Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells.

Cancer stem-like cells (CSCs) are expanded in the CSC niche by increased frequency of symmetric cell divisions at the expense of asymmetric cell divisions. The symmetric division of CSCs is important for the malignant properties of cancer; however, underlying molecular mechanisms remain largely elusive. Here, we show a cytokine, semaphorin 3 (Sema3), produced from the CSC niche, induces symmetric divisions of CSCs to expand the CSC population. Our findings indicate that stimulation with Sema3 induced sphere formation in breast cancer cells through neuropilin 1 (NP1) receptor that was specifically expressed in breast CSCs (BCSCs). Knockdown of MICAL3, a cytoplasmic Sema3 signal transducer, greatly decreased tumor sphere formation and tumor-initiating activity. Mechanistically, Sema3 induced interaction among MICAL3, collapsin response mediator protein 2 (CRMP2), and Numb. It appears that activity of MICAL3 monooxygenase (MO) stimulated by Sema3 is required for tumor sphere formation, interaction between CRMP2 and Numb, and accumulation of Numb protein. We found that knockdown of CRMP2 or Numb significantly decreased tumor sphere formation. Moreover, MICAL3 knockdown significantly decreased Sema3-induced symmetric divisions in NP1/Numb-positive BCSCs and increased asymmetric division that produces NP1/Numb negative cells without stem-like properties. In addition, breast cancer patients with NP1-positive cancer tissues show poor prognosis. Therefore, the niche factor Sema3-stimulated NP1/MICAL3/CRMP2/Numb axis appears to expand CSCs at least partly through increased frequency of MICAL3-mediated symmetric division of CSCs.

ErbB receptor tyrosine kinase/NF-κB signaling controls mammosphere formation in human breast cancer.

Breast cancer is one of the most common cancers in humans. However, our understanding of the cellular and molecular mechanisms underlying tumorigenesis in breast tissues is limited. Here, we identified a molecular mechanism that controls the ability of breast cancer cells to form multicellular spheroids (mammospheres). We found that heregulin (HRG), a ligand for ErbB3, induced mammosphere formation of a breast cancer stem cell (BCSC)-enriched population as well as in breast cancer cell lines. HRG-induced mammosphere formation was reduced by treatment with inhibitors for phosphatidyl inositol 3-kinase (PI3K) or NF-κB and by expression of IκBα-Super Repressor (IκBαSR), a dominant-negative inhibitor for NF-κB. Moreover, the overexpression of IκBαSR in breast cancer cells inhibited tumorigenesis in NOD/SCID mice. Furthermore, we found that the expression of IL8, a regulator of self-renewal in BCSC-enriched populations, was induced by HRG through the activation of the PI3K/NF-κB pathway. These findings illustrate that HRG/ErbB3 signaling appears to maintain mammosphere formation through a PI3K/NF-κB pathway in human breast cancer.

[Splenic rupture associated with aggressive conversion of indolent T-cell prolymphocytic leukemia].

A 65-year-old man was diagnosed with leukocytosis in a routine medical examination. Further laboratory examinations showed increased LDH and sIL-2R levels in the serum. There was no evidence of infiltrative lesions or organomegaly. Bone marrow aspiration revealed many atypical small-sized lymphocytes without apparent nucleoli. Flow cytometric analysis of atypical lymphocytes was positive for T-cell markers, and chromosome analysis showed a normal karyotype. He was diagnosed with the small cell variant of T-PLL. Approximately 34 months later, having received no treatment, his cervical lymph nodes increased in size and number, and his white blood cell count, LDH and sIL-2R levels also rapidly increased. He was then admitted to our hospital. Bone marrow aspiration and cervical lymph node biopsy revealed complex chromosome abnormalities including inv(14)(q11;q32). Computed tomography showed swollen lymph nodes all over his body and hepatosplenomegaly. On the fourth hospital day, spontaneous splenic rupture occurred. Transcatheter arterial embolization was unsuccessful and the patient died. We report this case with rare autopsy findings.

Gastrointestinal stromal tumor in the duodenum exhibiting hemangiopericytoma-like histological pattern.

