Treatment of Catheter-Associated Internal Jugular Vein Thrombosis Using Apixaban for Less Than Three Months in Two Patients With Aggressive B-cell Lymphoma Undergoing Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone Therapy.

The selection of anticoagulant therapy and appropriate duration of treatment for central venous (CV) catheter-associated internal jugular vein thrombosis in patients with malignant lymphoma remain unclear. Two cases of aggressive B-cell lymphomas treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), in which apixaban administered for less than three months was effective against CV catheter-associated internal jugular vein thrombosis, are reported. In one case, the right internal jugular vein thrombosis developed after eight courses of R-CHOP; when apixaban was orally administered for 37 days after the CV catheter was removed, the thrombus completely dissolved and did not recur for 27 months. In the other case, right internal jugular vein thrombosis developed after four courses of R-CHOP; two additional courses of the R-CHOP were administered alongside oral apixaban administration without catheter removal. After 66 days of oral apixaban, the thrombus completely dissolved, the CV catheter was removed, and no recurrence was observed for 8.5 months.

Two Older Hematological Malignancy Patients for Whom Nutrition Rehabilitation Was Effective Against Global Leadership Initiative on Malnutrition-Defined Malnutrition and Sarcopenia.

The long-term survival rate of hematological malignancy patients with Global Leadership Initiative on Malnutrition (GLIM)-defined malnutrition and sarcopenia is poor, but nutritional rehabilitation effects in such patients are unknown. Here, two cases of older hematological malignancy patients in whom nutritional rehabilitation was effective against GLIM-defined malnutrition and sarcopenia are reported. By undergoing nutritional rehabilitation, the myeloma patient increased her six-meter walking speed and her maintained body mass index (BMI), appendicular skeletal muscle mass (ASM), and hand grip strength, whereas the Hodgkin lymphoma patient regained his hand grip strength and maintained his BMI, ASM, and six-meter walking speed.

Limitations of the L3 skeletal muscle index and the Asian Working Group for Sarcopenia 2019 consensus diagnostic criteria for sarcopenia evaluation in a case of diffuse large B-cell lymphoma.

Sarcopenia is an adverse prognostic factor for diffuse large B-cell lymphoma. A case of diffuse large B-cell lymphoma whose diagnosis, severity, and therapeutic effect of sarcopenia were difficult to determine owing to lymphoma cell infiltration into the psoas major and femoral bone marrow is reported. At presentation, the cross-sectional area of left psoas major at L3 was enlarged owing to lymphoma cell infiltration; thus, sarcopenia evaluation was impossible by L3 skeletal muscle index. The patient was bedridden; thus, sarcopenia evaluation was impossible by the Asian Working Group for Sarcopenia 2019 consensus diagnostic criteria at presentation. At the terminal stage, she could not walk due to bilateral anterior thigh pain caused by lymphoma infiltration into femoral marrow; thus, sarcopenia evaluation was impossible by the Asian Working Group for Sarcopenia 2019 consensus diagnostic criteria. Although the L3 skeletal muscle index and the Asian Working Group for Sarcopenia 2019 consensus diagnostic criteria are representative sarcopenia evaluation systems, they cannot be used to evaluate sarcopenia in some diffuse large B-cell lymphoma patients.

Malignant triton tumor of the duodenum: report of a case.

We report a case of malignant triton tumor of the duodenum, which is extremely rare. A submucosal malignant tumor was detected in the duodenum of a 49-year-old woman. The tumor was completely resected by performing pancreaticoduodenectomy. Pathological examination revealed that the lesion was a malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation, i.e., a malignant triton tumor. Long-term survival has been achieved with no recurrence at 8.5 years after surgery.

Myelodysplastic syndrome diagnosed on the occasion of Fournier's gangrene.

Fournier's gangrene (FG) is a fulminant infective necrotizing fasciitis, which includes the genital, perineal, and perianal regions. A 77-year-old man had previously been diagnosed as having diabetes mellitus (DM) and was treated with pioglitazone (15 mg) and miglitol (150 mg). He developed sudden perineal discomfort, fever with painful penile, and scrotal edema, subsequently leading to urinary retention. According to physical examination and CT scan results for the swollen penis and scrotum, he was diagnosed with FG. FG was eventually controlled by extensive treatment with broad spectrum antibiotics and repeated surgical debridement including penectomy and scrotectomy. He showed persistent anemia and decreased neutrophils exhibiting hypogranulation. Bone marrow aspiration revealed hypercellularity with 9% myeloblasts, micromegakaryocytes, abnormal leukocyte granulation, and erythrocytic dyspoiesis, leading to a diagnosis of myelodysplastic syndrome (MDS) RAEB-1, and he was evaluated as high risk according to IPSS-R. After 4 courses of azacitidine treatment, he achieved HI-E and had no further recurrence of FG for more than 18 months. Although DM and alcohol misuse are common systemic comorbidities in patients with FG, MDS should be considered in elderly FG cases, even when DM complications are present.

