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1.
J Cancer Res Clin Oncol ; 148(7): 1641-1682, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35441887

RESUMO

PURPOSE: The mechanisms contributing to recurrence of glioblastoma (GBM), an aggressive neuroepithelial brain tumor, remain unknown. We have recently shown that nuclear respiratory factor 1 (NRF1) is an oncogenic transcription factor and its transcriptional activity is associated with the progression and prognosis of GBM. Herein, we extend our efforts to (1) identify influential NRF1-driven gene and microRNA (miRNA) expression for the aggressiveness of mesenchymal GBM; and (2) understand the molecular basis for its poor response to therapy. METHODS: Clinical data and RNA-Seq from four independent GBM cohorts were analyzed by Bayesian Network Inference with Java Objects (BANJO) and Markov chain Monte Carlo (MCMC)-based gene order to identify molecular drivers of mesenchymal GBM as well as prognostic indicators of poor response to radiation and chemotherapy. RESULTS: We are the first to report sex-specific NRF1 motif enriched gene signatures showing increased susceptibility to GBM. Risk estimates for GBM were increased by greater than 100-fold with the joint effect of NRF1-driven gene signatures-CDK4, DUSP6, MSH2, NRF1, and PARK7 in female GBM patients and CDK4, CASP2, H6PD, and NRF1 in male GBM patients. NRF1-driven causal Bayesian network genes were predictive of poor survival and resistance to chemoradiation in IDH1 wild-type mesenchymal GBM patients. NRF1-regulatable miRNAs were also associated with poor response to chemoradiation therapy in female IDH1 wild-type mesenchymal GBM. Stable overexpression of NRF1 reprogramed human astrocytes into neural stem cell-like cells expressing SOX2 and nestin. These cells differentiated into neurons and form tumorospheroids. CONCLUSIONS: In summary, our novel discovery shows that NRF1-driven causal genes and miRNAs involved in cancer cell stemness and mesenchymal features contribute to cancer aggressiveness and recurrence of aggressive therapy-resistant glioblastoma.


Assuntos
Neoplasias Encefálicas , Glioblastoma , MicroRNAs , Fator 1 Nuclear Respiratório , Teorema de Bayes , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Feminino , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Fator 1 Nuclear Respiratório/genética , Prognóstico , Transcriptoma
2.
Endocr Connect ; 10(4): 387-400, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33709954

RESUMO

OBJECTIVE: Posterior pituitary tumours (PPTs) are rare neoplasms with the four recognised subtypes unified by thyroid transcription factor -1 (TTF-1) expression, according to the 2017 WHO classification. Though traditionally defined as low-grade neoplasms, a substantial proportion of them show recurrence/persistence following surgery. METHODS: We selected patients with PPTs in our cohort of 1760 patients operated for pituitary tumours over the past 10 years (2010-2019). The clinical, radiological, hormonal, histopathological profiles and long-term outcomes of the three cases identified (two pituicytomas and one spindle cell oncocytoma, SCO) were analysed. Following a literature review, data of all published cases with documented TTF-1 positive pituicytomas and SCOs were analysed to determine the predictors of recurrence/persistence in these tumours. RESULTS: Patients presented with compressive features or hypogonadism. Two had sellar-suprasellar masses. One had a purely suprasellar mass with a pre-operative radiological suspicion of pituicytoma. Two were operated by transsphenoidal surgery and one transcranially guided by neuronavigation. Histopathology confirmed spindle cells in a storiform arrangement and low Ki67 index. Immunohistochemistry showed positive TTF-1, S-100 expression and variable positivity for EMA, vimentin and GFAP. Re-evaluation showed recurrence/persistence in two patients. A literature review of recurrent/persistent pituicytoma (n = 17) and SCO (n = 9) cases revealed clinical clues (headache for pituicytomas, male gender for SCO), baseline tumour size (≥20.5 mm with sensitivity exceeding 80%) and longer follow-up duration as determinants of recurrence/persistence. CONCLUSION: PPTs are rare sellar masses with quintessential TTF-1 positivity. Recurrent/persistent disease following surgery is determined by greater tumour size at baseline and duration of follow-up. This warrants intensive and long-term surveillance in these patients.

