RESUMO
The tumor microenvironment hosts antibody-secreting cells (ASCs) associated with a favorable prognosis in several types of cancer. Patient-derived antibodies have diagnostic and therapeutic potential; yet, it remains unclear how antibodies gain autoreactivity and target tumors. Here, we found that somatic hypermutations (SHMs) promote antibody antitumor reactivity against surface autoantigens in high-grade serous ovarian carcinoma (HGSOC). Patient-derived tumor cells were frequently coated with IgGs. Intratumoral ASCs in HGSOC were both mutated and clonally expanded and produced tumor-reactive antibodies that targeted MMP14, which is abundantly expressed on the tumor cell surface. The reversion of monoclonal antibodies to their germline configuration revealed two types of classes: one dependent on SHMs for tumor binding and a second with germline-encoded autoreactivity. Thus, tumor-reactive autoantibodies are either naturally occurring or evolve through an antigen-driven selection process. These findings highlight the origin and potential applicability of autoantibodies directed at surface antigens for tumor targeting in cancer patients.
Assuntos
Anticorpos Antineoplásicos , Neoplasias Ovarianas , Anticorpos Monoclonais , Autoanticorpos , Autoantígenos , Feminino , Humanos , Neoplasias Ovarianas/genética , Microambiente TumoralRESUMO
BACKGROUND: Primary cutaneous B-cell lymphoma (PCBCL) classically presents with papules, plaques, and nodules/tumors. Previous reports of PCBCL manifesting with macular lesions are scarce and focused on primary cutaneous follicle-center cell lymphoma (PCFCL). OBJECTIVES: The objective of this study was to report our experience with PCBCL presenting with erythematous macules. METHODS: Patients with low-grade PCBCL manifesting with erythematous patches, diagnosed and managed between January 2000 through December 2019 at 2 tertiary cutaneous-lymphoma outpatient clinics, were included. Clinical data were retrospectively collected, and biopsy specimens of the macules, and if present of the typical nodular/tumoral lesions, were reviewed. RESULTS: There were 14 patients, aged 16-67 years, 8 had PCFCL and 6 marginal zone lymphoma (PCMZL). All had 1-15 cm erythematous macules, mimicking: interstitial granuloma annulare/vascular tumors/early-stage folliculotropic mycosis fungoides, or presenting with figurate erythema or livedo reticularis-like/net-like pattern. In 3 patients, macules were the presenting lesions, in 2 as the sole manifestation, whereas in 12 patients, typical PCBCL lesions were observed during disease course. The macules showed in all, superficial and deep perivascular infiltrates, and in most, periadnexal infiltrates. Micronodules were observed in 11 specimens, with nodular infiltrates also observed in 4. B cells comprised the majority of the lymphocytes in only 4. Seven of 11 cases tested showed immunoglobulin heavy chain monoclonality. CONCLUSIONS: PCMZL and PCFCL may manifest with erythematous macules. Physicians should be aware of this unusual manifestation of low-grade PCBCL, which may represent a clinicopathological diagnostic pitfall.
