Prognosis of Indolent Adult T-Cell Leukemia/Lymphoma.

A retrospective chart survey of the clinical features of indolent adult T-cell leukemia/lymphoma (ATL) was conducted in the Miyazaki Prefecture, Japan. This study enrolled 24 smoldering-type ATLs, 10 favorable chronic-type ATLs, and 20 unfavorable chronic-type ATLs diagnosed between 2010 and 2018. Among them, 4, 3, and 10 progressed to acute-type ATLs during their clinical course. The median survival time (MST) in smoldering-type ATL and favorable chronic-type ATL was not reached, and their 4-year overall survival (OS) was 73% and 79%, respectively. Compared with this, the prognosis of unfavorable chronic-type ATL was poor. Its MST was 3.32 years, and the 4-year OS was 46% (p = 0.0095). In addition to the three features that determine the unfavorable characteristics of chronic-type ATL, namely, increased lactate dehydrogenase, increased blood urea nitrogen, and decreased albumin, the high-risk category by the indolent ATL-Prognostic Index, which was defined by an increment of soluble interleukin-2 receptor (sIL2-R) of >6000 U/mL, could explain the poor prognosis in indolent ATL patients. The level of sIL-2R might be an indicator of the initiation of therapy for indolent ATL.

Higher average chemotherapy dose intensity improves prognosis in patients with aggressive adult T-cell leukemia/lymphoma.

OBJECTIVE AND METHOD: Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell lymphoma with poor prognosis. We retrospectively reviewed the medical records of 312 patients with aggressive ATL and analyzed the effect of chemotherapy dose intensity on prognosis in clinical practice. RESULT: As first-line therapy, 62 patients underwent best supportive care (BSC) or single-agent chemotherapy, and 235 underwent intensive chemotherapy. The median survival time (MST) was 0.58 years in the 312 total patients, and 0.13 years and 0.75 years in the BSC/single-agent chemotherapy group and intensive chemotherapy group, respectively. The median average relative dose intensity (ARDI) of patients who received intensive chemotherapy was 60%. We divided patients into 3 groups according to ARDI. Those in the top tertile of ARDI (ARDI ≥ 75%, n = 82) had better overall survival compared with those in the intermediate tertile (45% ≤ ARDI < 75%, n = 79) (P < .0001), with MSTs of 4.69 and 0.75 years, respectively. The occurrence of organ dysfunction and infectious complications was comparable between the two ARDI groups. CONCLUSION: Higher ARDI improves prognosis in patients with aggressive ATL in clinical practice.

Acceleration of opportunistic atrial fibrillation screening for elderly patients in routine primary care.

Cardio-embolic ischemic stroke caused by atrial fibrillation is more severe compared with other types of stroke, such as lacunar infarction and atherothrombotic infarction in patients without atrial fibrillation. Therefore, it is important to prevent cardio-embolic ischemic stroke by detecting atrial fibrillation early in at-risk patients and administering appropriate anticoagulation therapy. This prospective observational study aimed to evaluate the effectiveness of opportunistic atrial fibrillation screening at 12 primary clinics in Japan. The study included a 12-month pre-campaign period and a 12-month campaign period. During the campaign period, an awareness campaign was conducted to encourage physicians to be mindful of screening patients aged ≥65 years for atrial fibrillation by checking their pulses and performing subsequent electrocardiography when an irregular pulse was detected. The primary outcome was the proportion of patients with newly diagnosed atrial fibrillation. A sub-analysis focusing on first-time outpatients was performed. There were 9921 and 10,282 patients with no history of atrial fibrillation in the pre-campaign and campaign periods, respectively. In the whole population, the proportion of patients with newly diagnosed atrial fibrillation was 0.9% throughout the pre-campaign and campaign periods. In the sub-analysis limited to first-time outpatients, the detection proportion increased from 1.6% to 1.9% during the campaign period. In terms of age stratification, a large increase in detection was observed, especially among patients aged 65-74 years (detection increased from 0.9% to 1.5%) and ≥85 years (detection increased from 2.9% to 3.3%) during the campaign period. Our findings suggest the feasibility of opportunistic atrial fibrillation screening in routine primary care practice in Japan. Of note, our findings suggest that opportunistic atrial fibrillation screening targeting first-time outpatients may be of clinical value.

Real-World Data on Clinical Features, Outcomes, and Prognostic Factors in Multiple Myeloma from Miyazaki Prefecture, Japan.