3.
Mol Neurobiol ; 57(9): 3827-3845, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32594352

RESUMO

Despite tremendous progress in understanding the pathobiology of astrocytoma, major gaps remain in our knowledge of the molecular basis underlying the aggressiveness of high-grade astrocytoma (glioblastoma - GBM). Recently, we and others have shown nuclear respiratory factor 1 (NRF1) transcription factor being highly active in human cancers, but its role in astrocytoma remains unknown. Therefore, the purpose of this study was to uncover the role of NRF1 in the progression of GBM. NRF1 has higher mRNA expression and transcription factor activity in astrocytoma compared to non-tumor brain tissue. NRF1 activity also correlated with the aggressiveness of cancer. Increased NRF1 TF activity coupled with overexpression of RHOG was associated with poor survival of GBM patients. NRF1 activity was associated with transcriptomic signatures of neurogenesis, cell stemness, epithelial-mesenchymal transition and cell cycle progression. Overexpression of CDK4, AKT1, APAF1, HDAC1, NBN, TGFB1, & TNFRSF1A and downregulation of CASP3, IL7, STXBP1 and OPA1 predicted GBM malignancy in high expressors of NRF1 activity. Increased expression of the NRF1 motif containing genes, H6PD, NAT10, NBEAL2, and RNF19B predicted poor survival of IDH1 wild-type GBM patients. Poor survival outcomes and resistance to Temozolomide therapy were associated with higher NRF1 expression including its targets - LDHA, ZMAT3, NSUN2, ARMC5, NDEL1, CLPTM1L, ALKBH5, YIPF5, PPP2CA, and TFG. These findings suggest that aberrant NRF1 activity may contribute to the pathogenesis of GBM and severity of astrocytoma. Further analyses of NRF1 gene signatures will pave the way for next generation targeted therapies and drug combination strategies for GBM patients.


Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Perfilação da Expressão Gênica , Glioblastoma/genética , Fator 1 Nuclear Respiratório/metabolismo , Índice de Gravidade de Doença , Transcrição Gênica , Adulto , Apoptose/efeitos dos fármacos , Apoptose/genética , Astrocitoma/patologia , Astrocitoma/fisiopatologia , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/fisiopatologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Estudos de Coortes , Quinase 4 Dependente de Ciclina/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/patologia , Glioblastoma/fisiopatologia , Humanos , Masculino , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurogênese/efeitos dos fármacos , Neurogênese/genética , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fator 1 Nuclear Respiratório/genética , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Transcrição Gênica/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética , Resultado do Tratamento
4.
J Egypt Natl Canc Inst ; 32(1): 23, 2020 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-32462353

RESUMO

BACKGROUND: Central neurocytomas represent 0.25-0.5% of all intracranial tumors in adults. Leptomeningeal spread is uncommon, and the exact incidence of meningeal spread is unknown due to sparse literature. We present the clinical course and management outcome of a case of atypical central neurocytoma with leptomeningeal spread. CASE PRESENTATION: A young gentleman, who initially presented with memory loss, was found to have a right intra-axial periventricular mass on imaging. He underwent subtotal resection, and operative histopathology suggested a periventricular atypical neurocytoma. In view of subtotal resection, adjuvant focal radiation therapy was recommended, but he developed headache and blurring of vision 10 days postoperatively. Contrast enhanced craniospinal magnetic resonance imaging (MRI) showed residual primary tumor as well as diffuse leptomeningeal spread. Cerebrospinal fluid cytology also showed malignant cells. After tumor board discussion, craniospinal axis irradiation was advised and delivered. He remained disease-free for 10 months after radiation therapy, but then developed local and spinal recurrence, and offered salvage chemotherapy. His general condition deteriorated following chemotherapy with disease progression, and he was subsequently advised best supportive care. CONCLUSION: Leptomeningeal dissemination in atypical neurocytomas portends an aggressive course and adverse prognosis; management decisions may need tailoring as per individual presentation.


