The clinical utility of serum free light chain and heavy/light chain assays in monitoring disease activity in patients with IgG myeloma after achieving a deep response.

Heavy/light chain (HLC) assay will enable us to evaluate the changes in the concentrations of iHLC and uHLC separately and to better identify whether the change observed is clonal or reactive. It would therefore aid in decision making for earlier implementation or discontinuation of treatment for patients with intact immunoglobulin multiple myeloma (MM).

Inverse correlation between serum interleukin-6 and iron levels among Japanese adults: a cross-sectional study.

BACKGROUND: Interleukin-6 (IL-6) is a multifunctional cytokine that is produced by many different cell types, and plays an important role in the regulation of inflammation, immune responses, the acute-phase response, and hematopoiesis. Previous laboratory and clinical studies have shown that IL-6 causes a significant decrease in serum iron levels. Therefore, we conducted an epidemiological study to examine the association between serum IL-6 and iron levels. METHODS: In total, 280 Japanese individuals aged 20-78 years were enrolled when they visited a clinic located in an urban area for Helicobacter pylori (H. pylori) infection tests and subsequent eradication; 65.3% were infected with H. pylori. Subjects with gastric cancer, idiopathic thrombocytopenia, or IL-6 > 10 pg/mL were excluded from the study. Serum iron and IL-6 levels were measured using the 2-nitroso-5-(N-propyl-3-sulfopropylamino) phenol method and chemiluminescence enzyme immunoassay, respectively. RESULTS: Geometric mean iron and IL-6 levels were 111.5 µg/dL and 1.77 pg/mL, respectively, for men, and 89.4 µg/dL and 1.55 pg/mL, respectively, for women. The logarithm of serum iron levels was negatively correlated with the logarithm of IL-6 levels in men (r = -0.19, p = 0.047), but not in women (r = -0.035, p = 0.65). Regression analysis, adjusted for sex, age, and H. pylori infection status, showed that the logarithm of serum iron levels was significantly associated with a decreased logarithm of IL-6 levels (ß = -0.053, p = 0.041). The odds ratio for low serum iron levels adjusted for sex, age, and H. pylori infection status was 7.88 (95% CI 1.29-48.06) in those with an IL-6 level > 4 pg/mL. CONCLUSION: Lower serum iron levels are significantly associated with higher serum IL-6 levels among Japanese adults.

Association between Helicobacter pylori infection detected by the (13) C-urea breath test and low serum ferritin levels among Japanese adults.

BACKGROUND: Helicobacter pylori infection is a major risk factor for chronic gastritis, digestive ulcers, and gastric cancer. Previous studies have shown associations between H. pylori infection and decreased iron storage. Therefore, this study aimed to examine the associations between H. pylori infection and serum iron and ferritin levels in Japan. MATERIALS AND METHODS: Overall, 268 Japanese individuals who visited a clinic located in an urban area for H. pylori infection tests and subsequent eradication were enrolled. H. pylori infection was diagnosed by a (13) C-urea breath test, with positive results defined as values ≥2.5‰. RESULTS: The overall infection rate was 65.3% (175/268). The geometric mean serum iron levels in uninfected and infected subjects were 115.7 µg/dL and 108.9 µg/dL, respectively, in men, and 83.9 and 91.8 µg/dL, respectively, in women. The geometric mean serum ferritin levels were 128.9 and 81.0 ng/mL, respectively, in men, and 25.5 and 27.0 ng/mL, respectively, in women. Regression analysis adjusted for age showed that lower geometric mean serum ferritin levels were significantly associated with H. pylori infection in men (131.8 vs 79.4 ng/mL p = .009) and in women (33.9 vs 23.4 ng/mL p = .041). The difference was greater in subjects ≥50 years old, although the interaction was not statistically significant. Helicobacter pylori infection was not significantly associated with serum iron levels. CONCLUSION: This study showed that H. pylori infection was significantly associated with altered serum ferritin levels in Japanese individuals, particularly in those aged ≥50 years.

Significant association between serum interleukin-6 and Helicobacter pylori antibody levels among H. pylori-positive Japanese adults.

