RESUMO
Triple-negative apocrine carcinomas (TNACs) are rare breast tumors with limited studies evaluating their molecular characteristics and clinical behavior. We performed a histologic, immunohistochemical, genetic, and clinicopathologic assessment of 42 invasive TNACs (1 with a focal spindle cell component) from 41 patients, 2 pure apocrine ductal carcinomas in situ (A-DCIS), and 1 A-DCIS associated with spindle cell metaplastic carcinoma (SCMBC). All TNACs had characteristic apocrine morphology and expressed androgen receptor (42/42), gross cystic disease fluid protein 15 (24/24), and CK5/6 (16/16). GATA3 was positive in most cases (16/18, 89%), and SOX10 was negative (0/22). TRPS1 was weakly expressed in a minority of tumors (3/14, 21%). Most TNACs had low Ki67 proliferation (≤10% in 67%, 26/39), with a median index of 10%. Levels of tumor infiltrating lymphocytes were low (≤10% in 93%, 39/42, and 15% in 7%, 3/42). Eighteen percent of TNACs presented with axillary nodal metastasis (7/38). No patients treated with neoadjuvant chemotherapy achieved pathologic complete response (0%, 0/10). Nearly all patients with TNAC (97%, n = 32) were without evidence of disease at the time of study (mean follow-up of 62 months). Seventeen invasive TNACs and 10 A-DCIS (7 with paired invasive TNAC) were profiled by targeted capture-based next-generation DNA sequencing. Pathogenic mutations in phosphatidylinositol 3-kinase pathway genes PIK3CA (53%) and/or PIK3R1 (53%) were identified in all TNACs (100%), including 4 (24%) with comutated PTEN. Ras-MAPK pathway genes, including NF1 (24%), and TP53 were mutated in 6 tumors each (35%). All A-DCIS shared mutations, such as phosphatidylinositol 3-kinase aberrations and copy number alterations with paired invasive TNACs or SCMBC, and a subset of invasive carcinomas showed additional mutations in tumor suppressors (NF1, TP53, ARID2, and CDKN2A). Divergent genetic profiles between A-DCIS and invasive carcinoma were identified in 1 case. In summary, our findings support TNAC as a morphologically, immunohistochemically, and genetically homogeneous subgroup of triple-negative breast carcinomas and suggest overall favorable clinical behavior.
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Neoplasias da Mama , Carcinoma in Situ , Carcinoma Intraductal não Infiltrante , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Carcinoma Intraductal não Infiltrante/patologia , Neoplasias da Mama/patologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Fatores de Transcrição , Fosfatidilinositol 3-Quinases , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proteínas RepressorasRESUMO
Adeno-associated virus (AAV)-mediated gene therapy is a novel treatment promising to reduce morbidity associated with hemophilia. Although multiple clinical trials continue to evaluate efficacy and safety, limited cost-effectiveness data have been published. This study compared the potential cost-effectiveness of AAV-mediated factor IX (FIX)-Padua gene therapy for patients with severe hemophilia B in the United States vs on-demand FIX replacement and primary FIX prophylaxis, using either standard or extended half-life FIX products. A microsimulation Markov model was constructed, and transition probabilities between health states and utilities were informed by using published data. Costs were aggregated by using a microcosting approach. A time horizon from 18 years old until death, from the perspective of a third-party payer in the United States, was conducted. Gene therapy was more cost-effective than both alternatives considering a $150 000/quality-adjusted life-year threshold. The price for gene therapy was assumed to be $2 000 000 in the base case scenario; however, one of the 1-way sensitivity analyses was conducted by using observed manufacturing, administration, and 5-year follow-up costs of $87 198 for AAV-mediated gene therapy vector as derived from the manufacturing facility and clinical practice at St Jude Children's Research Hospital. One-way sensitivity analyses revealed 10 of 102 scenarios in which gene therapy was not cost-effective compared with alternative treatments. Notably, gene therapy remained cost-effective in a hypothetical scenario in which we estimated that the discounted factor concentrate price was 20% of the wholesale acquisition cost in the United States. Probabilistic sensitivity analysis estimated gene therapy to be cost-effective at 92% of simulations considering a $150 000/quality-adjusted life-year threshold. In conclusion, based on detailed simulation inputs and assumptions, gene therapy was more cost-effective than on-demand treatment and prophylaxis for patients with severe hemophilia B.
