Clinicopathologic characteristics of 342 patients with multicentric Castleman disease in Japan.

Objectives: To assess the clinicopathologic features of Multicentric Castleman disease (MCD) patients in Japan.Methods: We assessed baseline data for 342 Japanese MCD patients with a biopsy-proven diagnosis, enrolled in a prospective, observational study for tocilizumab treatment.Results: Of 342 patients, 86.0% had plasma-cell type. None had a family history of MCD. Median disease duration of MCD was 3.7 years. Mean body weight and body mass index tended to be lower than those in the general Japanese population. The most common clinical presentations besides lymphadenopathy included fatigue (61.7%), pulmonary involvement (42.7%), and splenomegaly (41.8%). Secondary amyloidosis was reported in 34 patients (9.9%). Laboratory abnormalities included decreased hemoglobin and albumin, and increased acute-phase proteins, serum immunoglobulins, and interleukin-6 (IL-6). IL-6 levels among the MCD patients tested in this study were correlated with levels of albumin, hemoglobin, triglyceride, total cholesterol, C-reactive protein, fibrinogen and immunoglobulin G (Spearman's correlation coefficient, |r| = 0.28-0.59).Conclusion: The clinical features and laboratory abnormalities are similar to those previously reported in other countries, besides higher rates of pulmonary involvement, secondary amyloidosis, and ECG abnormalities. Our results imply that IL-6 is involved in MCD pathogenesis. These findings would be informative for diagnosis and appropriate treatment for MCD.

Tentative diagnostic criteria and disease severity classification for Castleman disease: A report of the research group on Castleman disease in Japan.

OBJECTIVES: To determine the tentative diagnostic criteria and disease severity classification for Castleman disease (CD) and describe the clinical and pathologic features among human herpesvirus 8 (HHV-8) negative idiopathic multicentric CD (iMCD) in the Japanese population. METHODS: We established the working groups for the research of CD in Japan and had meetings to discuss and define the tentative diagnostic criteria and disease severity classification for CD. We subsequently analyzed 142 patients classified into iMCD by using the nationwide Japanese patient registry. RESULTS: We proposed the preliminary diagnostic criteria and disease severity classification for CD based on our discussion. In addition, we made a proposal for the disease activity score. We identified clinical and pathological features of patients with iMCD diagnosed by these diagnostic criteria. In the disease severity classification, 37, 33 and 30% patients were categorized into mild, moderate and severe diseases, respectively. CONCLUSION: This is the first proposal for diagnosis and classification of CD by the Japanese group. Further studies are required to validate whether they can distinguish CD from other inflammatory diseases and to determine their sensitivity and specificity.

Risk factors for cytarabine-induced cutaneous toxicity in patients with haematological malignancies.

BACKGROUND: The risk factors for cytarabine (Ara-C)-induced cutaneous toxicity are unclear. METHODS: We retrospectively reviewed the medical charts of patients with haematopoietic malignancies treated with Ara-C and examined risk factors for Ara-C-induced cutaneous toxicity. RESULTS: We reviewed 114 patients (76 men, 38 women) and found that 47 patients (41.2%) experienced cutaneous toxicity. In 93 patients (81.6%) with non-Hodgkin's lymphoma (NHL) and acute myeloid leukaemia (AML), the toxicity was significantly associated with the cancer type [AML/NHL: odds ratio (OR) = 4.84; 95% confidence interval (CI) = 1.99-11.81; p = 0.001], age (<50/≥50 years: OR = 2.54; 95% CI = 1.08-5.95; p = 0.032) and concurrent steroid administration (yes/no: OR = 0.22; 95% CI = 0.09-0.56; p = 0.001). AML was the only significant association (OR = 3.83; 95% CI = 1.21-12.06; p = 0.022) in the multivariate logistic analysis. CONCLUSION: AML, age <50 years and no steroid use are considered to be risk factors for Ara-C-induced cutaneous toxicity.

[Effect of the administration of zoledronic acid on life expectancy in patients with multiple myeloma with or without renal impairment].

