Plasma exosomal DOK3 reflects immunological states in lung tumor and predicts prognosis of gefitinib treatment.

To identify liquid biomarkers that predict clinical outcomes of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), we enrolled patients with EGFR gene mutation-positive non-small-cell lung cancer who were intended to receive gefitinib treatment. Using plasma samples obtained prior to gefitinib treatment from 12 enrolled patients, we performed comprehensive proteomic analysis of plasma exosomes to explore proteins correlating with tumor reduction rate (TRR), progression-free survival (PFS), or overall survival (OS). Of the detected 1769 proteins, 119, 130, or 119 proteins demonstrated a strong correlation (|r| > 0.5) with TRR, PFS, or OS, respectively. Interestingly, 34 (29%), 41 (32%), or 27 (23%) of them, respectively, were functionally involved in the regulation of the immune response. CD8α chain was consistently listed as a molecule positively correlated with PFS and OS, suggesting that the long-lasting effects of gefitinib may be due to the antitumor effects of CD8+ T cells, as well as the induction of immunogenic apoptosis of tumor cells by blocking the EGFR signaling pathway. Notably, Doking Protein 3 (DOK3), a molecule involved in B-cell receptor signaling, and some immunoglobulin and complement molecules exhibited a clear correlation with PFS longevity of gefitinib treatment. Indeed, the strong expression of DOK3 in B cells was confirmed within tertiary lymphoid structures of lung cancer tissues derived from patients with long PFS. These findings suggest that the patients with active B-cell and T-cell immunity as a host immunological feature are more likely to benefit from gefitinib therapy. Circulating exosomal DOK3 has the potential as a predictive marker of response to gefitinib indicating this immunological feature.

The first case report of pediatric acute appendicitis caused by "Candidatus Actinobaculum timonae".

A 14-year-old boy presented to the hospital with pain in the right lower abdomen. His condition was diagnosed as acute appendicitis. An emergency operation was performed, and histopathological examination revealed an actinomycete-related organism in the excised appendicitis specimen. On 16S rRNA gene sequence analysis, "Candidatus Actinobaculum timonae" was identified, which is the first known case in a pediatric patient.

[Giant Anastomotic Aneurysm Associated with Albumin/Glutaraldehyde Sealant as a Late Complication after Acute Aortic Dissection Surgery:Report of a Case].

A 74-year-old woman was taken to our hospital with a chief complaint of chest and back pain. She was diagnosed with Stanford type A acute aortic dissection and underwent ascending aortic replacement. Fifteen months after surgery, a giant anastomotic aneurysm was found at the proximal and distal anastomoses on chest computed tomography (CT), and reoperation was indicated. Following sternal re-entry, anastomotic dehiscence was found where BioGlue, albumin/glutaraldehyde sealant, had been applied during the previous surgery, and caused aneurysm. Severe postoperative adhesion precluded extensive surgery, and redo replacement of the ascending aorta was carried out. Histopathological examination revealed extensive necrosis of smooth muscle cells in the aortic wall at the anastomotic site and a marked inflammatory cell infiltration around the aortic wall and the artificial graft, and association of BioGlue use was suggested. The use of appropriate tissue adhesives to reinforce the dissected aortic wall is important, as well as careful long-term follow-up.

Skeletal EWSR1-NFATC2 sarcoma previously diagnosed as Ewing-like adamantinoma: A case report and literature review emphasizing its unique radiological features.

Ewing-like adamantinoma (EAD) is a rare bone tumor. It remains unclear whether EAD belongs to adamantinoma, Ewing sarcoma (ES), or an independent category. Herein, we present a case of femoral sarcoma previously diagnosed as EAD in a 26-year-old woman. We observed amplified EWSR1 and NFATC2 fusion signals using fluorescence in situ hybridization. Prompted by its unique radiological features, we reviewed the current literature on skeletal EWSR1-NFATC2 sarcoma (ENS) and EAD. In addition to the similar histological features, we found that both ENS and EAD displayed similar characteristic radiological features, such as the tendency to occur in the diaphysis of long bones, cortical expansion and buttressing-type thickening, and bone surface involvement with saucer-like erosion without cortical destruction. We believe that these unique radiological features were related to its indolent behavior. Altogether, it is possible that previously reported EAD cases may be neither ES nor the classic adamantinoma but ENS. Further studies are needed to clarify the relationship between EAD and ENS.