Assuntos
Neoplasias Encefálicas/patologia , Neoplasias Meníngeas/etiologia , Neurocitoma/patologia , Adulto , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Humanos , Imageamento por Ressonância Magnética , Masculino , Neurocitoma/diagnóstico por imagem , Neurocitoma/terapia
6.
Turk Patoloji Derg ; 36(2): 173-177, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30632123

RESUMO

Inflammatory myofibroblastic tumor (IMT) of lung is a rare tumor, accounting for ~0.7% of all lung tumors with varied clinical and radiological presentations. The origin of this tumor is unknown but some studies suggest that it might be a true neoplasm as some mutations on chromosome 2p23 of anaplastic lymphoma kinase (ALK) have been found to be related to this tumor. The morphology of IMT is quite vague and the histopathological diagnosis is predominantly given on excision specimens; in fact, only 6.3% of cases are diagnosed based on analysis of biopsy specimens alone. We illustrate a case of IMT diagnosed in a young male on core biopsy, where the case presented with a large tumor in the lung with metastases to multiple sites that was hence unresectable. Post 3 months of treatment with Crizotinib, there was significant reduction in the tumor size. Another interesting finding was that the ALK immunostain, which helped immensely in the diagnosis, was appreciated better on the Ventana platform rather than on the Dako platform.


Assuntos
Quinase do Linfoma Anaplásico/análise , Neoplasias Pulmonares/diagnóstico , Miofibroma/diagnóstico , Adulto , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Biópsia com Agulha de Grande Calibre , Crizotinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Miofibroma/tratamento farmacológico , Miofibroma/patologia
7.
Asian J Neurosurg ; 14(4): 1295-1297, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31903382

RESUMO

Coexisting vestibular schwannoma (VS) with fibrous dysplasia is extremely rare. Here, we represent the case of a 48-year-old female with coexisting VS and fibrous dysplasia of overlying occipital bone. After proper evaluation, the patient underwent surgery and microscopic total excision of the right cerebellopontine angle lesion was achieved. However, during surgery, bone work was extremely tedious and exposure to reach up to lesion was difficult. To the best of our knowledge, this is the first reported case of coexisting fibrous dysplasia of overlying bone and VS as histopathological diagnosis.

9.
Int J Surg Pathol ; 25(7): 592-598, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28530163

RESUMO

Histoplasmosis is an invasive mycosis caused by inhalation of the spores of dimorphic fungi Histoplasma capsulatum. The disease manifests in the lung as acute or chronic pulmonary histoplasmosis and in severe cases gets disseminated in multiple organs like skin, adrenal gland, central nervous system, lymph node, liver, spleen, bone marrow, and gastrointestinal tract. It occurs most commonly in immunodeficient patients like HIV-positive patients and transplant recipients, while immunocompetent hosts are affected rarely. In cases of gastrointestinal histoplasmosis, the samples are collected for culture and biopsy should be sent for histopathological examination for definitive diagnosis. We conducted a retrospective study of colonic biopsies performed in the department of gastroenterology in a tertiary care hospital of north India from January 2014 to December 2015. Five cases of colonic histoplasmosis were diagnosed on histopathology out of which 4 patients were from north India while 1 patient was from Myanmar. The patients presented with various complaints, including loose stools, diarrhea, altered bowel habits, and gastrointestinal bleeding. The prognosis is very good after early and aggressive treatment while the disease is fatal if it remains untreated. In our study, 2 patients died within few days of diagnosis due to delay in the diagnosis, dissemination, and associated complications. Other patients were started on amphotericin B deoxycholate and are under follow-up. An early diagnosis of gastrointestinal histoplasmosis is important as appropriate treatment leads to long-term survival while untreated cases are almost fatal.


Assuntos
Antifúngicos/uso terapêutico , Colo/patologia , Diarreia/patologia , Hemorragia Gastrointestinal/patologia , Histoplasmose/patologia , Adulto , Idoso , Anfotericina B/uso terapêutico , Biópsia , Colonoscopia , Ácido Desoxicólico/uso terapêutico , Diarreia/tratamento farmacológico , Diarreia/microbiologia , Diarreia/mortalidade , Combinação de Medicamentos , Feminino , Seguimentos , Hemorragia Gastrointestinal/tratamento farmacológico , Hemorragia Gastrointestinal/microbiologia , Hemorragia Gastrointestinal/mortalidade , Histoplasma/isolamento & purificação , Histoplasmose/tratamento farmacológico , Histoplasmose/microbiologia , Histoplasmose/mortalidade , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Tempo
12.
Indian J Med Paediatr Oncol ; 38(4): 495-501, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29333019