A novel nuclear DnaJ protein, DNAJC8, can suppress the formation of spinocerebellar ataxia 3 polyglutamine aggregation in a J-domain independent manner.

Polyglutamine (polyQ) diseases comprise neurodegenerative disorders caused by expression of expanded polyQ-containing proteins. The cytotoxicity of the expanded polyQ-containing proteins is closely associated with aggregate formation. In this study, we report that a novel J-protein, DNAJ (HSP40) Homolog, Subfamily C, Member 8 (DNAJC8), suppresses the aggregation of polyQ-containing protein in a cellular model of spinocerebellar ataxia type 3 (SCA3), which is also known as Machado-Joseph disease. Overexpression of DNAJC8 in SH-SY5Y neuroblastoma cells significantly reduced the polyQ aggregation and apoptosis, and DNAJC8 was co-localized with the polyQ aggregation in the cell nucleus. Deletion mutants of DNAJC8 revealed that the C-terminal domain of DNAJC8 was essential for the suppression of polyQ aggregation, whereas the J-domain was dispensable. Furthermore, 22-mer oligopeptide derived from C-termilal domain could suppress the polyQ aggregation. These results indicate that DNAJC8 can suppress the polyQ aggregation via a distinct mechanism independent of HSP70-based chaperone machinery and have a unique protective role against the aggregation of expanded polyQ-containing proteins such as pathogenic ataxin-3 proteins.

[Effective treatment of metastatic rhabdomyosarcoma with pazopanib].

Pazopanib, an oral tyrosine kinase inhibitor, is the first molecular-targeted agent approved for the treatment of advanced soft tissue sarcoma(STS). Rhabdomyosarcoma in adults is rare, accounting for less than 3%of all adult STS cases. A 57-year old woman presented with cervical lymphadenopathy. Computed tomography revealed a heterogeneous mass in the retroperitoneum, replacing the entire right kidney. On the basis of the above findings, the patient was diagnosed with alveolar rhabdomyosarcoma. She was first treated with 4 courses of vincristine, actinomycin D, and cyclophosphamide(VAC), which resulted in a partial response. Dose reduction and delay occurred owing to hematological toxicity and febrile neutropenia. As second-line chemotherapy, the patient was administered a single daily dose of 800 mg of pazopanib. Because of an episode of hand-foot syndrome and hepatic impairment, the 800-mg daily dose of pazopanib was reduced to a daily dose of 600 mg, which had to be further reduced to a daily dose of 400 mg owing to fatigue and anorexia. The patient maintained a partial response for a total of 4.3 months when treated with pazopanib. Therefore, this drug may be a new treatment option for patients showing metastatic STS after previous chemotherapy.

Diagnostic utility of NCOA2 fluorescence in situ hybridization and Stat6 immunohistochemistry staining for soft tissue angiofibroma and morphologically similar fibrovascular tumors.

Soft tissue angiofibroma (STA), a recently suggested new histologic entity, is a benign fibrovascular soft tissue tumor composed of bland spindle-shaped tumor cells with abundant collagenous to myxoid stroma and branching small vessels. The lesion has a characteristic AHRR-NCOA2 fusion gene derived from chromosomal translocation of t(5;8)(p15;q13). However, morphologically similar tumors containing abundant fibrovascular and myxoid stroma can complicate diagnosis. We designed an original DNA probe for detecting NCOA2 split signals on fluorescence in situ hybridization (FISH) and estimated its utility with 20 fibrovascular tumors: 4 each of STAs, solitary fibrous tumors (SFTs), and cellular angiofibromas and 3 each of low-grade myxofibrosarcomas, myxoid liposarcomas, and low-grade fibromyxoid sarcomas. We also performed FISH for 13q14 deletion and immunohistochemistry (IHC) staining for estrogen receptor, progesterone receptor, retinoblastoma protein, and MUC-4 expression. Furthermore, IHC for Stat6 was conducted in the 20 cases analyzed by FISH and in an additional 26 SFTs. We found moderate to strong nuclear Stat6 expression in all SFTs but no expression in the other tumors. Both estrogen receptor and progesterone receptor expressions were observed in STAs, SFTs, and cellular angiofibromas. Expression of retinoblastoma protein was found in less than 10% of cells in all tumor types except myxoid liposarcoma. The low-grade fibromyxoid sarcomas were strongly positive for MUC-4. All STAs showed NCOA2 split signals on FISH. All tumors, regardless of histologic type, had 13q14 deletion. The NCOA2 FISH technique is a practical method for confirming STA diagnosis. The combination of NCOA2 FISH and Stat6 IHC proved effective for the differential diagnosis of STA, even when using small biopsy specimens.

