Cefepime-induced encephalopathy in patients with haematological malignancies: clinical features and risk factors.

BACKGROUND: Cefepime is an antibiotic that is widely used in patients with haematological malignancies (HM). Although its use has been reported to be associated with encephalopathy, only case reports or small case series have been reported so far. PATIENTS AND METHODS: We conducted a retrospective cohort study of 243 patients with HM treated with cefepime at our hospital between August 2011 and May 2013. We also investigated the clinical features of patients with cefepime-induced encephalopathy (CIE). RESULTS: Among 243 HM patients treated with cefepime, 10 were diagnosed with CIE, indicating a cumulative incidence of approximately 4.1%. The median creatinine level on commencement of treatment was 2.13 mg/dl (range 0.60-19.85) and the median initial dose of cefepime was 4.0 g/day (range 1.0-6.0). The median time between commencement of treatment and symptoms was 4.0 days (range 2-5). The most common clinical manifestations were decreased level of consciousness and myoclonus. Symptoms resolved fully in all patients. Univariate analyses showed that impaired renal function (creatinine clearance (CLCr) < 30 ml/min, acute renal failure, and chronic dialysis) was significantly associated with the development of CIE (univariate p < 0.0001, p = 0.020, and p = 0.0025, respectively). Receiver operating characteristic (ROC) analysis demonstrated that the threshold levels of creatinine, CLCr, and estimated glomerular filtration rate for CIE were 1.22 mg/dl, 22.96 ml/min, and 43.9 ml/min/1.73 m(2), respectively. CONCLUSIONS: This study indicated that the development of CIE is associated with severely impaired renal function in patients with HM.

Acquisition of t(11;14) in a patient with chronic lymphocytic leukemia carrying both t(14;19)(q32;q13.1) and +12.

A rare recurrent chromosomal translocation, t(14;19)(q32;q13), has been identified in a variety of B-cell malignancies, including chronic lymphocytic leukemia (CLL). We report a unique case of CLL in a patient carrying both trisomy 12 and t(14;19) (q32;q13.1), in whom t(11;14)(q13;q32) developed at relapse. The patient was a 77-yr-old woman, and her lymphoma cells at presentation showed CD5(+), CD10(-), CD19(+), CD20(+)(dim), CD23(+), CD38(+), and CD11c(+). At relapse, the patient's lymphoma cells showed positive staining for cyclin D1 in addition to CD5, CD20, and CD23. Lymphoma cells in specimens at both presentation and relapse were positive for lymphoid enhancer factor 1 (LEF1) and negative for sex-determining region Y-box 11 (SOX11). IGH-BCL1 FISH became positive at relapse. Split FISH assay using BCL1, BCL3, IGH, and CCND1 probes on lymph node specimens obtained at presentation and at autopsy confirmed that the translocation of BCL3 was solely detected in the lymph node at presentation and detected BCL3 and CCND1 translocations in the specimen at autopsy. These observations indicated that IGH-BCL3 and IGH-CCND1 had occurred in the same clone after treatment of the disease. In line with immunohistochemical and cytogenetic studies, additional PCR analysis of the FR3-JH region showed the same sequence derived from IGHV4-34 in specimens obtained at disease onset and relapse.

Normalization of free light chain kappa/lambda ratio is a robust prognostic indicator of favorable outcome in patients with multiple myeloma.

