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1.
J Clin Pathol ; 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32376712

RESUMO

AIMS: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder caused by germline mutations in fumarate hydratase (FH). Affected families have an increased risk of renal cell carcinoma (RCC). HLRCC-associated RCC (HLRCC-RCC) is highly aggressive. Clinicopathological information of genetically diagnosed patients with HLRCC-RCC contributes to the establishment of effective therapies. METHODS: Ten Japanese patients with HLRCC-RCC were enrolled in the study. Genetic testing for FH was carried out. Somatic mutations in FH and immunohistochemical analyses of FH and B7 family ligands (PD-L1 and B7-H3) were investigated in 13 tumours. Copy number variations were evaluated in two tumours. RESULTS: All patients had FH germline mutations. Regarding histology, most tumours had type 2 papillary architecture or tubulocystic pattern or both. All tumours were FH deficient by immunohistochemistry. Ten tumours were positive for PD-L1, and 12 tumours were positive for B7-H3. Somatic mutation analysis demonstrated loss of heterozygosity of FH in 10 tumours. Copy number variation analysis revealed uniparental disomy between 1q24.2 and 1q44 encompassing FH; gain of chromosome 2 p was also common. All patients had either metastases or residual tumours. Three patients died of HLRCC-RCC and one of colon cancer, whereas the other six are currently alive, including two without recurrence. CONCLUSIONS: HLRCC-RCCs appear to have unique molecular profiles, including PD-L1 expression. One patient had complete response to immunotherapy, which may be an option for HLRCC-RCC.

2.
BMC Cancer ; 20(1): 302, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32293349

RESUMO

BACKGROUND: Although docetaxel-based chemohormonal therapy (CHT) is one of the standard treatments for castration-resistant prostate cancer (CRPC), pertinent biomarkers and precise mechanisms involved in the resistance for CHT for CRPC remain unknown. We investigated the relationship between chemohormonal resistance and the expression of steroid receptors and Hippo pathway proteins using a docetaxel-resistant prostate cancer (PCa) cell line and human PCa tissues in patients who underwent surgery with and without neoadjuvant therapy. METHODS: A docetaxel-resistant subline (22Rv1-DR) was generated to assess Hippo pathway protein expression and the effect of YAP1 inhibition on cellular characteristics. A tissue microarray with 203 cores from 70 high-risk localized PCa tissues was performed to assess steroid receptor and Hippo pathway protein expressions. RESULTS: Nuclear YAP (nYAP) expression was higher in 22RV-1-DR than in parental 22Rv-1 and YAP1 knockdown suppressed cell proliferation of 22Rv1-DR. Steroid receptor and Hippo pathway protein expressions varied among three different neoadjuvant groups, and nYAP1 expression was the highest in the CHT group. The patients with high nYAP in residual cancer after neoadjuvant CHT had a significantly higher biochemical recurrence (BCR) rate than those with low nYAP1. On multivariate analysis, the high nYAP1 was an independent prognostic factor for BCR. CONCLUSIONS: nYAP expression is a potential biomarker in high-risk patients treated with docetaxel-based CHT. Steroid receptors and Hippo pathway proteins may play a role in the chemohormonal resistance in advanced PCa.

3.
Esophagus ; 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32170544

RESUMO

BACKGROUND: Poor oral health is an independent risk factor for upper aerodigestive tract cancers, including esophageal squamous cell carcinoma (ESCC). The pattern recognition receptor Toll-like receptor 4 (TLR4) recognizes lipopolysaccharide in the cell walls of Gram-negative periodontal pathogens associated with the development and progression of ESCC. It is, therefore, plausible that TLR4 plays a crucial role in the pathogenesis of ESCC. METHODS: We used an ESCC tissue microarray to confirm expression of TLR4 in patients with ESCC and to determine whether TLR4 expression status correlates with the clinicopathological features of these patients or their prognosis after esophagectomy. We also tested whether the combined expression statuses of TLR4 and TLR3 better correlate with prognosis in these patients than either parameter alone. RESULTS: Clinical ESCC samples from all 177 patients tested showed expression of TLR4. Moreover, high TLR4 expression (3 + and 2 +) correlated with poorer 5-year overall survival after esophagectomy than lower TLR4 expression (1 +) (p = 0.0491). Patients showing high TLR4 expression tended to have a poorer prognosis whether treated with surgery alone or with surgery and adjuvant chemotherapy. Univariate and multivariate analyses showed TLR4 expression status to be an independent prognostic factor affecting 5-year overall survival. Patients exhibiting high TLR4 expression with low TLR3 expression had a much poorer prognosis than other patients (p = < 0.0001). CONCLUSION: High TLR4 expression predicts a poor prognosis in advanced thoracic ESCC patients after esophagectomy.

