Four successive cases of human fasciolosis in Japan.

Fasciolosis is a food-borne parasitic disease, caused by the large liver fluke, Fasciola. Humans acquire infection by ingesting fresh or undercooked water plants, on which infective metacercaria encyst. In spite of the rarity of the disease in Japan, we encountered four successive fasciolosis patients within a short period, who were all living in the same area. The patients were 70-82 years old, three females and the husband of one of the female patients. They started complaining of non-specific symptoms, such as fever, general fatigue, appetite loss, and abdominal pain, almost at the same time. All patients showed prominent peripheral blood eosinophilia, and the medical imaging indicated multiple hepatic lesions. No parasite eggs or worms were detected in any of the patients. Diagnosis was made serologically and they were treated with praziquantel and/or triclabendazole. No cattle or sheep were farmed in the area, but the wild sika deer, Cervus nippon, inhabited adjacent to the residential area. The intermediate host snail, Austropeplea ollula, were found near the residence of the patients, and one of the collected snails was positive for F. hepatica/gigantica hybrid type rediae. Our report should alarm the medical professionals for this rare and unfamiliar parasitic disease.

Clinicopathological significance of hyaluronan and hyaluronidase 2 (HYAL2) in breast cancer.

Hyaluronan (HA), as a component of extracellular matrix, has pivotal roles in both physiological and pathological condition. In breast cancer, while high molecular weight HA is produced by hyaluronan synthase, it is degraded by hyaluronidases (hyaluronidase-1 (HYAL1) and hyaluronidase-2 (HYAL2)) into low molecular weight HA (LMW HA), which is considered to have pro-tumorigenic effects in human malignancies. However, HA and HYAL2, the rate-limiting enzyme of HA degradation, have not been comprehensively examined in breast cancer and clinicopathological significance of LMW HA remains to be elucidated in breast cancer. We therefore histochemically localized HA as well as HYAL2 in 116 breast cancer tissues. In addition, we examined size-dependent function of HA on breast cancer cell proliferation and migration using MCF-7 and MDA-MB-231 breast cancer cell lines. HA was localized in both the stroma and breast carcinoma cells, while HYAL2 was predominantly localized in breast carcinoma cells. HA was significantly correlated with cell proliferation and invasion ability as well as increased risk of recurrence especially in HYAL2 positive group. On the other hand, HYAL2 was correlated with breast cancer cell proliferation and increased risk of recurrence. In addition, in vitro analyses revealed that lower molecular weight HA increased sphere forming ability and migration in MCF-7 and MDA-MB-231, whereas higher molecular weight HA inhibited them. It was concluded that HA needs to be degraded by HYAL2 to exert pro-tumorigenic effects and comprehensive HA/HYAL2 status serves as a potent prognostic factor in breast cancer.

Primary lung chordoma: a case report.

BACKGROUND: Chordoma, a rare malignant tumor arising from notochordal tissue, usually occurs along the spinal axis. Only a few published reports of primary lung chordomas exist. Herein, we present a case of primary lung chordoma and discuss important considerations for diagnosing rare chordomas. CASE PRESENTATION: We report a case of primary lung chordoma in a 39-year-old male with a history of testicular mixed germ-cell tumor of yolk sac and teratoma. Computed tomography revealed slow-growing solid lesions in the left lower lobe. We performed wedge resection for suspected germ-cell tumor lung metastasis. Histologically, large round or oval cells with eosinophilic cytoplasm were surrounded by large cells with granular, lightly eosinophilic cytoplasm. Tumor cells were physaliphorous. Immunohistochemistry was positive for brachyury, S-100 protein, epithelial membrane antigen, vimentin, and cytokeratin AE1/AE3, suggesting pulmonary chordoma. Re-examination of the testicular mixed germ-cell tumor revealed no notochordal elements. Although some areas were positive for brachyury staining, hematoxylin and eosin (HE) staining did not show morphological features typical of chordoma. Complementary fluorescence in situ hybridization (FISH) of the lung tumor confirmed the absence of isochromosome 12p and 12p amplification. Thus, a final diagnosis of primary lung chordoma was established. CONCLUSIONS: In patients with a history of testicular mixed germ cell tumors, comparison of histomorphology using HE and Brachyury staining of lung and testicular tumors, and analyzing isochromosome 12p and 12p amplification in lung tumors using FISH is pivotal for the diagnosis of rare lung chordomas.

