DNA hypomethylator phenotype reprograms glutamatergic network in receptor tyrosine kinase gene-mutated glioblastoma.

DNA methylation is crucial for chromatin structure and gene expression and its aberrancies, including the global "hypomethylator phenotype", are associated with cancer. Here we show that an underlying mechanism for this phenotype in the large proportion of the highly lethal brain tumor glioblastoma (GBM) carrying receptor tyrosine kinase gene mutations, involves the mechanistic target of rapamycin complex 2 (mTORC2), that is critical for growth factor signaling. In this scenario, mTORC2 suppresses the expression of the de novo DNA methyltransferase (DNMT3A) thereby inducing genome-wide DNA hypomethylation. Mechanistically, mTORC2 facilitates a redistribution of EZH2 histone methyltransferase into the promoter region of DNMT3A, and epigenetically represses the expression of DNA methyltransferase. Integrated analyses in both orthotopic mouse models and clinical GBM samples indicate that the DNA hypomethylator phenotype consistently reprograms a glutamate metabolism network, eventually driving GBM cell invasion and survival. These results nominate mTORC2 as a novel regulator of DNA hypomethylation in cancer and an exploitable target against cancer-promoting epigenetics.

[Effective therapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone chemotherapy with obinutuzumab for follicular lymphoma in leukemic phase].

The patient, a 56-year-old lady, also exhibited numerous lymphadenopathy, hepatosplenomegaly, hyperleukocytosis (167,200/µl, aberrant lymphocytes 91.5%), and fever. A lymph node biopsy revealed follicular lymphoma (FL), grade 1. Peripheral blood tumor cells did not express CD10, which was a distinctive characteristic of the lymph node specimen. To prevent tumor lysis syndrome (TLI), CHOP was delivered without an anti-CD20 antibody, but afterward, residual lymphoma cells were found in peripheral blood (>80%). As a result, obinutuzumab (Obi) was given on day 8 following the second round of CHOP, and the tumor cells in the peripheral blood vanished without any major side effects like TLI. She underwent six chemotherapy sessions before receiving maintenance therapy with Obi and achieving a full metabolic response. According to reports, leukemic FL exhibits negative CD10 expression in peripheral blood lymphoma cells, while leukemic mantle cell lymphoma also shows this trait. Therefore, it is important not to confuse the two types in diagnosis. Leukemic FL with significant leukocytosis is reportedly uncommon and has a bad prognosis. Our case indicates that CHOP with Obi would be a good alternative for cases like yours, however, there have been a few cases recorded. Further case accumulation or investigation is warranted.

Multiple Small Bowel Gastrointestinal Stromal Tumors Associated with Neurofibromatosis Type 1 that Were Not Detected by Endoscopy: A Case Report.

We treated a 39-year-old Japanese man who was admitted for an abdominal mass. He had had neurofibroma-like skin lesions since childhood. Computed tomography and endoscopic ultrasound results were consistent with a tumor in the small intestine. Although the tumor was undetectable by single-balloon endoscopy, the patient's background and imaging results led us to suspect a gastrointestinal stromal tumor (GIST). He also met the diagnostic criteria for neurofibroma type 1 (NF1). We performed a surgical removal of the tumor, and the biopsy results led to a definitive diagnosis of GIST. Small bowel GISTs should be considered in cases of NF1.

Papillary thyroid microcarcinoma with multiple pulmonary metastases following lung cancer surgery: a case report.

BACKGROUND: Distant metastasis is extremely rare for papillary thyroid microcarcinoma (PTMC) without lymph node metastasis or extrathyroidal extension, for which active surveillance (AS) is indicated. The evaluation of distant metastases in low-risk PTMC is controversial. A case of PTMC in which AS would have been performed if chest CT and lung surgery had not been performed is reported. CASE PRESENTATION: The patient was a 71-year-old woman undergoing follow-up in the Department of Thoracic Surgery at our hospital for multiple frosted glass shadows in both lung fields for one and a half years. To make a definitive diagnosis, thoracoscopic right middle lobectomy and left upper partial lobectomy were performed 4 and 6 months earlier, respectively. In both resected specimens, lung adenocarcinoma and small metastasis of papillary thyroid carcinoma (PTC) were found. The patient was transferred to our department for a thorough examination for PTC. Ultrasonography was performed to search for the primary lesion, and it showed an irregular hypoechoic mass of 4 mm and 6 mm in the middle of the right lobe of the thyroid gland. The patient was diagnosed with PTC. Its clinical stage was T1a (m) N0 M1 (stage IVC). Total thyroidectomy and prophylactic central node dissection were performed. The pathological diagnosis was PTC (typical type) pT1a (m) N0. Postoperatively, she received radioactive iodine therapy. CONCLUSIONS: We experienced an extremely rare case and struggled to determine a treatment plan. We might be aware that lung metastases could develop in low-risk PTMC.

