Hiromi Omura

Incidence of hepatitis virus infection and severe liver dysfunction in patients receiving chemotherapy for hematologic malignancies

Abstract: Hepatitis virus infection through virus reactivation has a high risk of mortality in patients with hematological malignancies receiving chemotherapy. We examined the incidence of both hepatitis B virus (HBV) and hepatitis C virus (HCV) infection and severe liver dysfunction (alanine aminotransferase >ten times the normal upper limit and total bilirubin >5 mg/dl) during chemotherapy in 268 patients with hematological malignancies. Eight patients (3.0%) were infected with HBV and 22 patients (8.2%) were infected with HCV. One patient (0.4%) was infected with both HBV and HCV. HBV‐ or HCV‐infected patients showed severe liver dysfunction at a significantly higher incidence than non‐infected patients (11/31 (35.5%) vs. 0/237 (0%), p<0.0001). Furthermore, the incidence of severe liver dysfunction in HBV‐infected patients was significantly higher than in HCV‐infected patients (6/8 (75.0%) vs. 4/22 (18.2%), p<0.01). Three of eight HBV‐infected patients were initially negative for hepatitis B surface antigen (HBsAg) by latex agglutination and became positive for HBsAg during chemotherapy. Furthermore, all three patients developed severe liver dysfunction and two developed fatal fulminant hepatitis. From an examination of the original stock of serum samples before chemotherapy, two patients were found to be positive for HBV‐DNA by polymerase chain reaction (PCR). Although post‐transfusion HBV infection was suspected in the one remaining patient, the cause of HBV infection could not be clarified due to the impossibility of examination in blood donors. Since HBV‐infected patients develop severe liver dysfunction at a higher incidence than either patients not infected with virus or HCV‐infected patients before chemotherapy for hematological malignancies, it is recommended that HBV‐DNA should be tested by PCR to detect HBV marker‐negative carriers and liver function tests should be carefully monitored.

Fulminant hepatitis type B after chemotherapy in a serologically negative hepatitis B virus carrier with acute myelogenous leukemia.

We report a case of a 41-year-old man with acute myelogenous leukemia who developed fulminant hepatitis from reactivation of trace hepatitis B virus (HBV) 2 months after complete remission.Although he became positive for HB surface antigen at the onset of fulminant hepatitis, he had been negative for HBV serum markers, and only HBV DNA was detected by polymerase chain reaction (PCR) amplification on admission. The original stocks of serum samples from all blood donors were tested again for HBV DNA by PCR, and all samples were negative. This case demonstrates that testing for HBV DNA by PCR is necessary before chemotherapy, because silent HBV carriers are rare and fulminant hepatitis may be induced by chemotherapy in patients with hematologic malignancies.

Serum soluble IL-6 receptor levels during the mobilization of stem cells to peripheral blood.

Serum soluble interleukin-6 receptors (sIL-6R) have been demonstrated to play an important role in hematopoiesis. We report here that serum sIL-6R levels reflect proliferative kinetics of the progenitors after stimulation by chemotherapy plus granulocyte colony-stimulating factor. Serum sIL-6R were serially evaluated in 26 courses of peripheral blood (PB) stem cell collections in 16 patients using enzyme-linked immunosorbent assay. Expressions of IL-6R and CD34 on PB mononuclear cells were examined by flow cytometric analysis and expressions of IL-6R mRNA were examined by reverse transcriptase polymerase chain reaction. There were no significant differences between the serum sIL-6R levels on day 0 in patients (27.8 ± 2.1   ng/ml, mean ± SEM) and those in controls (27.5 ± 1.5   ng/ml). Following chemotherapy the serum sIL-6R levels were significantly decreased, reaching a minimal level on day 14 (22.3 ± 1.2   ng/ml, p<0.01) and then significantly increased to above the baseline levels on day 21 (32.0 ± 2.1   ng/ml, p<0.01). Similar oscillations in the number of white blood cells, IL6R + cells, CD34 + cells and colony-forming unit-granulocyte/macrophage (CFU-GM) in PB could be observed and the peak expression of mRNA was compatible with the expression of antigen. Serum sIL-6R levels on day 17 and 19 were positively correlated with the number of CD34 + cells, IL-6R + cells, CFU-GM in PB and the number of collected CD34 + cells in leukapheresis products. In addition, when comparing the 2 groups divided by the number of prior chemotherapies, the status of disease or dose of the mobilizing regimen, the serum sIL-6R levels were significantly increased after day 17 in the group that received fewer courses of prior chemotherapy, the group in complete remission and the group of high-dose chemotherapy. These findings indicated that sIL-6R levels do not reflect the hematopoietic ability in the steady state, or the capability of the hematopoiesis after stimulation. Thus, sIL-6R levels may be a marker for the timing of PBSC collection or the prediction of the number of collected CD34 + cells.