BACKGROUND: Interleukin-6 (IL-6) is a multifunctional cytokine produced by many types of cells. Inflammation plays a key role in the pathogenesis of atherosclerosis that is an underlying cause of coronary heart disease (CHD). Since the 1990s, some studies have shown an association between H. pylori infection and CHD, which may be mediated by inflammation. Therefore, this study aimed to evaluate the association between serum anti-H. pylori IgG levels and serum IL-6 levels in H. pylori-infected adults. METHODS: We enrolled 158 subjects who visited a clinic located in an urban area to be tested for H. pylori infection, using the (13)C-urea breath test, and who were found to be infected and subsequently received eradication. RESULTS: The geometric mean serum IL-6 level was 1.78 pg/mL for men, 1.57 pg/mL for women, and 1.64 pg/mL overall. Logarithms of serum IL-6 levels were positively correlated with logarithms of serum H. pylori IgG levels (r = 0.24, P = 0.002). In multiple linear regression analysis adjusting for sex and age, the serum IL-6 level was still significantly associated with the IgG level in all subjects (ß = 0.18, P = 0.012). CONCLUSION: Higher H. pylori IgG levels were significantly associated with higher serum IL-6 levels among H. pylori-infected individuals.

Preventive medical services not covered by public health insurance at Daiko Medical Center in Japan, 2004-2011.

Preventive medical services not covered by public health insurance started in the Daiko Medical Center of Nagoya University in June, 2004. Those services included: (1) Helicobacter pylori (H. pylori) diagnosis and eradication treatments, for which CYP2C19 genotyping was introduced in November 2005; (2) smoking cessation support with genotype tests of CYP1A1 Ile462Val, GSTM1 present/null, GSTT1 present/null, and NQO1 Pro187Ser; (3) advice on alcohol consumption with genotype tests of ADH Arg47His and ALDH2 Glu487Lys; (4) advice on folate-associated diseases with a genotype test of MTHFR C677T; (5) advice on a tumor marker CA19-9 with genotype tests of Lewis and Secretor genes; and (6) raloxifene prescription aimed to prevent breast cancer for high-risk postmenopausal women. A total of 683 patients visited the Center until it closed in March 2011. Those given diagnoses and eradication treatments for H. pylori numbered 567, followed by 44 for smoking cessation support, 35 for advice on folate-associated diseases, 26 for advice on alcohol consumption, 8 for CA19-9, and 3 for raloxifene prescription. Around 2004, public interest in H. pylori was relatively high, but thereafter patient numbers dropped markedly. The Center closed in March 2011 due to the reduction in patient visits. Our unique trial showed that continuing to provide uninsured preventive services at a clinic was difficult in Japan without the affiliation of hospitals/clinics providing medical services covered by public health insurance.

Improvements in Helicobacter pylori eradication rates through clinical CYP2C19 genotyping.

Lansoprazole (LPZ), amoxicillin (AMPC) and clarithromycin (CAM) are commonly used drugs (LAC regimen) for Helicobacter pylori (H. pylori) eradication, but the eradication rate with this regimen was reported to be 70% to 90%. A few studies have reported that a successful eradication was associated with the CYP2C19 genotype, which influences the metabolism of proton pump inhibitors (PPI) including LPZ. This study examined the changes in the H. pylori eradication rates between the periods before and after the commencement of a routine genetic test for CYP2C19 at the Daiko Medical Center in Nagoya, Japan, in November, 2005. Subjects were patients who visited the Center during the period from June, 2004 to August, 2010. The patients were classified into three groups according to their CYP2C19 genotype: rapid metabolizers (RM) with a *1*1 genotype, intermediate metabolizers (IM) with a *1*2 or *1*3 genotype, and poor metabolizers (PM) with a *2*2, *2*3, or *3*3 genotype. Non-rapid metabolizers (IM and PM) were basically treated with a LAC regimen, while RMs were treated with a RAM reg imen(rabeprazole, AMPC, and metronidazole). The eradication rate was 80.0% (n=90) for the period without the genetic testing and 88.7% (n=124) for the period with the genetic testing (chi2=3.11, p=0.078). The age-sex adjusted odds ratio of eradication success was 2.29 (95% confidence interval, 0.99-5.28, p=0.051) for the latter period relative to the former period among those less than 70 years of age. Those results suggested that the routine genetic test which allows a choice of the RAM regimen for R M improved the eradication rate.

Outcome of allogeneic bone marrow transplantation from unrelated donors for adult Philadelphia chromosome-negative acute lymphocytic leukemia in first complete-remission.