Cytological features of BCOR-CCNB3 sarcoma: Comparison with Ewing sarcoma and synovial sarcoma.

INTRODUCTION: BCOR-CCNB3 sarcoma (BCS) is one of the histological types classified as an undifferentiated small round cell sarcoma of bone and soft tissue. This sarcoma frequently develops in males under 20 years of age. Histologically, a delicate capillary network has been reported as a conspicuous finding. In this study, the cytological findings of BCS were observed in two cases of primary lesions and one case of a lung metastatic lesion. The cytological findings of BCS were compared with its histological mimics, and the characteristic findings of BCS were examined. METHODS: Three cases of BCS were studied, and a cytological comparison was performed with 8 cases of Ewing sarcoma (ES) and 10 cases of synovial sarcoma (SS; monophasic type: 7 cases, biphasic type: 2 cases, poorly differentiated: 1 case). RESULTS: In all BCS cases, small clusters with thin and delicate vascular cores and tiny vascular fragments were conspicuous. In ES and SS cases, although small clusters with vascular cores were observed, the vascular cores were thicker than in BCS, and no tiny vascular fragments appeared in most cases. Cytomorphological differences of tumour cells were also observed among BCS, ES, and SS. Predominantly rounded nuclei with fine chromatin and inconspicuous nucleoli can be cytological clues for BCS. CONCLUSIONS: BCS shows characteristic cytological findings that make the diagnosis of BCS more likely than that of ES and SS. Cytological evaluation is a useful tool for appropriate differential diagnosis that leads to a more accurate final diagnosis and rapid treatment.

Portal hypertension in prolonged anorexia nervosa with laxative abuse: a case report with liver and kidney biopsy data.

PURPOSE: We previously reported three cases of portal hypertension in patients with prolonged anorexia nervosa (AN) with laxative abuse and self-induced vomiting; we now report a fourth, similar case. METHODS: A 34-year-old woman with anorexia nervosa, binge-eating/purging type (AN-BP), presented to the Kohnodai Hospital National Center for Global Health and Medicine Psychosomatic Medicine Department for treatment of low body weight. We conducted hepatic and renal biopsies and cardiac magnetic resonance imaging (CMR) to evaluate her complicated liver disease, renal failure, and cardiac insufficiency, respectively. RESULTS: Enhanced computed tomography revealed ascites, splenomegaly, and gastroesophageal varices, indicating portal hypertension. The liver and kidney biopsies demonstrated chronic hepatitis without evidence of hepatic cirrhosis and tubulointerstitial nephritis, respectively. CMR demonstrated decreased myocardial mass. CONCLUSION: We found tubulointerstitial nephritis and decreased myocardial mass in a patient with non-cirrhotic portal hypertension and prolonged AN with laxative abuse and habitual self-induced vomiting. We propose that reciprocal interactions between multiple factors related to AN, including laxative toxicity, dehydration, renal disorder, and cardiac insufficiency, result in portal hypertension. Level of Evidence Level V.

Comparison of antioxidative effects between radon and thoron inhalation in mouse organs.

Radon therapy has been traditionally performed globally for oxidative stress-related diseases. Many researchers have studied the beneficial effects of radon exposure in living organisms. However, the effects of thoron, a radioisotope of radon, have not been fully examined. In this study, we aimed to compare the biological effects of radon and thoron inhalation on mouse organs with a focus on oxidative stress. Male BALB/c mice were randomly divided into 15 groups: sham inhalation, radon inhalation at a dose of 500 Bq/m3 or 2000 Bq/m3, and thoron inhalation at a dose of 500 Bq/m3 or 2000 Bq/m3 were carried out. Immediately after inhalation, mouse tissues were excised for biochemical assays. The results showed a significant increase in superoxide dismutase and total glutathione, and a significant decrease in lipid peroxide following thoron inhalation under several conditions. Additionally, similar effects were observed for different doses and inhalation times between radon and thoron. Our results suggest that thoron inhalation also exerts antioxidative effects against oxidative stress in organs. However, the inhalation conditions should be carefully analyzed because of the differences in physical characteristics between radon and thoron.