Assuntos
Linfoma de Zona Marginal Tipo Células B , Neoplasias Cutâneas , Humanos , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Linfoma de Zona Marginal Tipo Células B/diagnóstico , EritemaRESUMO
BACKGROUND/PURPOSE: This study examined clinical and histological parameters of primary dermal melanoma (PDM) to aid in its distinction from dermal metastasis. METHODS: Retrospective analysis of a prospective cohort of PDM patients. Includes patients fulfilling the strict histologic criteria for PDM (N = 9) and patients who did not, but clinically, unequivocally had an intradermal melanoma-clinical PDM (cPDM; N = 17).Histopathology slides were re-examined. Prognosticators and outcome measures were compared between groups. Sentinel nodes' retrieval and wide local excision (WLE) were offered to all patients as primary treatment. RESULTS: 26 patients identified, 15 females with a median age of 69 years (range 3.5-85). Mean Breslow was 7.9 ± 5.7 mm (median 5.8, range 1.8-25.0), and the mean mitotic rate was 4.9 ± 3.8/mm2 (median 4.0, range 0-17). Initial treatment and follow-up were as for cutaneous melanoma. One patient in each group with a palpable stage III underwent primary radical dissection. Sentinel nodes were retrieved in all 20 lymphatic mappings performed and found to be metastatic in 5 (25%) patients. Treatment consisted of completion lymph-node dissection. At a median postoperative follow-up of 62 months (range 8-132), 20 patients were disease-free, including 6 of 7 patients with stage III disease at presentation. Six patients died all of cPDM; 5 of 6 patients had primary ulcerated or epidermal-abutting melanomas. CONCLUSIONS: This is the first study to highlight cPDM. Diagnosis requires expert pathology review and a tight correlation to the clinical parameters. Patients seem to benefit from WLE with sentinel node retrieval and complete dissection when appropriate. However, clinical guidelines for dissection have changed since the time period of this retrospective review. Based on this series, complete nodal dissection in these melanomas is associated with better than expected outcome, for stage III disease.
Assuntos
Excisão de Linfonodo , Melanoma/secundário , Melanoma/cirurgia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Melanoma/diagnóstico , Pessoa de Meia-Idade , Índice Mitótico , Estadiamento de Neoplasias , Estudos Retrospectivos , Linfonodo Sentinela/patologia , Linfonodo Sentinela/cirurgia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/secundário , Carga Tumoral , Adulto JovemRESUMO
Recent studies suggest that folliculotropic mycosis fungoides (FMF), the most common variant of mycosis fungoides (MF), presents with 2 distinct clinicopathological stages: early indolent stage and more aggressive advanced/tumour stage. To further characterize these stages, miR-155 expression was studied with qRT-PCR and found to be significantly higher in biopsies of tumour-stage FMF compared with early-stage FMF and inflammatory dermatoses. There was no statistically significant difference in miR-155 expression between early-stage FMF and early-stage MF, nor between tumour-stage FMF and tumour-stage MF. Immunohistochemical analysis revealed a significantly increased number of dermal Ki-67+ proliferating lymphocytes in tumour-stage FMF, together with an increased number of CD20+ B cells and CD68+ macrophages compared with early-stage FMF. Thus, similar to classic MF, miR-155, Ki-67 tumour cell immunoreactivity, and certain tumour-infiltrating inflammatory cells are differentially expressed in early- vs tumour-stage FMF. The results of this study corroborate the notion that FMF presents with 2 distinct stages.
Assuntos
MicroRNAs , Micose Fungoide , Neoplasias Cutâneas , Biópsia , Humanos , Antígeno Ki-67 , MicroRNAs/genética , Micose Fungoide/genética , Neoplasias Cutâneas/genéticaRESUMO
BACKGROUND/OBJECTIVES: Lichen sclerosus is a rare, pruritic, mucocutaneous disease affecting mostly the anogenital area. Reports have occasionally associated lichen sclerosus with overlapping vascular lesions. This study explores this association in children. METHODS: A retrospective study was conducted in the dermatology unit of a pediatric tertiary care medical center. Electronic medical records were searched for patients diagnosed with lichen sclerosus from 2006 to 2019. Review of the cases was performed to identify overlapping vascular lesions and review the clinical course of overlap cases. RESULTS: Of 74 children diagnosed with lichen sclerosus during the study period, five (6.75%) had overlapping vascular lesions and genital lichen sclerosus. Four patients presented with reticular telangiectatic macules and patches (n = 4, 5.4%) that appeared at or shortly after disease onset; resolution occurred a few months after treatment initiation. The fifth patient presented with telangiectases that appeared more than 2 years after the onset of the first symptoms of lichen sclerosus (n = 1, 1.3%). CONCLUSION: Vascular lesions in children with genital lichen sclerosus are common and have variable clinical manifestations. Early appearance of reticular macules, patches, and papules is a variant of the disease and is followed by prompt resolution of these lesions. Pathogenesis is attributed to structural changes and repositioning of the papillary vascular plexus. These changes may be alarming to parents and therefore must be recognized by physicians to prevent unnecessary concern and investigations.