RESUMO

OBJECTIVE: To evaluate early clinical outcome for anaplastic gliomas (AG) treated in the era of modulated radiotherapy (RT) and concurrent plus adjuvant temozolomide (TMZ) in an Indian setting. MATERIALS AND METHODS: Fifty-three patients with AGs treated with modulated RT and concurrent (95%) and adjuvant TMZ (90%) were analyzed. About 80% of patients had Karnofsky performance status (KPS) at least 90 with 30% seizure at presentation. Postoperative magnetic resonance imaging was available in 65% cases and RT dose was 60 Gy in 30 fractions. First posttreatment imaging was performed at 1 month and then at 3 and 6 months post-RT and then every 3 months. Kaplan-Meier analysis was used to estimate disease-free survival (DFS) and overall survival (OS), and analysis was done using SPSS version 18.0. RESULTS: With median follow-up of 25 months, 2-year DFS and OS were 75% and 88%. There were only 5% symptomatic central nerves system and 8% symptomatic hematological toxicities. At the 1st evaluation, 30.4% had complete response (CR), at 3 months 40%, and at 6 months 43%. At 6 months, only 4% had progressive disease. Forty-six patients were evaluable till the last follow-up with and 55% had stable to CR. On univariate analysis for DFS, KPS at presentation >90 (P = 0.001) and response at 6 months (P = 0.02) were significant and for OS KPS at presentation (P = 0.004) alone. CONCLUSION: Modulated RT with TMZ among Grade III glioma patients resulted in minimum treatment-related toxicities and encouraging survival. Molecular prognostic markers will determine most favorable groups in future.

13.
J Clin Diagn Res ; 10(7): ED01-2, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27630854

RESUMO

Primary Testicular Lymphoma (PTL) is a rare intermediate to high grade tumour, diffuse large cell being the most common type. Unlike nodal Diffuse Large B-Cell Lymphoma (DLBCL), testicular DLBCL has a less aggressive course and better prognosis. Metastasis is uncommon in testicular DLBCL. Commonly involved sites are contralateral testes, Waldeyer's ring, skin, lung, Central Nervous System (CNS) and prostate, however the kidneys, liver, bone marrow, pleura and bones are more rarely involved. We report a case of testicular DLBCL which has metastasized to skin and bone marrow with an aggressive clinical course in a year, in-spite of combined modality of therapy given to the patient. Bone marrow infiltration is common and well documented with nodal DLBCL, however there is no published literature for simultaneous bone marrow and skin infiltration in testicular DLBCL till date. Other large studies done in the west have shown that distinct metastasis is usually common but the median progression-free survival is usually in years. This case stresses on shorter period of progression after standard treatment protocol in this part of the world, thus highlighting the need for other extensive studies to define specific treatment protocol for testicular DLBCL.

14.
J Clin Diagn Res ; 9(9): ED15-7, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26500917

RESUMO

Renal Cell Carcinoma metastasizing to pancreas is uncommon, occurring in 1-2% of cases; lung being the most common site. It is usually asymptomatic, or may present as abdominal pain, weight loss, pancreatitis or gastrointestinal bleeding. Herein, we present a case of 75-year-old male presented as intraabdominal bleeding to the Emergency Department. Contrast enhanced computed tomography with angiography of abdomen showed lobulated soft tissue mass in the uncinate process region, infiltrating into the distal third and proximal fourth part of duodenum. A clinico-radiological diagnosis of carcinoma head of pancreas infiltrating into duodenum was made and the patient underwent Whipple's operation. With past history of nephrectomy 3 years back, microscopy and the immunoprofile; a final diagnosis of clear cell renal cell carcinoma metastasizing to pancreas was given on histopathology. A high index of suspicion is required for patients with a history of RCC and they should be monitored lifelong for early detection of metastases and to improve survival.