The prognosis of multiple myeloma (MM) has improved with the introduction of novel agents. These data are largely derived from clinical trials and might not reflect real-world patient outcomes accurately. We surveyed real-world data from 284 patients newly diagnosed with MM between 2010 and 2018 in Miyazaki Prefecture. The median follow-up period was 32.8 months. The median age at diagnosis was 71 years, with 68% of patients aged >65 years. The International Staging System (ISS) stage at diagnosis was I in 18.4% of patients, II in 34.1%, and III in 47.5%. Bortezomib-containing regimens were preferred as initial treatment; they were used in 147 patients (51.8%). In total, 80% of patients were treated with one or more novel agents (thalidomide, lenalidomide, or bortezomib). Among 228 patients who were treated with novel agents as an initial treatment, the overall response rate (partial response (PR) or better) to initial treatment was 78.4%, and the median time to next treatment (TTNT) was 11.6 months. In the multivariate analysis, PR or better responses to initial treatment were independently favorable prognostic factors for TTNT. The median survival time after initial therapy for patients with novel agents was 56.4 months and 3-year overall survival (OS) was 70.4%. In multivariate analysis, ISS stage I/II disease and PR or better response to initial treatment, and autologous stem cell transplantation (ASCT) were identified as independent prognostic factors for overall survival (OS).

Impact of care coordination on oral anticoagulant therapy among patients with atrial fibrillation in routine clinical practice in Japan: a prospective, observational study.

BACKGROUND: Care coordination between general practitioners (GPs) and cardiovascular specialists is expected to play a key role in establishing appropriate oral anticoagulant (OAC) treatment in atrial fibrillation (AF) patients. The aim of this study was to assess the impact of care coordination on oral anticoagulant therapy in the management of AF in Japan. METHODS: This study was a multi-center, single-arm, prospective cohort study with retrospective chart and claims data review for historical controls. The study included three study periods: a 12-month pre-campaign period; a 12-month campaign period for AF screening and care coordination; and a 3-month post-campaign period for follow-up of care coordination. During the campaign period, patients aged ≥65 years who attended participating GP clinics underwent opportunistic AF screening by GPs under the campaign. At the discretion of the GP, newly diagnosed AF patients after the screening were referred to a cardiovascular specialist for care coordination. To assess the impact of care coordination and evaluate the effects of the campaign, implementation of care coordination, antithrombotic therapies, and patient-reported outcomes were compared between patients with and without care coordination, and between patients during the pre-campaign and campaign periods. RESULTS: There were 86 newly diagnosed AF patients during the pre-campaign period and 90 during the campaign period. The percentage of patients with care coordination increased from 3.5% (3/86) in the pre-campaign period to 14.4% (n = 13/90) during the campaign period. The percentage of patients who received OAC therapies, according to the definition from the Japanese AF medication guideline, increased from 55.8% (48/86) to 71.1% (64/90) during the campaign period regardless of care coordination. Younger patients were referred to cardiovascular specialists for care coordination. Implementation of OAC therapy did not differ between patients with and without care coordination. Adherence to OAC therapy was low regardless of care coordination. CONCLUSIONS: This GP-targeted campaign was effective at raising awareness regarding the implementation of care coordination and appropriate OAC therapy at local clinical practices in Japan. Improvement of adherence to OAC therapy in elderly patients is a critical issue, and measures such as education programs targeted to patients and healthcare professionals should be undertaken.

Early/prefibrotic primary myelofibrosis in patients who were initially diagnosed with essential thrombocythemia.

A new entity, namely early/prefibrotic primary myelofibrosis (PMF), was introduced as a subtype of PMF in the 2016 revised World Health Organization (WHO) criteria for myeloproliferative neoplasms (MPN). It was diagnosed based on histopathological features of bone marrow (BM) biopsy specimens together with clinical parameters [leukocytosis, anemia, elevated lactate dehydrogenase (LDH) values, and splenomegaly]. The aim of this study was to evaluate the prevalence of early/prefibrotic PMF in patients who were previously diagnosed with ET, and to compare clinical features at diagnosis and outcomes between early/prefibrotic PMF and essential thrombocythemia (ET) patients. BM biopsy samples obtained at the time of ET diagnosis were available in 42 patients. Sample reevaluation according to the 2016 revised WHO criteria revealed that early/prefibrotic PMF accounted for 14% of patients who were previously diagnosed with ET, which was comparable to the rates in previous reports. Compared to patients with ET, patients with early/prefibrotic PMF had higher LDH values and higher frequencies of splenomegaly. Overall, myelofibrosis-free and acute myeloid leukemia-free survivals were comparable between the 2 groups. Accurate diagnosis is required to clarify the clinical features of Japanese ET patients.

Thrombohemorrhagic events, disease progression, and survival in polycythemia vera and essential thrombocythemia: a retrospective survey in Miyazaki prefecture, Japan.