Assuntos
Líquen Escleroso e Atrófico , Doenças Urológicas , Criança , Genitália , Humanos , Líquen Escleroso e Atrófico/complicações , Líquen Escleroso e Atrófico/diagnóstico , Líquen Escleroso e Atrófico/epidemiologia , Estudos RetrospectivosRESUMO
Systemic doxorubicin is effective for desmoid fibromatosis (DF), but its use is limited by dose-dependent cardiotoxicity. A protocol of selective intra-arterial doxorubicin drug-eluting embolization (DEE) was designed to maximize target tissue efficacy of doxorubicin, while minimizing systemic exposure. Four children with recurrent or refractory DF were treated between 2014 and 2017. Tumor volumes were reduced by 54%-97% over a follow-up interval of 6-32 months. A single patient experienced transient lower extremity paresthesia (Common Terminology Criteria for Adverse Events grade I). Further investigation is needed to better establish these promising results for doxorubicin DEE in DF treatment.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Quimioembolização Terapêutica/métodos , Doxorrubicina/administração & dosagem , Fibromatose Agressiva/tratamento farmacológico , Adolescente , Fatores Etários , Angiografia , Antibióticos Antineoplásicos/efeitos adversos , Quimioembolização Terapêutica/efeitos adversos , Pré-Escolar , Tomografia Computadorizada de Feixe Cônico , Doxorrubicina/efeitos adversos , Estudos de Viabilidade , Feminino , Fibromatose Agressiva/diagnóstico por imagem , Fibromatose Agressiva/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacosRESUMO
Acinic cell carcinoma of the parotid gland is a rare low-grade malignant neoplasm. Data on children are sparse. For the present study, the database of a tertiary pediatric medical center was reviewed for all patients with parotid gland acinic cell carcinoma diagnosed and treated between 2004 and 2013. Clinical, histologic, treatment, and outcome parameters were collected from the medical files. Four patients were identified, 3 female and 1 male, aged 13.5 to 18 years (median 15.7) at diagnosis. One patient had a family history of parotid tumor and 1 of hypothyroidism/hyperthyroidism. Two patients had L-thyroxin-treated Hashimoto thyroiditis, and 1 had a thyroid nodule. All presented with a localized parotid mass and negative lymph nodes. Treatment consisted of partial parotidectomy, with no damage to the facial nerve. Histology confirmed the diagnosis of acinic cell carcinoma with low proliferation rate (Ki67 immunostaining 1% to 8%). No evidence of disease was found on any patient with a median follow-up at 83 months (range, 32 to 93 mo) from presentation. In our experience, the prognosis of pediatric parotid gland acinic cell carcinoma is good, and surgery alone is sufficient for treatment of early stage tumors. This is the first report of findings of a family history of thyroid disease and/or thyroid abnormalities in patients with parotid gland acinic cell carcinoma.
Assuntos
Carcinoma de Células Acinares/patologia , Carcinoma de Células Acinares/cirurgia , Neoplasias Parotídeas/patologia , Adolescente , Feminino , Humanos , Masculino , Neoplasias Parotídeas/cirurgia , Prognóstico , Resultado do TratamentoRESUMO
Data on the treatment of early folliculotropic mycosis fungoides, a recently defined clinicopathological subgroup of folliculotropic mycosis fungoides with an indolent course, is limited. Treatment outcomes were studied in a retrospective cohort of 47 adults with early folliculotropic mycosis fungoides, with a focus on psoralen plus ultraviolet A (PUVA) monotherapy, including dosimetric data, and the findings were compared with data for PUVA in 18 adults with early-classic mycosis fungoides. PUVA was given to 27 patients with early folliculotropic mycosis fungoides: 70% achieved complete response and 26% partial response. Significantly more treatments were needed to achieve complete response in stage IB compared with stage IA. There was no significant difference in the complete response rate from classic plaque-stage disease, although the early folliculotropic mycosis fungoides group required more treatments to achieve complete response, and a higher cumulative dose of UVA. Thus, PUVA is an effective treatment for early folliculotropic mycosis fungoides. Its complete response rate might be equal to early-classic mycosis fungoides; however, a longer induction phase is needed to achieve complete response.
