BACKGROUNDThere are three distinct types of doxorubicin‐induced cardiotoxicity (acute, chronic, and late‐onset). Although previous studies with animal models suggest that angiotensin II plays a key role in the process of the doxorubicin‐induced cardiotoxicity, there has been no such observation in humans. This randomized study investigated whether valsartan, a new class of angiotensin II receptor blocker (ARB), can inhibit acute cardiotoxicity after doxorubicin‐based chemotherapy.METHODSForty consecutive patients with untreated non‐Hodgkin lymphoma who were scheduled to undergo standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) (mean age, 56 yrs; range, 24–70 yrs) were randomized with minimization methods to receive CHOP with or without 80 mg/day of valsartan. Acute cardiotoxicity was comprehensively evaluated with neurohumoral, echocardiographic, and electrocardiographic markers before and on Days 3, 5, and 7 after the initiation of CHOP.RESULTSCHOP induced transient increases in the left ventricular end‐diastolic diameter in an echocardiogram, the QTc interval and QTc dispersion in an electrocardiogram, and in the plasma brain and atrial natriuretic peptides. All these changes returned to nearly normal levels within a week after CHOP (P < 0.001). Notably, valsartan significantly prevented all these changes except for the elevation in atrial natriuretic peptide (P < 0.05). No significant change was observed in blood pressure or heart rate between the valsartan and control groups.CONCLUSIONSThe results indicate that angiotensin II may play an essential role in acute CHOP‐induced cardiotoxicity in humans. Future long‐term studies are necessary to judge whether ARBs have a potential to prevent the chronic or late‐onset types of doxorubicin‐induced cardiotoxicity. Cancer 2005. © 2005 American Cancer Society.

Thrombotic microangiopathy (TMA) impairs long-term survival after allogeneic hematopoietic stem cell transplantation (HSCT). As the allogeneic HSCT procedure has developed, addressing risk factors for TMA has become more complicated. The aim of this study was to investigate the impact of transplant-associated factors on TMA incidence in patients who have undergone HSCT in various settings. One hundred twenty-three consecutive allogeneic HSCT patients with hematologic diseases receiving myeloablative and reduced-intensity conditioning were evaluated retrospectively. Of 123 patients, 22 (17.9%) developed TMA after HSCT. Multivariate analysis showed the significance of GVHD grade II-IV, and the use of FK506 and the use of high-dose busulfan (Bu) (16 mg/kg) persisted. The hazard ratios of the use of FK506, the use of high-dose Bu (16 mg/kg), and GVHD grade II-IV for TMA were 8.7 (95% CI 2.0-37), 5.7 (95% CI 1.5-21), and 3.4 (95% CI 1.3-9.1), respectively. In the present study, reduced-intensity conditioning did not have an advantage over myeloablative conditioning in decreasing the incidence of TMA after HSCT. Our results also showed that highdose Bu (16 mg/kg) for the conditioning and FK506 for the prophylaxis of GVHD might contribute more significantly to TMA onset after HSCT than other agents. Am. J. Hematol. 81:525-531, 2006. V V C 2006 Wiley-Liss, Inc.

BackgroundRecently, maintaining higher relative dose intensity (RDI) of chemotherapeutic drugs has become a widespread practice in an attempt to achieve better outcomes in the treatment of aggressive lymphoma. The addition of rituximab to chemotherapy regimens has significantly improved outcome in diffuse large B-cell lymphoma (DLBL). However, it is unknown if higher RDI in chemotherapy when combined with rituximab leads to a better outcome in aggressive B-cell lymphoma.MethodsWe retrospectively evaluated the impact of the RDI of initial chemotherapy (consisting of cyclophosphamide, doxorubicin, vincristine and prednisolone with rituximab (R-CHOP) on outcome in 100 newly diagnosed DLBL patients.ResultsA multivariate Cox regression model showed that RDI trended towards a significant association with mortality [hazard ratio per 0.1 of RDI = 0.8; 95% confidence interval 0.6–1.0; P = 0.08]. Additionally, on multivariate logistic analysis, advanced age was a significant factor for reduced RDI.ConclusionOur data suggest that in DLBL patients, mortality was affected by RDI of R-CHOP as the initial treatment, and the retention of a high RDI could therefore be crucial.

Immunomodulation induced by dasatinib is reportedly related to better prognosis in chronic myeloid leukemia (CML). However, the underlying mechanism has not yet been fully elucidated. The immunoprofiles of 63 patients in the chronic phase of CML were evaluated during treatment with a tyrosine kinase inhibitor (imatinib, n = 36; nilotinib, n = 9; dasatinib, n = 18). The numbers of CD56 + CD57 + and CD3 + CD57 + cells increased significantly in the dasatinib group. The numbers of regulatory T-cells were comparable among the three groups. Dasatinib markedly enhanced natural killer (NK)-cell reactivity. Only one patient treated with dasatinib showed a slight cytomegalovirus (CMV) reactivation. In contrast, nilotinib suppressed NK-cell reactivity. Plasma levels of interleukin-8 (IL-8), interferon-γ inducible protein-10 (IP-10) and monocyte chemoattractant protein-1 (MCP-1) were significantly elevated in all three groups, and plasma levels of granulocyte macrophage-colony stimulating factor (GM-CSF) were significantly elevated in the imatinib and dasatinib groups. Our results suggest the presence of a mechanism for dasatinib-associated immunomodulatory effects that is distinct from CMV reactivation and a decreased number of regulatory T-cells.

