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1.
Cancers (Basel) ; 13(6)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33802174

RESUMO

Neuroendocrine carcinoma of the cervix (NECC) is a rare and highly aggressive tumor with no efficient treatment. We examined genetic features of NECC and identified potential therapeutic targets. A total of 272 patients with cervical cancer (25 NECC, 180 squamous cell carcinoma, 53 adenocarcinoma, and 14 adenosquamous carcinoma) were enrolled. Somatic hotspot mutations in 50 cancer-related genes were detected using the Ion AmpliSeq Cancer Hotspot Panel v2. Human papillomavirus (HPV)-positivity was examined by polymerase chain reaction (PCR)-based testing and in situ hybridization assays. Programmed cell death-ligand 1 (PD-L1) expression was examined using immunohistochemistry. Somatic mutation data for 320 cases of cervical cancer from the Project GENIE database were also analyzed. NECC showed similar (PIK3CA, 32%; TP53, 24%) and distinct (SMAD4, 20%; RET, 16%; EGFR, 12%; APC, 12%) alterations compared with other histological types. The GENIE cohort had similar profiles and RB1 mutations in 27.6% of NECC cases. Eleven (44%) cases had at least one actionable mutation linked to molecular targeted therapies and 14 (56%) cases showed more than one combined positive score for PD-L1 expression. HPV-positivity was observed in all NECC cases with a predominance of HPV-18. We report specific gene mutation profiles for NECC, which can provide a basis for the development of novel therapeutic strategies.

2.
Clin Lung Cancer ; 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33722498

RESUMO

BACKGROUND: The efficacy of anti-programmed death receptor 1 (PD-1) therapy in patients with large cell neuroendocrine carcinoma (LCNEC) remains unclear. We investigated the outcome of anti-PD-1 therapy and its predictive markers by evaluating the immune-related tumor microenvironment. PATIENTS: We retrospectively reviewed patients with advanced LCNEC treated with systemic chemotherapy. We also evaluated PD ligand 1 (PD-L1) expression (clone: 22C3), CD8-positive tumor-infiltrating lymphocytes (TILs), and the mutational profiles. RESULTS: Seventy patients were enrolled, and 13 of 70 patients received anti-PD-1 therapy. The progression-free survival (PFS) and objective response rate (ORR) of the anti-PD-1 therapy were 4.2 months and 39%, respectively. The overall survival of patients treated with anti-PD-1 therapy (n = 13) was significantly better than those treated without anti-PD-1 therapy (n = 57) (25.2 months vs 10.9 months; P = .02). Among the 13 patients treated with anti-PD-1 therapy, 10 patients (90%) had PD-L1-negative tumors. Patients with a high density of tumoral CD8-positive TILs (≥38/mm2) had a significantly better ORR and PFS than those with a low density of tumoral CD8-positive TILs (ORR: P = .02; PFS: P = .003). Additionally, all 3 patients with TP53 mutation co-occurring with PIK3CA mutation (2 of 8 patients) or RB1 mutation (1 of 8 patients) responded to anti-PD-1 therapy. CONCLUSIONS: Anti-PD-1 therapy was effective regardless of PD-L1 positivity in patients with advanced LCNEC. Our investigation might suggest that the density of tumoral CD8-positive TILs and the presence of co-occurring mutations are predictors of the efficacy of anti-PD-1 therapy in patients with advanced LCNEC.

4.
Pathol Int ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33631044

RESUMO

ALK, ROS1 and NTRK fusions are involved in the tumorigenesis of various organs, including colorectal cancer. This study aims to clarify the prevalence of these fusions in colorectal cancer in the Japanese population. Immunohistochemical analysis of 1012 specimens of colorectal cancer revealed two NTRK-positive cases (0.2%) whereas no ALK- or ROS1-positive cases were identified. Reverse transcription polymerase chain reaction (RT-PCR) detected an LMNA-NTRK1 fusion in a case of adenosquamous carcinoma and a TPM3-NTRK1 fusion in a case of tubular adenocarcinoma. Both NTRK1 fusion-positive cases lacked activating mutations in KRAS and BRAF and were mismatch repair-deficient with loss of MLH1 and PMS2 expression and MLH1 promoter methylation. Our results show that receptor tyrosine kinase fusions are rare but present in colorectal cancers in Japanese patients, with a prevalence similar to that reported in other countries.

