Masatoshi Kanno

Diffuse neurodeficits in intravascular lymphomatosis with ADAMTS13 inhibitor

Inhibitory antibody to von Willebrand factor (vWF)-cleaving protease (ADAMTS13) was detected in a patient with intravascular lymphomatosis. The increased serum level of the antibody paralleled an increase in the expression of uncleaved vWF, which might cause microvascular thrombosis and platelet consumption. Malignant cell proliferations with superimposed thrombosis within the lumina throughout the entire vasculature account for diffuse neurodeficits observed in the patient.

Primary T Cell Non-Hodgkin’s Lymphoma of the Central Nervous System

A 42-year-old man developed primary non-Hodgkins lymphoma of the central nervous system (CNS). Immunohistochemical examination suggested that tumor cells were derived from T cells. Primary T cell non-Hodgkins lymphoma of the CNS is a rare tumor, with only 12 well-documented cases in the literature. The clinical features of these 12 cases were similar to those of other CNS lymphomas, and the effect of treatment and prognosis were usually worse than those of extranodal lymphoma. Our patient, who was treated with partial tumor resection and whole-brain irradiation with a boost to the primary site and 5 courses of CHOP therapy (cyclophosphamide, doxorubicin, vincristine, prednisolone), is still alive and in remission 38 months after diagnosis.

Low-intensity ultrasound enhances the anticancer activity of cetuximab in human head and neck cancer cells

The potential clinical use of ultrasound in inducing cell apoptosis and enhancing the effects of anticancer drugs in the treatment of cancers has previously been investigated. In this study, the combined effects of low-intensity ultrasound (LIU) and cetuximab, an anti-epidermal growth factor receptor (EGFR) antibody, on cell killing and induction of apoptosis in HSC-3 and HSC-4 head and neck cancer cells, and its mechanisms were investigated. Experiments were divided into 4 groups: non-treated (CNTRL), cetuximab-treated (CETU), ultrasound-treated (UST) and the combination of cetuximab and US-treated (COMB). Cell viability was assessed by trypan blue staining assay and induction of apoptosis was detected by fluorescein isothiocyanate (FITC)-Annexin V and propidium iodide (PI) staining assay at 24 h after cetuximab and/or US treatment. To elucidate the effect of cetuximab and US on EGFR signaling and apoptosis in head and neck cancer cells after the treatments, the expression of EGFR, phospho-EGFR, and the activation of caspase-3 were evaluated with western blotting. More cell killing features were evident in the COMB group in HSC-3 and HSC-4 cells compared with the other groups. No differences in EGFR expression among the CETU, UST and COMB groups was observed, while the expression of phospho-EGFR in the CETU group was downregulated compared with that in the CNTRL group. Phospho-EGFR expression was much more downregulated in the COMB group compared with that in the other groups. In addition, the activation of caspase-3 in the UST group was upregulated compared with that in the CNTRL group. Caspase-3 activation was much more upregulated in the COMB group than that in the other groups. These data indicated that LIU was able to enhance the anticancer effect of cetuximab in HSC-3 and HSC-4 head and neck cancer cells.

A retrospective study of patients with follicular lymphoma (FL): identification of in situ FL or FL-like B cells of uncertain significance in lymph nodes resected at the time of previous surgery for carcinomas

Background and aims In situ follicular lymphoma (iFL)/intrafollicular neoplasia and follicular lymphoma (FL)-like B cells of uncertain significance represent proliferation of Bcl-2/t(14;18)-positive B cells solely in the germinal centres. The condition is interpreted as an early event in the multi-step lymphomagenesis of FL. The aim of this study is to examine the issue more specifically. Methods We reviewed medical history of FL patients in whom thoracoabdominal surgery with lymphadenectomy had been performed for management of carcinomas. These previously resected lymph nodes as well as the current FL nodes were analysed by immunohistochemistry, fluorescent in situ hybridisation, and PCR amplification with direct sequencing. Results We studied four such FL patients from a total of 150 patients with FL; all had iFL in the previously resected lymph nodes. Clonal relation was verified and suggested in one case each. The time from lymphadenectomy to the diagnosis of FL was 23–120 months. There appeared to be a reverse correlation between the rate of Bcl-2-positive follicle proliferation and the time from surgery to diagnosis of FL. Conclusions Although the rate for development of FL in individuals having iFL has been reported to be low from prospective studies, the present data indicate that follow-up studies for a longer period is necessary; the rate of Bcl-2-positive follicle proliferation could be a factor to predict development of FL in prospective studies. Such a retrospective study may contribute to elucidate mechanism(s) involved in lymphomagenesis of FL.