4.
Pathobiology ; 87(1): 45-50, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32023616

RESUMO

Echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (ALK) fusion gene rearrangement is a key driver mutation in non-small cell lung cancer (NSCLC). Although Break-Apart ALK fluorescence in situ hybridization (FISH) is a reliable diagnostic method for detecting ALK gene rearrangement, it is also costly and time-consuming to use as a routine screening test. Our aim was to evaluate the clinical utility of a novel one-step, automated, rapid FISH (Auto-RaFISH) method developed to facilitate hybridization. This method takes advantage of the non-contact mixing effect of an alternating-current electric field. Ten representative specimens from 85 patients diagnosed at multiple centers with primary lung cancer with identified ALK-FISH status were collected. The specimens were all tested using FISH, RaFISH, and Auto-RaFISH. With both RaFISH protocols, the ALK test was completed within 4.5 h, as compared to the 20 h needed for the standard protocol. We found 100% agreement between the standard FISH, RaFISH, and new Auto-RaFISH based on the ALK status, and all methods stained equally well. These findings suggest that Auto-RaFISH could potentially serve as an automated clinical tool for prompt determination of ALK status in NSCLC.

5.
Pathol Int ; 70(3): 171-178, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31944485

RESUMO

Desmoplastic small round cell tumor (DSRCT) is a rare aggressive malignant tumor. It is a refractory tumor and the median overall survival is very short. We report two autopsy cases of DSRCT, both of which were already advanced and metastasized at the first medical examination. Both cases showed typical DSRCT findings in terms of localization of the lesions, histopathology and genetics, but the rate of disease progression was quite different. Survival after initial symptoms in Case 1 was only 12 months. On the other hand, survival after primary hospitalization in Case 2 was 42 months. The Case 2 patient initially received chemotherapy for advanced pancreatic carcinoma, because a nodule of the pancreatic tail was found on computed tomography (CT) scan. After chemotherapy, tumor regression was observed on CT scan. It is thus implied that adoption of the regimen for pancreatic carcinoma might have been one of reasons of the long survival in Case 2.

6.
Intern Med ; 59(4): 495-499, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31588090

RESUMO

Inflammatory myofibroblastic tumor is a rare intermediate-grade tumor. We herein report the case of an 81-year-old man with rectal ulceration and abnormal retroperitoneal soft tissue with a high serum level of IgG4. The administration of prednisolone reduced the retroperitoneal lesion; however, the rectal ulceration expanded. Surgical resection was performed. A histopathological examination revealed proliferating spindle cells accompanied by inflammatory cells and plasma cells. Liver metastasis emerged two months after surgical resection, and the histology of the proliferating spindle cells sampled by a fine-needle biopsy was similar to that of the rectal tissue. The patient ultimately died of inflammatory myofibroblastic tumor.

7.
Hinyokika Kiyo ; 65(9): 363-367, 2019 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-31697878

RESUMO

A 68-year-old man was referred to our hospital with a right-sided renal tumor identified by ultrasonography at the time of his medical check-up. Computed tomography revealed a well-circumscribed but distorted mass measuring 64×45×57 mm in the right kidney with para-aortic lymph node swelling. Laparoscopic right nephrectomy with para-aortic lymphadenectomy was performed. Histopathological diagnosis was mucinous tubular and spindle cell carcinoma (MTSCC) (pT3a) without lymph node metastasis (pN0). Postoperatively, metastases were identified in the lungs, and the vertebral and iliac bones. The patient was treated with axitinib. The lung nodule progressed and left sacrum metastases appeared even after treatment with axitinib. Therefore, nivolumab was administered as second-line treatment. The metastases in the lungs, as well as vertebral and iliac bone showed complete response to this therapy. MTSCC of the kidney is a rare low-grade renal cell carcinoma without any established systemic therapy for metastatic or unresectable lesions. We report a case of metastatic MTSCC in a patient who showed a favorable response to nivolumab treatment. This is the first report to describe successful treatment of metastatic MTSCC with anti-programmed cell death 1 antibody.