5.
N Engl J Med ; 384(1): 42-50, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33406329

RESUMO

Two cases of pediatric lung cancer (in 23-month-old and 6-year-old boys) resulting from mother-to-infant transmission of uterine cervical tumors were incidentally detected during routine next-generation sequencing of paired samples of tumor and normal tissue. Spontaneous regression of some lesions in the first child and slow growth of the tumor mass in the second child suggested the existence of alloimmune responses against the transmitted tumors. Immune checkpoint inhibitor therapy with nivolumab led to a strong regression of all remaining tumors in the first child. (Funded by the Japan Agency for Medical Research and Development and others; TOP-GEAR UMIN Clinical Trials Registry number, UMIN000011141.).


Assuntos
Adenocarcinoma Mucinoso/etiologia , Carcinoma Neuroendócrino/etiologia , Neoplasias Pulmonares/etiologia , Complicações Neoplásicas na Gravidez , Neoplasias do Colo do Útero , Adenocarcinoma Mucinoso/diagnóstico por imagem , Adenocarcinoma Mucinoso/genética , Adulto , Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma Neuroendócrino/genética , Carcinoma de Células Escamosas/patologia , Criança , Evolução Fatal , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Mães , Gravidez , Vagina , Sequenciamento Completo do Exoma
6.
Lung Cancer ; 152: 58-65, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33352384

RESUMO

INTRODUCTION: The relationship between Body-Mass-Index (BMI) and lung cancer prognosis is heterogeneous. We evaluated the impact of sex, smoking and race on the relationship between BMI and overall survival (OS) in non-small-cell-lung-cancer (NSCLC). METHODS: Data from 16 individual ILCCO studies were pooled to assess interactions between BMI and the following factors on OS: self-reported race, smoking status and sex, using Cox models (adjusted hazard ratios; aHR) with interaction terms and adjusted penalized smoothing spline plots in stratified analyses. RESULTS: Among 20,937 NSCLC patients with BMI values, females = 47 %; never-smokers = 14 %; White-patients = 76 %. BMI showed differential survival according to race whereby compared to normal-BMI patients, being underweight was associated with poor survival among white patients (OS, aHR = 1.66) but not among black patients (aHR = 1.06; pinteraction = 0.02). Comparing overweight/obese to normal weight patients, Black NSCLC patients who were overweight/obese also had relatively better OS (pinteraction = 0.06) when compared to White-patients. BMI was least associated with survival in Asian-patients and never-smokers. The outcomes of female ever-smokers at the extremes of BMI were associated with worse outcomes in both the underweight (pinteraction<0.001) and obese categories (pinteraction = 0.004) relative to the normal-BMI category, when compared to male ever-smokers. CONCLUSION: Underweight and obese female ever-smokers were associated with worse outcomes in White-patients. These BMI associations were not observed in Asian-patients and never-smokers. Black-patients had more favorable outcomes in the extremes of BMI when compared to White-patients. Body composition in Black-patients, and NSCLC subtypes more commonly seen in Asian-patients and never-smokers, may account for differences in these BMI-OS relationships.

7.
Carcinogenesis ; 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33196828

RESUMO

AT-rich interactive domain 1A (ARID1A), which is a tumor suppressor gene, is frequently mutated in Epstein-Barr virus-positive gastric cancer [EBV (+) GC]. While most ARID1A mutations in GC are truncating mutations, leading to loss of ARID1A protein expression, epigenetic modifications appear to contribute to ARID1A deficiency in EBV (+) GC harboring wild-type ARID1A. Based on the significant role of epigenetic modifications in EBV (+) GC that contributes to ARID1A deficiency, the methylation status of ARID1A was evaluated in EBV-infected cells and GC patients using a publicly available microarray and the Cancer Genome Atlas (TCGA) database. EBV-encoded miRNAs that potentially target ARID1A were identified as an additional epigenetic modulator by computational prediction. In vitro experiments were conducted to evaluate how EBV-encoded miRNAs affected ARID1A mRNA and protein levels. In clinical GC samples, the expression of predicted miRNAs and ARID1A and the mutation status of ARID1A was evaluated. As results, ARID1A was not hypermethylated in EBV (+) GC samples or EBV-infected GC cells. EBV infection did not alter ARID1A mRNA levels, suggesting that ARID1A protein deficiency was caused by post-transcriptional gene silencing in ARID1A-WT EBV (+) GC. Overexpression of miR-BART11-3p and miR-BART12, which were identified as miRNAs that potentially bind ARID1A, suppressed ARID1A protein expression in MKN7 and NCI-N87 cells. Highly expressed miR-BART11-3p and miR-BART12 were correlated with decreased ARID1A levels in GC tumors which did not harbor ARID1A mutations. The present findings revealed that ARID1A expression was epigenetically regulated by miR-BART11-3p and miR-BART12 in EBV (+) GC.