Dipylidiasis cases in Japan-an update by literature survey.

Dipylidium caninum is a cosmopolitan parasite of companion animals such as dogs and cats. Accidental infection in humans occur mostly in children. Although considerable number of cases were reported from Europe and the Americas, case reports of this zoonotic disease are rather scarce from Asian countries. The aim of this study is to report the results of literature survey on dipylidiasis cases in humans in Japan. Conclusively, we have found a total of 17 cases since the first case report in from Aichi Prefecture in 1925.

Toll-like receptor (TLR) 4 is a potent prognostic factor in prostate cancer associated with proliferation and invasion.

Prostate cancer is one of the most common malignancies in men, and there is a need to explore novel biomarkers or therapeutic targets. Toll-like receptor 4 (TLR4) is expressed not only in antigen-presenting cells but also types of human malignancies, contributing to disease progression, although its clinical significance or functional role in prostate cancer remains unclear. Therefore, we immunolocalized TLR4 in 117 prostate cancer tissues to address its clinicopathological significance. Additionally, we performed in vitro assays to examine the effects of TLR4 on proliferation and migration of prostate cancer cell lines (LNCaP, DU-145 and PC-3). TLR4 immunoreactivity was predominantly detected in the cytoplasm of prostate cancer cells, and it was positively associated with proliferation and invasion abilities, as well as Gleason score. Subsequent in vitro experiments revealed that the inhibition of TLR4 by Sparstolonin B (SsnB) significantly suppressed the proliferation and migration of LNCaP, DU-145 and PC-3 cells. Therefore, we concluded that TLR4 was a potent prognostic factor associated with proliferation and invasion, and it might serve as a therapeutic target in prostate cancer.

Clinicopathological Significance and Prognostic Role of High Mobility Group Box 1 (HMGB1), Toll-Like Receptor (TLR) 2 and TLR4 in Breast Cancer.

High-mobility group box 1 (HMGB1) functions as damage-associated molecular pattern (DAMPs), released into extracellular space during cellular stress. Extracellular HMGB1 act as signal molecules through Toll-like receptor (TLR) 2 or TLR4, exerting diverse functions in both normal cells and malignant cells including breast cancer. However, their comprehensive examination in breast cancer tissues is lacking. Thus, we immunolocalized them in 112 breast cancer tissues, correlating their immunoreactivity with clinicopathological parameters and clinical outcomes to clarify their significance in breast cancer. We demonstrated that nuclear HMGB1 immunoreactivity was correlated with tumor progression and longer disease-free survival. In contrast, TLR2 immunoreactivity was correlated with increased cell proliferation and shorter disease-free survival, dependent on cytoplasmic HMGB1 immunoreactivity. Additionally, TLR4 immunoreactivity correlated with chemoresistance, regardless of cytoplasmic HMGB1 immunoreactivity. It was therefore considered that TLR2 collaboratively contributed to breast cancer progression with HMGB1-DAMPs to become a worse prognostic factor. Meanwhile, TLR4 served as a worse prognostic factor associated with chemoresistance, irrespective of HMGB1.

Localized anaplastic lymphoma kinase-positive histiocytosis in a cerebellar hemisphere with long-term treatment: illustrative case.

BACKGROUND: Anaplastic lymphoma kinase (ALK)-positive histiocytosis (ALK-H) is an emerging entity in the category of histiocytic neoplasms that was first reported as a multisystemic disease in three infants in 2008. The clinicopathological spectrum of ALK-H has been expanded to include localized disorders in specific organs, but the features of this subtype are not well known. The authors report a case of ALK-H localized in the central nervous system that was difficult to treat and review the relevant literature. OBSERVATIONS: The authors reviewed archival histiocytic tumors at their institute and found a pediatric case of ALK-H localized in a cerebellar hemisphere that had previously been reported as histiocytic sarcoma. Chemotherapy (approximately 1 year), additional surgery, and conventional chemotherapy (approximately 2.5 years) led to clinical remission, and maintenance chemotherapy was continued (approximately 1.5 years). Three years after completing treatment, a high-grade glioma was found in a cerebral hemisphere, and the patient died of the glioma 2 years later. LESSONS: Although the prognosis of ALK-H is generally good according to prior cases, the authors' case required long-term conventional chemotherapy, suggesting the tumor displayed aggressive characteristics. Early administration of ALK inhibitors may be necessary.