Assuntos
Adenocarcinoma Mucinoso , Neoplasias Renais , Nivolumabe/uso terapêutico , Adenocarcinoma Mucinoso/terapia , Idoso , Humanos , Neoplasias Renais/terapia , Masculino , Nefrectomia
8.
NMC Case Rep J ; 6(3): 95-99, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31417840

RESUMO

This paper reports on a case of pilocytic astrocytoma (PA), for which a diagnosis by conventional pathological diagnosis was difficult but an accurate diagnosis was possible by a new molecular diagnostic method. A 13-year-old girl whose tumor developed by a headache that gradually worsened, and a well-demarcated T2-hyperintense lesion was found in the left cerebellum by a magnetic resonance imaging while the apparent diffusion coefficient value was also high. While the finding was a typical PA, histological features of PA were not found in the surgical specimen. An initial diagnosis was anaplastic astrocytoma (AA), and the final diagnosis through a central review was diffuse astrocytoma (DA). On the other hand, using MethylationEPIC (850 K) array, an analysis by a DNA methylation-based tumor classifier tool as reported by Capper et al. showed that this case belonged to a methylation class of PA. The copy number profile calculated from the methylation array data showed hints of BRAF/KIAA1549 fusion and no other chromosomal alterations, which also supported the molecular diagnosis. The patient was treated with local radiotherapy concomitant with temozolomide based on the initial pathological diagnosis during the consultation, but maintenance temozolomide therapy was not done according to the final molecular diagnosis. The tumor showed no recurrence for 20 months. In this case, the integrated diagnostic approach based on histological and molecular findings was clinically significant to select proper adjuvant treatment. It is crucial that the usefulness and robustness of this new molecular diagnostic method be validated further.

9.
J Clin Pathol ; 72(9): 603-608, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31129615

RESUMO

AIMS: Human epidermal growth factor receptor 2 (HER2)-targeted agents are effective against HER2-positive breast cancers. However, their lack of survival benefit in HER2-negative patients as well as their toxic effects and high cost highlight the need for accurate assessment of HER2 status. Our aim was to evaluate the clinical utility of a reagent-saving in situ hybridisation (Saving ISH) that facilitates hybridisation and saves HER2/chromosome enumeration probe by taking advantage of the non-contact mixing effect of an alternating current (AC) electric field. METHODS: With a new device, we apply a high-voltage, low-frequency AC electric field to the tissue sections, which mixes the probe within microdroplets as the voltage is switched on and off. Specimens (n=113) from patients with breast cancers identified immunohistochemically as HER2 0/1(+), (2+) or (3+) were used. The specimens were all tested using conventional dual ISH (DISH), DISH with an automated slide stainer (ASS) and Saving ISH (1:1-1:3 dilution). RESULTS: The Saving ISH with 1:2 probe dilution produced stable results with less non-specific staining while using smaller amounts of probe. The accuracy of HER2 status with Saving ISH was equal to standard. We found 96.4% agreement between DISH using ASS and Saving ISH (kappa coefficient=0.912). CONCLUSIONS: These results suggest reagent-saving HER2 ISH could be used as a clinical tool for accurate and stable HER2 assessment, even when reagent concentrations vary.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Eletricidade , Amplificação de Genes , Hibridização In Situ/métodos , Receptor ErbB-2/genética , Biomarcadores Tumorais/análise , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Desenho de Equipamento , Feminino , Humanos , Imuno-Histoquímica , Hibridização In Situ/instrumentação , Valor Preditivo dos Testes , Receptor ErbB-2/análise , Reprodutibilidade dos Testes
10.
Clin Genitourin Cancer ; 17(1): e113-e122, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30391137

