = 11, 7.5%), T2 (n = 6, 4.1%), T3 (n = 73, 49.7%), or T4 (n = 57, 38.8%). When cases were analyzed according to depth of tumor invasion, most lesions were > or =5 mm (<5 mm, 9.5%; range, 5-12, 51.0%; >12 mm, 39.5%). The AJCC T classification was not associated with survival outcome (median survival, T1, 40.1 months; T2, 14.8 months; T3, 16.5 months; T4, 20.2 months; P = .17). In contrast, depth of tumor invasion was associated with a worse outcome as tumor depth increased (median survival, <5 mm, not reached; range, 5-12, 28.9 months; >12 mm, 12.9 months; P = .001). On multivariate analyses, tumor depth remained the factor most associated with outcome (<5 mm; hazard ratio [HR] = referent vs 5-12 mm; HR = 3.8 vs >12 mm; HR = 6.7 mm; P = .001). CONCLUSION: The AJCC T classification for distal cholangiocarcinoma does not accurately predict prognosis. Depth of the bile duct carcinoma invasion is a better alternative method to determine prognosis and should be incorporated into the pathologic assessment of resected distal cholangiocarcinoma.


Assuntos
Neoplasias dos Ductos Biliares/classificação , Ductos Biliares Intra-Hepáticos , Colangiocarcinoma/classificação , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Análise de Sobrevida
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