Tsunayuki Kakimoto

Elevated Level of Plasma Basic Fibroblast Growth Factor in Multiple Myeloma Correlates with Increased Disease Activity

Recent reports that bone marrow angiogenesis is increased in multiple myeloma prompted us to examine plasma concentrations of angiogenic growth factors and to elucidate their clinical and biological significance. In 45 cases including 36 cases of multiple myeloma and 9 cases of monoclonal gammopathies of undetermined significance (MGUS), plasma concentrations of basic fibroblast growth factor (FGF‐2) and vascular endothelial growth factor (VEGF) were evaluated. FGF‐2 was significantly elevated in 25 out of 45 (56%) of the patients with multiple myeloma compared with control subjects (median 9.01 pg/ml vs. 1.58 pg/ml, P<0.0001). The 25 cases were all active multiple myeloma, and none of the non‐active myeloma and MGUS patients showed a high FGF‐2 level. VEGF level was also elevated in 26 out of 45 patients (58%) compared with control subjects (median 42.0 pg/ml vs. 15.8 pg/ml, P<0.0001 for VEGF). VEGF concentration was high in 20 active myelomas, but also in one non‐active myeloma and five MGUS. Elevation of FGF‐2 level was associated with β2‐microglobulin level, anemia and bone marrow plasma cell percentage, which represent disease activity. Interestingly, none of five Bence‐Jones type myelomas, including four clinically active cases, revealed a high plasma FGF‐2 level, while all of them showed a high VEGF level. In all five responders, the plasma FGF‐2 levels were significantly decreased after chemotherapy. FGF‐2 was immunohistochemically detected in the bone marrow myeloma cells of the patients with high plasma FGF‐2 level. We conclude that plasma concentration of FGF‐2 can be a useful indicator of disease activity.

Thalidomide-Induced Severe Neutropenia during Treatment of Multiple Myeloma

Recent reports have shown that thalidomide has antiangiogenic activity and is effective for the treatment of refractory multiple myeloma. Unlike other antineoplastic drugs, thalidomide is reported to rarely cause severe hematologic toxicity. In Keio University Hospital, 44 patients with refractory multiple myeloma, including 18 who had relapsed after hematopoietic stem cell transplantation, were treated with this drug as a single agent. Severe grade 3 or 4 neutropenia during thalidomide treatment was observed in 10 patients.This phenomenon was not noted in previous reports. Neutropenia usually occurred in the first or second week of treatment. Concomitant progression of thrombocytopenia occurred in 5 cases, and bone marrow hypoplasia without a significant increase in myeloma cell numbers was also observed in 5 cases. Neutropenia was not correlated with antitumor response or the plasma concentration of thalidomide but was more frequently observed in patients with a low neutrophil and platelet count, anemia, or a high plasma cell percentage in the bone marrow before thalidomide treatment.Thus, this drug should be used carefully for patients with pretreatment cytopenia or a high tumor burden in the bone marrow.

Thalidomide for the treatment of refractory multiple myeloma: association of plasma concentrations of thalidomide and angiogenic growth factors with clinical outcome.

Recent reports showed that thalidomide has anti‐angiogenic activity and is effective for the treatment of refractory multiple myeloma (MM). We examined the relationship between the clinical efficacy and adverse effects of thalidomide and the plasma concentrations of this drug as well as angiogenic growth factors in refractory MM. Ten out of twenty‐four evaluable patients (42%) showed more than 25% reduction of M‐protein, and eight (33%) achieved more than 50% reduction. These changes were associated with restoration of anemia and recovery of normal immunoglobulin level. Somnolence and headache, constipation, peripheral neuropathy and skin rash were frequently observed, but were well tolerated. However, grade 2–4 severe neutropenia was also observed in nine cases. These adverse effects other than neutropenia occurred more frequently in the patients with higher plasma concentrations of thalidomide (≥2.0 μg/ml at 12 h after the last administration) and were readily alleviated by dose reduction. In contrast, neutropenia developed regardless of the plasma concentration. Plasma concentrations of angiogenic growth factors were frequently elevated before treatment. After thalidomide treatment, these growth factor levels tend to decrease to near‐normal ranges in responders but were still high in most non‐responders. After thalidomide treatment, plasma vascular endothelial growth factor (VEGF) level was significantly reduced in responders (P=0.025), but not in non‐responders (P=0.37). Reduction of plasma VEGF level might be an important indicator for anti‐myeloma effect of thalidomide.