16.
Asian J Neurosurg ; 9(1): 36-9, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24891889

RESUMO

Melanocytomas are present in leptomeninges and arise from neural crest during early embryonic development. They are a rare entity and usually occur in the thoracic spine and infratentorial region. We report a 32-year-old female with meningeal melanocytoma of D9-10. Magnetic resonance imaging revealed an intramedullary spinal tumor at D9-D10. Intraoperatively, the tumor was greyish-black in color with moderate vascularity, and was adherent to the cord. The clinical differential diagnoses included cavernoma and melanocytoma. On microscopic examination, the lesion showed sheets of cells with marked pigment deposition, which was obscuring the cellular morphology. The pigment was confirmed to be melanin by Masson's Fontana stain. Immunohistochemistry was performed, which showed positivity for HMB-45, S-100, Vimentin and Melan-A. The cells were negative for cytokeratin, epithelial membrane antigen, Glial fibrillary acidic protein and neuron-specific enolase. Mib-1 labeling index was less than 1%. In view of the lack of nuclear atypia, mitoses, necrosis and low Mib-1-labeling index along with immunohistochemistry profile, the diagnosis of Melanocytoma was made. Melanocytomas are rare pigmented tumors of the spinal cord and posterior cranial fossa. They are benign in nature, but can also be locally aggressive. Melanocytic lesions of the nervous system are to be differentiated from metastatic melanomas and also tumors showing melanin pigment deposition like schwanomma, paraganglioma, medulloblastoma and various gliomas.

17.
Indian J Pathol Microbiol ; 57(1): 98-100, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24739843

RESUMO

A 50-year-old male patient presented with pain abdomen of 6 months duration. Computed tomography scan revealed a large mass in the stomach occluding the lumen. Histopathology revealed a triple composite tumor comprising of tubular adenocarcinoma arising on a background of high-grade dysplasia, hepatoid adenocarcinoma (positive for Hep Par-1 and alpha fetoprotein) and large cell neuroendocrine carcinoma (positive for synaptophysin and chromogranin) with nodal metastasis.Triple composite tumors are distinctly rare with few reports in literature.


Assuntos
Adenocarcinoma/diagnóstico , Carcinoma Hepatocelular/diagnóstico , Carcinoma Neuroendócrino/diagnóstico , Neoplasias Gástricas/diagnóstico , alfa-Fetoproteínas/análise , Adenocarcinoma/complicações , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Carcinoma Neuroendócrino/complicações , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/cirurgia , Histocitoquímica , Humanos , Imuno-Histoquímica , Masculino , Microscopia , Pessoa de Meia-Idade , Radiografia Abdominal , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia
19.
Neuropathology ; 30(3): 251-9, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19925561

RESUMO

Atypical teratoid rhabdoid tumor (AT/RT) is a highly malignant embryonal CNS tumor, generally unresponsive to any form of therapy, uniformly fatal within 1 year. We report 15 cases of AT/RT diagnosed at our center over a period of 5 years (2003-08). Tumors were located in different sites of the neuraxis, posterior fossa being the most common (n = 10) followed by cerebral lobes (n = 3). There was one each at the supra sellar and cervical spinal regions, respectively. Radiologically most of the tumors were heterodense and enhancing heterogeneously. The tumors exhibited diverse histological profile that included rhabdoid and PNET areas in all cases, mesenchymal and epithelial areas in 73.3% and 53.3% cases, respectively. Necrosis was evident in all cases and one showed calcification. Tumor cells displayed a polyphenotypic immunoprofile. All cases were consistently positive for vimentin and epithelial membrane antigen and were negative for desmin. Variable positivity was seen for other markers. The number of cases positive for these were: CK (53%), SMA (60%), synaptophysin (66%), NFP (33.3%) and GFAP (85%). CK staining was prominent in epithelial areas, while PNET cells labeled prominently with synaptophysin. There was lack of INI1 expression in all cases. Follow-up was available in 46.6% of cases which revealed a uniform poor prognosis.


Assuntos
Neoplasias do Sistema Nervoso Central/química , Neoplasias do Sistema Nervoso Central/patologia , Tumor Rabdoide/química , Tumor Rabdoide/patologia , Teratoma/química , Teratoma/patologia , Neoplasias do Sistema Nervoso Central/imunologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Índia , Lactente , Masculino , Necrose , Estudos Retrospectivos , Tumor Rabdoide/imunologia , Teratoma/imunologia
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