Zoledronic acid(ZA)is believed to exert anticancer effects in patients with multiple myeloma(MM). For patients with impaired renal function, its dosage should be determined according to creatinine clearance(Ccr). However, there is no reported difference in life expectancy improvement between those with and without renal impairment. Therefore, we conducted a retrospective study to investigate this clinical question. Seventy-eight MM patients receiving ZA injections were selected and divided into 2 groups: (1)normal group(n=39), baseline Ccr≥60mL/min, and(2)impaired group(n=39), baseline Ccr<60mL/min. Patients in the normal group received a significantly higher initial dose(p<0.001), were of a younger age(p<0.001), had lower b2-microglobulin(b2-M)levels(p<0.001), and had higher rates of prior hematopoietic stem cell transplantation(p<0.001)than those in the impaired group. We then compared the survival rate between 31 patients in the normal group and 27 patients in the impaired group whose treatment outcome data were available and found no significant difference(p=0.251). Therefore, our results suggest that the survival rate on ZA administration may not differ between MM patients with and without renal impairment.

[The development history and future perspective of molecularly targeted therapy].

The origin of molecularly targeted drugs dates back to 'magic bullet' theory proposed by Paul Ehrlich. The success of Abl tyrosine kinase inhibitor, imatinib for the treatment of chronic myeloid leukemia realized that small molecules inhibiting ATP binding can become specific inhibitors for the relevant kinases. Subsequently, a number of kinase inhibitors which targets various signal transduction molecules, are in the clinical field or under development. The clinical success of antibody therapeutics has been achieved by the genetic engineering which makes human-mouse chimeric, humanized or human antibody. To augment the therapeutic effects of antibody, radioisotope-conjugate antibody and antibody-drug conjugate have come to the clinical field. In the near future, we have to develop the combination therapy of molecularly targeted drugs and also inhibitors for epigenetic and transcriptional regulators.

Managing hepatitis B virus carriers with systemic chemotherapy or biologic therapy in the outpatient clinic.

AIM: The number of outpatients receiving systemic chemotherapy in Japan has recently increased. We retrospectively examined whether hepatitis B virus (HBV) carriers were safely treated and managed with systemic chemotherapy or biologic agents as outpatients at our oncology center. METHODS: A total of 40 115 consecutive infusion chemotherapy or biologic therapies were administrated to 2754 outpatients in the Chemotherapy and Oncology Center at Osaka University Hospital from December 2003 to March 2011. We first studied the prevalence of outpatients with hepatitis B surface antigen (HBsAg), and then retrospectively evaluated a database to determine the frequencies of testing for other HBV-related markers and the incidence of developing hepatitis or HBV reactivation in patients positive for HBsAg. As a control for comparison, we also examined these same factors in patients with hepatitis C virus antibody (anti-HCV). RESULTS: The majority of physicians at our hospital screened for HBsAg (95%) and anti-HCV (94%) prior to administrating chemotherapy. Of the 2754 outpatients, 46 (1.7%) were positive for HBsAg and 90 (3.3%) were positive for anti-HCV. Fifteen patients that were HBsAg positive were treated with lamivudine or entecavir prior to chemotherapy. None of the patients with HBsAg taking a prophylactic antiviral developed hepatitis, and only one breast cancer patient without prophylactic antiviral treatment (1/31 [3.2%]) developed hepatitis due to HBV reactivation. CONCLUSION: HBV reactivation occurred in outpatients without prophylactic antiviral treatment, but the incidence was relatively low.

