Live attenuated VZV vaccination induces antitumor immunity in ATLL patients.

Adult T cell leukemia/lymphoma (ATLL) is a CD4-positive peripheral T cell lymphoma caused by human T cell lymphotropic virus type 1 (HTLV-1). Although ATLL is quite difficult to be cured, up-regulation of cellular immunity such as HTLV-1 Tax-specific cytotoxic T lymphocytes (CTLs) has been proved to be important to obtain long-term survival. At present, no efficacious method to activate ATLL-specific cellular immunity is available. This study aimed to investigate whether live attenuated varicella-zoster virus (VZV) vaccination to ATLL can activate HTLV-1 Tax-specific cellular immune response. A total of 3 indolent- and 3 aggressive-type ATLL patients were enrolled. All aggressive-type patients had the VZV vaccination after completing anti-ATLL treatment including mogamulizumab, which is a monoclonal antibody for C-C chemokine receptor 4 antigen, plus combination chemotherapy, whereas all indolent-type patients had the VZV vaccination without any antitumor treatment. Cellular immune responses including Tax-specific CTLs were analyzed at several time points of pre- and post-VZV vaccination. After the VZV vaccination, a moderate increase in 1 of 3 indolent-type patients and obvious increase in all 3 aggressive-type patients in Tax-specific CTLs percentage were observed. The increase in the cell-mediated immunity against VZV was observed in all indolent- and aggressive-type patients after VZV vaccination. To conclude, VZV vaccination to aggressive-type ATLL patients after mogamulizumab plus chemotherapy led to the up-regulation of HTLV-1 Tax-specific CTLs without any adverse event. Suppression of regulatory T lymphocytes by mogamulizumab may have contributed to increase tumor immunity in aggressive-type ATLL patients. Japan Registry of Clinical Trials number, jRCTs051180107.

Development of eosinophilic granulomatosis with polyangiitis during the clinical course of microscopic polyangiitis: A case report.

RATIONALE: Eosinophilic granulomatosis with polyangiitis (EGPA) is belongs to the antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) subgroups. EGPA, unlike other subgroups of AAV, including microscopic polyangiitis (MPA) and granulomatosis with polyangiitis, has the unique feature that both ANCA and eosinophilic inflammation are involved in its pathogenesis. Although AAV often relapses, there are currently no reports of EGPA developing during other subgroups of AAV. Herein, we document a case of EGPA that developed during the clinical course of MPA. PATIENT CONCERNS: A 61-year-old Japanese woman was diagnosed with MPA based on interstitial lung disease and myeloperoxidase-ANCA positivity. After starting immunosuppression therapy, including prednisolone and tacrolimus, she was expected to achieve clinical remission. Nonetheless, she occasionally experienced MPA relapse, which required an increased prednisolone dose, rituximab, intravenous cyclophosphamide, and plasma exchange. Three years after MPA onset, she developed renal amyloidosis; thus, subcutaneous tocilizumab was added to her regimen. Following clinical remission, the administration interval of her subcutaneous tocilizumab therapy was extended and immunosuppressants were discontinued. She then developed bronchial asthma and mild eosinophilia (eosinophilic count: ~1000/µL). Further, a year later, she underwent total hip replacement using a titanium implant. Subsequently, she developed abnormal sensation in both hands, numbness, and muscle weakness, as well as palpable purpura and massive eosinophilia (eosinophilic count: ~8500/µL). DIAGNOSIS: We diagnosed the patient with EGPA based on 5 items (asthma, multiple mononeuropathies, sinus abnormality, and extravascular eosinophils) of the 1990 American College of Rheumatology classification criteria. INTERVENTIONS: We administered 400 mg/kg intravenous immunoglobulin for 5 consecutive days, 300 mg mepolizumab subcutaneously every 4 weeks, and 40 mg/day prednisolone following pulsed methylprednisolone therapy (1000 mg/day for 3 consecutive days). OUTCOMES: After these treatments, the patient's symptoms improved, and eosinophilic count and inflammatory markers declined. LESSONS: The present case suggests that EGPA can be induced by the development of eosinophilic inflammation in other subgroups of AAV.