Assuntos
Terapia Genética/economia , Hemofilia B/terapia , Adulto , Simulação por Computador , Análise Custo-Benefício , Hemofilia B/economia , Hemofilia B/epidemiologia , Humanos , Cadeias de Markov , Probabilidade , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Extended half-life (EHL) factor VIII (FVIII) products may decrease the burden of prophylactic treatment in haemophilia A by reducing infusion frequency. However, these products still exhibit wide inter-patient variability and benefit from pharmacokinetic (PK) tailoring. OBJECTIVE: Identify limited sampling strategies for rFVIIIFc, an EHL FVIII product, that produce accurate estimates of PK parameters and relevant troughs. METHODS: We performed a limited sampling analysis on simulated populations of adults, adolescents, and children based on published population PK data. Sampling strategies were evaluated by comparing the error in estimates of half-life, clearance, and trough levels, to a full 6-sample design. Furthermore, we assessed the impact of incorporating knowledge about prior doses, and the day of the PK study within the regimen. We also evaluated the potential inappropriate dose adjustment rate (IDAR) among the modelled sampling strategies. RESULTS: Many sampling strategies, including several 2-sample designs, accurately predicted the PK and exposure measures (median absolute error <10%). When samples are only collected during a single visit (i.e., predose + peak), inclusion of prior dose information reduces median half-life error from >20% to ~5% for adults/adolescents. In this same scenario, appropriate scheduling of the PK study decreases likelihood of unmeasurable predose samples, reducing median error on the 72-h trough from 25% to <12% in the youngest population. CONCLUSIONS: The PK of rFVIIIFc can be accurately estimated using only peak and trough samples, provided that knowledge of prior doses is incorporated and the PK study is planned on an appropriate day within the dosing regimen.
Assuntos
Hemofilia A , Hemostáticos , Adolescente , Adulto , Criança , Fator VIII , Meia-Vida , Hemofilia A/tratamento farmacológico , HumanosRESUMO
OBJECTIVE: We aimed to describe the effect of education provided by a clinical pharmacy specialist at a patient's follow-up appointment after discharge, and to assess caregiver satisfaction. METHODS: A single-center, quality improvement study was conducted. A standardized data collection tool was created to characterize interventions made by clinical pharmacy specialists during an outpatient clinic appointment scheduled shortly after discharge. Pediatric patients with cancer who met the following criteria were included: 1) initial diagnosis without receiving chemotherapy, 2) first course of chemotherapy after initial diagnosis or relapsed disease, and 3) post-hematopoietic stem cell transplantation or cellular therapy. A survey was provided to families after the follow-up discharge appointment to assess the caregiver's satisfaction of the new process. RESULTS: From January to May 2021, a total of 78 first-time discharge appointments were completed. The most common reason for follow-up was discharge after first course of chemotherapy (77%). The average duration of each appointment was 20 minutes (range, 5-65). The clinical pharmacy specialist made an intervention during 85% of appointments. The most common intervention made during the visit was reinforcement of medications (31%). Thirteen surveys were completed by caregivers; 100% of the caregivers reported the follow-up appointment was helpful. Additionally, they reported the most useful resource provided at discharge was the medication calendar (85%). CONCLUSIONS: Investing clinical pharmacy specialist time with patients and caregiver after discharge appears to have a meaningful effect on patient care. Caregivers report this process is helpful in better understanding their child's medications.
RESUMO
Breast fine-needle aspiration (FNA) is highly sensitive and specific for detecting carcinoma under most circumstances. Immunostaining for the myoepithelial cell marker p63 has been shown to be useful to separate noninvasive from invasive breast lesions in histologic examination. Its usefulness for breast FNA specimens is less certain. We performed p63 immunostains on 17 clinical samples and 29 aspirates from excised surgical specimens. One Papanicolaou-stained ThinPrep slide (Cytyc, Marlborough, MA) from each case was scored as benign, atypical, "suspicious," or positive. Cytospin (Shandon, Pittsburgh, PA) slides stained with p63 antibody were scored as to the percentage of positive single cells and percentage of positive clusters. The staining pattern of p63 was significantly different (P < .0001) between malignant and benign lesions. Based on cytology alone, the sensitivity, specificity, and positive and negative predictive values were 88%, 90%, 83%, and 93%, respectively. The application of p63 staining to specimens with a less-than-definitive diagnosis (atypical and suspicious) improved the specificity and positive and negative predictive values to 97%, 94%, and 97%, respectively. When used in conjunction with morphologic examination, p63 immunostaining may be useful to categorize cases problematic by Papanicolaou staining.