PURPOSE: To clarify the impact of serum free light chain (sFLC) ratio normalization in patients with multiple myeloma (MM) treated with novel agents. PATIENTS AND METHODS: Treatment response in 126 consecutive patients over 7 years was assessed by IMWG criteria and sFLC assay. RESULTS: Thirty-four patients (27%) showed complete response (CR), 37 (29%) very good partial response (VGPR), 39 (31%) partial response (PR), and 16 (13%) stable disease (SD) or less at a median follow-up of 28 months. Fifty-two patients (41%) with sFLC ratio normalization showed superior progression-free survival (PFS) and overall survival (OS) compared to those who did not (3-yr OS, 94% vs. 48%; P < 0.001). This favorable effect of sFLC ratio normalization occurred irrespective of high (>1000 mg/dL) or low (<100 mg/dL) baseline sFLC. Rates of normal sFLC ratio were as follows: CR, 69%; VGPR, 64%; PR, 16%; and SD or less, 0%. OS was significantly superior in patients with than without normal sFCL ratio in respective response groups. Although various factors (advanced age >70, high LDH, ISS stage 3) showed negative prognostic impacts on PFS and OS on univariate analysis, normal sFLC ratio and achievement of CR emerged as the strongest prognostic predictors for longer OS in MM patients on multivariate analysis. CONCLUSIONS: This study demonstrated the significance of obtaining normal sFLC ratio independent of other clinical variables. Analysis of sFLC ratio could identify the favorable group of patients as well as immunofixation test and support the inclusion of sFLC ratio as part of the response criteria for MM.

The utility of positron emission tomography/computed tomography in the staging of extranodal natural killer/T-cell lymphoma.

Natural killer (NK)/T-cell lymphoma cases are rarely discovered using positron emission tomography/computed tomography (PET/CT). We compared the utility of PET/CT and that of conventional methods (CMs; CT with IV contrast, biopsies from primary sites, and bone marrow examinations) in the staging of extranodal NK/T-cell lymphoma. Nineteen untreated patients with extranodal NK/T-cell lymphoma at three institutions were analyzed. PET/CT and CMs were applied for initial workups following diagnosis. PET/CT and CMs were compared and evaluated for their ability to detect tumor lesions and their influence on the staging and treatment strategies. In total, 116 lesions were detected by CM and PET/CT. Using PET/CT, 108 lesions (93%) were discovered. The number of nodal lesions was 28: all were positive by PET/CT and 26 (93%) by CMs. The number of extranodal lesions was 89: 84 (94%) and 54 (61%) lesions were positive by PET/CT and CMs, respectively. PET/CT was superior to CMs in detecting cutaneous lesions [31/31 lesions (100%) vs. 20/31 lesions (65%), respectively; P=0.042]. Bone marrow involvement was confirmed pathologically in only seven patients; four cases (57%) were positive by PET/CT. Using CMs, ten patients (53%) were stages I-II and nine (47%) were stages III-IV. Using PET/CT, eight patients (42%) were in stages I-II and 11 (58%) were in stages III-IV. PET/CT findings altered the stage and treatment strategy in two cases (11%). Our study demonstrated that PET/CT is a useful tool for detecting extranodal lesions in NK/T-cell lymphoma, particularly cutaneous lesions. PET/CT may therefore influence future staging and treatment strategies.

High frequency of neurolymphomatosis as a relapse disease of intravascular large B-cell lymphoma.

BACKGROUND: Intravascular large B-cell lymphoma (IVL) is characterized by lymphoma cell proliferation in the lumina of small vessels in various organs. A high incidence of neurologic symptoms associated with the central nervous system has been reported, but peripheral nerve involvement (neurolymphomatosis [NL]) rarely has been described. METHODS: The medical records from patients who were diagnosed with IVL over the past 4 years were reviewed. A diagnosis of NL was made based on the combination of neurologic symptoms and their correspondence with imaging studies, such as magnetic resonance imaging (MRI), (18) F-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography/computed tomography (PET/CT), and/or the histologic confirmation of lymphoma cells within the peripheral nerves, nerve root/plexuses, or cranial nerves. RESULTS: Four patients with NL were identified among 11 patients who had IVL. All cases of NL occurred as relapsed disease during or shortly after the completion of chemotherapy. Although MRI studies of the brains and whole spines revealed nerve infiltration by gadolinium enhancement in 2 patients, the technology was not sensitive enough to detect such infiltration in the remaining 2 patients. In contrast, FDG-PET/CT studies successfully revealed cranial or peripheral nerve lesions in all 4 patients and was useful for evaluating therapeutic response. Patients received treatment with high-dose methotrexate with or without other systemic chemotherapy, which achieved varied success. Further studies will be needed to determine the optimal treatment. CONCLUSIONS: Considering the rarity of IVL and NL, the current observations suggested that IVL may have a predilection not only for the vessels but also for both the central and peripheral nervous systems.