Multiple intestinal lymphangiomas with episodic hemorrhage requiring partial laparoscopic resection: a case report.

BACKGROUND: Lymphangioma is a non-epithelial tumor marked by aggregates of abnormally dilated lymphatics. Mesenteric occurrences account for < 1% of all cases, and < 0.05% involve the gastrointestinal tract. Most are confined to children, rarely affecting adults. CASE PRESENTATION: Herein, we describe an elderly Japanese woman with anemia, hypoalbuminemia, and episodic bleeding due to multiple intestinal lymphangiomas. Abdominal computed tomography revealed multiple low-density defects of mesentery, with areas of intermediate (T1 images) or high (T2 images) signal intensity similarly dispersed in magnetic resonance scanning sequences. Single-balloon enteroscopy was undertaken, enabling identification and tattooing of a small intestinal bleeding source. Laparoscopy-assisted resection at this site served to control related hemorrhage, removing a histologically confirmed hemolymphangioma. Having recovered uneventfully, the patient remained stable 2 months postoperatively. CONCLUSIONS: Although rare in adults, mesenteric or gastrointestinal lymphangiomas must be considered in a setting of anemia and hypoalbuminemia. Complete resection is advantageous to improve patient symptoms, but limited resection of multiple lesions may be equally effective.

Gastric Signet-Ring Cell Carcinoma That Presented as an Elevated Lesion due to Fibromuscular Obliteration in the Lamina Propria.

The widespread use of Helicobacter pylori eradication therapy in recent years has reduced the H. pylori infection rate, indicating that gastric cancer cases diagnosed in the future may be H. pylori-naïve. The typical endoscopic presentation of signet-ring cell carcinoma, which accounts for the majority of H. pylori-naïve gastric cancer cases, is a discolored, flat, or depressed lesion; it is rarely presented as an elevated lesion. In this study, we treated a patient with elevated signet-ring cell carcinoma in an H. pylori-naïve stomach. Histopathological testing after endoscopic submucosal dissection showed proliferation of fibromuscular tissue in the tumor, which may have caused the formation of the elevated lesion.

Metabolic Reprogramming Drives Pituitary Tumor Growth through Epigenetic Regulation of TERT.

Pituitary adenomas are common, benign brain tumors. Some tumors show aggressive phenotypes including early recurrence, local invasion and distant metastasis, but the underlying mechanism to drive the progression of pituitary tumors has remained to be clarified. Aerobic glycolysis known as the Warburg effect is one of the emerging hallmarks of cancer, which has an impact on the tumor biology partly through epigenetic regulation of the tumor-promoting genes. Here, we demonstrate metabolic reprogramming in pituitary tumors contributes to tumor cell growth with epigenetic changes such as histone acetylation. Notably, a shift in histone acetylation increases the expression of telomerase reverse transcriptase (TERT) oncogene, which drives metabolism-dependent cell proliferation in pituitary tumors. These indicate that epigenetic changes could be the specific biomarker for predicting the behavior of pituitary tumors and exploitable as a novel target for the aggressive types of the pituitary tumors.

Diffuse gliomas to date and beyond 2016 WHO Classification of Tumours of the Central Nervous System.

The updated 2016 World Health Organization (WHO) Classification of Tumours of the Central Nervous System (CNS) has incorporated molecular parameters into pathological diagnosis, for the first time in the molecular era. While it has led to the more precise diagnoses of well-understood entities and the better comprehension of less-understood entities, its practical application has also created some concerns whether or not genotypes predominate over phenotypes in tumor diagnostics. In response to these concerns, the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official WHO (cIMAPCT-NOW) was established under the sponsorship of the International Society of Neuropathology to provide a forum to evaluate and recommend proposed changes to future CNS tumor classifications. cIMPACT has thus far published five updates on the proposal and clarification of existing and new terms and entities. Also, recent studies have shown that WHO grading based on histology has lost its prognostic relevance, which necessitates novel, improved grading criteria. We herein highlight the current status of clinical application of WHO 2016 classification and cIMPACT proposals, and the future endeavor to incorporate DNA methylation profiling of the CNS tumors for better clinical decision-making to achieve a goal of precision medicine for each patient with brain tumors.