[A Case of Lung Metastasis of the Breast Cancer with a Remarkable Response to Stereotactic Body Radiation Therapy(SBRT)].

A 69-year-old woman admitted to our hospital with the lump in the left breast. Further examination was performed for the lesion, and it was diagnosed as invasive ductal carcinoma. Partial resection and sentinel lymph node biopsy were performed. Pathological diagnosis was metaplastic carcinoma with squamous metaplasia. As the adjuvant treatment, docetaxel and cyclophosphamide(TC)therapy and radiotherapy was performed. Following the treatment of those, tegafur-uracil was administered for 2 years. Three years after the surgery, an isolated lung metastasis was revealed by CT. Capecitabine and cyclophosphamide(XC)therapy was administered, but not effective. Stereotactic body radiation therapy(SBRT)was performed for the lesion. As a result, the metastatic lesion was obscured. Drug therapy was stopped due to adverse events, and she is observed by no medication. Thirty-six months after SBRT and 78 months after the surgery, the patient is alive without recurrence. SBRT could be an effective treatment strategy for the oligometastais of the lung.

A rare case of perivascular epithelioid cell tumor (PEComa) of the greater omentum.

BACKGROUND: A tumor composed exclusively or predominantly of human melanin black 45 (HMB45)-positive epithelioid cells is called a perivascular epithelioid cell tumor (PEComa). We report a very rare case of a PEComa of the greater omentum. CASE PRESENTATION: MRI conducted to examine the orthopedic disease of the patients, a 49-year-old Japanese woman, also identified a tumor in her pelvis. A CT scan revealed a tumor mass on the right side of the pelvic floor and clear nutrient vessels originating from the splenic and celiac arteries. An omental primary tumor or accessory spleen was thus suspected, and tumor resection was performed. The tumor was a light brown solid tumor with a smooth margin, measuring 5.2 × 3.8 × 3.5 cm. Histopathologically, the tumor was composed mainly of spindle and epithelioid cells, and large and small blood vessel formation was observed. In the immunohistochemical staining, tumor cells were positive for human melanin black 45 (HMB-45) and Melan-A and partially positive for alpha-smooth muscle actin. The final diagnosis was PEComa of the greater omentum. CONCLUSIONS: Although omental PEComa is very rare, it should be considered as a differential disease of an omental primary tumor.

[A Case Report of Surgery and Chemotherapy for a Patient with Rapidly Progressing Breast Cancer during Pregnancy].

A 33-year-old woman became aware of a right breast mass at her 28th week of pregnancy. From the biopsy results, we diagnosed her with right breast cancer. At her 33rd week of pregnancy, she underwent modified radical mastectomy (pT2N3aM0, Stage III C, ER-negative, PR-negative, HER2-positive), and she elected to receive adjuvant therapy after the surgery during her pregnancy. She received the first course of EC (epirubicin plus cyclophosphamide) therapy on the 13th postoperative day (35 weeks of gestation) and gave a natural, vaginal delivery at 36 weeks and 5 days of gestation. On the 4th day after birth, the patient noticed a contralateral left breast mass and was diagnosed with left breast cancer, after core needle biopsy. She received 4 courses of EC therapy and is currently undergoing PTX plus HER (paclitaxel plus trastuzumab) therapy. Regarding chemotherapy during pregnancy, we recommend that there is no need to perform artificial preterm birth, because chemotherapy has little influence on children after their second-trimester. After the second-trimester, chemotherapy can be safely performed.

TMEM119 marks a subset of microglia in the human brain.