Experience of Peripherally Inserted Central Venous Catheter in Patients with Hematologic Diseases

Objective Although use of the peripherally inserted central venous catheter (PICC) has become increasingly common, there are few reports of PICCs used for patients with hematologic diseases. In this study, we analyzed the safety of PICC placement in patients with hematologic diseases where PICCs had been placed to perform blood collection, blood transfusion, drug administration, and hematopoietic stem cell transplantation. Methods This study included 142 PICCs placed in 95 patients managed at our department from November 2013 to December 2015. The PICCs used were the GroshongⓇ Catheter (NXT single-lumen; BARD Inc.). Results A total of 95 patients underwent the placement of 142 PICCs. The mean patient age was 65.5 years. The total duration of catheterization was 8,089 days, with a mean duration of 57.0 days. Chemotherapy was administered through 107 catheters. Stem cells were injected through 12 catheters. Although a fever was observed in association with 103 catheters, it was generally controlled by antimicrobial therapy. There were 18 catheter-related bloodstream infection (CRBSI) cases, an incidence equivalent to 2.1 cases per 1,000 catheter-days. Conclusion The present study demonstrated a low CRBSI incidence rate and found no evidence of serious complications with PICC placement. PICCs can be used for blood collection, blood transfusion, drug administration, and hematopoietic stem cell transplantation without problems. Thus, PICC placement appears to be a safe procedure for patients with hematologic diseases. Safe catheters are therefore urgently needed for these patients. We expect that PICCs will be widely adopted in Japan in the near future.

Successful bone reconstruction after bortezomib therapy in a myeloma patient

A 50-year-old Japanese woman was referred to our hospital with intractable back pain. Laboratory examination revealed that she was suffering from Bence-Jones kappa multiple myeloma (Stage III A, ISS: Stage II). Plain X-ray revealed multiple lytic lesions in her cranial bones, ribs, and ilium. The left iliac bone defect was particularly large (Fig. 1a). She was considered to be a candidate for autologous peripheral blood stem cell transplantation (PBSCT), and received vincristine, adriamycin, and dexamethasone (VAD) as an initial induction therapy. After the first course of VAD, she experienced severe bradycardia with hypotension. In addition, on treatment with zolendronic acid (ZA), she developed a high fever. Due to her adverse responses to VAD and ZA, she was administered bortezomib (1.3 mg/m, intravenously, on days 1, 4, 8, and 11). Her serum ALP level was elevated from 2 weeks after the beginning of bortezomib treatment, but she experienced no adverse effects other than peripheral neuropathy (Grade 2 for CTCAE ver. 4). After five courses of bortezomib treatment, her CT showed new bone formation at the lytic lesion of the left iliac bone (Fig. 1b). Moreover, improvement of the bone lesion was maintained even after the cessation of eight courses of bortezomib treatment (Fig. 1c, d), and it was determined that she had achieved a very good partial response (VGPR). As she strongly desired to be followed without any therapy, PBSCT has not been performed subsequently. Bone disease in myeloma is commonly characterized by increased bone resorption. However, in myeloma patients, there is also impaired osteoblast activity. Bortezomib is a proteasome inhibitor that has been shown to exhibit antimyeloma activity and to stimulate bone formation. In this case, we observed the radiographic improvement of a myeloma bone lesion during and following bortezomib therapy. We suggest that bortezomib may play an important role in reducing the risk of skeletal complications such as pathological fractures. T. Tanaka (&) R. Yamasaki H. Omura N. Hino Department of Internal Medicine, Hematology, Tottori Prefectural Central Hospital, 730 Ezu, Tottori, Tottori 680-0901, Japan e-mail: tanaka-tak@pref.tottori.jp Fig. 1 Images of 3-dimensional computed tomography. a Before bortezomib therapy. A large bone defect in the left iliac bone. b After five courses of bortezomib therapy. New bone formation is demonstrated in the osteolytic lesion. c Two months after treatment. d Eighteen months after treatment. The bone defect has been completely replaced by normal bone tissue