Polycythemia vera (PV) and essential thrombocythemia (ET) are associated with life-threatening thrombohemorrhagic events, and disease progression and development of non-hematological malignancies also reduce long-term survival. We retrospectively surveyed thrombohemorrhagic events and overall survival (OS) in 62 PV and 117 ET patients. The cumulative incidences of thrombohemorrhagic events in PV and ET patients were 11.3 and 10.3%, and the incidence rates were 2.42 and 1.85 per 100 person-years. The combined incidence rates of disease progression and development of non-hematological malignancies in PV and ET patients were 1.73 and 1.69 per 100 person-years. The incidence rates of thrombohemorrhagic events in our Japanese PV/ET patients were lower than those reported by most Western studies, but were comparable to those in the largest prospective observational study in ET patients. The combined incidence rates of disease progression and development of non-hematological malignancies were similar between Japanese and Western PV/ET patients. In ET patients, the conventional risk stratification model based on the presence of advanced age or history of thrombosis was useful to predict thrombosis risk, and both the conventional model and the International Prognostic Score of thrombosis in ET based on the above 2 risk factors plus increased leukocyte count could predict poor survival.

Effects of mogamulizumab in adult T-cell leukemia/lymphoma in clinical practice.

OBJECTIVE: The efficacy of mogamulizumab in adult T-cell leukemia/lymphoma (ATLL) was reported in a previous phase 2 study. Compared with patients in clinical trials, however, most patients in real-life settings have demonstrated worse outcomes. METHOD: We retrospectively analyzed 96 patients with relapsed/refractory ATLL who received mogamulizumab treatment. RESULTS: Relapsed/refractory ATLL patients with a median age of 70 years received a median of five courses of mogamulizumab. Hematologic toxicity and skin rash were the most common adverse events, and both were manageable. Of 96 patients, 87 were evaluable for efficacy. The overall response rate was 36%, and the median progression-free survival (PFS) and overall survival (OS) from the start of mogamulizumab therapy were 1.8 and 4.0 months, respectively. Of the original 96 patients, only 25 fulfilled the inclusion criteria of the phase 2 study. Those who met the criteria demonstrated longer median PFS and OS durations of 2.7 and 8.5 months, respectively. The median OS from diagnosis in relapsed/refractory ATLL patients receiving mogamulizumab was 12 months, longer than the 5.8 months in a historical cohort without mogamulizumab. CONCLUSION: In clinical practice, mogamulizumab exhibited antitumor activity in patients with relapsed/refractory ATLL, with an acceptable toxicity profile. Mogamulizumab therapy improved the OS of ATLL patients.

Treatment and survival among 1594 patients with ATL.

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature T lymphocytes caused by human T-lymphotropic virus type I. Intensive combination chemotherapy and allogeneic hematopoietic stem cell transplantation have been introduced since the previous Japanese nationwide survey was performed in the late 1980s. In this study, we delineated the current features and management of ATL in Japan. The clinical data were collected retrospectively from the medical records of patients diagnosed with ATL between 2000 and 2009, and a total of 1665 patients' records were submitted to the central office from 84 institutions in Japan. Seventy-one patients were excluded; 895, 355, 187, and 157 patients with acute, lymphoma, chronic, and smoldering types, respectively, remained. The median survival times were 8.3, 10.6, 31.5, and 55.0 months, and 4-year overall survival (OS) rates were 11%, 16%, 36%, and 52%, respectively, for acute, lymphoma, chronic, and smoldering types. The number of patients with allogeneic hematopoietic stem cell transplantation was 227, and their median survival time and OS at 4 years after allogeneic hematopoietic stem cell transplantation was 5.9 months and 26%, respectively. This study revealed that the prognoses of the patients with acute and lymphoma types were still unsatisfactory, despite the recent progress in treatment modalities, but an improvement of 4-year OS was observed in comparison with the previous survey. Of note, one-quarter of patients who could undergo transplantation experienced long survival. It is also noted that the prognosis of the smoldering type was worse than expected.

[Two cases of acute hepatitis E infected with descendant strains of hepatitis E virus genotype 3 strain isolated from swine herd in Miyazaki Prefecture 12 years ago - one case had acute facial paralysis].

We experienced two cases of acute hepatitis E in Miyazaki Prefecture in the same period. The patients were unknown to each other and did not have any clear causes or common risk factors of hepatitis E virus (HEV) infection. Nucleotide sequences of the HEV isolates revealed that the two isolates were closely related but with different HEV genotype 3 strains. The two cases appeared to be infected from unknown and different sources. Molecular phylogenetic analysis indicated that the strains were probably descendants of the strains which had been isolated from swine herd in Miyazaki Prefecture 12 years previously. This result indicates that the strains persisted in pig farms, in wild life, or in the natural environment in this region. The source should be identified, and efforts should be made to prevent of the spread of the infection. One of the cases had acute facial paralysis, which might be an extra-hepatic manifestation of HEV infection.

Image sensor pixel with on-chip high extinction ratio polarizer based on 65-nm standard CMOS technology.