Assuntos
Micose Fungoide/tratamento farmacológico , Terapia PUVA , Neoplasias Cutâneas/tratamento farmacológico , Adolescente , Adulto , Idoso , Feminino , Humanos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Micose Fungoide/patologia , Estadiamento de Neoplasias , Indução de Remissão , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Adulto JovemRESUMO
Ependymoma is a malignant pediatric brain tumor, often incurable under the current treatment regimen. We aimed to evaluate the expression of microRNAs (miRs) in pediatric ependymoma tumors in an attempt to identify prognostic molecular markers which would lead to potential therapeutic targets. Following miR-array expression analysis, we focused on 9 miRs that correlated with relapse which were further validated by quantitative real-time PCR (qRT-PCR) in a cohort of 67 patients. Western blotting and immunohistochemistry were used to measure target protein expression in 20 and 34 tumor samples, respectively. High expression of miR-124-3p significantly correlated with the lower progression-free survival (PFS) of 16% compared to 67% in those expressing low levels (P = .002). Interestingly, in the group of patients with local disease (n = 56) expression levels of this miR distinguished 2 subgroups with a significantly different outcome (P = .001). miR-124-3p was identified as an independent prognostic factor of relapse in the multivariate analysis performed in the whole cohort and in the group with localized disease. In the localized group, a patient expressing high levels of miR-124-3p had a 4.1-fold increased risk for relapse (P = .005). We demonstrated the direct binding of miR-124-3p to its target TP53INP1. Negative TP53INP1 protein levels correlated with a poor outcome (P = .034). We propose miR-124-3p and TP53INP1 as new biomarkers for prognostic stratification that may be possible therapeutic targets for ependymoma.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Proteínas de Transporte/genética , Ependimoma/genética , Proteínas de Choque Térmico/genética , MicroRNAs/genética , Adolescente , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proteínas de Transporte/metabolismo , Criança , Pré-Escolar , Intervalo Livre de Doença , Ependimoma/diagnóstico , Ependimoma/metabolismo , Ependimoma/patologia , Feminino , Proteínas de Choque Térmico/metabolismo , Humanos , Lactente , Masculino , MicroRNAs/metabolismoRESUMO
Nevi and melanocytic proliferations are known to appear in multiple extracutaneous sites, including lymph nodes and meninges. We report a case of an anterior mediastinal mass in a patient with a giant congenital nevus and neurofibromatosis type I. Histologically, the tumor was found to be a malignant melanoma in the thymus arising in association with a nevus that involved most of the thymic tissue. There was no sign of cutaneous melanoma on skin examination. We suggest that the tumor originated from the benign nevus in the thymus, a rare extracutaneous location for nevi and malignant melanoma.
Assuntos
Melanoma/patologia , Nevo Pigmentado/patologia , Nevo/patologia , Neoplasias Cutâneas/patologia , Neoplasias do Timo/patologia , Adulto , Feminino , HumanosRESUMO
BACKGROUND: It is generally accepted that folliculotropic mycosis fungoides (FMF) is usually typified by indurated plaques and tumors mainly on the head/neck and an aggressive course. However, its clinical manifestations have long been recognized to be quite variable, and some studies indicate a better prognosis for certain presentations. OBJECTIVE: We sought to summarize our experience with the clinicopathological presentations of FMF and impact on prognosis. METHODS: Data were collected retrospectively for adults with FMF followed up prospectively at a tertiary medical center in 1995 through 2014. RESULTS: In all, 34 patients presented with follicle-based patch/flat plaques, keratosis pilaris-like lesions, and/or acneiform lesions, defined clinically as early stage (IA, IB), and 15 presented with follicle-based infiltrated plaques and/or tumors, defined as advanced stage (IIB). The head/neck was involved in all tumor-stage cases, whereas early-stage lesions involved mainly the trunk/limbs. The tumor stage was characterized by more pruritus, heavier perifollicular infiltrates, greater vertical depth, and more frequent presence of eosinophils. On multivariate analysis, infiltrate density was the only significant histopathological discriminator between the stages. Estimated 5-year survival was 0.94 in the early-stage group and 0.69 in the tumor-stage group. LIMITATIONS: Lack of long-term follow-up and relatively small sample are limitations. CONCLUSION: FMF presents with 2 distinct patterns of clinicopathologic features, early stage and advanced stage, each with different prognostic implications.