8.
Cancer Epidemiol Biomarkers Prev ; 29(10): 1983-1992, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32699080

RESUMO

BACKGROUND: Lung cancer remains the leading cause of cancer death worldwide, with 15% to 20% occurring in never smokers. To assess genetic determinants for prognosis among never smokers, we conducted a genome-wide investigation in the International Lung Cancer Consortium (ILCCO). METHODS: Genomic and clinical data from 1,569 never-smoking patients with lung cancer of European ancestry from 10 ILCCO studies were included. HRs and 95% confidence intervals of overall survival were estimated. We assessed whether the associations were mediated through mRNA expression-based 1,553 normal lung tissues from the lung expression quantitative trait loci (eQTL) dataset and Genotype-Tissue Expression (GTEx). For cross-ethnicity generalization, we assessed the associations in a Japanese study (N = 887). RESULTS: One locus at 13q22.2 was associated with lung adenocarcinoma survival at genome-wide level, with carriers of rs12875562-T allele exhibiting poor prognosis [HR = 1.71 (1.41-2.07), P = 3.60 × 10-8], and altered mRNA expression of LMO7DN in lung tissue (GTEx, P = 9.40 × 10-7; Lung eQTL dataset, P = 0.003). Furthermore, 2 of 11 independent loci that reached the suggestive significance level (P < 10-6) were significant eQTL affecting mRNA expression of nearby genes in lung tissues, including CAPZB at 1p36.13 and UBAC1 at 9q34.3. One locus encoding NWD2/KIAA1239 at 4p14 showed associations in both European [HR = 0.50 (0.38-0.66), P = 6.92 × 10-7] and Japanese populations [HR = 0.79 (0.67-0.94), P = 0.007]. CONCLUSIONS: Based on the largest genomic investigation on the lung cancer prognosis of never smokers to date, we observed that lung cancer prognosis is affected by inherited genetic variants. IMPACT: We identified one locus near LMO7DN at genome-wide level and several potential prognostic genes with cis-effect on mRNA expression. Further functional genomics work is required to understand their role in tumor progression.

9.
Breast Cancer Res Treat ; 182(2): 491-502, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32488393

RESUMO

PURPOSE: Homologous recombination deficiency (HRD), which influences the efficacy of PARP inhibitor- and platinum agent-based therapies, is a prevalent phenotype of breast cancer in adolescents and young adults (AYAs; 15-39 years old). However, HRD score, indicating HRD status, is not routinely assessed in the breast oncology clinic, particularly in patients without germline BRCA1/2 mutations. Hence, we sought to develop a model for determining HRD status based on genetic and clinicopathological factors. METHODS: Subjects were our own cohort of 46 Japanese AYA breast cancer patients and two existing breast cancer cohorts of US and European patients. Models for prediction of the HRD-high phenotype, defined as HRD score ≥ 42, were constructed by logistic regression analysis, using as explanatory variables genetic and clinicopathological factors assessable in the clinical setting. RESULTS: In all three cohorts, the HRD-high phenotype was associated with germline BRCA1/2 mutation, somatic TP53 mutation, triple-negative subtype, and higher tumor grade. A model based on these four factors, developed using the US cohort, was validated in the Japanese and European AYA cases: area under the receiver operating characteristic curve [AUC] was 0.90 and 0.96, respectively. A model based on three factors excluding germline BRCA1/2 mutation also yielded high-predictive power in cases from these two cohorts without germline BRCA1/2 mutations: AUC was 0.92 and 0.90, respectively. CONCLUSIONS: The HRD-high phenotype of AYA breast cancer patients can be deduced from genomic and pathological factors that are routinely examined in the oncology clinic, irrespective of germline BRCA1/2 mutations.