Pneumocystis jiroveci pneumonia detected by FDG-PET

Dear Editor, A 57-year-old woman suffered a relapse of follicular lymphoma and underwent high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (auto-PBSCT). Six months after auto-PBSCT, she developed dyspnea on exertion. Her chest X-ray findings were normal (Fig. 1a). The laboratory data revealed increased serum levels of LDH (723 IU/l) and soluble interleukin-2 receptor (3,945 U/ml). A recurrence of follicular lymphoma was suspected, and a whole-body FDG-PET was performed. FDG-PET images showed patchy increased FDG uptake in both lungs (Fig. 1b). An elevated level of β-D glucan of 2,645 pg/ml and KL-6 of 814 U/ml suggested Pneumocystis jiroveci pneumonia (PCP). Computed tomography (CT) scanning revealed patchy interstitial infiltrates in both lungs (Fig. 1c). Bronchoscopy with transbronchial lung biopsies was performed. Bronchoscopy revealed normal airways, and the biopsies demonstrated nonspecific findings. Microscopy for Pneumocystis was negative but a PCR analysis of bronchoalveolar lavage fluid revealed the P. jiroveci DNA to be positive. She was therefore administered with sulfamethoxazole-trimethoprim (ST) and prednisolone and thereafter the symptoms clinically improved. FDG-PET images after ST treatment of PCP showed complete resolution of the abnormal uptake in both lungs (Fig. 1d). A gallium scan is known to demonstrate changes resulting from Pneumosystis pneumonia even before chest X-ray changes occur [1]. The use of FDG-PET imaging has been documented in human immunodeficiency virus disease [2–4] and in infectious diseases [5]. FDG-PET may therefore also play a role in the early diagnosis of P. jiroveci pneumonia in immunocompromised patients with hematological malignancies.

Single‐institute phase 2 study of thalidomide treatment for refractory or relapsed multiple myeloma: Prognostic factors and unique toxicity profile

We previously reported a pilot study of thalidomide monotherapy for Japanese patients with refractory or relapsed multiple myeloma. In the present work, we have extended this clinical trial to a single‐institute phase 2 study with a larger number of patients and longer follow‐up time. New information on the optimal dose and prognostic factors as well as the correlation of toxicities with treatment schedule was obtained. Fifteen of 56 (27%) patients achieved a partial response, including three cases with near‐complete remission. Most patients suffered toxicities at a dose of 400 mg per day, but there was no clear dose–response relationship. Thus, a lower dose such as 200 mg per day or less is considered optimal. Multivariate analyses identified only lack of response to therapy as an adverse prognostic factor for progression‐free survival. Chromosomal abnormality, C‐reactive protein >10 mg/L, and more than six previous courses of chemotherapy were significantly associated with shorter overall survival. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 23 and 11% of patients, respectively. Grade 4 interstitial pneumonia and grade 5 pulmonary hypertension were observed; however, no patient suffered deep vein thrombosis, which has frequently been observed in other studies. Duration of therapy was closely related to the development of peripheral neuropathy. The efficacy and prognostic factors of this treatment were confirmed in long‐term observation. However, special attention should be paid to toxicities such as hematological and pulmonary complications as well as peripheral neuropathy in long‐term users. (Cancer Sci 2008; 99: 1243–1250)