Metronomic Chemotherapy for Pediatric Refractory Solid Tumors: A Retrospective Single-center Study.

Metronomic chemotherapy (MC) is based on chronic administration of chemotherapeutic agents at minimally toxic doses without prolonged drug-free breaks, that inhibits tumor angiogenesis and induces tumor dormancy. This study aimed to determine the efficacy of MC for pediatric refractory solid tumors. We retrospectively analyzed the data of pediatric patients with relapsed/refractory solid tumors who received treatment, including low-dose continuous administration of anticancer drugs, at our institute. Of the 18 patients, the disease statuses at the initiation of MC were complete remission (n=2), partial remission/stable disease (n=5), and progressive disease (n=11). The overall survival rate was 61% at 12 months and 34% at 24 months, and the progression-free survival rate was 21% at 12 and 24 months. Although only 5 of the 18 patients showed certain tumor regression or maintained remission, tumors that stabilized, maintained remission/stable disease, and showed certain advantages in terms of overall survival rate, even if limited to progressive disease. Approximately half of the patients demonstrated temporal tumor stabilization and improved survival time. Overall, previous reports and the present study support the conclusion that MC has the potential to play an important role in pediatric cancer treatment during the advanced stage.

A delayed diagnosis of fascioliasis: The importance of appropriate fecal diagnostic method.

Fascioliasis, a zoonotic helminthiasis, occurs sporadically in Japan. In this report, we describe a case of fascioliasis that was initially difficult to diagnose because the fecal examination method was negative for the Fasciola sp. eggs. A 64-year-old man living in Shimonoseki City, Japan, presented with fatigue and anorexia. Laboratory tests showed hepatic dysfunction and eosinophilia. Abdominal dynamic contrast-enhanced computed tomography and magnetic resonance cholangiopancreatography suggested intrahepatic biliary cysts. Thereafter, fever and night sweats persisted, and positron emission tomography and biopsy of the porta hepatis lymph node were performed on suspicion of malignancy. However, histopathological diagnosis found non-specific inflammation. As fascioliasis was suspected due to eosinophilia and the multiple hepatic masses, fecal egg examination was performed by an external private laboratory, which adopted the flotation method and reported the absence of parasite eggs. However, fecal examination was retried in our laboratory using the formalin-ether concentration method, and we detected Fasciola sp. eggs. This case suggests that misdiagnosis may occur depending on the fecal examination method; thus, it is necessary to choose a suitable method for certain parasite species.

A short-term three dimensional culture-based drug sensitivity test is feasible for malignant bone tumors.

The feasibility of a short-term, three-dimensional (3D) culture-based drug sensitivity test (DST) for surgically resected malignant bone tumors, including osteosarcoma (OS), was evaluated utilizing two OS cell line (KCS8 or KCS9)-derived xenograft (CDX) models. Twenty-three (KCS8) or 39 (KCS9) of 60 tested drugs were likely effective in OS cells derived from a cell line before xenografting. Fewer drugs (19: KCS8, 26: KCS9) were selected as effective drugs in cells derived from a CDX tumor, although the drug sensitivities of 60 drugs significantly correlated between both types of samples. The drug sensitivity of a CDX tumor was not significantly altered after the depletion of non-tumorous components in the sample. In a surgically resected metastatic tumor obtained from a patient with OS, for whom a cancer genome profiling test detected a pathogenic PIK3CA mutation, DST identified mTOR and AKT inhibitors as effective drugs. Of two CDX and six clinical samples of OS and Ewing's sarcoma, DST identified proteasome inhibitors (bortezomib, carfilzomib) and CEP-701 as potentially effective drugs in common. This unique method of in vitro drug testing using 3D-cell cultures is feasible in surgically resected tissues of metastatic malignant bone tumors.

Case report: Hepatectomy with Rex bypass for a child with hepatoblastoma and portal vein thrombosis.