Assuntos
Micose Fungoide/patologia , Neoplasias Cutâneas/patologia , Adulto , Idoso , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Micose Fungoide/complicações , Estadiamento de Neoplasias , Prognóstico , Prurido/etiologia , Estudos Retrospectivos , Neoplasias Cutâneas/complicações , Adulto JovemRESUMO
The options for fertility preservation include cryopreservation of ovarian tissue. Although transplantation of cryopreserved-thawed ovarian tissue in cancer survivors has resulted in live births, there is evidence of malignancy involvement in ovarian tissue, especially in leukaemia. The objectives of this study were to investigate the involvement of chronic myeloid leukaemia (CML) in ovaries by both pathological/immunohistochemical methods and PCR for the identification of the Philadelphia chromosome (BCR-ABL transcripts). The patient was a survivor of paediatric CML whose ovaries were cryopreserved. The patient became infertile and requested ovarian reimplantation in adulthood. Pathological examinations of ovarian tissue with immunohistochemical stainings, quantitative PCR and two-step nested PCR were applied to identify BCR-ABL transcripts. Despite the lack of positive pathological/immunohistochemical evidence, PCR and two-step nested PCR revealed that the ovary was contaminated by malignant minimal residual CML. Survivors of childhood CML may harbour minimal residual disease in the ovaries. This finding stresses the danger of reseeding cancer by ovarian grafting, especially in patients with leukaemia. If ovarian grafting is considered, reimplantation should be preceded by examination of ovarian samples both pathologically and by molecular techniques. On the basis of molecular findings, ovarian autografting was not recommended in this case report.
Assuntos
Criopreservação , Leucemia Mieloide/patologia , Ovário/patologia , Feminino , Genes abl/genética , Humanos , Imuno-Histoquímica , Ovário/anatomia & histologia , Ovário/transplante , Cromossomo Filadélfia , Reação em Cadeia da Polimerase , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SobreviventesRESUMO
BACKGROUND: The literature on mycosis fungoides (MF) in children/adolescents is sparse. OBJECTIVE: We sought to evaluate the characteristics of juvenile MF in a large cohort. METHODS: Data were collected on all patients with MF, aged 18 years or younger at the time of clinicopathologic diagnosis, who attended the Rabin Medical Center Dermatology Department, Petach Tikva, Israel, between 1994 and 2012 and were followed up prospectively. RESULTS: There were 50 patients (30 male; mean age 11.4 years at diagnosis); 18 (36%) had Fitzpatrick skin type IV or higher. All were given a diagnosis of early-stage disease (IA-IIA) except 1 (tumor stage, IIB). Eight had classic MF lesions only and 42 had other variants, alone or in combination; these were mainly hypopigmented MF (n = 29) and cases with subtle but clear clinicopathologic features of folliculotropic MF (FMF) (n = 18). Among the various skin-targeted therapies, psoralen plus ultraviolet A (systemic/bath) proved beneficial for FMF. During a follow-up period of 0.25 to 15 years (mean 4.5), 2 patients progressed from stage IA to IB or IIA. LIMITATIONS: Relatively short follow-up is a limitation. CONCLUSIONS: This case series shows that FMF is not uncommon in children and adolescents. It is characterized by more superficial clinical features and less heavy perifollicular lymphocytic infiltrates than adult FMF, and responds well to psoralen plus ultraviolet A. The prognosis of childhood FMF remains unclear.