Bilateral Occipital Lobe Invasion in Chronic Lymphocytic Leukemia

In October 2004, a 58-year-old, alcoholic Japanese man was referred to our hospital with a temporary seizure. He also had a history of leukocytosis for about 10 years without any therapeutic agents, and chronic inflammatory disorders. His WBC counts were 36 10/ L, hemoglobin level was 10.0g/dL, and platelet counts were 11.2 10/ L. The leukocytosis was almost entirely comprised of small round mature lymphocytes with scant cytoplasm. The cell surface markers of these lymphocytes were examined and were positive for CD5, CD19, CD20, and negative for CD10, unfortunately CD23 was not examined and the patient declined to undergo a bone marrow examination. We diagnosed as Rai stage III chronic lymphocytic leukemia (CLL) and a blood analysis was performed regularly each month. In January 2005, he was admitted to our hospital again because due to a poor memory and progressive blindness. No significant changes were seen in the size of the lymphadenopathy, and no increased number of prolymphocytes and no infiltration of large lymphoid cells were seen in the peripheral blood. A lumbar puncture was performed and no CLL cells were found to have infiltrated the CSF. Brain magnetic resonance imaging (MRI) was performed immediately; a T2 high signal intensity lesion was described in the bilateral occipital lobe (Fig 1A). As for the differential diagnosis, we considered reversible posterior leukoencephalopathy syndrome (RPLS) and expected the lesion to improve naturally. But, 1 month later his symptoms were progressive and the occipital lobe lesions in the brain were widely spread, as displayed by brain MRI (Fig 1B). An open brain biopsy was performed to establish the diagnosis. Small round mature lymphocytes were infiltrated diffusely in the meninges and brain, moreover these lymphocytes were positive for CD79a with increased fibers by immunostain and silver stain both meninges (Figs 2A to 2C) and brain (Figs 2D to 2F). These lymphocytes were negative for CD3, CD5, CD10, CD23, and cyclinD1 by immunostain. We diagnosed the patient as having direct meningeal and cerebral invasion of CLL. The patient received an intermediate dose of intravenous (IV) methotrexate (MTX; 30 mg/kg/d at day1) injection and next, IV fludarabine phosphate (25 mg/m at 5 days), again an intermediate dose of IV MTX (100 mg/kg/d at day 1) injection and finally cranial radiation (total dose of 30 Gy) was performed, but all treatment was ineffective and the patient died 6 months after receiving chemotherapy. CLL is the most common type of leukemia in North America and Europe. However, it is rare in the Far East. The involvement of extranodal sites such as the skin, liver, spleen, and other organs are common in CLL, but CNS and leptomeningeal involvement are very rare. Some reports have shown that progressive disease states, such as prolymphocytic leukemia and Richter’s syndrome, are considered as possibly predisposing to meningeal infiltration. However, invasion of the CNS in patients with CLL has been reported even in early-stage CLL. CNS involvement in CLL is not uncommon in some autopsy reports. In fact, Barcos et al reported that the percentage of CNS involvement in the brain, dura mater and leptomeningeal were 7%, 21%, and 8%, respectively, in their autopsy study. Cramer et al reviewed the neuropathologic findings of 12 autopsy cases with

Immune-mediated peripheral neuropathy occurring simultaneously with recurrent graft-versus-host disease after allogenic hematopoietic stem cell transplantation