Reported herein is a gastrointestinal stromal tumor (GIST) that exhibited a hemangiopericytoma (HPC)-like histological pattern. Such a morphological variant of GIST has not been described previously. A 57-year-old woman presented with bloody stools. On upper digestive tract endoscopy a submucosal tumor of diameter 2 cm was detected at the duodenal bulb, and enucleated. Grossly, the tumor was well-circumscribed, grayish to whitish, and solid, and its central portion was ulcerated. Histology indicated round to fusiform tumor cells that had proliferated around branching vessels that had a staghorn configuration. Immunohistochemistry showed that the tumor cells were diffusely positive for vimentin and KIT; partially positive for CD34 and muscle actin; and negative for alpha-smooth muscle actin. On mutation analysis a 42 bp deletion was found from codons 560 to 573 of exon 11 of the KIT gene, which is a mutational hot spot of GIST. In diagnosis of gastrointestinal tract tumors with an HPC-like histological pattern, pathologists should consider the possibility of GIST.

Large Cell Neuroendocrine Carcinoma of the Mediastinum Successfully Treated with Systemic Chemotherapy after Palliative Radiotherapy.

Large cell neuroendocrine carcinoma (LCNEC) is a highly malignant cancer originally found in lung in 1991. In extremely rare occasions, primary LCNEC is found in the mediastinum; approximately 40 of such cases have been reported. Due to the limited number of reported cases, a standardized treatment protocol has yet to be established. We report a case of a 66-year-old woman with primary mediastinal LCNEC who presented with superior vena cava syndrome. Emergent radiotherapy was performed, followed by systemic chemotherapy with cisplatin and etoposide, which resulted in a dramatic tumor reduction. This is the first report describing the achievement of a complete response after systemic chemotherapy in a patient with primary LCNEC.

Primary malignant melanoma of the anterior mediastinum: CT and MR findings.

Malignant melanoma presenting in the mediastinum without an extrathoracic primary is extremely rare. To our knowledge, its imaging findings have not been described in the radiologic literature. We report a case of primary malignant melanoma of the anterior mediastinum and discuss its imaging findings on computed tomography and magnetic resonance imaging.

Systemic Epstein-Barr virus-positive T-cell lymphoproliferative disorders of childhood with fulminant leukocytosis and tumor lysis: a case report with autopsy findings.

Systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disorders (T-LPD) of childhood is an extremely rare disease characterized by an aggressive clinical course and very poor prognosis. We report an adolescent male with systemic EBV-positive T-LPD of childhood after primary EBV infection, resulting in a fatal clinical course within 9 days, along with autopsy findings. A 19-year-old male without an immunocompromised status presented with an acute onset of high fever, and was hospitalized for persistent fever, vomiting and diarrhea on the 5th day from onset. Laboratory data showed severe thrombocytopenia, increased ferritin level, liver dysfunction, disseminated intravascular coagulation, and anti-EBV-IgM positivity. Peripheral blood smears identified a number of atypical lymphocytes. Bone marrow aspiration revealed many atypical various-sized lymphocytes with apparent nucleoli and hemophagocytosis. Atypical lymphocytes displayed a CD8+ T-cell phenotype with monoclonal rearrangement of T-cell receptors. EBV-encoded RNA was also observed in lymphoid cells by in situ hybridization. The patient received dexamethasone and cyclosporine with no improvement, and died of tumor lysis by leukocytosis on the 9th day from onset.

Plexiform angiomyxoid myofibroblastic tumor of the stomach.

We report 2 cases of plexiform angiomyxoid myofibroblastic tumor of the stomach, a tumor entity that has not been described previously. The patients were a 50-year-old man (case 1) and a 68-year-old man (case 2). In case 1, the patient presented with acute abdominal pain. The tumor in case 2 was incidentally found at laparoscopic cholecystectomy. Grossly, the tumors were 4.0 cm (case 1) and 4.5 cm (case 2) in their greatest dimension, and they were recognized as submucosal tumors. The tumor caused gastric perforation in case 1. Histologically, the tumors extended from the serosa to the submucosa of the gastric wall, showing a plexiform growth pattern. Bland spindle tumor cells were observed, and they were separated by abundant intercellular myxoid matrix. The stroma was rich in small vessels. Immunohistochemically, the tumor cells were positive for alpha-smooth muscle actin and muscle actin, and negative for KIT, CD34, and S-100 protein. Electron microscopic findings were consistent with the myofibroblastic nature of the tumor cells. No mutations were found in the c-kit and platelet-derived growth factor receptor alpha genes. Although clinical follow-up data were insufficient, the histologic appearances suggested the benign nature of the tumors. However, the tumor in case 1 caused gastric perforation and necessitated an emergency operation.

Coexistence of IgA nephropathy and undifferentiated spondyloarthropathy in a female patient.