RESUMO

BACKGROUND: To investigate the clinical outcomes in patients with high-risk prostate cancer (PCa) treated with neoadjuvant chemohormonal therapy (NCHT) before radical prostatectomy (RP). PATIENTS AND METHODS: Our NCHT protocol involved complete androgen blockade followed by 6 cycles of docetaxel (30 mg/m2) plus estramustine phosphate (560 mg). NCHT was provided to 60 patients with PCa before RP, and we compared the clinical and pathologic outcomes with those of 349 patients with high-risk PCa who underwent RP alone using propensity score matching. The data for those who underwent RP alone were obtained from the Michinoku Japan Urological Cancer Study Group database. RESULTS: In the NCHT group, 10.0% experienced pathologic complete response, 3.3% had positive surgical margins, and 13.3% developed severe complications (Clavien-Dindo grade III or higher) after RP. The median follow-up duration was 42.5 months, and the 5-year biochemical recurrence (BCR)-free survival was 60.1%. In multivariate analysis, pN+ was an independent prognostic factor for BCR (hazard ratio = 5.251, 95%CI 1.300-21.201; P = .020). In propensity score matching, the BCR rate in the NCHT group was significantly lower than that in the RP alone group (P = .021). In subgroup analyses, the BCR rate in patients with a single high-risk factor was significantly lower in the NCHT group than in the RP-alone group (P = .027). CONCLUSION: NCHT before RP can reduce the risk of BCR in patients with high-risk PCa, particularly if a single high-risk factor is present. However, the potential for perioperative complications should be considered.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Neoadjuvante/mortalidade , Pontuação de Propensão , Prostatectomia/mortalidade , Neoplasias da Próstata/terapia , Idoso , Estudos de Coortes , Terapia Combinada , Docetaxel/administração & dosagem , Estramustina/administração & dosagem , Seguimentos , Humanos , Masculino , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/patologia , Taxa de Sobrevida , Resultado do Tratamento
11.
J Clin Pathol ; 72(1): 25-30, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30228214

RESUMO

AIMS: Human epidermal growth factor receptor 2 (HER2)-targeted agents are an effective approach to treating patients with HER2-positive breast cancer. However, the lack of survival benefit in HER2-negative patients, as well as the toxic effects and high cost of the drugs, highlight the need for accurate and prompt assessment of HER2 status. Our aim was to evaluate the clinical utility of a novel reagent-saving immunohistochemistry method (AC-IHC) that saves HER2 antibody by taking advantage of the non-contact mixing effect in microdroplets subjected to an alternating current electric field. METHODS: Ninety-five specimens were used from patients diagnosed with primary breast cancers identified immunohistochemically as HER2 0/1+, 2+ or 3+ using ASCO/CAP guideline-certified standard IHC. The specimens were all tested using the conventional IHC method (1:50 antibody dilution) as well as AC-IHC (1:50 dilution) and reagent-saving AC-IHC (1:100 dilution). RESULTS: The reagent-saving AC-IHC produced stable results with less non-specific staining using smaller amounts of labelled antibody. Moreover, the staining and accuracy of HER2 status evaluated with the reagent-saving AC-IHC method was equal to that achieved with standard IHC. CONCLUSIONS: These results suggest reagent-saving AC-IHC could be used as a clinical tool for accurate and stable HER2 IHC, even when reagent concentrations vary.


Assuntos
Anticorpos/imunologia , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Testes Diagnósticos de Rotina , Eletricidade , Feminino , Humanos , Imuno-Histoquímica/instrumentação , Imuno-Histoquímica/métodos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
12.
Histopathology ; 73(6): 1013-1022, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30099776

RESUMO

AIMS: Uterine adenomatoid tumour (AT) is a benign proliferation of cells showing mesothelial differentiation within the myometrium that usually presents as a single nodule. Rare diffuse uterine ATs have been reported, often in patients undergoing immunosuppressive therapy. Herein, we aimed to elucidate the general association between the incidence of uterine AT and iatrogenic immunosuppression by cohort analysis. METHODS AND RESULTS: We analysed 611 consecutive hysterectomy specimens to determine the incidence of AT and its correlation with the immunosuppressive status. Mesothelial lineage, p16 expression, mismatch repair (MMR) protein alterations, and the possible integration of tumorigenic viruses were examined by in situ hybridizasion and immunohistochemistry. ATs were detected in 14 of 611 hysterectomy cases (2.3%). The incidence of AT was significantly higher in the immunosuppressed (IS) group (5/20, 25.0%) than in the non-IS group (9/591, 1.52%), with a relative risk of 16.4. Of the five ATs in the IS group, three were multifocal or diffuse. Latent uterine AT was detected, by in toto sectioning, in one of four immunosuppressed autopsy cases. The tumor cells of ATs commonly expressed calretinin and podoplanin. Characteristic block-type (≥90%) positivity for p16 was observed in most ATs. None of the ATs were positive for human herpes virus type 8, Merkel cell polyomavirus, SV40 large T antigen, Epstein-Barr virus, and human papilloma virus, and the MMR proteins were retained. A TRAF7 mutation was identified from macrodissected tissue in one of 12 ATs by Sanger sequencing. CONCLUSION: Uterine AT is an immunosuppression-associated mesothelial lesion characterised by p16 overexpression.