HTLV-1 Tax-specific memory cytotoxic T lymphocytes in long-term survivors of aggressive-type adult T-cell leukemia/lymphoma.

PURPOSE: Adult T-cell leukemia/lymphoma (ATLL) is a relatively refractory peripheral T-cell lymphoma caused by human T-cell lymphotropic virus type 1 (HTLV-1). The objective of this study was to investigate the characteristics of long-term survivors with ATLL. METHODS: We conducted an observational study of 75 aggressive-type ATLL patients. Flow cytometry was conducted to analyze HTLV-1 Tax-specific cytotoxic T-lymphocytes (CTLs) and T-cell receptor Vß gene repertoire. RESULTS: We first evaluated six long-term survivors among 37 patients who were newly diagnosed with ATLL and then treated with intensive chemotherapy without mogamulizumab, a monoclonal antibody for C-C chemokine receptor four antigen. Reversal of the CD4-to-CD8 ratio (CD4/CD8) in peripheral mononuclear cells was observed in all six patients. Three of these six patients showed reversed CD4/CD8 immediately after herpes virus infection. Four of these six patients who could be examined demonstrated long-term maintenance of HTLV-1 Tax-specific CTLs. We subsequently identified four long-term survivors among 38 patients who were newly diagnosed with ATLL and then treated with intensive chemotherapy plus mogamulizumab. All four patients showed reversed CD4/CD8, and three of the four patients contracted herpes virus infection during immunochemotherapy. Six of the total 10 patients were subjected to CTL analyses. Tax-specific CTLs were observed, and the CTLs that were almost entirely composed of memory CTLs in all patients were recorded. HTLV-1 provirus was also detected in all six patients. CONCLUSIONS: These data suggest that Tax-specific memory CTLs probably, together with anticancer agents, eradicate ATLL cells and exhibit long-term preventive effects from relapse ATLL. Thus, the strong activation of cellular immunity, such as herpes virus infection, seems to be necessary to induce such a potent number of Tax-specific CTLs.

Colorectal paragangliomas with immunohistochemical deficiency of succinate dehydrogenase subunit B.

Recent progress in paraganglioma (PGL) revealed genotype-phenotype relationship, especially succinate dehydrogenase complex subunit B (SDHB) gene mutation-related to the extra-adrenal origin and metastasis. SDHB-immunohistochemistry can detect all types of SDH-subunit mutations, and is a useful tool to detect SDH-mutation tumors. PGLs usually occur along with sympathetic, and parasympathetic chains, however, colorectal paraganglioma is extremely rare. We have experienced one sigmoid colon PGL and one rectal PGL. These colorectal PGLs: a sigmoid colon PGL measuring 25 mm associated with a gastrointestinal stromal tumor (GIST) of the stomach, and a rectal PGL measuring 75 × 45 mm with elevated norepinephrine level were analyzed by immunohistochemistry for INSM1, chromogranin A, synaptophysin, tyrosine hydroxylase, dopamine-beta-hydroxylase, and SDHB and SDHA. The tumors were strongly positive for above markers, however, negative for SDHB. Both PGLs negative for SDHB immunohistochemistry were defined SDHB-deficient PGLs. Histologic grading of the PGLs by GAPP was well differentiated in sigmoid PGL versus poorly differentiated in rectal PGL. Although these PGLs were the same Stage II of TNM classification, the patient with sigmoid colon PGL had neither recurrence nor metastasis for 5 years after the operation, however, the patient with rectal PGL suffered the recurrent multiple metastases and expired 5 years after the operation. Herein, we compared these colorectal PGLs in regard to the patients' prognostic factors. Patient prognosis with these colorectal PGLs was mostly related to the tumor size and histologic grade under the same situation of SDH-deficiency.