Microglia are resident myeloid cells of the central nervous system (CNS), activated in the brains of various neurological diseases. Microglia are ontogenetically and functionally distinct from monocyte-derived macrophages that infiltrate the CNS under pathological conditions. However, a lack of specific markers that distinguish resident microglia from circulating blood-derived macrophages in human brain tissues hampers accurate evaluation of microglial contributions to the human brain pathology. By comparative analysis of five comprehensive microglial transcriptome datasets, we identified an evolutionarily conserved protein TMEM119 as the most promising candidate for human microglial markers. TMEM119 was expressed on immortalized human microglia, in which the expression levels were not elevated by exposure to lipopolysaccharide, IFNγ, IL-4, IL-13 or TGFß1. Notably, TMEM119 immunoreactivity was expressed exclusively on a subset of Iba1(+) CD68(+) microglia with ramified and amoeboid morphologies in the brains of neurodegenerative diseases, such as Alzheimer's disease (AD), whereas Iba1(+) CD68(+) infiltrating macrophages do not express TMEM119 in demyelinating lesions of multiple sclerosis and necrotic lesions of cerebral infarction. TMEM119 mRNA levels were elevated in AD brains, although the protein levels were not significantly different between AD and non-AD cases by western blot and morphometric analyses. TMEM119-positive microglia did not consistently express polarized markers for M1 (CD80) or M2 (CD163, CD209) in AD brains. These results suggest that TMEM119 serves as a reliable microglial marker that discriminates resident microglia from blood-derived macrophages in the human brain.

A case of intraductal papillary mucinous neoplasm with high serum pepsinogen II level.

We report the case of a 65-year-old woman who had a high level of serum pepsinogen II. Several months earlier, she had found a mass on the right side of her upper abdomen. Esophagogastroduodenoscopy did not reveal atrophic or inflammatory findings. She had not taken proton pump inhibitors, and there was no indication of renal dysfunction. Imaging tests showed a mass of approximately 80mm in the pancreatic head. We performed pancreatoduodenectomy, and the histopathological examination revealed an intraductal papillary mucinous neoplasm (IPMN) of gastric type. Serum pepsinogen II levels substantially lowered after surgery. To the best of our knowledge, this is the first report on a relationship between IPMN and serum pepsinogen II.

Immunohistochemical characterization of CD33 expression on microglia in Nasu-Hakola disease brains.

Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by formation of multifocal bone cysts and development of leukoencephalopathy, caused by genetic mutations of either DNAX-activation protein 12 (DAP12) or triggering receptor expressed on myeloid cells 2 (TREM2). Although increasing evidence suggests a defect in microglial TREM2/DAP12 function in NHD, the molecular mechanism underlying leukoencephalopathy with relevance to microglial dysfunction remains unknown. TREM2, by transmitting signals via the immunoreceptor tyrosine-based activation motif (ITAM) of DAP12, stimulates phagocytic activity of microglia, and ITAM signaling is counterbalanced by sialic acid-binding immunoglobulin (Ig)-like lectins (Siglecs)-mediated immunoreceptor tyrosine-based inhibitory motif (ITIM) signaling. To investigate a role of CD33, a member of the Siglecs family acting as a negative regulator of microglia activation, in the pathology of NHD, we studied CD33 expression patterns in five NHD brains and 11 controls by immunohistochemistry. In NHD brains, CD33 was identified exclusively on ramified and amoeboid microglia accumulated in demyelinated white matter lesions but not expressed in astrocytes, oligodendrocytes, or neurons. However, the number of CD33-immunoreactive microglia showed great variability from case to case and from lesion to lesion without significant differences between NHD and control brains. These results do not support the view that CD33-expressing microglia play a central role in the development of leukoencephalopathy in NHD brains.

Cytopathology of Chondromyxoid Fibroma: Report of 2 Cases with Immunocytochemical Expression of GRM1.