The indication of allogeneic stem cell transplantation (allo-SCT) for Philadelphia chromosome-negative acute lymphocytic leukemia [Ph(-) ALL] from unrelated donors is not established. To assess its potency of unrelated patients in first complete-remission (CR1) transplanted from unrelated donors and the potential prognostic factors affecting the probability of survival, we retrospectively analyzed a total of 41 adult Ph(-) ALL patients in CR1 who underwent unrelated bone marrow transplantation at 6 transplantation centers of the Nagoya Blood and Marrow Transplantation Group between 1993 and 2006. The median age of the 41 patients was 28 years (range, 18-51 years). HLA was matched in 33 transplants, with mismatches in 8 (HLA-A allele mismatch:1, HLA-DR serological mismatch: 2, HLA-DRB1 mismatch: 5). Leukemia-free survival (LFS) at 3 and 6 years from allo-SCT was 60.3 and 47.7%, respectively. LFS at 5 years was 62.1% for those transplanted from HLA-matched donors. LFS was significantly lower with HLA-mismatched donors due to higher transplantation-related mortality. Relapse was observed in 3 patients. Our study suggested that unrelated allo-SCT could improve LFS of patients with a potential graft-versus-leukemia effect. Unrelated allo-SCT for Ph(-) ALL patients in CR1 could be more beneficial by reducing TRM, such as selecting a HLA-matched donor.

Insomnia and depression during protective isolation in patients with hematological disorders.

OBJECTIVE: Patients treated in a protective isolation unit (PIU) often experience loneliness and increased feelings of seclusion, leading to elevated levels of distress, but the relationship between psychiatric distress and environmental factors is unclear. Therefore, we retrospectively compared the impact of environmental factors on insomnia and depression between patients in the PIU and those in a standard ward (SW). METHODS: Subjects were 246 patients with hematological disorders hospitalized in Meitetsu Hospital between April 1, 2007 and July 31, 2008 (62 PIU patients and 184 SW patients). We assessed insomnia and depression, as well as concomitant corticosteroid (CS) administration, stem cell transplantation (SCT) therapy, and complications resulting from these therapies. Details of medical history and patient information were retrospectively extracted from patients' charts, medical records and the electronic laboratory database at the hospital. RESULTS: Patients in the PIU tended to be complicated by insomnia or depression more than those in the SW, but the stay in the PIU was not significantly related to the incidence of insomnia or depression. Our findings indicated that use of CS was a risk factor for insomnia. The prevalence of depression was higher in patients with therapeutic complications. All PIU patients with depression also received SCT. CONCLUSION: Our findings suggest an increased potential for insomnia after administration of CS and depression in cases with complications after SCT, which is important to keep in mind for patients with hematological disorders.

Primary hepatic follicular lymphoma : a case report and discussion of chemotherapy and favorable outcomes.

This report concerns a rare case of follicular lymphoma with features suggestive of primary hepatic lymphoma. At the disease onset, multiple nodular lesions in the liver and small para-aortic nodes were detected by abdominal magnetic resonance imaging without generalized lymphadenopathy. After careful observation for three months, lymphadenopathy was observed in the right occipital, para-aortic, and bilateral inguinal regions. The patient was treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) and achieved complete remission for more than 2 years. To the best of our knowledge, this is the ninth report of primary hepatic follicular lymphoma. Insufficient cases have been reported to determine the long-term outcome and clinical characteristics of primary hepatic follicular lymphoma. However, it seems that patients with primary hepatic follicular lymphoma that are treated with appropriate chemotherapy with or without surgical resection have favorable outcomes.

Age-related EBV-associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: a study of 96 patients.

PURPOSE: We have recently reported EBV+ B-cell lymphoproliferative disorders (LPD) occurring predominantly in elderly patients, which shared features of EBV+ B-cell neoplasms arising in the immunologically deteriorated patients despite no predisposing immunodeficiency and were named as senile or age-related EBV+ B-cell LPDs. To further characterize this disease, age-related EBV+ B-cell LPDs were compared with EBV-negative diffuse large B-cell lymphomas (DLBCL). EXPERIMENTAL DESIGN: Among 1,792 large B-cell LPD cases, 96 EBV+ cases with available clinical data set were enrolled for the present study. For the control group, 107 patients aged over 40 years with EBV-negative DLBCL were selected. We compared clinicopathologic data between two groups and determined prognostic factors by univariate and multivariate analysis. RESULTS: Patients with age-related EBV+ B-cell LPDs showed a higher age distribution and aggressive clinical features or parameters than EBV-negative DLBCLs: 44% with performance status >1, 58% with serum lactate dehydrogenase level higher than normal, 49% with B symptoms, and higher involvement of skin and lung. Overall survival was thus significantly inferior in age-related EBV+ group than in DLBCLs. Univariate and multivariate analyses further identified two factors, B symptoms and age older than 70 years, independently predictive for survival. A prognostic model using these two variables well defined three risk groups: low risk (no adverse factors), intermediate risk (one factor), and high risk (two factors). CONCLUSIONS: These findings suggest that age-related EBV+ B-cell LPDs constitute a distinct group, and innovative therapeutic strategies such as EBV-targeted T-cell therapy should be developed for this uncommon disease.