Mogamulizumab Plus EPOCH Therapy for Patients With Newly Diagnosed Aggressive Adult T-cell Leukemia/lymphoma.

BACKGROUND/AIM: Adult T-cell leukemia/lymphoma (ATLL) is a relatively refractory CD4-positive peripheral T-cell lymphoma. VCAP-AMP-VECP (mLSG15) is one of the standard chemotherapeutic regimens for patients with aggressive ATLL. Mogamulizumab (moga), a monoclonal antibody for C-C chemokine receptor 4 antigen expressed on the cell surface, has recently been poised for use as monotherapy and in combination with chemotherapy. However, to date, a significant survival benefit has not been obtained with the combination of moga + mLSG15 therapy. PATIENTS AND METHODS: We retrospectively analyzed 77 patients diagnosed with aggressive ATLL. Of them, 22 were treated with moga + a chemotherapy regimen comprised of etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisolone (EPOCH), 16 with moga + mLSG15, and 39 with chemotherapy alone. RESULTS: A risk reduction of approximately 30% was obtained with moga + EPOCH compared with moga + mLSG15. CONCLUSION: The addition of moga to chemotherapy did not result in a survival benefit compared with chemotherapy alone. However, a statistically significant overall survival benefit was observed in patients with moga-induced skin disorders.

Successful Treatment of a Patient with Brentuximab Vedotin-Refractory ALK-Negative Anaplastic Large Cell Lymphoma with Romidepsin.

We present the case of a 78-year-old male patient who was diagnosed with anaplastic lymphoma kinase (ALK)-negative, CC chemokine receptor 4 (CCR4)-negative, and CD30-positive anaplastic large cell lymphoma (ALCL). The patient had a past medical history of adult T-cell leukemia/lymphoma and colon cancers that had developed simultaneously approximately 2 years prior to the development of ALCL that were treated with immunochemotherapy and resection, respectively. Initial treatment for ALCL included brentuximab vedotin, an anti-CD30 monoclonal antibody-monomethyl auristatin E conjugate; however, we were unable to achieve a sufficient treatment effect. Romidepsin, an oral histone deacetylase inhibitor, was introduced as salvage chemotherapy; complete remission was attained. Interestingly, a reversal of the CD4/CD8 ratio and a reduction in human T-lymphotropic virus type 1 (HTLV-1) virus load was observed after 2 cycles of immunochemotherapy; the patient experienced upregulation of HTLV-1 Tax-specific cytotoxic T lymphocytes after a herpes zoster infection and the completion of immunotherapy. The immunologic status was maintained from the time of diagnosis through the completion of romidepsin therapy. Our findings indicate that romidepsin can be used safely and effectively to treat ALCL without impairing cellular immunity to HTLV-1.

Clinical and computed tomography characteristics of non-small cell lung cancer with ALK gene rearrangement: Comparison with EGFR mutation and ALK/EGFR-negative lung cancer.

BACKGROUND: The study was conducted to evaluate the clinical and computed tomography (CT) findings of non-small cell lung cancer (NSCLC) patients to distinguish between ALK gene rearrangement, EGFR mutation, and non-ALK/EGFR (no genetic abnormalities). METHODS: We enrolled 201 patients with primary NSCLC who had undergone molecular testing for both ALK gene rearrangement and EGFR mutation. The clinical features and CT findings of the main lesion and associated pulmonary abnormalities were investigated. RESULTS: Female gender (P = 0.0043 vs. non-ALK/EGFR), young age (P = 0.0156 vs. EGFR), and a light or never smoking history (P = 0.0039 vs. non-ALK/EGFR) were significant clinical characteristics of NSCLC with ALK gene rearrangement. The significant CT characteristics compared to NSCLC with EGFR mutation were a large mass (P = 0.0155), solid mass (P = 0.0048), and no air bronchogram (P = 0.0148). A central location (P = 0.0322) and lymphadenopathy (P = 0.0353) were also more frequently observed. Coexisting emphysema was significantly less frequent in NSCLC patients with ALK gene rearrangement (P = 0.0135) than non-ALK/EGFR. CONCLUSIONS: NSCLC with ALK gene rearrangement was more likely to develop in younger women with a light or never smoking history. The characteristic CT findings of NSCLC with ALK gene rearrangement were a large solid mass, less air bronchogram, a central location, and lymphadenopathy.