10.
Nat Genet ; 52(7): 669-679, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32514122

RESUMO

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10-9). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Estudos de Coortes , Feminino , Predisposição Genética para Doença/etnologia , Variação Genética , Humanos , Padrões de Herança , Japão , Masculino , Fatores Sexuais , Fatores de Transcrição/genética
11.
Gynecol Oncol ; 156(1): 203-210, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31757465

RESUMO

OBJECTIVE: Cervical cancer is the fourth most common cause of cancer-related deaths in Asian women, due to its poor prognosis. This study aimed to decipher genomic alteration profiles of a cohort of Japanese cervical cancer patients to understand why certain patients benefited from molecular targeted therapies and their prognostic significance. METHODS: During 2008-2018, 154 cervical cancer patients underwent a potentially curative resection procedure at the National Cancer Center Hospital. Genomic DNA samples were analyzed using Ion AmpliSeq™ Cancer Hotspot Panel v2. Alterations in the copy number of PIK3CA, ERBB2, PTEN, and STK11 were detected using the TaqMan assay. HPV-positive results were confirmed by genomic testing and in situ hybridization assay. RESULTS: The frequency of genomic alterations in PIK3CA (36%), STK11 (16%), PTEN (11%), TP53 (11%), and KRAS (8%) was >5%. KRAS mutations were preferentially detected in patients with adenocarcinomas, and the frequency of PIK3CA mutations in patients with squamous cell carcinomas was higher than that in patients with other histological cancer types. HPV-positive results were observed in 139/154 (90.3%) patients, and TP53 mutants were detected in HPV-negative specimens. In this study, the overall survival of patients with genomic alterations in STK11 was worse than in patients with wild-type STK11 (hazard ratio = 10.6, P = 0.0079) and TCGA dataset (hazard ratio = 2.46, P = 0.029). CONCLUSIONS: More than one-third of Japanese cervical cancer patients exhibit mutations targeted by molecular targeted therapies. We have proposed the prognostic value of STK11 genomic alterations.


Assuntos
Proteínas Serina-Treonina Quinases/genética , Neoplasias do Colo do Útero/genética , Grupo com Ancestrais do Continente Asiático/genética , Análise Mutacional de DNA , DNA de Neoplasias/genética , DNA de Neoplasias/isolamento & purificação , Feminino , Humanos , Pessoa de Meia-Idade , Papillomaviridae/genética , Infecções por Papillomavirus/enzimologia , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Valor Preditivo dos Testes , Proteínas Serina-Treonina Quinases/metabolismo , Neoplasias do Colo do Útero/enzimologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia
12.
Genomics ; 112(2): 1223-1232, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31306748

RESUMO

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.

13.
PLoS One ; 14(10): e0223371, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31584970

RESUMO

Drug-induced interstitial lung disease (DIILD) is a serious side effect of chemotherapy in cancer patients with an extremely high mortality rate. In this study, to identify genetic variants with greater risk of DIILD, we carried out whole genome sequencing (WGS) of germline DNA samples from 26 patients who developed DIILD, and conducted a case-control association study between these 26 cases and general Japanese population controls registered in the integrative Japanese Genome Variation Database (iJGVD) as a screening study. The associations of 42 single nucleotide variants (SNVs) showing P < 0.0001 were further validated using an independent cohort of 18 DIILD cases as a replication study. A further combined analysis of the screening and replication studies showed a possible association of two SNVs, rs35198919 in intron 1 of the chromosome 22 open reading frame 34 (C22orf34) and rs12625311 in intron 1 of the teashirt zinc finger homeobox 2 (TSHZ2), with DIILD (Pcombined = 1.87 × 10-5 and 5.16 × 10-5, respectively). Furthermore, in a subgroup analysis of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)-induced interstitial lung disease (ILD), we observed seven candidate SNVs that were possibly associated with ILD (P < 0.00001). This is the first study to identify genetic markers for the risk of DIILD using WGS. Collectively, our novel findings indicate that these SNVs may be applicable for predicting the risk of DIILD in patients receiving chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Predisposição Genética para Doença , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/etiologia , Neoplasias/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Prognóstico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Sequenciamento Completo do Genoma
14.
Gynecol Oncol Rep ; 30: 100498, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31538107

RESUMO

Malignant struma ovarii presenting with follicular carcinoma is extremely rare, and its mechanism of tumorigenesis remains unknown. Here, we present a case of malignant struma ovarii with peritoneal dissemination of follicular carcinoma, for which a molecular analysis for major oncogenic gene alterations in follicular thyroid carcinoma was performed. A 39-year-old nulliparous woman was referred with a diagnosis of highly differentiated follicular carcinoma of ovarian origin. Primary thyroid cancer was not diagnosed, and she had a normal thyroid function. 123I scintigraphy revealed multiple peritoneal dissemination that was surgically resected. Histologically, the tumor consisted of numerous follicles without nuclear features of papillary thyroid carcinoma. Tumor samples were investigated for 50 cancer-related genes, including RAS, BRAF, and p53, and PPARg-PAX8 gene fusion by targeted DNA sequencing and fluorescence in situ hybridization, respectively. No major oncogenic gene alterations were detected. These negative findings suggest a different mechanism of tumorigenesis from that of adult-type follicular thyroid carcinoma.