Assuntos
Tumor Adenomatoide/etiologia , Imunossupressão/efeitos adversos , Imunossupressores/efeitos adversos , Neoplasias Uterinas/etiologia , Tumor Adenomatoide/patologia , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Uterinas/patologia
13.
Lung Cancer ; 123: 127-135, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30089583

RESUMO

OBJECTIVE: Tumor-associated macrophages (TAMs) are believed to influence tumor progression and the prognosis of patients. The purpose of this study was to clarify the correlation between the TAM density or location and the clinicopathological features of non-small-cell lung cancer (NSCLC) as well as to explore the prognostic impact of TAMs in NSCLC. MATERIALS AND METHODS: CD68- and CD204-positive macrophages were detected in tumor islets, tumor stroma and alveolar space in 297 patients with NSCLC using immunochemistry. The clinicopathological and genetic factors surveyed were the disease-free survival, age, gender, smoking status, histological type, disease stage, histological grade, pleural invasion, lymph node metastasis, EGFR gene mutations and ALK rearrangements. RESULTS: There were significantly more CD68-positive macrophages than CD204-positive macrophages in each location of the tumor islets, tumor stroma and alveolar spaces, and they were strongly correlated (P < 0.0001 each). Factors such as male gender, being a smoker, an advanced disease stage and histological grade, positive pleural invasion and node status and wild-type EGFR gene status were significantly correlated with a higher density of CD68- and CD204-positive TAMs in tumor stroma (P < 0.05 each). In contrast, the age of patients was not correlated with CD68- and CD204-positive TAMs (P > 0.05 each). Furthermore, survival analysis revealed that a high number of CD68- and CD204-positive TAMs in tumor stroma, but not in tumor islets or alveolar space, was a significant prognostic factor for the disease-free survival time of NSCLC (P < 0.05, respectively). Moreover, both univariate and multivariate analyses confirmed that higher numbers of CD204-positive TAMs in tumor stroma were an independent worse prognostic predictor for adenocarcinoma. CONCLUSION: The tumor stroma is the most suitable intratumoral area for the evaluation of TAMs in the setting of the prognostic prediction of NSCLC patients. CD204-positive TAMs are the preferable marker for prognostic prediction in NSCLC, especially in lung adenocarcinoma.


Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Receptores Depuradores Classe A/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular , Receptores ErbB/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Microambiente Tumoral
14.
Hum Pathol ; 81: 89-95, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29944972

RESUMO

In the female genital tract, extrauterine leiomyomas such as those that arise in the ovary and paraovarian/paratubal regions are rare. Currently, little is known about the background genetic changes in such adnexal leiomyomas. Recent studies have found that the MED12 mutation is common in uterine leiomyomas, which suggests that such mutations may play an oncogenic role in smooth muscle neoplasms in females. Herein, we examined a series of ovarian and other adnexal leiomyomas in terms of MED12 mutational status to investigate possible MED12 involvement in the pathogenesis of extrauterine smooth muscle tumors. We evaluated 10 cases of adnexal leiomyomas (5 ovarian, 3 paraovarian, and 2 paratubal) and 49 cases of ovarian sex cord-stromal tumors as controls. We performed polymerase chain reaction followed by direct sequencing of exon 2 of MED12, and immunohistochemical staining for smooth muscle actin and desmin. We identified somatic MED12 mutations in 90% (9/10) of the adnexal leiomyomas. None of the sex cord-stromal tumors in the control group harbored MED12 mutations. Diffuse immunoreactivity for both smooth muscle actin and desmin was characteristic of adnexal leiomyomas only. Thus, we conclude that ovarian leiomyomas are distinct from sex cord-stromal tumors. MED12 mutations are key molecular features of ovarian and other adnexal leiomyomas. We speculate that the pathogenesis of adnexal leiomyoma is similar to that of its uterine counterpart.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias das Tubas Uterinas/genética , Leiomioma/genética , Complexo Mediador/genética , Mutação , Neoplasias Ovarianas/genética , Actinas/análise , Adulto , Idoso , Biomarcadores Tumorais/análise , Diferenciação Celular , Análise Mutacional de DNA , Desmina/análise , Neoplasias das Tubas Uterinas/química , Neoplasias das Tubas Uterinas/patologia , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Leiomioma/química , Leiomioma/patologia , Pessoa de Meia-Idade , Taxa de Mutação , Neoplasias Ovarianas/química , Neoplasias Ovarianas/patologia , Fenótipo , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Fatores de Risco , Tóquio
15.
Jpn J Clin Oncol ; 48(8): 765-770, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29931077