Rectal Paraganglioma.

A 57-year-old woman was admitted with lower abdominal pain and bloody bowel discharge. She was diagnosed with rectal tumor by colonoscopy, and a biopsy was performed. Surgery was performed, resulting in a diagnosis of rectal paraganglioma. Since recurrence was confirmed three years later, reoperation was done, and chemotherapy with cyclophosphamide, vincristine and dacarbazine (CVD) was subsequently carried out for further recurrence. After the administration of up to 15 courses of CVD, we delivered best supportive care due to disease progression. She died a year and a half after starting chemotherapy. We herein report this rare disease with a review of the relevant literature.

Clinicopathological study of 5 cases of renal cell carcinoma with t(6;11)(p21;q12).

Renal cell carcinoma (RCC) with t(6;11)(p21;q12) has been incorporated into the recent WHO classification. We performed a clinicopathological study of 5 cases with such a tumor. The patients consisted of 4 males and 1 female. The age of patients ranged from 17 to 57 years with a mean age of 38.6 years. Tumor sizes ranged from 2.8 to 11 cm with a mean value of 6.5 cm. Despite immunotherapy and molecular-targeted therapy, one patient died of the disease 28 months after the surgery. Grossly, the cut surface of this tumor showed grayish white color in at least the focal area of all tumors. Furthermore, hemorrhage, daughter nodules and cystic changes were observed in two, three, and two tumors, respectively. Morphologically, all the tumors consisted of two components of large cells and small cells, and the latter surrounded basement membrane-like materials, forming rosette-like structures. Immunohistochemically, nuclei of tumor cells in all cases were positive for TFEB. Fluorescence in situ hybridization study confirmed the TFEB gene break in two tumors. Finally, urologists and pathologists should bear in mind that this tumor may occur in young adults to adults and might behave in an aggressive fashion. Break-apart FISH is useful for the definite diagnosis.

CT and MRI findings of thymic carcinoid.

OBJECTIVE: To evaluate the CT and MRI findings of thymic carcinoid and to compare these findings with previously published findings of thymoma. METHODS: 11 cases of pathologically proven thymic carcinoid were reviewed retrospectively. Three patients had typical carcinoid, and eight patients had atypical carcinoid. The characteristics of the tumours and related thoracic abnormalities were assessed in each case on CT and/or MRI by two chest radiologists. The final decisions on the findings were reached by consensus. RESULTS: Thymic carcinoids were more likely to have a large mass (ranging from 18 to 105 mm), irregular contours (n = 8), heterogeneous intensity on T2 weighted images (n = 6; eight patients underwent MRI), heterogeneous enhancement (n = 9) and local invasion (n = 7). A necrotic or cystic component was identified in seven patients (one typical carcinoid and six atypical carcinoids). Lymphadenopathy was seen in four patients. Septum, capsule, haemorrhage and calcification were seen in three patients, two patients, two patients and one patient, respectively, with atypical carcinoid. CONCLUSION: Thymic carcinoids tend to have a high prevalence of large masses, irregular contours, heterogeneous intensity on T2 weighted images, heterogeneous enhancement and local invasion on CT and/or MRI. A necrotic or cystic component is often seen in atypical carcinoid. Advances in knowledge: Radiologic features of thymic carcinoid mimic those of high-risk thymomas and/or thymic carcinomas.