Phase I and pharmacokinetic study of edotecarin, a novel topoisomerase I inhibitor, administered once every 3 weeks in patients with solid tumors.

PURPOSE: Edotecarin (J-107088) is a potent indolocarbazole topoisomerase I inhibitor which is structurally distinct from the camptothecins. This study aimed to determine the maximum tolerated dose (MTD), the recommended dose for future Phase II studies and the safety, pharmacokinetic profile, and preliminary antitumor activity of edotecarin in a population of patients with advanced solid tumors. EXPERIMENTAL DESIGN: Edotecarin was administered as a single dose by IV infusion over 2 h every 21 days (with 1 week permitted for recovery from toxicities, if needed) in patients with advanced solid tumors. Doses ranged from 8 to 15 mg/m(2). Pharmacokinetic assessments were performed during and after the first administration. RESULTS: Twenty-four patients received 61 cycles of therapy. Dose-limiting toxicities (infection, febrile neutropenia, constipation, ileus, and prolonged grade 4 granulocytopenia) were observed in 3 of 5 evaluable patients at the 15 mg/m(2) dose, defining the MTD. The most commonly reported non-hematologic toxicities were anorexia, nausea, malaise, and constipation. Diarrhea was neither frequent nor severe. Neutropenia was the most common hematologic toxicity (grade 3-4 in 21/23 patients during cycle 1). Plasma concentrations of edotecarin rose rapidly following the start of the 2-hour infusion, reaching C (max) values of 103+/-17 ng/ml at the 13 mg/m(2) dose, and decreased steeply after the end of the infusion. Plasma concentrations declined to approximately 1-2 ng/ml at 26 h post start of infusion, the last PK sampling time point. The mean apparent plasma half-life of the drug was 20 h, which should be considered a preliminary estimate until results from studies with a longer duration of plasma sampling are available. A mean of 1.4-3.6% of the dose was recovered as unchanged drug in the urine over 48 h. Unconfirmed tumor regression > or =50% was observed in 2 patients, 1 with metastatic gastric carcinoma and 1 with esophageal cancer. CONCLUSIONS: The MTD of edotecarin administered IV over 2 h every 21 days was 15 mg/m(2). The recommended dose for Phase II studies with a 3-week schedule (with 1 week permitted for recovery from toxicities, if needed) is 13 mg/m(2). The observed safety profile and preliminary evidence of antitumor activity warrant further investigation of this drug in solid tumors.

CD56/NCAM-positive Langerhans cell sarcoma: a clinicopathologic study of 4 cases.

This report concerns the clinicopathologic features of 4 patients with CD56/neural cell adhesion molecule (NCAM)-positive Langerhans cell sarcoma (LCS). Three of the patients were elderly, between 59 and 62 years of age at presentation, and the other was 35 years old. The presenting symptoms included fever, bone pain, and weakness. The patients shared some clinical findings, such as multiorgan involvement of lymph nodes, skin, lung, bone marrow, and spleen. LCS carries a poor prognosis, and 3 of the patients died of the disease within several years of presentation despite multiagent chemotherapy and radiotherapy. Of special interest is that all of the cases showed CD56 expression on the tumor cells in addition to expression of CD1a, S100beta, and langerin, the presence of which suggests derivation from Langerhans cells. For control, CD56 was also examined in 8 cases of Langerhans cell histiocytosis (LCH), a single-system unifocal or multifocal disease, and the results of staining of the tumor cells were negative. Our findings indicated that CD56 may be a clinically relevant biologic marker for predicting an intractable course of Langerhans cell neoplasms, although it is often difficult to draw a definite morphologically-based distinction between LCS and LCH.

A study of transdermal fentanyl in cancer pain at Aichi-Cancer Center.