Random skin biopsy and bone marrow biopsy for diagnosis of intravascular large B cell lymphoma.

Intravascular lymphoma (IVL) is a rare type of extranodal lymphoma in which the lymphoma cells proliferate exclusively in the lumina of small vessels. The diagnosis of IVL requires histological confirmation. Although random skin biopsy from healthy-appearing skin in patients with suspected IVL appeared to be useful, the sensitivity of this method for the diagnosis of IVL remains unknown. We performed a random skin biopsy from 12 consecutive cases of IVL diagnosed at our institution over the past 4 years and evaluate its relevance of clinical and laboratory characteristics, presence or absence of skin lesions, and bone marrow involvement. All 12 patients were diagnosed antemortem by either random skin biopsy or bone marrow biopsy and treated with rituximab-containing chemotherapy. Random skin biopsy was performed in all 12 patients, and the results were positive in ten patients (83.3%). Erythematous skin lesions were seen in 3 of 12 patients, but biopsy was positive for lymphoma lesion in two patients. Bone marrow invasion was seen in 11 of the 12 patients (91.6%) by bone marrow smear and/or flow cytometric analysis, but was detected in only half of the patients by trephine biopsy. We concluded that random skin biopsy from normal-appearing skin is highly sensitive in the diagnosis of IVL comparable to bone marrow trephine biopsy. It should be performed irrespective of the presence or absence of skin lesions in patients who were suspicious of IVL.

Reactivation of hepatitis B virus after rituximab-containing treatment in patients with CD20-positive B-cell lymphoma.

BACKGROUND: Reactivation of hepatitis B virus (HBV) after rituximab-containing chemotherapy in patients with B-cell lymphoma has been recognized as a potentially serious complication in HBV immune patients. METHODS: To determine the HBV reactivation in patients treated with rituximab, a retrospective study of HBV-related markers was performed before and after rituximab-containing treatment in 261 consecutive patients with CD20-positive B-cell lymphoma. RESULTS: Of the 261 patients, 230 patients were tested for both hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc) before treatment. Fifty-six (24.3%) of 230 patients were anti-HBc positive, and the remaining 174 (75.6%) patients were anti-HBc negative. Among the 56 anti-HBc-positive patients, 5 (8.9%) became HBsAg positive (HBV reactivation), whereas none of the 174 anti-HBc-negative patients became HBsAg positive with a median follow-up of 24 months (P = .001). Among the 5 patients with HBV reactivation, 4 were negative for antibody to HBsAg (anti-HBs), and 1 patient was positive for anti-HBs. All 5 of these patients were treated successfully with entecavir on detection of HBsAg, although 4 of the 5 patients exhibited mild to moderate elevation of alanine aminotransferase. Among 56 anti-HBc-positive patients, those negative for anti-HBs had a higher probability of developing HBV reactivation compared with those positive for anti-HBs (4 of 19; 21.1% vs 1 of 37; 2.7%, P = .014). CONCLUSIONS: Patients with isolated anti-HBc are at high risk of HBV reactivation and should be monitored closely for HBsAg, anti-HBs, HBV-DNA, and transaminase levels during and after rituximab-containing treatment. Although preemptive use of entecavir enabled successful management of HBV reactivation, mild to moderate hepatic flare was still observed. These approaches should be further evaluated in a prospective study with regard to clinical usefulness, safety, and cost-effectiveness.

Reversal of dialysis-dependent renal failure in patients with advanced multiple myeloma: single institutional experiences over 8 years.