Successful treatment of childhood hypocellular acute myeloid leukemia.

Hypocellular acute myeloid leukemia (AML) is extremely rare in childhood. We report on a 7-year-old girl with hypocellular AML who was treated successfully with granulocyte-colony stimulating factor (G-CSF) and combined chemotherapy. High-dose G-CSF induced complete remission and she subsequently received reduced intensity conditioning and unrelated cord blood transplantation; however, this resulted in early rejection. After a complete hematological recovery, she received 3 courses of combination chemotherapy oriented toward AML. She has remained in complete remission for over 1 year after the completion of the therapy. G-CSF effectively induced remission, and combination chemotherapy has been proven to be feasible for patients with childhood hypocellular AML.

Detection of specific genetic abnormalities by fluorescence in situ hybridization in soft tissue tumors.

For the detection of chromosome translocations/chimeric genes and specific genetic abnormalities in soft tissue tumors, we conducted fluorescence in situ hybridization (FISH) analysis on 280 cases of soft tissue and other tumors using formalin-fixed paraffin-embedded tissue sections. The detection rate of the FISH split-signal was 84% (129/154 cases) for the translocation-associated soft tissue tumors, such as Ewing's sarcoma/primitive neuroectodermal tumor, synovial sarcoma, alveolar rhabdomyosarcoma, myxoid liposarcoma, clear cell sarcoma and so forth. Positive split-signals from EWSR1, SS18 and FOXO1A probes were detected in 3% (2/64) of various histological types of carcinoma, lymphoma, melanoma, meningioma and soft tissue tumors. In FISH using the INI1/CEP22 probe, the INI1 deletion signal was detected in 100% (9/9) of epithelioid sarcoma. In well-differentiated and dedifferentiated liposarcomas, detection of MDM2 amplification signals in FISH using the MDM2/CEP12 probe were both as high as 85% (11/13) and 100% (13/13), respectively. In other adipocytic and non-adipocytic tumors requiring differentiation from these types, detection was only 13% (5/39), and CEP12 polysomy was frequently detected. As these results demonstrate the high sensitivity and specificity of FISH, we concluded FISH to be a useful pathological diagnostic adjunct for definite and differential diagnosis of soft tissue tumors.

Tumor-produced secreted form of binding of immunoglobulin protein elicits antigen-specific tumor immunity.

Binding of immunoglobulin protein (BiP) is a major molecular chaperone localized in endoplasmic reticulum (ER). It has been demonstrated to interact with nascent Ig. However, contrary to other ER-resident heat shock proteins such as gp96, calreticulin, and ORP150, it is not clear whether tumor-derived BiP plays a role in inducing antitumor immunity. In this study, we show that the tumor-derived secreted form of BiP is capable of inducing antitumor CD8(+) T cell responses. We constructed an ER-retention signal KDEL-deleted mutant of BiP cDNA and transfected it to tumor cells, which resulted in continuous secretion of tumor-derived BiP into the extracellular milieu. We show that this secreted BiP is taken up by bone marrow-derived dendritic cells, and thereafter BiP-associated Ag peptide is cross-presented in association with MHC class I molecules, resulting in elicitation of an Ag-specific CD8(+) T cell response and antitumor effect. This strategy to boost antitumor immune responses shows that a tumor could be its own cellular vaccine via gene modification of the secretion of the tumor Ag-BiP complex.

Increased expression of erythropoietin receptor in human pterygial tissues.