Recurrent pericardial effusion with pericardial amyloid deposition: a case report and literature review.

Pericardial amyloidosis is a rare cause of pericardial effusion. Here, we report a case of recurrent pericardial effusion because of pericardial amyloid deposition. The patient was a man in his 40s admitted for pulmonary embolism. During hospitalization, arterial fibrillation and cardiac tamponade were observed, and an initial pericardial puncture was performed. Thereafter, pericardial puncture was repeated nine times over the next two years. Cytological examination of the pericardial effusion suggested malignant mesothelioma. Afterward, pericardial fenestration and partial resection were performed. Intraoperatively, a thickened pericardium and hemorrhagic pericardial effusion were noted. Histologically, the surface of the pericardium was covered by an eosinophilic amorphous material. Congo red and DYLON stains, electron microscopy, and immunohistochemical findings revealed localized amyloidosis composed of an immunoglobulin lambda light chain. Although the patient did not receive further treatment for 5 years postoperatively, his renal and cardiac functions remained within normal limits. Based on these findings, the patient was diagnosed with localized amyloidosis. So far, hemorrhagic pericardial effusion has been reported in few cases with systemic amyloidosis. Because localized immunoglobulin light-chain-derived (AL) amyloidosis may progress to systemic disease (although it is a very rare occurrence), long-term follow-up is necessary to detect recurrence or progression to a systemic form.

mTORC2 links growth factor signaling with epigenetic regulation of iron metabolism in glioblastoma.

In cancer, aberrant growth factor receptor signaling reprograms cellular metabolism and global gene transcription to drive aggressive growth, but the underlying mechanisms are not well-understood. Here we show that in the highly lethal brain tumor glioblastoma (GBM), mTOR complex 2 (mTORC2), a critical core component of the growth factor signaling system, couples acetyl-CoA production with nuclear translocation of histone-modifying enzymes including pyruvate dehydrogenase and class IIa histone deacetylases to globally alter histone acetylation. Integrated analyses in orthotopic mouse models and in clinical GBM samples reveal that mTORC2 controls iron metabolisms via histone H3 acetylation of the iron-related gene promoter, promoting tumor cell survival. These results nominate mTORC2 as a critical epigenetic regulator of iron metabolism in cancer.

Thoracoscopic surgical case of an ectopic mediastinal parathyroid adenoma detected by chance: a case report.

BACKGROUND: Ectopic mediastinal parathyroid tumor (EMPT) is a rare cause of primary hyperparathyroidism (PHPT); it is difficult to resect using the cervical approach. We describe a case of using video-assisted thoracic surgery (VATS) for EMPT resection. CASE PRESENTATION: A 67-year-old woman with a history of postoperative thyroid cancer had no symptoms. She was diagnosed with PHPT and underwent thyroid cancer surgery. She had serum calcium and intact parathyroid hormone (PTH) levels of 11.1 mg/dL and 206 pg/mL, respectively. Chest computed tomography showed a 10-mm nodule in the anterior mediastinum. Technetium-99 m methoxyisobutyl isonitrile scintigraphy showed an abnormal uptake lesion in the anterior mediastinum. She was diagnosed with PHPT caused by EMPT and underwent VATS. The pathological examination confirmed parathyroid adenoma. Her serum calcium and intact PTH levels were normal from 15 min after tumor resection. She has had no recurrence of EMPT. CONCLUSIONS: The VATS approach was effective for the resection of EMPT.

p.N345K mutation in TARDBP in a patient with familial amyotrophic lateral sclerosis: An autopsy case.