Acute renal failure in patients with multiple myeloma (MM) requiring dialysis is a serious complication and is associated with extremely poor survival. In addition, its treatment included high-dose dexamethasone and/or thalidomide-containing regimens on the reversibility of renal function, which has not been adequately evaluated previously. We studied the impact on the reversibility of high-dose dexamethasone and/or thalidomide-containing regimen in 12 newly diagnosed MM patients (median 74 years, range; 63-85 years) who required dialysis at Kameda General Hospital from 2001 to 2008. There were seven light chain only myelomas, three IgD myelomas, and two IgG myelomas. Ten patients initially received high-dose dexamethasone-based treatment and two received thalidomide-based treatment, with modifications. Complete (CR) and partial responses (PR) were obtained in three and five patients, respectively. Dialysis independency was achieved in all eight patients (67%) who achieved better than PR, with a median duration of 2.0 months. Six of the ten patients who received high-dose dexamethasone-containing regimen and all of the two patients received thalidomide-containing regimen became dialysis-independent. A high concentration of serum-free light chain was detected in all patients examined, before the start of anti-myeloma treatment, and this was associated with the presence of advanced renal failure. Improved renal function was preceded by a significant decrease in serum-free light chain in patients who achieved dialysis independence. These results suggest that dialysis-dependent renal failure is reversible by dexamethasone- or thalidomide-based treatments in most patients with MM, even if the patient is in advanced age, and that serum-free light chain monitoring might be useful for predicting improvements in renal function.

Detection of sputum Aspergillus galactomannan for diagnosis of invasive pulmonary aspergillosis in haematological patients.

We investigated the diagnostic utility of Aspergillus galactomannan (GM) in sputum for diagnosis of invasive pulmonary aspergillosis (IPA) in haematologic patients and compared the results with those of bronchial lavage fluid (BLF) and serum. Patients were classified into 4 groups using modified European Organization for Research and Treatment of Cancer criteria: group A, proven IPA; group B, probable IPA; group C, possible IPA; group D, others. Groups A and B were considered the IPA group (n = 6); group D was considered non-IPA group (n = 37); group C (n = 13) was equivocal for IPA. As a true negative control, sputa from patients with community-acquired pneumonia (CAP) without risk factors (group E, n = 22) were used. From the receiver-operating characteristic curves, the cut-off levels were determined as 1.2 in sputum, 0.5-1.3 in BLF and 0.5 in serum. The sensitivity and specificity of sputum, BLF and serum GM were 100 and 62.2%, 66.7 and 100%, and 83.3 and 81.1%, respectively. Twenty-two patients with CAP (group E) showed median GM levels in the sputa of 0.1 (range 0.0-1.0). Sputum GM is a useful non-invasive test for screening of IPA in haematological patients, and may also be useful for assessment of the risk of developing IPA.

High risk of hepatitis B-virus reactivation after hematopoietic cell transplantation in hepatitis B core antibody-positive patients.

We investigated the serological changes in hepatitis B virus (HBV)-related markers in 55 and 26 hepatitis B surface antigen (HBsAg)-negative patients undergoing allogeneic and autologous stem cell transplantation, respectively, over the past 4 yr. Five of the 17 allogeneic and one of the five autologous patients with pretransplant anti-hepatitis B core antigen antibodies (anti-HBc) were HBsAg-positive after transplantation, whereas none of the patients negative for anti-HBc were HBsAg-positive in both groups. All patients who became HBsAg-positive received steroid-containing immunosuppressive therapy for chronic graft versus host disease (GVHD) or myeloma. Four of the six patients developed flare of HBV hepatitis, and two patients did not. One patient developed fulminant hepatitis treated with lamivudine and plasma exchange. Other five patients received entecavir from the detection of HBsAg. Although HBV-DNA levels became below the limit of detection in all patients, HBsAg positivity remained in three patients after 6 months of treatment. We concluded that anti-HBc positivity is a risk factor for reactivation of HBV after both autologous and allogeneic transplantation, and HBV-related markers should be monitored regularly in these patients. We also stress the efficacy of pre-emptive use of antiviral agents in controlling HBV replication and limiting hepatic injury due to reactivation of HBV in these patients.