Erythropoietin (Epo) induces physiological activities such as cell proliferation, migration, and angiogenesis in Epo receptor (EpoR)-expressing vascular endothelial and tumor cells. Recently, it has been demonstrated that growth factor-independent proliferation is frequently observed during the cell transformation process. Pterygium is a fibrovascular proliferating tissue that includes transformed cells. The aim of this study was to examine the localization of Epo and EpoR proteins in human pterygial tissues. Eleven samples including nine pterygia and two normal bulbar conjunctivas, which were surgically excised, were studied. Formalin-fixed, paraffin-embedded tissue sections were constructed and then were examined by immunohistochemistry with anti-Epo and EpoR antibodies. Cytoplasmic immunoreactivity for EpoR was heterogeneously detected in basal and suprabasal cells of the pterygium epithelium. In the pterygium stroma, a variety of endothelial cells forming vascular cavities showed cytolasmic immunoreactivity for EpoR. In normal conjunctival epithelium, a few basal cells showed a weak homogeneous immunoreactivity for EpoR in the cytoplasm. The number of EpoR-expressing epithelial cells was much higher in the pterygium compared to the normal conjunctiva. EpoR expression was marginally detected in stromal microvessels of the normal conjunctiva. Immunoreactivity for Epo was not noted in pterygium epithelium and stroma, and in normal conjunctiva. These results suggest that the Epo-independent EpoR-signaling pathway plays a potential role in cell proliferation and angiogenesis in human pterygium.

Immunolocalisation of E-cadherin and beta-catenin in human pterygium.

AIM: The pterygium represents an invasion of a wing of altered ocular surface tissue into the normal cornea. The head itself is slightly elevated and white, which is the only site of firm adhesion to the globe. The mechanisms of cell proliferation and adhesion in pterygium epithelium, however, are unknown. The aim of this study was to analyse the expression of cell adhesion molecules in pterygium tissues. METHODS: Six pterygia were surgically removed using the bare-sclera procedure, and two normal corneas and a normal bulbar conjunctiva were also obtained. Formalin-fixed, paraffin-embedded tissues were analysed by immunohistochemistry with anti-E-cadherin and beta-catenin antibodies. RESULTS: Immunoreactivity for E-cadherin was not detected in the normal cornea and conjunctiva. In contrast, all corneal and conjunctival epithelial cells showed a weak homogeneous immunoreaction for beta-catenin on the cell membrane. In the pterygium head, the thickness was relatively marked compared with the body, and normal conjunctival and corneal epithelia. E-cadherin as well as beta-catenin was heterogeneously expressed in the cell membrane and cytoplasm of a variety of epithelial cells, whereas the expression was less marked in the body. Several epithelial cells showed intense nuclear immunoreactivity for beta-catenin. Immunoreactivity of beta-catenin, but not E-cadherin, was detected in only a few stromal cells, which were less marked than in epithelial cells. CONCLUSION: It is suggested that E-cadherin and beta-catenin are concentrated in pterygium tissue, and are possibly involved with epithelial proliferation and adhesion.

Expression of p27(KIP1) and cyclin D1, and cell proliferation in human pterygium.

BACKGROUND: The pterygium is a growth onto the cornea of fibrovascular tissue that is continuous with the conjunctiva, whereas the mechanisms of cell proliferation in pterygium epithelium are unknown. AIM: To analyse the histopathology and the expression of cell cycle-related molecules in pterygium tissues. METHODS: Seven pterygia were surgically removed using the bare-sclera procedure, and three normal bulbar conjunctivas were also obtained. Formalin-fixed, paraffin-wax-embedded tissues were analysed by immunohistochemistry with anti-p27(KIP1), cyclin D1 and Ki-67 antibodies. RESULTS: Conjunctival epithelium consisted of several layers of round cells with a few goblet cells. Nuclear immunoreactivity for p27(KIP1) was noted in many normal epithelial cells, where cyclin D1 and Ki-67-positive nuclei were intermingled. A variety of goblet cells were located in the superficial layer of the pterygium head as well as those of the body epithelia. Several pterygium epithelial cells were p27(KIP1) positive, whereas nuclear immunoreactivity for cyclin D1 and Ki-67 was detected in many epithelial cells. By contrast, immunoreactivity for p27(KIP1), cyclin D1 and Ki-67 was hardly detected in the pterygium stroma. CONCLUSION: It is suggested that pterygium growth and development are associated with the proliferation of epithelium, which is possibly involved in the expression of cell cycle-related molecules.

A novel isoform of TUCAN is overexpressed in human cancer tissues and suppresses both caspase-8- and caspase-9-mediated apoptosis.