We report the neuropathology of a patient with a family history of amyotrophic lateral sclerosis (ALS) and a p.N345K mutation in the transactivation response DNA-binding protein 43 kDa (TDP-43) gene (TARDBP). A 62-year-old man had bulbar palsy with progressive weakness in the extremities. Neurological examination revealed evident upper motor neuron signs and lower motor neuron involvement corroborated by needle electromyography. The patient was diagnosed as having probable ALS according to the revised El Escorial diagnostic criteria and was eventually diagnosed with familial ALS. At 65 years of age, respiratory failure became critical, and artificial ventilation was initiated. At 70 years of age, the patient died from a urinary tract infection. Histopathological investigation showed Bunina bodies in the remaining motor neurons and anterolateral funicular myelin pallor in the spinal cord. TDP-43-positive cytoplasmic inclusions were quite rare in the spinal cord motor neurons, being predominantly present in the glial cells (especially astrocytes) of the spinal cord anterior horn. Although the reason for the preferential vulnerability of spinal glial cells to TARDBP mutations remains unclear, our findings indicate that TARDBP p.N345K mutation could have an influence on the topography of TDP-43 aggregation.

A case of ovarian teratoma with nephroblastoma presenting spontaneous rupture.

Nephroblastoma (also known as Wilms' tumor) mainly occurs in the kidneys of children. Nephroblastoma outside the kidneys may be observed in three situations: primary disease, metastatic disease and nephroblastoma arising in teratoma. Teratoma with nephroblastoma (TWN) of the adult ovary is a rare tumor and only one case has been reported. We report an unusual adult case of ovarian TWN presented to us with acute abdomen due to the spontaneous rupture of the ovary. The rupture occurred at the site of TWN, while contralateral ovary with only mature cystic teratoma component had no rupture. After one and a half months of the ovary sparing surgery, the tumor disseminated to the splenic hilum and the omentum. A complete staging with maximum cytoreduction followed by adjuvant chemotherapy were performed. She remains disease free until present.

Metabolic reprogramming in the pathogenesis of glioma: Update.

Cancer is a genetic disease that is currently classified not only by its tissue and cell type of origin but increasingly by its molecular composition. Increasingly, tumor classification and subtyping is being performed based upon the oncogene gains, tumor suppressor losses, and associated epigenetic and transcriptional features. However, cancers, including brain tumors, are also characterized by profound alterations in cellular metabolism. At present, even though signature mutations in known metabolic enzymes are recognized as being important, the metabolic landscape of tumors is not currently incorporated into tumor diagnostic categories. Here we describe a set of recent discoveries on metabolic reprogramming driven by mutations in the genes for the isocitrate dehydrogenase (IDH) and receptor tyrosine kinase (RTK) pathways, which are the most commonly observed aberrations in diffuse gliomas. We highlight the importance of oncometabolites to dynamically shift the epigenetic landscape in IDH-mutant gliomas, and c-Myc and mechanistic target of rapamycin (mTOR) complexes in RTK-mutated gliomas to adapt to the microenvironment through metabolic reprogramming. These signify the integration of the genetic mutations with metabolic reprogramming and epigenetic shifts in diffuse gliomas, shedding new light onto potential patient subsets, coupled with information to guide the development of new therapeutic opportunities against the deadly types of brain tumors.

Recurrent Cerebral Infarction Due to Benign Uterine Myoma.

The hypercoagulable state in patients with cancer has been shown to be closely associated with ischemic stroke. However, it is unlikely that benign tumors are related to stroke. The development of benign uterine tumors is common in middle-aged women. Previous studies have shown cases of ischemic stroke with benign uterine tumor, but the causal relationship between these 2 remain unknown. We report a case of recurrent ischemic stroke in a middle-aged woman who had a benign uterine tumor. After excision, there was no recurrence for 2 years. Microemboli detection, clinical course and histological findings support a relationship between uterine tumor and ischemic stroke.

FDG-PET and CT findings of activated brown adipose tissue in a patient with paraganglioma.

A 17-year-old female had been complaining of a headache for 6 years. She presented severe hypertension (200/138 mmHg) on admission. CT showed a hypervascular tumor behind the urinary bladder and a swelling of the right internal obturator node. Intense FDG uptakes were identified in the both lesions. High FDG accumulation was also observed in the brown adipose tissue (BAT) throughout the patient's body, and intense contrast enhancement was found in the BAT on CT. The diagnosis was a malignant paraganglioma with obturator node metastasis. The post-surgery FDG-PET/ CT examination revealed that the FDG accumulations in the BAT had completely disappeared.