Pediatric liver tumors with portal vein obstruction are often candidates for liver transplantation. However, lifelong use of immunosuppressants and invasiveness to healthy donors in the case of living-donor liver transplantation is inevitable. Moreover, when lung metastasis is involved, the lung recurrence rate after liver transplantation is still high. Therefore, transplantation should be avoided as much as possible. In cases of tumors in the right lobe of the liver, complete resection of the portal vein trunk may be possible by creating a Rex bypass, but with the original method, end-to-side anastomosis to the umbilical portal vein is difficult in small children. We report a case of a 2-year-old girl with hepatoblastoma in whom a Rex shunt was created by end-to-end anastomosing the recanalized umbilical vein to the portal vein stump with interposing a vein graft, and the right lobe was successfully resected along with the tumor.

Kallikrein-Related Peptidase 12 (KLK12) in Breast Cancer as a Favorable Prognostic Marker.

Kallikrein-related peptides (KLKs) form an evolutionally conserved subgroup of secreted serine proteases that consists of 15 members (KLK1-15). Previous studies have shown that KLKs regulate diverse biological processes, but the clinical significance of KLKs remains largely unclear in human breast cancers. We examined the expression profile of 15 KLK genes in breast carcinomas using microarray data. Next, we immunolocalized KLK12 in 140 breast carcinomas and evaluated its clinical significance. Subsequently, we examined the effects of KLK12 on proliferation and migration in breast cancer cell lines. From microarray analyses, it turned out that KLK12 was the most strongly associated with low-grade malignancy in breast carcinomas among the 15 KLK members. Immunohistochemical KLK12 status was positively associated with ER and PR status, while it was inversely associated with stage, pathological T factor, lymph node metastasis, and distant metastasis. Prognostic analyses demonstrated that KLK12 was a favorable prognostic factor for both disease-free and breast cancer-specific survival of the patients. Furthermore, the knockdown of KLK12 significantly increased cell proliferation activity and cell migration of breast cancer cells. These results suggest that KLK12 has antitumorigenic effects associated with proliferation and migration and immunohistochemical KLK12 status as a potent favorable prognostic factor in breast carcinoma patients.

Severe Hepatitis-associated Aplastic Anemia Following COVID-19 mRNA Vaccination.

We herein report a case of hepatitis-associated aplastic anemia (HAAA) that occurred after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. In this patient, progressive pancytopenia observed two months after acute hepatitis following the second dose of the SARS-CoV-2 vaccine indicated the development of HAAA. Although some reports have suggested that SARS-CoV-2 vaccination may be involved in the development of autoimmune diseases, no cases of HAAA developing after SARS-CoV-2 vaccination have been reported. SARS-CoV-2 vaccination in children has only started relatively recently, so the range of side effects in children has not yet been thoroughly described. Therefore, we need to strengthen surveillance for symptoms of children who are vaccinated.

The Pro-Tumorigenic Role of Chemotherapy-Induced Extracellular HSP70 from Breast Cancer Cells via Intratumoral Macrophages.

Tumor-associated macrophages (TAMs) contribute to tumor progression and chemoresistance; it is therefore important to clarify the altered functions of macrophages following chemotherapy. While extracellular heat shock protein (HSP) 70 is associated with therapeutic resistance, the effects of HSP70 on TAMs remain largely unknown. Here, we conducted in vitro experiments and immunohistochemistry in 116 breast carcinoma specimens to determine whether the secretion of HSP70 from breast cancer cells following chemotherapy affects macrophage function. It was revealed that the interaction of epirubicin (EPI)-exposed breast cancer cells with macrophages enhanced tumor progression, and EPI promoted the secretion of extracellular HSP70 from breast cancer cells. The expression of pro-tumorigenic macrophage marker CD163 was decreased in macrophages treated with a conditioned medium (CM) from HSP70-silenced breast cancer cells. Breast cancer cells treated with CM from HSP70-silenced breast cancer cells showed decreased expression of transforming growth factor (TGF)-ß, and the pro-tumorigenic effects of macrophages were impaired when TGF-ß signaling was inhibited. Immunohistochemistry demonstrated that HSP70 served as a poor prognostic factor in conjunction with macrophage infiltration. It was therefore concluded that extracellular HSP70 levels increased following chemotherapy and enhanced the pro-tumorigenic effects of TAMs, either directly or indirectly, by regulating TGF-ß expression in breast cancer cells.