We report a female patient with IgA nephropathy associated with undifferentiated spondyloarthropathy. The patient manifested proteinuria and microhematuria and was diagnosed as having IgA nephropathy based on the histopathologic findings of the renal biopsy. Two years later, the bone X-ray demonstrated syndesmophytes and multiple calcifications in the ligament and tendon insertions, suggestive of long-term enthesitis, but the patient had occasionally noticed mild lumbago up to the time she visited our hospital, with spontaneous pain in the bilateral shoulders and lower back. IgA nephropathy can be concomitant with a mild form of seronegative spondyloarthropathy in women. Possible association of this disorder should be carefully checked in patients with IgA nephropathy irrespective of clinical symptoms suggesting the arthropathy, particularly in women.

Extremely Delayed Multiple Brain Metastases from Renal Cell Carcinoma: Remission Achieved with Total Surgical Removal: Case Report and Literature Review.

BACKGROUND: Late brain metastasis from renal cell carcinoma (RCC), which is generally considered as metastasis occurring more than 10 years after nephrectomy, often occurs as a solitary lesion, and total resection is recommended to achieve remission. CASE DESCRIPTION: We describe a rare case of multiple late brain metastases from RCC in a 60-year-old man who presented with 3 brain metastases from RCC 22 years after nephrectomy. Total removal of the 3 lesions achieved remission without adjuvant therapy. CONCLUSIONS: Total removal of late brain metastasis from RCC, even occurring with multiple lesions, can achieve total remission under specific conditions.

Prevalence of ischemic enterocolitis in patients with acute pancreatitis.

BACKGROUND: A considerable number of acute pancreatitis cases have been reported to be complicated by nonocclusive mesenteric ischemia. However, no reports have ever referred to the incidence of ischemic enterocolitis in patients with acute pancreatitis, using a series of autopsy cases. Here, we report our review of autopsy cases of patients with acute pancreatitis to examine the incidence of associated ischemic enterocolitis. METHODS: The intestinal and pancreatic slides of 48 autopsy cases of patients with acute pancreatitis were reviewed and the incidence of ischemic enterocolitis was determined. Clinical case records were also reviewed. RESULTS: Thirteen (27%) of 48 autopsy cases of patients with acute pancreatitis were complicated by ischemic enterocolitis. The frequency of shock was significantly higher in patients with ischemic enterocolitis than in those without ischemic enterocolitis. The intestinal lesion was diffuse in many cases and gangrene was not an unusual finding. CONCLUSIONS: The incidence of ischemic enterocolitis in patients with acute pancreatitis was much higher than that in the previous reports. Clinicians who treat patients with acute pancreatitis should consider ischemic enterocolitis as one of the frequent and severe complications of this condition.

Repeated de novo aneurysm formation after anastomotic surgery: Potential risk of genetic variant RNF213 c.14576G>A.

BACKGROUND: De novo aneurysm formation after intracranial anastomotic surgery is a relatively rare complication with fewer than 20 reported cases, and the mechanism is still unclear. CASE DESCRIPTION: A 63-year-old male treated for symptomatic internal carotid artery occlusion developed de novo aneurysms twice after anastomoses first of the superficial temporal artery-middle cerebral artery and second of the external carotid artery-radial artery-middle cerebral artery over a 10-year period. The first de novo aneurysm was successfully resected with pathological diagnosis of true aneurysm. The second de novo aneurysm thrombosed naturally after gradual growth. Genetic testing of the patient revealed the c.14576G>A (p.R4859K) variant in ring finger protein 213, which is a susceptibility gene for moyamoya disease. CONCLUSIONS: This genetic variant was probably involved in the repeated de novo aneurysm formation, and this case represents a rare phenotype of the genetic variant.

Russell body duodenitis in a patient with retroperitoneal metastasis of ureteral cancer.

Russell bodies are globular and eosinophilic inclusion bodies in the cytoplasm of mature plasma cells. Plasma cells whose cytoplasm is filled with Russell bodies are designated as Mott cells. Russell body duodenitis (RBD) is a unique form of chronic duodenitis that is characterized by infiltration of numerous Mott cells. RBD is very rare; only two cases have been reported to date. In this paper, we report a case of RBD in a patient with retroperitoneal metastasis of ureteral cancer. A 77-year-old man was admitted to our hospital complaining of appetite loss, vomiting, and upper abdominal distension. He had undergone left nephroureterectomy for ureteral cancer 4 years earlier. Upper digestive tract endoscopy revealed edema, stenosis, and punctate redness of the mucosa of the duodenum, and a biopsy was performed. Histological analysis showed that numerous Mott cells had infiltrated the lamina propria mucosae, and the condition was diagnosed as RBD. A mass lesion in the retroperitoneum adjacent to the duodenum was detected by abdominal computed tomography, and was diagnosed as metastatic urothelial carcinoma by biopsy. It is possible that chemokines produced by tumor cells caused RBD in this case.