High numbers of programmed cell death-1-positive tumor infiltrating lymphocytes correlate with early onset of post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication of transplantation. In addition to reactivation of Epstein-Barr virus in immunocompromised patients, impaired tumor immunity is suggested to be a risk factor for PTLD. However, it remains unclear whether immune suppressive tumor-infiltrating lymphocytes (TILs) correlate with the occurrence or prognosis of PTLD. We analyzed TILs in 26 patients with PTLD to elucidate the clinicopathological significance of the expression of PD-1 and FoxP3, which are associated with exhausted T-cells and regulatory T-cells (Tregs), respectively. Numbers of PD-1+ TILs in the PTLD specimens were significantly higher in patients who developed PTLD early after transplantation (P = 0.0040), while numbers of FoxP3+ TILs were not (P = 0.184). There was no difference in overall response rate regardless of the expression of PD-1 or FoxP3. FoxP3high patients tended to have a shorter time to progression compared with FoxP3low patients, especially in the case of FoxP3high patients with diffuse large B-cell lymphoma-subtype PTLD (P = 0.011), while PD-1high patients did not. These results suggest that T-cell exhaustion may be mainly associated with PTLD development, while immune suppression by Tregs may be dominant in enhanced progression of PTLD following disease occurrence.

Intravascular lymphomatosis initially suspected from uterine cytology: a case report.

BACKGROUND: Because recognizable lesions are often absent, selection of biopsy sites for diagnosis of intravascular large B-cell lymphoma (IVL) is frequently problematic. CASE: A 59-year-old woman was admitted with fever and general fatigue. Combined physical and roentgenographic examinations revealed neither lymphadenopathy, hepatosplenomegaly nor mass lesions in other organs. Serum lactate dehydrogenase level was 1412 IU/L. There were no genital symptoms, but uterine cytologic examination revealed large cells distributed in a noncohesive pattern. These cells had a large, irregularly shaped nucleus in which several nucleoli were discernible and showed positive immunoreactivity for leukocyte common antigen. Three months after admission, neurologic symptoms appeared, and magnetic resonance imaging revealed multiple nodular lesions in the brain. Biopsy specimens from the brain lesion showed the proliferation of large lymphoid cells filling the lumina of small vessels and Virchow-Robin's space. Immunohistochemistry revealed that the tumor cells were positive for CD20 and CD79a but negative for CD3, indicative of IVL. CONCLUSION: Uterine cytologic and/or histologic examinations could be the choice for diagnosis of IVL, even when genital symptoms are absent.

Roles for deregulated receptor tyrosine kinases and their downstream signaling molecules in hematologic malignancies.

Growth, survival and differentiation of hematopoietic cells are regulated by the interactions between hematopoietic growth factors and their receptors. The defect in these interactions results in a failure of hematopoiesis, while aberrantly elevated and/or sustained activation of these signals cause hematologic malignancies. Among them, constitutively activating mutations of the receptor tyrosine kinases (RTKs), such as c-Kit, platelet-derived growth factor receptor (PDGFR) and FLT3, are often involved in the pathogenesis of various types of hematologic malignancies. Constitutive activation of RTKs is provoked by several mechanisms including chromosomal translocations and various mutations involving their regulatory regions. Chromosomal translocations commonly generate chimeric proteins consisting of the cytoplasmic domain of RTKs and the dimerization or multimerization motif of the fusion partner, resulting in the constitutive dimerization of RTKs. On the other hand, missense, insertion or deletion mutations in the regulatory regions, such as juxtamembrane domain, activation loop, and extracellular domain, also cause constitutive activation of RTKs mainly by preventing the auto-inhibitory regulation. Oncogenic RTKs activate downstream signaling molecules such as Ras/MAPK, PI3-K/Akt/mTOR, and STATs as well as ligand-activated wild type RTKs. However, their signals are quantitatively and qualitatively different from wild type RTKs. Based on these findings, several agents that target oncogenic RTKs or their downstream molecules have been developed: imatinib and FLT3 inhibitors for RTKs themselves, farnesyltransferase inhibitors, mTOR inhibitors and MEK inhibitors for the downstream signaling molecules. As promising results have been obtained in several clinical trials using these agents, the establishment of these molecular targeted agents is expected.

[Trial of "Huber Plus" in outpatients with chemotherapy by blood port system].