15.
J Thorac Oncol ; 14(9): 1594-1607, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31163278

RESUMO

INTRODUCTION: The relationships between morbid obesity, changes in body mass index (BMI) before cancer diagnosis, and lung cancer outcomes by histology (SCLC and NSCLC) have not been well studied. METHODS: Individual level data analysis was performed on 25,430 patients with NSCLC and 2787 patients with SCLC from 16 studies of the International Lung Cancer Consortium evaluating the association between various BMI variables and lung cancer overall survival, reported as adjusted hazard ratios (aHRs) from Cox proportional hazards models and adjusted penalized smoothing spline plots. RESULTS: Overall survival of NSCLC had putative U-shaped hazard ratio relationships with BMI based on spline plots: being underweight (BMI < 18.5 kg/m2; aHR = 1.56; 95% confidence interval [CI]:1.43-1.70) or morbidly overweight (BMI > 40 kg/m2; aHR = 1.09; 95% CI: 0.95-1.26) at the time of diagnosis was associated with worse stage-specific prognosis, whereas being overweight (25 kg/m2 ≤ BMI < 30 kg/m2; aHR = 0.89; 95% CI: 0.85-0.95) or obese (30 kg/m2 ≤ BMI ≤ 40 kg/m2; aHR = 0.86; 95% CI: 0.82-0.91) was associated with improved survival. Although not significant, a similar pattern was seen with SCLC. Compared with an increased or stable BMI from the period between young adulthood until date of diagnosis, a decreased BMI was associated with worse outcomes in NSCLC (aHR = 1.24; 95% CI: 1.2-1.3) and SCLC patients (aHR=1.26 (95% CI: 1.0-1.6). Decreased BMI was consistently associated with worse outcome, across clinicodemographic subsets. CONCLUSIONS: Both being underweight or morbidly obese at time of diagnosis is associated with lower stage-specific survival in independent assessments of NSCLC and SCLC patients. In addition, a decrease in BMI at lung cancer diagnosis relative to early adulthood is a consistent marker of poor survival.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Neoplasias Pulmonares/fisiopatologia , Carcinoma de Pequenas Células do Pulmão/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Carcinoma de Pequenas Células do Pulmão/mortalidade , Análise de Sobrevida , Adulto Jovem
16.
Int J Surg Pathol ; 27(7): 792-797, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31104528

RESUMO

Primary vulvar clear cell carcinoma (CCC) is extremely rare. In this article, we report a primary vulvar CCC along with immunohistochemical and gene mutation analyses results and literature review to discuss the clinicopathological features and tumorigenesis of this rare tumor. A 70-year-old (gravida 2 para 2) Japanese woman complained of bleeding from a vulvar mass at a past episiotomy site. A 1.8 × 1.8 × 0.5 cm exophytic sessile mass was present on the vestibular area inside the left labium minora. Radical local excision of the tumor and resection of the inguinal lymph nodes on both sides were performed. Histopathology revealed a vulvar CCC with immunohistochemical positivity for PAX8, HNF-1ß, ER, and CA125, and negativity for p16, CD10, GATA3, PTEN, and PAX2, suggesting its Müllerian origin. No lymph node metastasis was observed. The tumor was a 5-mm exophytic growth without deep stromal invasion; thus, it was difficult to measure the invasion depth assuming a squamous cell carcinoma. To investigate pathogenic/oncogenic mutations in 50 cancer-related genes, we used the AmpliSeq Cancer Hotspot Panel. However, no pathogenic/oncogenic mutations were detected. Literature review revealed that most cases of vulvar CCC are associated with vulvar endometriosis. In particular, cases with clinically evident endometriosis at the episiotomy scar should be carefully observed. Evidence-based pathological stages of vulvar adenocarcinoma including CCC remain to be established owing to its rarity, with nationwide or global accumulation of cases required in future.