AP-VAS 2012 case report: a case of myeloperoxidase antineutrophil cytoplasmic antibody-positive microscopic polyangiitis with rapidly progressive glomerulonephritis and hearing loss.

A 74-year-old Japanese woman was admitted to our hospital because of fever, fatigue, and hearing loss associated with vertigo. She had a 1-year history of hearing impairment that got worse gradually and had been treated as otitis media with effusion, but without remarkable improvement. After admission, she developed renal dysfunction associated with hematuria and proteinuria. Laboratory tests showed leukocytosis and elevated C-reactive protein. Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) was elevated, but proteinase-3 antineutrophil cytoplasmic antibody (PR3-ANCA) was negative. Renal biopsy revealed pauci-immune focal necrotizing glomerulonephritis with crescents. She was diagnosed as having MPO-ANCA-associated polyangiitis. After treatment with 500 mg methylprednisolone applied intravenously for 3 days, followed by 40 mg prednisolone administered orally, renal function recovered completely. Her hearing also improved. Although otolaryngological symptoms are common in PR3-ANCA associated vasculitis, hearing loss is a rare manifestation of MPO-ANCA associated vasculitis (MPO-AAV). Our case suggests that AAV should be considered in the differential diagnosis of hearing loss.

Atypically located pericardial cyst in a patient who underwent off-pump myocardial revascularization.

Pericardial cysts are rare benign mediastinal lesions and most commonly located at the cardiophrenic angle. We present a case of an atypically located pericardial cyst in a patient who underwent myocardial revascularization. A 61-year-old man with acute myocardial infarction was scheduled for coronary artery bypass grafting (CABG). Preoperative chest computed tomography revealed a homogenous cystic lesion in the superior mediastinum. The mass was located between the ascending aorta, the superior vena cava, and the left innominate vein. It was growing to the anterior of the aorta and to the right anterior paratracheal area. The density of the mass was close to that of water; thus, the contrast medium failed to enhance its visualization. A concomitant resection of the mass and the CABG was scheduled. After a medial sternotomy and bypass graft harvest, a median pericardectomy was performed. The surgeon found the cystic mass along the roof of the pericardium and located between the ascending aorta and superior vena cava. There was no adhesion between the mass and cardiovascular components. The mass was resected en bloc; therefore, off-pump CABG was completed. Histopathological examination of the resected specimen confirmed diagnosis of a pericardial cyst.

Usefulness of (18)F-FDG positron emission tomography/computed tomography for the diagnosis of pyothorax-associated lymphoma: A report of three cases.

Pyothorax-associated lymphoma (PAL) is a unique and rare non-Hodgkin's lymphoma developing in the pleural cavity following a long-standing history of chronic pyothorax (CP). The development of F-18 2'-deoxy-2fluoro-D-glucose (FDG) positron emission tomography combined with computed tomography (PET/CT) has contributed to the evaluation of lymphoma staging. However, only a few studies describing FDG-PET/CT findings in PAL have been published. This study reported three cases of PAL; all 3 patients had previously undergone artificial collapse therapy for pulmonary tuberculosis. Both the first case (an 84-year-old male) and second case (an 83-year-old male) complained of abdominal pain. An ultrasound scan revealed a mass shadow in the left chest wall without abnormal findings in the abdomen, and the CT and magnetic resonance imaging scans suggested malignant lymphoma of the left chest. FDG-PET/CT imaging showed extremely intense FDG uptake only in the left pleura and chest wall. Diagnosis was CP in the two patients, showing a high maximum standardized uptake value (SUVmax: early, 14.8 and delayed, 19.4 in the first case; early, 20.8 and delayed, 27.3 in the second case, respectively). Histopathological analysis of the specimens obtained by biopsy of the PET/CT-positive pleural mass showed non-Hodgkin's, diffuse large B cell lymphoma in the two cases. The third case was a 79-year-old male with relapse after right pleuropneumonectomy for PAL (diffuse large B cell lymphoma) 4 years earlier. PET/CT showed intense FDG uptake (SUVmax: early, 19.9 and delayed, 35.7) in the right pleura and chest wall. Diagnosis was CP, suggesting the recurrence of PAL. Furthermore, abnormal intense FDG uptake was noted in the hilar, mediastinal and supraclavicular lymph nodes, as well as in the spleen. In conclusion, FDG-PET/CT imaging is useful in the evaluation of the area of invasion in PAL.