Assuntos
Biópsia por Agulha/métodos , Neoplasias da Mama/diagnóstico , Mama/patologia , Proteínas de Membrana/análise , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Feminino , Humanos , Imuno-Histoquímica , Estudos ProspectivosRESUMO
Fibroepithelial lesions with cellular stroma (FELCS) in breast core needle biopsy (CNB) specimens may result in either fibroadenoma or phyllodes tumor at excision. We evaluated histologic features, proliferation indices (by Ki-67 and topoisomerase II a immunostaining) and p53 expression in 29 cases of FELCS in CNB specimens and correlated these with excision findings in a blinded manner. On excision, 16 patients had fibroadenomas and 12 had phyllodes tumors. All CNB specimens with mildly increased stromal cellularity were fibroadenomas on excision (n=4), and all with markedly cellular stroma were phyllodes tumors (n=4). Among CNB specimens with moderate cellularity (12 fibroadenomas and 8 phyllodes tumors), only stromal mitoses were discriminatory histologically. Stromal proliferation indices were significantly higher in CNB that were phyllodes tumors vs fibroadenomas. Assessment of stromal cellularity, mitoses, and proliferation indices might help determine the probability of phyllodes tumor occurring and guide management of these cases.
Assuntos
Neoplasias da Mama/patologia , Mama/patologia , Fibroadenoma/patologia , Tumor Filoide/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-IdadeRESUMO
We evaluated whether moderate alcohol consumption is associated with increased risk of developing benign breast disease (BBD), a potential "precursor" or marker for breast cancer development. This study evaluated associations between reported alcohol consumption and BBD diagnosis among 75,826 women in the Nurses' Health Study II. Between 1989 and 1997, 16,035 women reported a first diagnosis of BBD (317/10,000 person-years), of which 2,999 diagnoses were confirmed by tissue biopsy (59/10,000 person-years). Of the pathology specimens reviewed, 532 were nonproliferative benign breast conditions, and 932 were proliferative conditions. Person-time models provided estimates of the rate ratio (RR) and 95% confidence interval (CI). Reported recent adult consumption of alcohol was not associated with increased BBD incidence. Compared with women who did not drink alcohol, the age- and body mass index (BMI)-adjusted RRs for any reported BBD were 0.98 (95% CI, 0.95-1.02) for those who consumed <5 g/day, 0.93 (95% CI, 0.89-0.98) for those who consumed 5-14.9 g/day, and 0.90 (95% CI, 0.83-0.98) for those who consumed >or=15 g/day. The adjusted RRs for biopsy confirmed BBD and any proliferative benign condition were similiar. However, reported alcohol consumption of >or=15 g/day between ages 18 and 22 years was associated with higher rates of biopsy-confirmed BBD (age- and body mass index-adjusted RR = 1.14; 95% CI, 1.00-1.30), nonproliferative BBD (RR = 1.46; 95% CI, 1.09-1.96), and any proliferative BBD (RR = 1.33; 95% CI, 1.05-1.69), but not atypical hyperplasia. In this study, recent alcohol consumption was associated with slightly lower rates of reported BBD. However, greater alcohol consumption earlier in life (ages 18-22 years) was associated with higher proliferative BBD rates, suggesting that timing of exposure may be relevant to disease incidence.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Doenças Mamárias/epidemiologia , Doenças Mamárias/etiologia , Adulto , Biópsia , Índice de Massa Corporal , Mama/patologia , Doenças Mamárias/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Neoplasias da Mama/patologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Incidência , Menopausa , Neoplasias/epidemiologia , Neoplasias/etiologia , Neoplasias/patologia , Estudos Prospectivos , Fatores de Risco , Fumar , Inquéritos e Questionários , Saúde da MulherRESUMO
Much attention has been paid to the relation between diet and breast cancer risk. Because benign breast disease (BBD), particularly atypical hyperplasia (AH), is a marker of increased breast cancer risk, studies of diet and BBD may provide evidence about the effect of diet at an early stage in the process of breast carcinogenesis. We evaluated the relationship between fat, fiber, antioxidant and caffeine intake and incidence of non-proliferative BBD, proliferative BBD without atypia and AH in the Nurses' Health Study II. We calculated rate ratios (RR) and 95% confidence intervals (95% CI) for each quartile of energy-adjusted intake using the lowest quartile as reference. There was no increase in risk of BBD with increasing fat intake, rather increasing vegetable fat was associated with a significant reduction in the rate of proliferative BBD without atypia. There was no significant association between any type of BBD and micronutrient intake. High caffeine consumption was positively associated (RR = 2.46, 95% CI 1.11-5.49 for the highest quartile), and use of multivitamin supplements inversely associated (RR = 0.57, 95% CI 0.33-0.98) with risk of AH although these analyses were based on small numbers. These data do not support the hypothesis that higher fat consumption increases risk of BBD, with or without atypia, and also provide little evidence for a major role of antioxidants in the development of breast disease. They do, however, raise the possibility that high caffeine intake may increase, and use of vitamin supplements may decrease risk of developing AH.