In Japan, transdermal fentanyl (Durotep Patch) was launched in March 2002, and it was regarded as making opioid rotation possible. When changing from morphine to transdermal fentanyl, the efficacy ratio of 1:150 is used in Japan as well as in many other countries. However, the ratio of 1:100 is used in Germany. As a result, a dose increase in transdermal fentanyl is often required to control pain. We studied transdermal fentanyl use in the Aichi Cancer Center (ACC) to investigate the actual conversion ratio and appropriate switching by following up 144 patients (81 men, 63 women) who had received transdermal fentanyl in the ACC from March 19, 2002, to April 30, 2003. Transdermal fentanyl improved pain control in patients who had difficulty in tolerating oral medication or in continuing morphine because of side effects. Regression analysis indicated that the efficacy ratio of oral morphine to transdermal fentanyl was 1:78. As the fentanyl dosage was excessive even in some patients who followed the recommended morphine/fentanyl conversion of 150:1, it is dangerous to use the conversion ratio of 78:1 at first. Morphine side effects were reduced in some patients who changed to transdermal fentanyl, but there was no reduction in those who needed high-dose morphine for rescue analgesia. Therefore it is safe and effective to use low-dose transdermal fentanyl in the beginning and to control pain promptly using rescue morphine based on the present recommended dosage. For opioid rotation, quick-acting opioids other than morphine are expected to be launched in Japan.

Phase I and pharmacokinetic study of KRN5500, a spicamycin derivative, for patients with advanced solid tumors.

BACKGROUND: KRN5500, a novel spicamycin derivative, shows an inhibitory effect on protein synthesis. This phase I study was aimed at investigating the toxicity, maximum tolerated dose (MTD) and pharmacokinetics of this compound. PATIENTS AND METHODS: Patients with solid tumors not amenable to standard forms of treatment were eligible. KRN5500 was administered as a 2 h intravenous infusion every 4 weeks at doses of 3, 6, 10, 15 and 21 mg/m(2). Pharmacokinetic evaluation was performed at the first cycle. RESULTS: Eighteen patients with advanced solid tumors were enrolled. A total of 26 cycles of KRN5500 were administered. The major toxicities were nausea, vomiting, diarrhea, fatigue and a mild reversible prolongation of prothrombin time. Grade 4 pulmonary toxicity (interstitial pneumonitis) was observed in one patient at a dose level of 15 mg/m(2). Severe fatigue was observed in one patient at a dose level of 21 mg/m(2) and the duration of fatigue tended to increase with the dose of KRN5500. Nausea and vomiting were frequently observed and became prolonged with increasing dose of KRN5500. These toxicity profiles were identified as unacceptable and further dose escalation above 21 mg/m(2) was withheld. The MTD was therefore determined as 21 mg/m(2). The peak plasma concentration and the area under the concentration-time curve of KRN5500 increased proportionally to the dose, suggesting linear pharmacokinetics. No objective antitumor response was observed. CONCLUSION: KRN5500, a structurally novel protein synthesis inhibitor, warrants further investigation to overcome these toxicity profiles and improve its efficacy.

Senile EBV+ B-cell lymphoproliferative disorders: a clinicopathologic study of 22 patients.

Twenty-two Epstein-Barr virus-associated B-cell lymphoproliferative disorders (LPDs) without predisposing immunodeficiencies were evaluated clinically and pathologically. All patients were Japanese and negative for anti-human immunodeficiency virus antibody. They were all more than 60 years old with a median age of 75.5 years. Eighteen (82%) patients showed extranodal involvement. Biopsied specimens contained variable numbers of centroblasts, immunoblasts, and Reed-Sternberg-like giant cells often with necrosis and an angiocentric pattern. The 13 cases showing polymorphous composition and inflammatory background were categorized as polymorphic LPD subtype. The other nine cases contained diffuse proliferative lesions of large lymphoid cells and were categorized as large cell lymphoma subtype. Tumor cells expressed CD20 and/or CD79a, and in situ hybridization showed them to be associated with Epstein-Barr virus. LMP1 was detected in all cases and EBNA2 in seven. Eighteen patients initially received combination chemotherapy, and 12 achieved complete remission. However, six patients were refractory to chemotherapy and four patients with complete remission later relapsed. Eight of the 18 patients who received chemotherapy showed an aggressive disease course within a year after the diagnosis. There was a significant difference in prognosis between the group with polymorphic LPDs and the one with large cell lymphomas (p = 0.003). Although the disease profile of the 22 cases was analogous to that of immunodeficiency-associated B-cell LPDs, none of the patients showed evidence of underlying immunodeficiency-related diseases. These findings suggest that Epstein-Barr virus-associated LPD without immunodeficiency mainly occurs in elderly patients. Further investigations are needed to clarify the pathogenesis of this disease and to determine the optimal treatment strategy.