Chemotherapy-resistant intravascular lymphoma accompanied by ADAMTS13 inhibitor successfully treated with rituximab

Intravascular large B-cell lymphoma (IVL) is a subtype of diffuse large B-cell lymphoma (DLBCL), in which lymphoma cells infiltrate blood vessels without mass formation, and its prognosis is generally poor due to diagnostic difficulties. The authors previously described a patient with IVL accompanied by features of thrombotic thrombocytopenic purpura (TTP), expression of ADAMTS13 inhibitor, and a severe deficiency in ADAMTS13 activity [1]. Although standard CHOP chemotherapy was initially effective, the disease gradually became resistant despite intensive high-dose chemotherapy with autologous peripheral blood stem cell support. However, the chimeric anti-CD20 monoclonal antibody, rituximab, induced complete remission (CR) for a prolonged period. We describe the clinical course of this patient and the unique effects of treatment with rituximab alone. A 54-year-old man was admitted to our hospital with the onset of a psychological disorder and convulsions. Laboratory data revealed obvious thrombocytopenia (3.6 9 10/ lL) accompanied by elevated levels of serum lactic dehydrogenase (LDH) and soluble interleukin-2 receptor. Multiple cerebral venous embolisms, bilateral adrenal gland swelling, and hepatosplenomegaly were present without nodal disease. Despite normal chest X-rays and thoracic CT scans, the patient developed rapidly progressive respiratory failure. A definitive diagnosis of IVL was made from transbronchial lung biopsy (TBLB) specimens. Bone marrow smears revealed no obvious lymphoma cell invasion and megakaryocyte hyperplasia without hemophagocytic syndrome (HPS), although the peripheral blood platelet count was markedly decreased. We concluded that the thrombocytopenia was caused by the same pathogenesis as TTP, since plasma ADAMTS13 activity had decreased to below 3%, and active ADAMTS13 inhibitor (IgG-type autoantibody) was confirmed. After standard CHOP chemotherapy cycles, the platelet counts immediately recovered to within normal limits and all symptoms improved. The ADAMTS13 activity improved to 49% and inhibitor levels, which had never been negative, decreased. Whole brain irradiation after chemotherapy resulted in relapse of systemic disease. Although we performed highdose conditioning chemotherapy followed by autologous peripheral stem cell transplantation, respiratory failure and high-grade fever appeared with severe thrombocytopenia and massive serum LDH elevation at day 50 after transplantation. Salvage combination chemotherapies had extremely limited effects against the disease, and we started to administer 375 mg/m of rituximab after its use for CD20-positive DLBCL was permitted according to the regulations established by the Japanese National Health Insurance system. The patient did not develop any major M. Kanno (&) Tumor Center, Nara Medical University Hospital, 840 Shijo-cho, Kashihara 634-8522, Japan e-mail: mkanno@naramed-u.ac.jp

Successful chemo-endocrine therapy for multiple bone metastases and myelophthisis caused by occult breast carcinoma

Abstract We report a 55-year-old postmenopausal woman with occult breast carcinoma with multiple bone metastases and myelophthisis in whom complete response (CR) was achieved with chemo-endocrine therapy. At the time of admission, she had anemia and left axillary lymph node enlargement, with extremely high levels of serum tumor markers and no breast mass on physical examination or on a mammogram. Roentgenograms and bone scintigrams showed multiple bone, lung, and pleural metastases. Bone marrow biopsy and aspiration cytology from the left axillary lymph node revealed an invasion of adenocarcinoma cells. On immunohistochemical staining, the cancer cells were positive for estrogen receptor (ER), progesterone receptor (PgR), and gross cystic disease fluid protein-15 (GCDFP-15). CR was induced with a combination chemotherapy of doxorubicin, cyclophosphamide, and 5-fluorouracil (CAF), and has been maintained with sequential docetaxel administration with endocrine therapy. Her performance status (Eastern Cooperative Oncology Group) improved from 4 to 0. This patient represents a very specific and rare case in whom a primary tumor could not be detected despite severe advanced breast carcinoma, and in whom CR was achieved by chemo-endocrine therapy.