The aim of our study was to evaluate whether corrected QT dispersion (QTc dispersion), an electrocardiographic marker, is a good predictor of the development of acute heart failure after high-dose chemotherapy followed by autologous or allogeneic hematopoietic stem cell transplantation. We enrolled 50 consecutive patients, from age 15 to 63 years, with hematopoietic diseases scheduled to undergo autologous or allogeneic hematopoietic stem cell transplantation, and compared QTc dispersion with other markers before transplantation conditioning. In univariate logistic analysis, QTc dispersion was a significant factor for acute heart failure after hematopoietic stem cell transplantation (odds ratio, 3.7 per 10 msec; confidence interval, 1.6-8.5; P = 0.002). There were no significant differences as age, sex, systolic or diastolic echocardiographic function markers, cumulative anthracycline dose, or QTc before transplantation between patients with and without acute heart failure. After multiple adjustments for left ventricular ejection fraction, cumulative anthracycline dose, cyclophosphamide conditioning dose, QTc dispersion was a significant and independent factor for acute heart failure after hematopoietic stem cell transplantation (odds ratio, 48.0 per 10 msec; confidence interval, 1.4-1666.3; P = 0.03). This study demonstrated that QTc dispersion could be used as a powerful noninvasive predictor of the development of acute heart failure after hematopoietic stem cell transplantation. Am.

Acute graft-versus-host disease (aGVHD) is a serious complication of allogeneic peripheral blood stem cell transplantation (PBSCT). Patients with severe aGVHD not responding to treatment with steroids have a poor prognosis. We treated three patients with severe aGVHD refractory to steroids with infliximab. Patients (MDS 1, NHL 1, ALL 1) developed grade II-IV GVHD at a median of 13 days (range 9-17) after non-myeloablative PBSCT (HLA mismatched). All patients had received treatment with high-dose steroids for a median of 7 days (range 7-10) in addition to mycophenolate mofetil (MMF) (one). Infliximab was given in 3 weekly doses of 5 mg/kg. In one of three patients a partial resolution of diarrhea and minor improvement of skin were observed. One patient died with refractory GVHD. Infliximab is apparently an effective drug for the treatment of aGVHD, but can be more effective at doses of 5 mg/kg or higher and/or by administering it repeatedly every week.

We report the case of a 39-year-old male patient who died of severe BK virus (BKV) pneumonia 168 days after hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia. After suffering from BKV-associated late-onset hemorrhagic cystitis (HC) with long-term sustained BKV viremia, he died of rapidly progressive pneumonia. On autopsy, numerous viral intranuclear inclusions were seen in his lungs and bladder. An immunohistochemical examination of his lungs was positive for simian virus 40. Based on these pathological results and the high sustained BKV viral load in his blood, we reached a diagnosis of BKV pneumonia. Viral infection can occasionally become life threatening among HSCT recipients. It is widely known that BKV can cause late-onset HC, but BKV-associated pneumonia is rare. Because of its rapid progression and poor prognosis, it is difficult to make an antemortem diagnosis of BKV pneumonia. A treatment strategy for BKV pneumonia also needs to be formulated. Similar to other viral pathogens, BKV can cause pneumonia and the clinician should therefore be aware of it in immunocompromised patients.

Bronchiolitis obliterans syndrome (BOS) and idiopathic pneumonia syndrome (IPS) cause high mortality and impaired survival after allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Early recognition of patients at high risk of developing BOS/IPS may lead to improving the outcome of allo-HSCT. We retrospectively analyzed serum surfactant protein A, D (SP-A, -D) and Kerbs von Lungren 6 Ag (KL-6) levels before allo-HSCT in 56 patients who survived more than 90 days after allo-HSCT and compared values of these serum markers and other transplant factors in BOS/IPS patients with those in non-BOS/IPS patients. Five patients developed BOS and two developed IPS at a median interval of 303 and 117 days (range, 100-452 and 95-153) from transplantation. As a result of univariate analysis, pretransplant serum SP-D levels but not SP-A, KL-6 in BOS/IPS patients were significantly lower than those in non-BOS/ IPS patients (P ¼ 0.03). In multivariate analysis, the patients with lower pretransplant serum SP-D level had a trend toward frequent development of BOS/IPS (P ¼ 0.08). Constitutive serum SP-D level before allo-HSCT may be a useful, noninvasive predictor for the development of BOS/IPS.