We evaluated the advantages and disadvantages of Huber Plus through three outpatients treated with central venous (CV) port chemotherapy (FOLFOX). One of the three outpatients first received chemotherapy with safety huber (Huber Plus) in this study, and the huber needle was changed from non-safety to a safety huber (Huber Plus) in two of the three outpatients. All three outpatients were taught about needle removal methods and port care. In patients? education, 1) we used a skin model and training CV port, and 2) dressing materials were used as film dressing plus three-point fixation by Fixomull stretch. As a result, the safety system assured zero incidents. Moreover, the evaluation revealed that operability and pain of Huber Plus were not clinical problems. We suggest that Huber Plus is applicable in outpatient chemotherapy and that our care plan with patients? education might become a standard treatment.

[Our experience using "Huber Plus" needles in our infusion center].

We conducted a pilot trial to compare the operability and safety of two huber needles in the infusion center. In the present study, we used huber needles without the safety cover and one huber needle with the safety cover (Huber Plus(R)). Both huber needles were used nine times. The successful puncture rate of the first time puncture and the incidence of needle accidents with both huber needles were 100% and 0%, respectively. The evaluation of pain and uneasiness by VAS (Visual Analogue scale)revealed the superiority of the safety needle over the than non-safety needle(pain: 3.8 vs 2.6, uneasiness: 3.7 vs 0.5). To our knowledge, this is the first report of the safety of the huber needle in Japan. This system may be recommended in Japan to avoid needle stick injuries, patient pain and uneasiness.

A New Approach for Determining Short-Term, Objective Prognostic Predictive Methods for Terminal Cancer Patients Based on the Change Point of Laboratory Test Values.

BACKGROUND: In terminal phase cancer, predicting a prognosis precisely plays an important role for patients and their families to live meaningful lives. However, there are no established short-term, objective prognostic predictive methods. OBJECTIVE: To develop simple, short-term, objective prognostic predictive methods through detecting a change point for laboratory test values. DESIGN: A retrospective chart review. SETTING/SUBJECTS: Subjects were cancer patients aged ≥16 years and discharged dead from Osaka University Hospital in 2008. MEASUREMENTS: Using different laboratory test values, new prognostic predictive methods were determined based on either six laboratory test values (white blood cell [WBC], platelet [PLT], C-reactive protein, blood urea nitrogen [BUN], aspartate aminotransferase [AST], and lactase dehydrogenase [LDH]): the WPCBAL score, or five test values (WBC, PLT, BUN, AST, and LDH): the WPBAL score. Their utility, including sensitivity and specificity, was compared with that of Glasgow prognostic scores (GPSs). RESULTS: In total, 121 cancer patients were enrolled. WPCBAL and WPBAL scores showed higher sensitivity (0.88 and 0.91 vs. 0.68), specificity (0.79 and 0.70 vs. 0.53), negative predictive value (0.98 and 0.97 vs. 0.76), and a much larger relative risk (16.5 and 14.2 vs. 1.78) as prognostic predictors within two weeks of death than GPS as a prognostic predictor within three weeks of death. CONCLUSION: This is the first study that suggests that the objective prognostic predictive methods, through detecting the change point of laboratory test values, are useful for predicting short-term prognosis. The WPCBAL score and WPBAL score could objectively predict the remaining lifetime within two weeks of mortality.

[Incident surveillance in outpatients treated with hepatic arterial infusion (HAI) chemotherapy with infusion pump].

PURPOSE: An incident situation of hepatic arterial infusion (HAI) chemotherapy was investigated, and the improvement methods were evaluated. METHODS: As a result of surveillance, all incidents were observed in patients during five day continuous HAI infusion conditions: 1) Reverse-flow hemorrhage occurred at home by disconnection of the catheter; and 2) hemorrhage by natural withdrawal of the huber needle, were diagnosed. For 1) we further taped the catheter connection area by Tegaderm and changed the dressing material from SILKYPORE DRESSING (10 x 13 cm and 4 x 6.5 cm in absorption part) plus two-person fixation by Fixomull stretch to IV3000 (9 x 12 cm non-absorption part) plus three-person fixation by Fixomull stretch. Moreover, we changed the needle type (subcutaneous adiposus thickness) from 22 G x 3/4 inch to 20 G x 1 inch. RESULTS AND CONCLUSIONS: The incidents were not observed in 72 patients treated with HAI after improvement. We suggest that prevention of hemorrhage by further taping the catheter connection and improved stability of the needle by dressing proved effective. In conclusion, HAI incident surveillance may well be an important way to care for outpatients treated with HAI chemotherapy, and we thus intend to continue the HAI incident surveillance to improve the nursing care.