Prognosis of Node-Positive Breast Cancer Patients Who Underwent Parasternal Lymph Node Biopsy During Surgery Followed by Doxorubicin- or Mitoxantrone-Containing Adjuvant Chemotherapy

Abstract The authors examined the survival rates of 60 patients with breast cancer who underwent parasternal lymph node biopsy during surgery with axillary lymph node dissection and had histologically confirmed axillary node metastasis followed by adjuvant doxorubicin- or mitoxantrone-containing combination chemotherapy to ascertain whether administration of anthracycline or its analogue improved the prognosis of both axillary and parasternal node-positive patients. The overall survival rate (OS) for the parasternal node-positive patients (n=13, 21.7%) was 30.6%, and relapse-free survival rate (RFS) fell to 0% at the 104-month follow-up. Although the survival rate for all axillary node-positive patients was similar to those in previous reports, the OS and RFS for both axillary and parasternal node-positive patients were significantly worse than that for axillary node-positive and parasternal node-negative patients, despite treatment with adjuvant doxorubicin- or mitoxantrone-containing combination chemotherapy. Other intensive adjuvant treatment strategies are needed to reduce distant metastases for high-risk breast cancer patients having both axillary and parasternal nodes positive.

Does more intensive therapy have effects on mantle cell lymphoma? A clinical experience from the Lymphoma Treatment Study Group in Japan

Mantle cell lymphoma (MCL) is a rare subtype of B-celllymphoma characterized by amplification of cyclin D1.The effect of chemotherapies, such as CHOP (cyclophos-phamide, doxorubicin, vincristine, and prednisone), is oftentransient, and most patients die at median 3–5 years fromdiagnosis [1]. Before the rituximab era, a number of smallstudies evaluated the efficacy of high-dose chemotherapy(HDC) supported with autologous stem cell transplantation(ASCT), but did not find an evident contribution to survivalbenefit [2, 3]. Consequently, no single standard treatmentfor MCL has been established to date [4]. We thereforeconducted a nation-wide multicenter retrospective analysisof newly diagnosed patients with MCL in order to inves-tigate the efficacy and clinical outcome of each initialtreatments and HDC/ASCT in the rituximab era.Clinical data of 64 newly diagnosed MCL cases treated in12 institutions participating in the Lymphoma TreatmentStudyGroupinJapanbetween2001and2008werecollectedand analyzed by the end of April 2009. The data includedpatient characteristics [age, sex, performance status definedby European Cooperative Oncology Group (ECOG PS),clinical stage according to the Ann Arbor staging system,complete blood count, and serum lactate dehydrogenaselevel], as well as details of treatment and clinical outcome.Positivity of cyclin D1 and/or chromosomal abnormalityt(11;14)(q13;q32) in the biopsy specimen were required forthe diagnosis of MCL following the World Health Organi-zation classification system. This study was approved by theinstitutional review board in Nihon University ItabashiHospital, where the analysis was performed.Table 1 shows the clinical characteristics of all patientsand risk factors that might influence overall survival,including MCL international prognostic index (MIPI) [5].The median age of patients and median observation periodwere 64 years (range 47–80 years) and 34 months (range2–91 months), respectively. Most of patients were treatedwith rituximab-combined CHOP (R-CHOP)-based che-motherapy for a median 6 (range 2–8) cycles or R-Hyper-CVAD/MA regimen (rituximab, hyperfractionatedcyclophosphamide, vincristine, doxorubicin, and dexameth-asone alternating with high-dose methotrexate and cytara-bine), as initial treatment. As a result, 5-year overallsurvival (OS) and progression-free survival (PFS) for allpatients were 62 and 34%, respectively (Fig. 1a). Thecomplete response rate of the R-CHOP group was lowerthan that of the R-Hyper-CVAD/MA group (49 vs. 80%,P = 0.031), but there was no significant difference in OSor PFS (Fig. 1b, c). Sixteen patients (25%) received vari-ous combinations of HDC followed by ASCT. Amongthese patients, nine underwent HDC/ASCT in their firstcomplete remission, six were in a refractory phase of thedisease, and one was in a second remission. The clinicaloutcome of this group was quite encouraging, withouttreatment-related mortality or secondary malignancy dur-ing the observation period (93% of 5 year OS) (Fig. 1d).In this study, the majority of patients were treated withR-CHOP-based chemotherapy. After rituximab becameclinically available for treating B-cell lymphomas, theclinical outcome of MCL appeared to be improved.