Peripheral neuropathy is a rare but important complication f allogenic hematopoietic stem cell transplantation (allo-HSCT). lthough it is potentially curable, it sometimes has a tremendous mpact on a patient’s quality of life. There have been reports of nflammatory peripheral neuropathy associated with chronic graftersus-host disease (GVHD), but its pathogenesis has not been ully revealed. We report a case of immune-mediated neuropahy after allo-HSCT for Philadelphia-chromosome-positive acute ymphoblastic leukemia (Ph-ALL). After conditioning with cyclophosphamide + total body irradition, a 44-year-old woman in the second molecular complete emission (mCR) of Ph-ALL underwent allogenic peripheral blood ematopoietic stem cell transplantation from her sister, with a oneocus mismatch of histocompatibility leukocyte antigen-B antigen. yclosporine A (CsA), short-term methotrexate, and mycophenoatemofetil were administered for GVHD prophylaxis. Grade 3 acute VHD (skin: stage 1, liver: stage 0, gut: stage 2) had diagnosed on ay24 had occurred and was treated effectively with methylpredisolone (mPSL) 2 mg/kg/day. Thereafter, no recurrence of GVHD ymptoms had been seen, despite a gradual reduction in the doses f CsA and steroid, and bone marrow examinations had revealed hat the patient continued to be in mCR from Ph-ALL (Fig. 1). On day 240, the patient developed a self-limiting common cold. rom around day 250, she became aware of gradually worsening uscle weakness in the left upper extremity (at the time CsA was 0 mg b.i.d. and steroid was 10 mg q.d. as prednisolone, CsA had still ept on being reduced every two weeks). At a regular consultation n day 273, GVHD symptoms (generalized skin rash, dry eyes, and tomatitis) were noticed. Blood examination showed extremely levated hepatic enzymes (AST 192 U/L [normal range: 13–33 U/L], LT 408 U/L [6–30 U/L], -GTP 766I U/L [10–47 U/L], ALP 1018 U/L 115–359 U/L], and T-bil 0.6 mg/L [0.2–1.0 mg/L]). As for immune econstitution, serum IgG was 955 mg/dL [870–1700 mg/dL], WBC as 7700/ L [3800–8500/ L] and lymphocyte was 14% [20–45%]. ymphocyte subsets were not examined. The patient was admited to hospital and underwent skin biopsy and echo-guided liver iopsy. The biopsy specimens were consistent with GVHD. Manual uscle testing (MMT) showed a weakness of 4 in the left trapezus, 3 in the left deltoid muscle, 0 in the left biceps and 4 in the

Successful treatment with rituximab for angioimmunoblastic T-cell lymphoma

We experienced a patient with angioimmunoblastic T-cell lymphoma (AITL) without Epstein-Barr virus-positive B (EBV-B) cells at initial presentation who progressed to AITL with expansion of EBV-B cells at relapse. Based on the results of repeated biopsy, the patient was successfully treated with rituximab in combination with chemotherapy at relapse. A repeat biopsy may be necessary to determine the optimum therapeutic strategy at relapse, particularly for patients with suspected expansion of B cell and/or EBV-B cells. Although a recent report found no significant prognostic advantage of rituximab, it is one of the active drugs for selected patients with AITL.

Reversible posterior leukoencephalopathy syndrome of bilateral thalamus in acute lymphoblastic leukemia

Numerous cases of reversible posterior leukoencephalopathy syndrome (RPLS) are reported in patients having risk factors such as malignant hypertension, eclampsia, receiving solid organ/hematopoietic stem cell transplant, and exposure to chemotherapeutic agents and immunosuppressive drugs. We experienced a very interesting case of atypical RPLS in the thalamus bilaterally accompanied by brain hemorrhage in acute lymphoblastic leukemia (ALL), and described here. A 62-year-old Japanese female was referred to our hospital with fever, general fatigue and leukocytosis in May 2011. Her white blood cell count was 139.6 10 9 /L, of which lymphoblasts constituted 96%, hemoglobin level was 8.2 g/ dL and platelet count was 15.0 10 9 /L. Leukemic lymphoblasts were peroxidase negative and their surface markers were positive for CD10, CD19, CD34 and human leukocyte antigen (HLA)-DR. Th e karyotype was 46, XY; the BCR/ABL fusion gene was not detected. Th e patient was diagnosed as having ALL and treated with cyclophosphamide, vincristine, adriamycin and prednisolone. Although leukemia cells were not present in peripheral blood at 9 days after starting chemotherapy, febrile neutropenia occurred, and antibiotic treatment was started immediately. After the administration of antibiotic and antifungal agents, erythroderma developed on her trunk, extremities and back. Stevens – Johnson syndrome (SJS) was diagnosed, and high-dose methylprednisolone was given. Hyponatremia (124 mEq/L) also occurred at this time, as an eff ect of the chemotherapeutic agents. Although the erythroderma and hyponatremia improved slowly over the next 4 days, her level of consciousness decreased gradually before falling suddenly, accompanied by high fever. Blood culture was positive for Pseudomonas aeruginosa while cerebrospinal fl uid (CSF) culture was negative. Th e patient ’ s level of consciousness improved after antibiotic treatment for sepsis; however, she lost consciousness once more, accompanied by high blood pressure (180/118 mmHg). Emergency computed tomography (CT) of the brain revealed multiple low-density areas in the thalamus, midbrain and pons bilaterally. Magnetic resonance imaging (MRI) of the brain performed 2 days after the CT scan showed multiple high signal intensity lesions with small hemorrhagic areas on T2-weighted fl uid attenuated inversion recovery imaging, T2 star-weighted imaging and diff usion-weighted imaging (Figure 1). No thrombosis of the bilateral internal vein and Galen vein was detected in brain CT and MRI. At 10 days after completion of treatment for sepsis and control of blood pressure, the patient was fully conscious. She was diagnosed with hemorrhage in atypical RPLS. MRI obtained 2 months after treatment showed no RPLS lesions