Assuntos
Linfoma Cutâneo de Células T/patologia , Micose Fungoide/patologia , Neoplasias Cutâneas/patologia , Adolescente , Fatores Etários , Biópsia por Agulha , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Imuno-Histoquímica , Incidência , Israel , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/epidemiologia , Linfoma Cutâneo de Células T/radioterapia , Masculino , Micose Fungoide/diagnóstico , Micose Fungoide/epidemiologia , Micose Fungoide/radioterapia , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/radioterapia , Resultado do Tratamento , Terapia Ultravioleta/métodosRESUMO
Biopsy specimens from 23 early stage and 19 tumor-stage mycosis fungoides (MF) patients were evaluated for miR-155 expression by real-time qualitative PCR and compared with 15 biopsy specimens from patients with T-cell-rich inflammatory skin diseases. Significant upregulation of miR-155 was found in MF tumors compared with both early-stage MF lesions and controls. There was no difference in miR-155 expression between early-stage and inflammatory dermatoses. Using laser capture microdissection, it was found that miR-155 was significantly higher in the lymphoma cells in tumor stage compared with the intraepidermal lymphocytes in early stage. In contrast, there was no difference in miR-155 expression between the intraepidermal lymphocytes and the dermal lymphocytes in early-stage MF. These findings suggest that although miR-155 expression cannot serve to discriminate early-stage MF from inflammatory dermatoses; however, it is involved in the switch from the indolent early stage into the aggressive tumor stage of the disease.
Assuntos
Regulação Neoplásica da Expressão Gênica , Regulação da Expressão Gênica , MicroRNAs/metabolismo , Micose Fungoide/metabolismo , Neoplasias Cutâneas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Progressão da Doença , Feminino , Humanos , Inflamação/patologia , Microdissecção e Captura a Laser , Linfócitos/metabolismo , Linfoma/metabolismo , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Pele/patologia , Dermatopatias , Linfócitos T/citologia , Linfócitos T/metabolismo , Regulação para CimaRESUMO
We present a young patient with metastatic Ewing sarcoma that had hepatic lesions. As we were unaware of hepatic metastases in Ewing sarcoma, liver biopsy was performed. The pathologic findings were diagnostic of mesenchymal hamartoma of the liver. Surprisingly, the combined chemotherapy for metastatic sarcoma resulted in almost complete resolution of the hamartoma in the liver. This option may be useful in extreme cases when resection is not feasible.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/diagnóstico , Erros de Diagnóstico , Hamartoma/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Mesoderma/patologia , Sarcoma de Ewing/diagnóstico , Adulto , Ciclofosfamida/administração & dosagem , Dactinomicina/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Hamartoma/patologia , Humanos , Ifosfamida/administração & dosagem , Neoplasias Hepáticas/secundário , Prognóstico , Vincristina/administração & dosagem , Adulto JovemRESUMO
Solid organ transplantation is currently the treatment of choice for renal, heart, and pancreas insufficiency and selected bowel diseases. Thanks to advances in medical technology, the lifespan of transplanted organs is currently about 10 years. To prevent graft rejection, patients need to take immunosuppressive drugs, usually for the rest of their Lives. Pathologists play a crucial role in organ transplantation. They are responsible for recognizing allograft rejection, both acute and chronic, differentiating rejection from drug toxicity, and identifying recurrent disease. In addition, pathologists identify new diseases in the graft, opportunistic infections in the transplanted organ or other organs, and the development of malignant tumors, which are more common in immunocompromised patients. Accordingly, transplant pathologists require a wide range of knowledge in many complex laboratory techniques, such as immunofluorescence, electron microscopy, immunohistochemical analysis, and molecular pathology. These tests are performed in dedicated Laboratories in departments of pathology. TranspLant pathology is an inseparable part of the field of transplantation medicine and greatly assists clinicians in the diagnosis of disease processes in transplanted organs and in the selection of appropriate treatment.