[Present situation and problems of the ordering system type infusion center].

We examined four problems of the ordering system type infusion center. In this system,regimen is made by chief physician and cared by the staff in the infusion center. 1) In securing of the staff, an upbringing of doctors and IV nurses are important. 2) An evidence-based regimen is necessary in order to minimize the differences of regimen made by each doctor. 3) A facility expansion might reduce an incident risk. 4) As the condition of patient suddenly changes,the chief physician of the patient should be contacted. We suggest that it is particularly important to make these problems clarified and solved by the team within the institution.

Roles of tyrosine residues 845, 892 and 922 in constitutive activation of murine FLT3 kinase domain mutant.

FLT3 tyrosine kinase domain (TKD) mutations are detected in approximately 7% of acute myeloid leukemia patients, and suggested to correlate with poor prognosis and confer resistance to FLT3 inhibitors. To explore activation mechanism of FLT3 TKD mutation, we analysed critical tyrosine residues for the constitutive activation and downstream signaling of the mutant by generating a series of single Tyr --> Phe substitution mutant of all 22 cytoplasmic tyrosine residues of murine FLT3 TKD-mutant (mFLT3Asp838Val). Tyr845Phe, Tyr892Phe and Tyr922Phe substitutions suppressed the phosphorylation of mFLT3Asp838Val itself, the activation of Erk1/2, STAT3 and STAT5, and the factor-independent cell proliferation and survival. In contrast, these three Tyr --> Phe mutations partially suppressed but maintained the ligand-dependent activation and anti-apoptotic activity of wild-type FLT3, suggesting that these tyrosine residues were more critical for the constitutive activation and signaling of mFLT3Asp838Val. These three Tyr --> Phe mutations also inhibited the constitutive activation of other FLT3 mutants bearing internal tandem duplication, Asp838Tyr or Ile839del. The suppression of mFLT3Asp838Val activation and signaling by these substitutions was partially recovered by shifting the culture temperature from 37 to 33 degrees C, or by the introduction of Cdc37 and Hsp90. Taken together, Tyr845, Tyr892 and Tyr922 are the critical residues in mFLT3Asp838Val activation, possibly through stabilizing the active conformation of mFLT3Asp838Val.

Endolymphatic hydrops as a cause of audio-vestibular manifestations in relapsing polychondritis.

Relapsing polychondritis (RP) is characterized by inflammation and subsequent degeneration of cartilage. We report a 61-year-old woman who had RP with audio-vestibular manifestations. She was also diagnosed as having a myelofibrosis with myeloid metaplasia (MMM). Bilateral endolymphatic hydrops (EH) was confirmed by dominant -SP/AP of the electrocochleogram (ECochG). When thalidomide and prednisolone were prescribed for the treatment of MMM, symptoms of RP -- including the inner ear dysfunction -- were ameliorated. Isosorbide, one of the osmotic diuretics commonly used for the treatment of Meniere's disease (MD) in Japan, was also effective in keeping her free from inner ear dysfunction. This is the first report to confirm the existence of EH in a patient with RP with audio-vestibular manifestations. We suppose that an immunological imbalance due to MMM, in conjunction with a specific immunogenetic background, may have played a role in the pathogenesis of RP and the formation of EH in this patient.

Quantitative polymerase chain reaction analysis with allele-specific oligonucleotide primers for individual IgH VDJ regions to evaluate tumor burden in myeloma patients.