Long-term follow-up of non-syphilitic paroxysmal cold hemoglobinuria in an adult.

Dear Editor, Paroxysmal cold hemoglobinuria (PCH) is a rare autoimmune hemolytic anemia defined by the Donath–Landsteiner (DL) antibody, which binds to the P antigen on erythrocytes at lower temperatures, leading to complement-mediated hemolysis at 37 °C (biphasic hemolysis). Early experiences observed PCH as a chronic adult disease in association with syphilis. With the advent of antibiotic treatments for syphilis, current PCH is almost exclusively a transient pediatric disease following viral infection [1].We describe a non-syphilitic chronic case in adult, which remains least understood due to its extreme rarity. In early December 2012, a 29-year-old Japanese female was referred to us for a week history of discolored urine. A week-long sore throat and cough preceded this occurrence. Hemolytic anemia was diagnosed: hemoglobin, 9.5 g/dl; reticulocytes, 4.2 %; total/direct bilirubin level, 3.7/0.1 mg/dl; haptoglobin, < 10mg/dl; and lactate dehydrogenase, 1609U/l. Blood film revealed no erythrophagocytosis or agglutination. The direct antiglobulin test was positive for complement C3 but negative for IgG. The indirect antiglobulin test was negative. Serological tests for syphilis, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, and Mycoplasma pneumoniaewere negative, while those for Epstein–Barr virus were consistent with past infection. Antinuclear antibodies were negative. No monoclonal components were detected on immunoelectrophoresis. The DL test diagnosed PCH (Fig. 1a) and established the anti-P specificity (Fig. 1b). The patient was advised to avoid the cold and closely followed up on an outpatient basis. The hemoglobinuria persisted with no association with cold exposure, even in her warm office (hospital pharmacy). Consistent with her complaint, hemolysis in vitro was observed up to 25 °C (Fig. 1c). With the progression of anemia (8.0 g/dl), we initiated prednisolone (30 mg/day) on day 7 of referral. By day 10, the hemoglobinuria disappeared, and the hemoglobin level started to rise. Prednisolone was subsequently tapered, maintained at 5 mg/day to cover the next winter, and ceased at day 440. The biphasic hemolysis has persisted, albeit asymptomatic, since the initial demonstration 40-month previously and has become chronic at a titer of 8 (Fig. 1c). The thermal characteristic of this patient’s DL antibody is distinct with a thermal range of 25 °C and a titer of 256, making a contrast with syphilitic PCH (<15 °C) and nonsyphilitic acute PCH (<20 °C), and typical PCH titer (<32– 64) [1–3]. The biphasic hemolysis is the hallmark of PCH, and the presence of monophasic hemolysis could confuse the diagnosis [2, 4]. Heddle hypothesized that DL antibodies may be monophasic and biphasic in the extreme situation where the antibody demonstrates a high titer and a high thermal range [3]. Our long-term follow-up observed that the monophasic component disappeared as the thermal range and titer lowered over the clinical course, aptly supporting the hypothesis. While cases with monophasic hemolysis have been documented as unusual PCH [5, 6], this is the first to report the transition from the atypical acute phase to the chronic phase with the typical presentation. * Kohei Hagiwara hagiwara@pharma1.med.osaka-u.ac.jp