Assuntos
Rejeição de Enxerto/prevenção & controle , Hospedeiro Imunocomprometido , Transplante de Órgãos/métodos , Patologia/organização & administração , Rejeição de Enxerto/diagnóstico , Humanos , Imunossupressores/uso terapêutico , Israel , Infecções Oportunistas/diagnósticoRESUMO
The pioneering design of chimeric antigen receptor (CAR) T-cell therapy demonstrated the potential of reprogramming the immune system. Nonetheless, T-cell exhaustion, toxicity, and suppressive microenvironments limit their efficacy in solid tumors. We previously characterized a subset of tumor-infiltrating CD4+ T cells expressing the FcγRI receptor. Herein, we detail engineering of a receptor, based on the FcγRI structure, allowing T cells to target tumor cells using antibody intermediates. These T cells showed effective and specific cytotoxicity only when an appropriate antibody was added. Only target-bound antibodies activated these cells, while free antibodies were internalized without activation. Their cytotoxic activity was correlated to target protein density, therefore targeting tumor cells with high antigen density while sparing normal cells with low or no expression. This activation mechanism prevented premature exhaustion. Furthermore, during antibody-dependent cytotoxicity these cells secreted attenuated cytokine levels compared with CAR T cells, thereby enhancing their safety profile. These cells eradicated established melanomas, infiltrated the tumor microenvironment, and facilitated host immune cell recruitment in immunocompetent mice. In NOD/SCID gamma mice the cells infiltrate, persist, and eradicate tumors. As opposed to CAR T-cell therapies, which require changing the receptor across different types of cancer, our engineered T cells remain the same across tumor types, while only the injected antibody changes. Overall, we generated a highly flexible T-cell therapy capable of binding a wide range of tumor cells with high affinity, while preserving the cytotoxic specificity only to cells expressing high density of tumor-associated antigens and using a single manufacturing process.
Assuntos
Imunoterapia Adotiva , Melanoma , Animais , Camundongos , Receptores de IgG , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos SCID , Camundongos Endogâmicos NOD , Melanoma/terapia , Imunoglobulinas , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Background: Telomerase (human telomerase reverse transcriptase (hTERT) is considered a hallmark of cancer, being active in cancer cells but repressed in human somatic cells. As such, it has the potential to serve as a valid cancer biomarker. Exosomal hTERT mRNA can be detected in the serum of patients with solid malignancies but not in healthy individuals. We sought to evaluate the feasibility of measuring serum exosomal hTERT transcripts levels in patients with lung cancer. Methods: A prospective analysis of exosomal hTERT mRNA levels was determined in serum-derived exosomes from 76 patients with stage III-IV lung cancer (11 SCLC and 65 NSCLC). An hTERT level above RQ = 1.2 was considered "detectable" according to a previous receiver operating characteristic curve (ROC) curve. Sequential measurements were obtained in 33 patients. Demographic and clinical data were collected retrospectively from patients' charts. Data on response to systemic therapy (chemotherapy, immunotherapy, and tyrosine kinase inhibitors) were collected by the treating physicians. Results: hTERT was detected in 53% (40/76) of patients with lung cancer (89% of SCLC and 46% of NSLCC). The mean hTERT levels were 3.7 in all 76 patients, 5.87 in SCLC patients, and 3.62 in NSCLC patients. In total, 25 of 43 patients with sequential measurements had detectable levels of hTERT. The sequential exosomal hTERT mRNA levels reflected the clinical course in 23 of them. Decreases in hTERT levels were detected in 17 and 5 patients with partial and complete response, respectively. Eleven patients with a progressive disease had an increase in the level of exosomal hTERT, and seven with stable disease presented increases in its exosomal levels. Another patient who progressed on the first line of treatment and had a partial response to the second line of treatment exhibited an increase in exosomal hTERT mRNA levels during the progression and a decrease during the response. Conclusions: Exosomal hTERT mRNA levels are elevated in over half of patients with lung cancer. The potential association between hTERT levels and response to therapy suggests its utility as a promising cancer biomarker for response to therapy. This issue should be further explored in future studies.