INTRODUCTION: Chondromyxoid fibroma (CMF) is a rare, benign bone tumor that occurs predominantly in the second and third decades of life, more frequently in males. Overexpression of GRM1 as a consequence of tumor-specific gene rearrangement of GRM1 has recently been reported as a useful immunohistochemical marker for histopathological diagnosis of CMF. However, the usefulness of GRM1 staining of cytology specimens has not yet been evaluated. In this report, the cytological findings and GRM1 immunocytochemistry of two cases of CMF are described. CASE PRESENTATIONS: Case 1 was a 15-year-old girl with a rib tumor. Imaging findings suggested a benign neurogenic tumor such as schwannoma. The tumor had increased in size over a 2-year period and was resected. Case 2 was a 14-year-old boy with a metatarsal tumor involving his left first toe. Imaging findings were suspicious of a benign neoplastic lesion. Biopsy findings suggested a benign tumor, and the patient underwent tumor resection. Cytologically, in both cases the tumor cells were predominantly spindle-shaped or stellate, with a myxoid to chondromyxoid background matrix and multinucleated giant cells, and these matrices were metachromatic with Giemsa staining. Cellular atypia was more accentuated in case 2 than in case 1. Immunocytochemical staining for GRM1 was positive in both cases. CONCLUSION: Due to the overlap in cytological findings, it is often difficult to differentiate CMF from chondroblastoma and chondrosarcoma grade 2. Immunocytochemical staining for GRM1 may support the diagnosis of CMF, and the reuse of Papanicolaou-stained specimens is applicable. The present cases further demonstrated the difficulty of differentiating CMF from other mimicking tumors such as chondroblastoma and chondrosarcoma grade 2. In such instances, immunocytochemistry for GRM1 is applicable to the diagnostic process, the value of which is strengthened by reusing Papanicolaou-stained specimens.

A case of adult-onset Still's disease complicated by thrombotic thrombocytopenic purpura with retinal microangiopathy and rapidly fatal cerebral edema.

We present a patient who had adult-onset Still's disease (AOSD) complicated by thrombotic thrombocytopenic purpura (TTP) that resulted in retinal microangiopathy and rapidly fatal cerebral edema. The patient was a 37-year-old male who developed fever, eruption, arthritis and hepatic dysfunction, that, based on close examination, was diagnosed as AOSD. Despite treatment with corticosteroids, the patient developed acute visual field defect, neurological deterioration including convulsions and impaired consciousness, as well as acute renal failure that ultimately resulted in death. Pathological examination of autopsy specimens revealed multiple fibrin thrombi disseminated in small vessels of the brain and kidney, which was consistent with TTP, along with marked cerebral edema. Although TTP has rarely been reported in association with AOSD, awareness of the possible coexistence of these two diseases is important for diagnosis and treatment.

[Primary adenosquamous carcinoma of the liver presenting with hematochezia due to tumor invasion of the colon].

A 69-year-old female was referred to our hospital with hematochezia. Dynamic computed tomography demonstrated a large tumor with rim enhancement and central necrosis that invaded into the transverse colon. The tumor was resected, and histopathological examination revealed mixed adenocarcinoma and squamous cell carcinoma with partial abscess formation. On the basis of a literature review and the findings from the present case, rim enhancement with central necrosis on imaging appears to be characteristic of this disease.

A Case of Fibula Regeneration after Below-the-knee Amputation in an Adult.

We report the case of an adult with fibula regeneration after below-the-knee amputation. Fibula regeneration conventionally occurs at the donor site of children after autogenous fibula transplantation when the periosteum is preserved. However, the patient was an adult, and the regenerated fibula was 7-cm long and grew directly from the stump. A 47-year-old man was referred to the plastic surgery department owing to stump pain. He had an open comminuted fracture of the right fibula and tibia due to a traffic accident when he was 44 years old and underwent below-the-knee amputation and negative pressure wound therapy for skin defects. The patient recovered and was able to walk using a prosthetic limb. Upon radiography, the fibula was found to have regenerated 7 cm directly from the stump. Pathological examination revealed that the regenerated fibula contained normal bone tissue and neurovascular bundles in the cortex. The periosteum, mechanical stimuli with limb proteases, and negative pressure wound therapy were suspected to have accelerated bone regeneration. He had no inhibitory factors for bone regeneration, including diabetes mellitus, peripheral arterial disease, or active smoking status. After the resection of the regenerated fibula, the patient was ambulatory without further bone regeneration or pain. This case report suggests that bone regeneration may occur even in adults. The surgeon should not leave any part of the periosteum behind in patients undergoing amputation. In adult amputees complaining of stump pain, the possibility of bone regeneration may be considered.