Assuntos
Doenças Mamárias/etiologia , Gorduras na Dieta/administração & dosagem , Suplementos Nutricionais/estatística & dados numéricos , Vitaminas/administração & dosagem , Adulto , Antioxidantes/administração & dosagem , Antioxidantes/análise , Doenças Mamárias/classificação , Doenças Mamárias/diagnóstico , Doenças Mamárias/patologia , Neoplasias da Mama/etiologia , Inquéritos sobre Dietas , Gorduras na Dieta/análise , Gorduras na Dieta/classificação , Fibras na Dieta/administração & dosagem , Fibras na Dieta/análise , Suplementos Nutricionais/classificação , Feminino , Humanos , Hiperplasia , Pessoa de Meia-Idade , Enfermeiras e Enfermeiros , Estudos Prospectivos , Fatores de Risco , Estados Unidos , Vitaminas/análise , Vitaminas/classificação , Saúde da MulherRESUMO
Large core needle biopsies using stereotactic mammography or ultrasound guidance are now commonly performed as the initial diagnostic approach to nonpalpable breast lesions. Although the subsequent management of patients with invasive cancer, ductal carcinoma in situ, and most benign lesions diagnosed on core needle biopsy specimens is straightforward, certain nonmalignant lesions pose dilemmas with regard to the most appropriate clinical management following core needle biopsy. The purpose of this article is to review the available data regarding several nonmalignant breast lesions, which when encountered in core needle biopsy specimens raise repeated management questions. These include atypical ductal hyperplasia, lobular neoplasia (atypical lobular hyperplasia and lobular carcinoma in situ), papillary lesions, radial scars, fibroepithelial lesions, mucocele-like lesions, and columnar cell lesions.
Assuntos
Biópsia por Agulha , Neoplasias da Mama/patologia , Carcinoma/patologia , Fibroadenoma/patologia , Lesões Pré-Cancerosas/patologia , Neoplasias da Mama/cirurgia , Carcinoma/cirurgia , Feminino , Fibroadenoma/cirurgia , Humanos , Lesões Pré-Cancerosas/cirurgia , Resultado do TratamentoRESUMO
We recently reported that radial scars are an independent histologic risk factor for breast cancer. The reason for this association is not known. Given the importance of stromal-epithelial interactions in the pathogenesis of breast cancer, we studied radial scars for the expression of a number of factors known to be involved in the formation of vascular stroma in breast cancer. In situ hybridization was performed on formalin-fixed paraffin sections using (35)S-labeled riboprobes for collagen type 1, total fibronectin, extra domain A (ED-A)+ fibronectin, thrombospondin 1, vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF), and one of its endothelial receptors, kinase insert domain-containing receptor (KDR) (vascular endothelial growth factor receptor [VEGFR-2]). Expression levels in radial scars (9 cases) were compared with those in normal breast tissue (15 cases) and infiltrating ductal breast carcinoma (4 cases). Factor VIII-related antigen immunostaining was used to define the distribution of microvessels in radial scars, carcinoma, and normal breast tissue. Compared with normal breast tissue, the radial scars showed focally increased numbers of blood vessels and focally increased expression of messenger RNA (mRNA) for collagen type 1, total fibronectin, ED-A+ fibronectin, thrombospondin 1, VPF/VEGF, and KDR. This pattern of mRNA overexpression was similar to that seen in the 4 invasive cancers. We conclude that there are similarities between radial scars and invasive breast cancers with regard to the level of mRNA expression for several factors involved in the formation of vascular stroma. These results suggest that a similar disturbance in stromal-epithelial interactions is present in both lesions.
Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Intraductal não Infiltrante/metabolismo , Cicatriz/metabolismo , Neovascularização Patológica/metabolismo , Adulto , Idoso , Mama/anatomia & histologia , Mama/irrigação sanguínea , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/irrigação sanguínea , Carcinoma Intraductal não Infiltrante/secundário , Cicatriz/patologia , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Ectodisplasinas , Fatores de Crescimento Endotelial/genética , Fatores de Crescimento Endotelial/metabolismo , Feminino , Fibronectinas/genética , Fibronectinas/metabolismo , Humanos , Hibridização In Situ , Linfocinas/genética , Linfocinas/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Microcirculação/anatomia & histologia , Microcirculação/metabolismo , Microcirculação/patologia , Pessoa de Meia-Idade , Neovascularização Patológica/patologia , RNA/metabolismo , RNA Neoplásico/análise , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento/genética , Receptores de Fatores de Crescimento/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular , Células Estromais/metabolismo , Células Estromais/patologia , Trombospondina 1/genética , Trombospondina 1/metabolismo , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
This article focuses on current issues relating to fibroepithelial lesions, predominantly those with cellular stroma, and covers key pathologic features, differential diagnosis, and pitfalls. Phyllodes tumors are emphasized, including the histologic categorization and prognostic features of these lesions. The management of fibroepithelial lesions on needle core biopsy is reviewed.
RESUMO
The clinical, pathologic, and molecular features of pleomorphic lobular carcinoma in situ (PLCIS) and the relationship of PLCIS to classic LCIS (CLCIS) are poorly defined. In this study, we analyzed 31 cases of PLCIS (13 apocrine and 18 nonapocrine subtypes) and compared the clinical, pathologic, immunophenotypic, and genetic characteristics of these cases with those of 24 cases of CLCIS. Biomarker expression was examined using immunostaining for E-cadherin, gross cystic disease fluid protein-15, estrogen, progesterone, androgen receptor, human epidermal growth factor receptor2, CK5/6, and Ki67. Array-based comparative genomic hybridization to assess the genomic alterations was performed using microdissected formalin-fixed paraffin-embedded samples. Patients with PLCIS presented with mammographic abnormalities. Histologically, the tumor cells were dyshesive and showed pleomorphic nuclei, and there was often associated necrosis and microcalcifications. All lesions were E-cadherin negative. Compared with CLCIS, PLCIS showed significantly higher Ki67 index, lower estrogen receptor and progesterone receptor expression, and higher incidence of HER2 gene amplification. The majority of PLCIS and CLCIS demonstrated loss of 16q and gain of 1q. Apocrine PLCIS had significantly more genomic alterations than CLCIS and nonapocrine PLCIS. Although lack of E-cadherin expression and the 16q loss and 1q gain-array-based comparative genomic hybridization pattern support a relationship to CLCIS, PLCIS has clinical, mammographic, histologic, immunophenotypic, and genetic features that distinguish it from CLCIS. The histologic features, biomarker profile, and genomic instability observed in PLCIS suggest a more aggressive phenotype than CLCIS. However, clinical follow-up studies will be required to define the natural history and most appropriate management of these lesions.
Assuntos
Neoplasias da Mama/patologia , Carcinoma in Situ/patologia , Carcinoma Lobular/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneuploidia , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma in Situ/genética , Carcinoma in Situ/metabolismo , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 16/genética , Hibridização Genômica Comparativa , DNA de Neoplasias/análise , Feminino , Técnica Direta de Fluorescência para Anticorpo , Humanos , Processamento de Imagem Assistida por Computador , Técnicas Imunoenzimáticas , Imunofenotipagem , Pessoa de Meia-Idade , Análise de Sequência com Séries de OligonucleotídeosRESUMO
We report the third case of a solid serous adenoma of the pancreas, a rare variant of tumor within the family of pancreatic serous cystic neoplasms. This asymptomatic tumor presented in a 66-year-old man during imaging for another problem. Computed tomography of the abdomen demonstrated a 3.5-cm hypervascular mass in the head of the pancreas. A pylorus preserving pancreaticoduodenectomy was performed. Histological examination demonstrated a neoplasm identical to a serous cystadenoma-glycogen-rich cuboidal or polygonal cells with finely granulated eosinophilic or clear cytoplasm. More often, the neoplasm contained solid areas and tubules but no microcysts. Periodic acid Schiff's-glycogen staining was positive in some cells, turning negative after diastase was applied. Immunostaining was positive for CK7, CK8, neuron specific enolase, and MUC6. The microscopic findings of a solid neoplasm of cuboidal cells rich in glycogen and the immunostaining listed associate this tumor with the previously 2 reported cases of solid serous adenoma. All 3 reported cases thus far have proven to be benign lesions by pathological examination. Because clinical follow-up is reported only in the present case, caution should be exercised in declaring the solid serous adenoma of the pancreas as a benign lesion.