RESUMO
BACKGROUND: Cancers of unknown primary origin (CUP) constitute 3%-5% (50,000 to 70,000 cases) of all newly diagnosed cancers per year in the United States. Including cancers of uncertain primary origin, the total number increases to 12%-15% (180,000 to 220,000 cases) of all newly diagnosed cancers per year in the United States. Cancers of unknown/uncertain primary origins present major diagnostic and clinical challenges because the tumor tissue of origin is crucial for selecting optimal treatment. MicroRNAs are a family of noncoding, regulatory RNA genes involved in carcinogenesis. MicroRNAs that are highly stable in clinical samples and tissue specific serve as ideal biomarkers for cancer diagnosis. Our first-generation assay identified the tumor of origin based on 48 microRNAs measured on a quantitative real-time polymerase chain reaction platform and differentiated 25 tumor types. METHODS: We present here the development and validation of a second-generation assay that identifies 42 tumor types using a custom microarray. A combination of a binary decision-tree and a k-nearest-neighbor classifier was developed to identify the tumor of origin based on the expression of 64 microRNAs. RESULTS: Overall assay sensitivity (positive agreement), measured blindly on a validation set of 509 independent samples, was 85%. The sensitivity reached 90% for cases in which the assay reported a single answer (>80% of cases). A clinical validation study on 52 true CUP patients showed 88% concordance with the clinicopathological evaluation of the patients. CONCLUSION: The abilities of the assay to identify 42 tumor types with high accuracy and to maintain the same performance in samples from patients clinically diagnosed with CUP promise improved utility in the diagnosis of cancers of unknown/uncertain primary origins.
Assuntos
Biomarcadores Tumorais/análise , Regulação Neoplásica da Expressão Gênica , MicroRNAs/análise , Neoplasias Primárias Desconhecidas/diagnóstico , Neoplasias Primárias Desconhecidas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Bioensaio , Biomarcadores Tumorais/genética , Árvores de Decisões , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Neoplasias Primárias Desconhecidas/classificação , Reação em Cadeia da Polimerase em Tempo Real/métodos , Sensibilidade e Especificidade , Transdução de Sinais , Estados UnidosRESUMO
BACKGROUND: Some authorities consider alopecia mucinosa (AM)/follicular mucinosis (FM) to invariably represent mycosis fungoides (MF). This understanding of AM/FM derives from observations in adults. OBJECTIVES: We sought to explore the clinicopathologic features and natural history of pediatric AM/FM. METHODS: Medical records were searched for children given the diagnosis of AM/FM from 1998 through 2009. Diagnosis of AM/FM was defined as the presence of well-demarcated hairless plaques with follicular prominence plus an abundance of mucin on histopathologic examination. RESULTS: Forty children with a clinical diagnosis of AM/FM were identified. Nine did not meet the inclusion criteria. In the 31 remaining cases (16 boys, 15 girls) the mean age at onset was 9 ± 3.5 years. Histopathologic examination showed folliculotropism in 28 patients (90%) and epidermotropism in 15 (48%). Twelve cases fulfilled the International Society of Cutaneous Lymphomas (ISCL) diagnostic criteria for early MF. The histopathologic findings were typical of MF in only in two of these cases. T-cell receptor gene rearrangement was positive in 3 of 6 (50%) of tested samples, one in a patient who fulfilled the ISCL criteria for early MF. Mean duration of follow-up was 6.2 ± 3.7 years. All skin lesions resolved and none persisted or recurred. Hodgkin lymphoma was diagnosed 6 months after diagnosis of AM/FM in one patient. LIMITATIONS: This was a retrospective study. CONCLUSIONS: Although some pediatric cases meet the diagnostic criteria for MF, AM/FM cannot be regarded unequivocally as early follicular MF in this age group. We suggest the current diagnostic criteria for early MF should exclude children with AM/FM. Long-term follow-up of children with AM/FM is nevertheless warranted.