RESUMO

Objective: To evaluate the positive surgical margin rates and locations in radical prostatectomy among three surgical approaches, including open radical prostatectomy, laparoscopic radical prostatectomy and robot-assisted radical prostatectomy. Methods: We retrospectively reviewed clinical outcomes at our institution of 450 patients who received radical prostatectomy. Multiple surgeons were involved in the three approaches, and a single pathologist conducted the histopathological diagnoses. Positive surgical margin rates and locations among the three approaches were statistically assessed, and the risk factors of positive surgical margin were analyzed. Results: This study included 127, 136 and 187 patients in the open radical prostatectomy, laparoscopic radical prostatectomy and robot-assisted radical prostatectomy groups, respectively. The positive surgical margin rates were 27.6% (open radical prostatectomy), 18.4% (laparoscopic radical prostatectomy) and 13.4% (robot-assisted radical prostatectomy). In propensity score-matched analyses, the positive surgical margin rate in the robot-assisted radical prostatectomy was significantly lower than that in the open radical prostatectomy, whereas there was no significant difference in the positive surgical margin rates between robot-assisted radical prostatectomy and laparoscopic radical prostatectomy. In the multivariable analysis, PSA level at diagnosis and surgical approach (open radical prostatectomy vs robot-assisted radical prostatectomy) were independent risk factors for positive surgical margin. The apex was the most common location of positive surgical margin in the open radical prostatectomy and laparoscopic radical prostatectomy groups, whereas the bladder neck was the most common location in the robot-assisted radical prostatectomy group. The significant difference of positive surgical margin locations continued after the propensity score adjustment. Conclusions: Robot-assisted radical prostatectomy may potentially achieve the lowest positive surgical margin rate among three surgical approaches. The bladder neck was the most common location of positive surgical margin in robot-assisted radical prostatectomy and apex in open radical prostatectomy and laparoscopic radical prostatectomy. Although robot-assisted radical prostatectomy may contribute to the reduction of positive surgical margin, dissection of the bladder neck requires careful attention to avoid positive surgical margins.


Assuntos
Laparoscopia , Margens de Excisão , Prostatectomia , Neoplasias da Próstata/cirurgia , Robótica , Idoso , Humanos , Incidência , Laparoscopia/efeitos adversos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Cuidados Pré-Operatórios , Pontuação de Propensão , Antígeno Prostático Específico , Prostatectomia/efeitos adversos , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Fatores de Risco
16.
Acta Neuropathol ; 136(1): 153-166, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29687258