Assuntos
Adenocarcinoma de Células Claras/diagnóstico , Biomarcadores Tumorais/genética , Endometriose/complicações , Doenças Raras/diagnóstico , Neoplasias Vulvares/diagnóstico , Adenocarcinoma de Células Claras/etiologia , Adenocarcinoma de Células Claras/patologia , Idoso , Biomarcadores Tumorais/análise , Análise Mutacional de DNA , Feminino , Humanos , Canal Inguinal , Excisão de Linfonodo , Linfonodos/patologia , Linfonodos/cirurgia , Doenças Raras/epidemiologia , Doenças Raras/etiologia , Vulva/patologia , Vulva/cirurgia , Neoplasias Vulvares/etiologia , Neoplasias Vulvares/patologia
17.
Asian Cardiovasc Thorac Ann ; 27(1): 45-48, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30417682

RESUMO

Pulmonary collision tumors have been described as a special entity of synchronous multiple lung cancer. There have been no reports detailing the chronological changes in primary collision lung cancers on chest computed tomography. We report a case of ground-glass lung nodules gradually colliding with each other. The collision tumors of the lung were composed of minimally invasive adenocarcinoma and adenocarcinoma in situ with epidermal growth factor mutations. Immunohistochemically, the Ki-67 labeling indices were different in the 2 components. Ki-67 staining was useful to distinguish the 2 components. The 2 dominant ground-glass tumors grew slowly with radiologic and pathologic heterogeneity.


Assuntos
Adenocarcinoma in Situ/diagnóstico por imagem , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Primárias Múltiplas/diagnóstico por imagem , Neoplasias Primárias Múltiplas/patologia , Tomografia Computadorizada por Raios X , Adenocarcinoma in Situ/química , Adenocarcinoma in Situ/genética , Adenocarcinoma in Situ/patologia , Adenocarcinoma de Pulmão/química , Análise Mutacional de DNA , Receptores ErbB/genética , Feminino , Humanos , Imuno-Histoquímica , Antígeno Ki-67/análise , Neoplasias Pulmonares/química , Neoplasias Pulmonares/genética , Excisão de Linfonodo , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Neoplasias Primárias Múltiplas/química , Neoplasias Primárias Múltiplas/genética , Pneumonectomia , Valor Preditivo dos Testes
18.
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
19.
Jpn J Clin Oncol ; 48(7): 603-608, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29762727

RESUMO

Targeted therapy against druggable genetic aberrations has shown a significantly positive response rate and longer survival in various cancers, including lung cancer. In lung adenocarcinoma (LADC), specific thyroxin kinase inhibitors against EGFR mutations and ALK fusions are used as a standard treatment regimen and show significant positive efficacy. On the other hand, targeted therapy against driver gene aberrations has not been adapted yet in small cell lung cancer (SCLC). This is because driver genes and druggable aberrations are rarely identified by next generation sequencing in SCLC. Recent advances in the understanding of molecular biology have revealed several candidate therapeutic targets. To date, poly [ADP-ribose] polymerase (PARP), enhancer of zeste homologue 2 (EZH2) or delta-like canonical Notch ligand 3 (DLL3) are considered to be druggable targets in SCLC. In addition, another candidate of personalized therapy for SCLC is immune blockade therapy of programmed death-1 (PD-1) and its ligand, PD-L1. PD-1/PD-L1 blockade therapy is not a standard therapy for SCLC, so many clinical trials have been performed to investigate its efficacy. Herein, we review gene aberrations exploring the utility of targeted therapy and discuss blockade of immune checkpoints therapy in SCLC.


Assuntos
Imunoterapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Terapia de Alvo Molecular , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/terapia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação/genética , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia
20.
Mol Clin Oncol ; 8(2): 310-314, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29435295

RESUMO

A useful candidate for small-cell lung cancer (SCLC) therapy is immune checkpoint blockade therapy targeting programmed death-1 (PD-1) and its ligand, PD-L1. Furthermore, rovalpituzumab tesirine (Rova-T), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate, and enhancer of zeste homologue 2 (EZH2) inhibitor are expected to be the first targeted therapy for SCLC. The aim of the present study was to evaluate PD-L1, DLL3 and EZH2 expression in SCLCs to find a candidate responder to those therapies. Immunohistochemical (IHC) staining for PD-L1, DLL3 and EZH2 was performed in 20 patients with SCLC and the clinicopathological characteristics and IHC staining intensity were compared. It was demonstrated that 1/20 patients (5.0%) exhibited positive PD-L1 expression in the metastatic lesions, as well as in the primary lung tumor. DLL3 was highly expressed in 14/20 patients (70%) and EZH2 was positive in 17/20 patients (85%). None of these cases exhibited any correlation with age, sex, smoking, stage or treatment, whereas IHC staining was able to identify candidate responders to anti-PD-L1/PD-1 immunotherapy, Rova-T therapy, or EZH2 inhibitor therapy.

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