Chlamydia Peritonitis Mimicking Juvenile Carcinomatous Peritonitis Diagnosed by Exploratory Laparoscopy: A Case Report.

Chlamydia trachomatis infections may occur in multiple organs, including the lungs, lymph nodes, peritoneal cavity, and genitourinary systems. This disease results in significant ascites, the swelling of lymph nodes, and elevated tumor markers (CA125), sometimes mimicking an ovarian malignancy. At our hospital, we often perform examination laparoscopic surgery in cases of suspected gynecologic cancers before initial treatment. In this paper, we report the case of a 19-year-old woman who came to our hospital because of an ovarian tumor and ascites. There was no history of sexual intercourse (self-reported). We suspected ovarian cancer from image inspections, so we performed laparoscopic surgery for diagnosis. The final pathological diagnosis was acute-to-chronic inflammation of the bilateral fallopian tubes, and a cytologic examination of the ascites was negative for malignant cells. The C. trachomatis antigen was positive on vaginal examination after the operation. Based on this result, we diagnosed this patient with C. trachomatis infection. Chlamydia peritonitis should be a differential diagnosis for cancer peritonitis in juvenile patients with abnormal ascites. Exploratory laparoscopy should help confirm the pathological diagnosis.

Phosphorylated Syk expression is enhanced in Nasu-Hakola disease brains.

Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by a loss-of-function mutation of DNAX-activation protein 12 (DAP12) or triggering receptor expressed on myeloid cells 2 (TREM2). TREM2 and DAP12 constitute a receptor/adaptor complex on myeloid cells. The post-receptor signals are transmitted via rapid phosphorylation of the immunoreceptor tyrosine-based activating motif (ITAM) of DAP12, mediated by Src protein tyrosine kinases, followed by binding of phosphorylated ITAM to Src homology 2 (SH2) domains of spleen tyrosine kinase (Syk), resulting in autophosphorylation of the activation loop of Syk. To elucidate the molecular mechanism underlying the pathogenesis of NHD, we investigated Syk expression and activation in the frontal cortex and the hippocampus of three NHD and eight control brains by immunohistochemistry. In NHD brains, the majority of neurons expressed intense immunoreactivities for Syk and Y525/Y526-phosphorylated Syk (pSyk) chiefly located in the cytoplasm, while more limited populations of neurons expressed Src. The levels of pSyk expression were elevated significantly in NHD brains compared with control brains. In both NHD and control brains, substantial populations of microglia and macrophages expressed pSyk, while the great majority of reactive astrocytes and myelinating oligodendrocytes did not express pSyk, Syk or Src. These observations indicate that neuronal expression of pSyk was greatly enhanced in the cerebral cortex and the hippocampus of NHD brains, possibly via non-TREM2/DAP12 signaling pathways involved in Syk activation.

A case of paravertebral mediastinal chordoma without bone destruction.

We report a unique case of mediastinal paravertebral chordoma without bone destruction in a 47-year-old Japanese woman. She was admitted to hospital after a tumor was incidentally detected on a chest radiograph. The tumor was located in the paravertebral region of the mediastinum and did not show any destruction of the thoracic vertebra radiologically. The tumor was clinically diagnosed as a benign neurogenic tumor and the tumor was easily removed surgically. Microscopically, the tumor mainly consisted of tumor cells with extensively vacuolated cytoplasm, arranged in cord- and nest-like fashion against a myxoid matrix background. Immunohistochemically, the tumor cells showed diffuse positivity for pancytokeratin (AE1/AE3) and vimentin. The tumor cell nuclei were positive for brachyury, which is a key transcription factor of notochordal development. These results confirmed the tumor to be an extraosseous chordoma in the paravertebral mediastinal region, which is an extremely rare location for a chordoma.