Caspase-associated recruitment domains (CARD) are protein-protein interaction modules found extensively in proteins that play important roles in apoptosis. One of the CARD-containing proteins, TUCAN (CARD8), was reported previously as an antiapoptotic protein with a molecular weight of 48 kDa, which was up-regulated in colon cancer cells. We identified a novel isoform of TUCAN with a molecular weight of 54 kDa. The new variant of TUCAN, termed TUCAN-54, was expressed in gastric, colon, and breast cancer tissues but was barely detected in normal noncancerous tissues, whereas 48-kDa TUCAN was detected in tumor tissues and noncancerous tissues. To know the function of TUCAN-54 in the apoptosis of cancer cells, TUCAN-54 was overexpressed in tumor cells by gene transfection. Its overexpression inhibited pro-caspase-9 activation, leading to the suppression of the cell death induced by a protein kinase inhibitor, staurosporine, or a chemotherapeutic reagent, etoposide (VP-16). In contrast, specific small interfering RNA-mediated suppression of TUCAN-54 expression in tumor cells increased the VP-16-induced cell death rate, indicating that expression of TUCAN-54 might be associated with chemoresistance of tumor cells. In addition, it inhibited caspase-8 activation as well, thereby suppressing Fas-induced cell death. It was revealed that Fas-associated death domain was physically associated with TUCAN-54 but not with 48-kDa TUCAN. Thus, TUCAN-54 might be a novel tumor-specific antiapoptotic molecule expressed in a variety of human cancer tissues, which might aggravate malignant potential of cancer cells, such as chemoresistance and immunoresistance.

Aberrant expression and potency as a cancer immunotherapy target of inhibitor of apoptosis protein family, Livin/ML-IAP in lung cancer.

CD8(+) CTLs have an essential role in immune response against tumor. Although an increasing number of tumor-associated antigens that can be recognized by CTLs have been identified from human tumors, a limited number of tumor-associated antigens is known in lung cancer. In addition, because some of them are expressed in noncancerous tissues, there exist limitations in their application to tumor immunotherapy. Livin/ML-IAP is one of recently identified inhibitor of apoptosis protein (IAP) family, which is overexpressed in melanoma cells. In this report, we show that Livin/ML-IAP is aberrantly expressed in many lung cancer cell lines and primary lung cancer tissues, whereas it is not detectable in normal tissues, including lung by reverse transcription-PCR methods. To identify HLA-A24-restricted T-cell epitopes of Livin/ML-IAP, eight peptides were selected from the amino acid sequence of this protein and screened for their binding affinity to HLA-A24. It was revealed that Livin7 peptide (amino acid sequence, KWFPSCQFLL) had the highest affinity to HLA-A24. By stimulating peripheral blood lymphocytes of HLA-A24-positive lung cancer patients with Livin7 peptide in vitro, the peptide-specific CTLs were successfully induced from four of five patients with Livin/ML-IAP-positive lung cancer but not from any of four patients without Livin/ML-IAP expression in their cancer tissues. Furthermore, the CTLs induced by Livin7 peptide showed cytotoxicity against Livin/ML-IAP(+) lung cancer cell lines in an HLA-A24-restricted manner. Our data suggest that Livin/ML-IAP may be an excellent target antigen in immunotherapy for lung cancer and Livin7 peptide may serve as a potent peptide vaccine for HLA-A*2402(+)/Livin(+) lung cancer patients.

Localization and function in endoplasmic reticulum stress tolerance of ERdj3, a new member of Hsp40 family protein.

Heat shock protein 40 (Hsp40) family proteins are known to bind to Hsp70 through their J-domain and regulate the function of Hsp70 by stimulating its adenosine triphosphatase activity. In the endoplasmic reticulum (ER), there are 5 Hsp40 family proteins known so far, 3 of which were recently identified. In this report, one of the novel Hsp40 cochaperones, ERdj3, was characterized in terms of its subcellular localization, stress response, and stress tolerance of cells. By using ERdj3-specific polyclonal antibody, endogenous ERdj3 protein was shown to reside in the ER as gene transfer-mediated exogenous ERdj3. Analysis of the expression level of endogenous ERdj3 protein revealed its moderate induction in response to various ER stressors, indicating its possible action as a stress protein in the ER. Subsequently, we analyzed whether this molecule was involved in ER stress tolerance of cells, as was the case with the ER-resident Hsp70 family protein BiP. Although overexpression of ERdj3 by gene transfection could not strengthen ER stress tolerance of neuroblastoma cells, reduction of ERdj3 expression by small interfering ribonucleic acid decreased the tolerance of cells, indicating that ERdj3 might have just a marginal role in the ER stress resistance of neuroblastoma cells. In contrast, overexpression of ERdj3 notably suppressed vero toxin-induced cell death. These data suggest that ERdj3 might have diverse roles in the ER, including that of the molecular cochaperone of BiP and an as yet unknown protective action against vero toxin.