Quantitative polymerase chain reaction (PCR) with patient-specific, allele-specific oligonucleotide (ASO) primers for individual immunoglobulin H VDJ region (ASO-PCR) amplification was performed using several sources of clinical material, including mRNA from peripheral blood cells (PBMNCs), whole bone marrow cells (BMMNCs), and the CD20+ CD38- B-cell population in bone marrow, as well as cell-free DNA from the sera of patients with multiple myeloma (MM). We designed the ASO primers and produced sufficient PCR fragments to evaluate tumor burden in 20 of 30 bone marrow samples at diagnosis. Polymerase chain reaction amplification efficiency depended on primer sequences because the production of ASO-PCR fragments did not correlate with serum M-protein levels. However, the ASO-PCR levels in BMMNCs showed statistically significant correlations with those in PBMNCs and CD20+ CD38- B-cells. The good association between the BMMNC and PBMNC data indicated that PBMNCs could be a suitable source for monitoring minimal residual disease (MRD). In the case of cell-free DNA, ASO-PCR levels showed a unique pattern and remained high even after treatment. Because the sequence information for each ASO-PCR product was identical to the original, the cell-free DNA might also be useful for evaluating MRD. Moreover, the ASO-PCR products were clearly detected in 17 of 22 mRNA samples from CD20+ CD38- populations, suggesting that MM clones might exist in relatively earlier stages of B cells than in plasma cells. Thus, ASO-PCR analysis using various clinical materials is useful for detecting MRD in MM patients as well as for clarifying MM pathogenesis.

Footwear exchange has no influence on the incidence of febrile neutropenia in patients undergoing chemotherapy for hematologic malignancies.

OBJECTIVE: To determine whether footwear exchange affects the incidence of febrile neutropenia among patients undergoing chemotherapy for hematologic malignancies. DESIGN: Open trial with historical comparison. SETTING: The 12-bed high-efficiency particulate air-filtered hematology unit at Osaka University Hospital, Suita, Japan. PATIENTS: Those with hematologic malignancies who underwent chemotherapy from January 1997 through January 2003. Footwear exchange was discontinued in January 2000. METHODS: The surveillance system was based on the National Nosocomial Infections Surveillance System of the Centers for Disease Control and Prevention. Rates of febrile neutropenia were calculated for neutropenic patient-days (ie, days with neutropenia < 500/microL). RESULTS: From January 1997 through December 1999 and from February 2000 through January 2003, 58 and 54 patients endured 237 and 184 neutropenic periods following chemotherapy, and their total neutropenic days were 3,123 and 2,503, respectively. They showed episodes of febrile neutropenia 89 and 68 times, respectively. Infection rates were 28.5 and 27.2 per 1,000 neutropenic patient-days (P = .83), respectively. CONCLUSION: The incidence of febrile neutropenia was not affected by footwear exchange. In hematology units, changing shoes does not appear to affect the rate of infections during neutropenic periods.

Constitutive activation of c-kit by the juxtamembrane but not the catalytic domain mutations is inhibited selectively by tyrosine kinase inhibitors STI571 and AG1296.

The c-kit receptor tyrosine kinase (KIT) is constitutively activated by 2 types of naturally occurring mutations, the Val559-->Gly (G559) mutation in the juxtamembrane domain and the Asp814-->Val (V814) mutation in the catalytic domain. We evaluated the effects of the tyrosine kinase inhibitors STI571 and AG1296 on BaF3 cells expressing wild-type KIT (KIT(WT)) or activating mutants of KIT (KIT(G559) and KIT(V814)) in the presence or absence of the KIT ligand, stem cell factor (SCF). Both STI571 and AG1296 inhibited SCF-dependent activation of KIT(WT) and SCF-independent activation of KIT(G559) more efficiently, whereas SCF-independent activation of KIT(V814) was scarcely affected. Furthermore, both inhibitors inhibited SCF-dependent growth of BaF3-KIT(WT) cells and, with higher potencies, SCF-independent growth of BaF3-KIT(G559) cells through the induction of apoptosis. In contrast, the inhibitors had little or no effect on SCF-independent growth of BaF3-KIT(V814) cells or on IL-3-dependent growth of BaF3-Mock cells. These results suggested that both inhibitors may be effective therapeutic agents for oncogenic KIT with the juxtamembrane domain mutation, but not with the catalytic domain mutation, and that the activation mechanism of the catalytic domain mutant KIT is complex and entirely different from that of the wild-type KIT or the juxtamembrane domain mutant KIT.