RESUMO

According to the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), IDH-mutant astrocytic gliomas comprised WHO grade II diffuse astrocytoma, IDH-mutant (AIIIDHmut), WHO grade III anaplastic astrocytoma, IDH-mutant (AAIIIIDHmut), and WHO grade IV glioblastoma, IDH-mutant (GBMIDHmut). Notably, IDH gene status has been made the major criterion for classification while the manner of grading has remained unchanged: it is based on histological criteria that arose from studies which antedated knowledge of the importance of IDH status in diffuse astrocytic tumor prognostic assessment. Several studies have now demonstrated that the anticipated differences in survival between the newly defined AIIIDHmut and AAIIIIDHmut have lost their significance. In contrast, GBMIDHmut still exhibits a significantly worse outcome than its lower grade IDH-mutant counterparts. To address the problem of establishing prognostically significant grading for IDH-mutant astrocytic gliomas in the IDH era, we undertook a comprehensive study that included assessment of histological and genetic approaches to prognosis in these tumors. A discovery cohort of 211 IDH-mutant astrocytic gliomas with an extended observation was subjected to histological review, image analysis, and DNA methylation studies. Tumor group-specific methylation profiles and copy number variation (CNV) profiles were established for all gliomas. Algorithms for automated CNV analysis were developed. All tumors exhibiting 1p/19q codeletion were excluded from the series. We developed algorithms for grading, based on molecular, morphological and clinical data. Performance of these algorithms was compared with that of WHO grading. Three independent cohorts of 108, 154 and 224 IDH-mutant astrocytic gliomas were used to validate this approach. In the discovery cohort several molecular and clinical parameters were of prognostic relevance. Most relevant for overall survival (OS) was CDKN2A/B homozygous deletion. Other parameters with major influence were necrosis and the total number of CNV. Proliferation as assessed by mitotic count, which is a key parameter in 2016 CNS WHO grading, was of only minor influence. Employing the parameters most relevant for OS in our discovery set, we developed two models for grading these tumors. These models performed significantly better than WHO grading in both the discovery and the validation sets. Our novel algorithms for grading IDH-mutant astrocytic gliomas overcome the challenges caused by introduction of IDH status into the WHO classification of diffuse astrocytic tumors. We propose that these revised approaches be used for grading of these tumors and incorporated into future WHO criteria.


Assuntos
Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Isocitrato Desidrogenase/genética , Mutação/genética , Adolescente , Adulto , Idoso , Algoritmos , Astrocitoma/mortalidade , Neoplasias Encefálicas/mortalidade , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Gradação de Tumores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Organização Mundial da Saúde , Adulto Jovem
17.
Int Immunopharmacol ; 58: 57-63, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29550576

RESUMO

The impact of CYP3A5 polymorphisms on clinical outcomes is controversial. The present study investigated the impact of CYP3A5 genetic differences on the development of interstitial fibrosis (IF) from 0 h to 1 year post-transplantation in biopsy sections from 96 living kidney recipients under the same target trough regimen of tacrolimus. The relationships between CYP3A5 polymorphisms and long-term graft function and death-censored graft survival were also examined. A quantitative analysis of IF was performed using computer-assisted imaging on virtual slides. Percent IF (%IF) in the cortical region at 0 h was defined as the baseline, and increases in the ratio of %IF 1 year post-transplantation were calculated. The relationships between CYP3A5 genetic differences and the development of IF, the incidence of clinical events, and the long-term function and death-censored survival of grafts were assessed. The mean increase in the ratio of %IF from 0 h to 1 year was 1.38 ±â€¯0.74-fold. Despite therapeutic drug monitoring (TDM), trough levels of tacrolimus were lower in carriers with the CYP3A5*1 allele (expressers) than in those with the CTP3A5*3/*3 genotype (non-expressers) throughout the 1-year post-transplantation period. However, CYP3A5 genetic differences were not associated with the development of IF, any clinical events, or the long-term function and survival of grafts. The clinical impact of CYP3A5 genetic differences may be small under the current immunosuppressive regimen consisting of mycophenolate mofetil, steroids, basiliximab, and lower target trough levels of tacrolimus with suitable TDM in a low immunological risk population.


Assuntos
Citocromo P-450 CYP3A/genética , Imunossupressores/uso terapêutico , Transplante de Rim , Rim/patologia , Complicações Pós-Operatórias/mortalidade , Insuficiência Renal/terapia , Tacrolimo/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Combinada , Feminino , Fibrose , Genótipo , Humanos , Rim/cirurgia , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Complicações Pós-Operatórias/genética , Insuficiência Renal/genética , Insuficiência Renal/mortalidade , Análise de Sobrevida , Resultado do Tratamento
18.
Sci Rep ; 8(1): 3156, 2018 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-29453407