Cutaneous Mycobacterium chelonae infection following autologous peripheral blood stem cell transplantation for POEMS syndrome

Although hematopoietic stem cell transplantation (HSCT) may increase the curability of refractory hematologic diseases, it requires complication management due to a long-term immunocompromised state. We experienced a case who received an autologous peripheral blood stem cell transplantation (Auto-PBSCT) for POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) and developed cutaneous Mycobacterium chelonae infection. It is clear that attention needs to be paid to prevent bacterial, fungal and viral infection after HSCT. It is also important to keep in mind that tuberculous and nontuberculous mycobacteria (NTM), in rare cases, lead to lethal complications.

Validation of previous prognostic models for thrombosis and exploration of modified models in patients with essential thrombocythemia

We examined the prognostic factors to validate previous prognostic models for survival and thrombosis with large‐scale data on Japanese patients with essential thrombocythemia (ET).

The Relationship between Multiple Myeloma with Renal Failure and Metastatic Calcification

While cases of multiple myeloma (MM) with metastatic calcification have been reported, the mechanisms for this calcification have yet to be explained. We observed a case of MM in a patient with end-stage renal failure who developed vascular and pulmonary calcification. A 51-year-old male was diagnosed with Bence-Jones type MM and required maintenance hemodialysis. He was treated with bortezomib-dexamethasone, vincristine-doxorubicin-dexamethasone, the M2 protocol, and lenalidomide-dexamethasone (Rd) therapy. During the sixth cycle of Rd therapy, he complained of pain in both lower legs. Well-demarcated ulcers with severe pain had developed on the right lower leg, both exterior thighs, and penis. We found that the patients serum intact parathyroid hormone level was elevated, while it had previously been permissively controlled. Computed tomography scan showed widespread centrilobular opacities of the bilateral lungs and high-density lesions along small blood vessels in the trunk and all four extremities. Histological calcifications were identified in small blood vessels and the alveolar walls. The risk of metastatic calcification in MM appears to be associated with renal failure, but not with MM itself.

Effect of Interferon-α on Patients with Previously Untreated Chronic Myelogenous Leukemia in the Early Chronic Phase: Comparison between Interferon-α Continued Patients and Interferon-α Discontinued Patients.

In order to confirm the effect of interferon-α (IFN-α) in inducing a prolonged duration of the chronic phase (CP) on patients with chronic myelogenous leukemia (CML), we retrospectively compared the duration of CP between patients who continued on IFN-α and the patients in whom IFN-α was discontinued before the blast phase. Of the 32 patients not pretreated for CML in the early CP who received IFN-α therapy, 25 continued on IFN-α while seven discontinued the therapy (side effects, 5; resistance, 1; patients refusal, 1). Only four of the 25 patients in whom IFN-α was continued (16.0%) progressed to the blast phase or accelerated phase, but six of the seven patients who discontinued IFN-α (85.7%) progressed to the blast phase or accelerated phase. Fourteen of the 25 patients who continued on IFN-α therapy showed cytogenetic response (complete cytogenetic response, 3; minimal cytogenetic response, 11) whereas 11 patients showed no cytogenetic response. However, non-responders showed a longer duration of CP than the patients whom IFN-α was discontinued. Although elderly patients showed a high incidence of side effects, and some patients progressed early after the beginning of IFN-α therapy, our data clearly demonstrated that in accordance with previous large multi-centric randomized studies the continuation of IFN-α, even in low doses, prevents disease progression.