RESUMO

Arteriovenous malformations consist of tangles of arteries and veins that are often connected by a fistula. The causes and mechanisms of these clinical entities are not fully understood. We discovered that suturing an arterial patch into the common jugular vein of rabbits led to spontaneous neovascularization, the formation of an arteriovenous fistula and the development of an arteriovenous shunt. An arterial patch excised from the common carotid artery was sutured into the common jugular vein. Within a month, a dense nidus-like neovasculature formed around the patch. Angiography and pulse-oximeter analyses showed that the blood flowing into the neovasculature was arterial blood. This indicated that an arteriovenous shunt had formed. Fluorescence in situ hybridization with a Y chromosome probe in female rabbits that received an arterial patch from male rabbits showed that the vessels close to the graft bore the Y chromosome, whereas the vessels further away did not. Enzyme-linked immunosorbent assays and cDNA microarray analysis showed that multiple angiogenic factors were upregulated after patch transplantation. This is the first in vivo model of spontaneous arteriovenous fistula formation. Further research on these differences may help to improve understanding of human vascular anomaly diseases and the basic principles underlying vasculogenesis and/or angiogenesis.


Assuntos
Fístula Arteriovenosa/etiologia , Fístula Arteriovenosa/fisiopatologia , Artéria Carótida Primitiva/cirurgia , Neovascularização Fisiológica , Enxerto Vascular/efeitos adversos , Veias/cirurgia , Animais , Modelos Animais de Doenças , Feminino , Masculino , Coelhos
19.
Am J Surg ; 216(2): 319-325, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29395019

RESUMO

BACKGROUND: The relationship between Toll-like receptors (TLRs) and esophageal squamous cell carcinoma (ESCC) is not completely understood. METHODS: RT-qPCR was used to evaluate the mRNA expression of TLR1-10 in 13 ESCC lines. We then used ESCC tissue microarray (TMA) to confirm expression of TLR3 protein in patients with ESCC. RESULTS: All ESCC lines showed 10-60 times higher TLR3 mRNA expression than PBLs. High expression of TLR3 correlated with favorable 5-year overall survival (OS) and disease specific survival (DSS) among patients with ESCC after esophagectomy (p < 0.01). Additionally, In the adjuvant chemotherapy group, TLR3 high patients had significantly better 5-year OS compared to TLR3 low patients (60.2%, 34.4%, respectively) but not in the surgery alone group. CONCLUSION: High TLR3 expression is an independent prognostic factor and has the potential to serve as a clinically useful marker of the need for adjuvant chemotherapy after esophagectomy in patients with advanced thoracic ESCC.


Assuntos
Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Esofagectomia , Regulação Neoplásica da Expressão Gênica , RNA Neoplásico/genética , Receptor 3 Toll-Like/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/cirurgia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise Serial de Tecidos , Receptor 3 Toll-Like/biossíntese
20.
Sci Rep ; 7(1): 15116, 2017 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-29118432

RESUMO

Echinoderm microtubule-associated protein-like 4 gene and anaplastic lymphoma kinase gene (EML4-ALK) rearrangement is a key driver mutation in non-small cell lung cancer (NSCLC). Although Break-Apart ALK fluorescence in situ hybridization (FISH) is a reliable diagnostic method for detecting ALK gene rearrangement, it is too costly and time-consuming for use as a routine screening test. Our aim was to evaluate the clinical utility of a novel rapid FISH (RaFISH) method developed to facilitate hybridization. RaFISH takes advantage of the non-contact mixing effect of an alternating current (AC) electric field. Eighty-five specimens were used from patients diagnosed with NSCLC identified immunohistochemically as ALK 0, (1/2+) or (3+). With RaFISH, the ALK test was completed within 4.5 h, as compared to 20 h needed for the standard FISH. Although RaFISH produced results more promptly, the staining and accuracy of the ALK evaluation with RaFISH was equal to the standard. We found 97.6% agreement between FISH and RaFISH based on the status of the ALK signals. These results suggest RaFISH could be used as a clinical tool to promptly determine ALK status.


Assuntos
Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas de Ciclo Celular/genética , Técnicas Eletroquímicas/métodos , Hibridização in Situ Fluorescente/métodos , Neoplasias Pulmonares/genética , Proteínas Associadas aos Microtúbulos/genética , Serina Endopeptidases/genética , Idoso , Quinase do Linfoma Anaplásico/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/metabolismo , Feminino , Rearranjo Gênico , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Mutação , Reprodutibilidade dos Testes , Serina Endopeptidases/metabolismo
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