In this study, we demonstrate a polarization sensitive pixel for a complementary metal-oxide-semiconductor (CMOS) image sensor based on 65-nm standard CMOS technology. Using such a deep-submicron CMOS technology, it is possible to design fine metal patterns smaller than the wavelengths of visible light by using a metal wire layer. We designed and fabricated a metal wire grid polarizer on a 20 × 20 µm(2) pixel for image sensor. An extinction ratio of 19.7 dB was observed at a wavelength 750 nm.

Comparison of autologous hematopoietic cell transplantation and chemotherapy as postremission treatment in non-M3 acute myeloid leukemia in first complete remission.

UNLABELLED: Randomized trials of acute myeloid leukemia (AML) in first complete remission (CR1) showed that autologous hematopoietic cell transplantation (auto-HCT) improves relapse-free survival (RFS) but not overall survival (OS), compared with chemotherapy. Using a database of 2518 adult patients with AML in CR1, we conducted a 5-month landmark analysis and found that auto-HCT improves 3-year RFS but not OS compared with chemotherapy. INTRODUCTION: A number of randomized trials in patients with AML in CR1 have been conducted and they showed that auto-HCT improves RFS but not OS, compared with chemotherapy. However, because these trials have had compliance problems, the value of auto-HCT still has not been clearly established. PATIENTS AND METHODS: Using a database of 2518 adult patients with AML in CR1, we retrospectively analyzed the outcome of auto-HCT and compared it with intensive nonmyeloablative chemotherapy using landmark analyses. RESULTS: In 103 auto-HCT recipients, OS and RFS at 3 years from treatment were 65% and 57%, respectively. Multivariate analysis showed that unfavorable risk cytogenetics and entry into CR1 after 2 courses of induction treatment predicted a poor outcome. Because the median time interval between CR1 and auto-HCT was 153 days, landmark analyses at 5 months after CR1 were performed to compare 1290 patients who received chemotherapy alone (median age, 52 years; range, 16-70) with 103 who received auto-HCT (median age, 48 years; range, 16-67). Auto-HCT improves 3-year RFS (58% vs. 37%; P < .001) but not OS compared with chemotherapy alone. Among patients with unfavorable risk cytogenetics or those who required 2 courses to reach CR1, there was no significant difference in RFS between the 2 groups. CONCLUSION: Auto-HCT can be considered as a postremission therapy for AML patients with favorable or intermediate risk cytogenetics who achieve CR1 after a single course of induction treatment.

Acute myeloid leukemia in clinical practice: a retrospective population-based cohort study in Miyazaki Prefecture, Japan.

We performed a retrospective population-based cohort study of acute myeloid leukemia (AML) in Miyazaki Prefecture, Japan. Over 6 years, we diagnosed 221 patients (211 adults and 10 children) with AML, indicating an incidence of AML in Miyazaki Prefecture of 3.2 per 100,000 per year. In 193 adult patients with non-acute promyelocytic leukemia (APL), the proportion of patients with myelodysplasia, unfavorable risk karyotypes, antecedent hematologic diseases, prior chemotherapy for other malignancies, and small proportion of blasts in the marrow was higher in patients ≥65 years, and patients with poor performance status (PS) and higher WBC counts at diagnosis were more prevalent among patients ≥75 years. One-third of the adult non-APL patients met the inclusion criteria usually applied in clinical trials: de novo AML, age ≤64 years with PS 0-2 and no key organ dysfunction. The 5-year overall survival (OS) rate of adult non-APL patients was 21.1 % (patients ≤64 years, 33.8 %; 65-74 years, 21.6 %; ≥75 years, 0 %). Multivariate analysis revealed that French-American-British subtypes M0, M6, and M7, poor PS (3, 4), unfavorable risk karyotypes, and higher WBC counts at diagnosis were independent adverse prognostic factors associated with OS. This analysis provides real world data.

Prognostic index for acute- and lymphoma-type adult T-cell leukemia/lymphoma.

PURPOSE: The prognosis of acute- and lymphoma-type adult T-cell leukemia/lymphoma (ATL) is poor, but there is marked diversity in survival outcomes. The aim of this study was to develop a prognostic index (PI) for acute- and lymphoma-type ATL (ATL-PI). PATIENTS AND METHODS: In a retrospective review, data from 807 patients newly diagnosed with acute- and lymphoma-type ATL between January 2000 and May 2009 were evaluated. We randomly divided subjects into training (n = 404) and validation (n = 403) samples, and developed a PI using a multivariable fractional polynomial model. RESULTS: Median overall survival time (MST) for the 807 patients was 7.7 months. The Ann Arbor stage (I and II v III and IV), performance status (0 to 1 v 2 to 4), and three continuous variables (age, serum albumin, and soluble interleukin-2 receptor [sIL-2R]) were identified as independent prognostic factors in the training sample. Using these variables, a prognostic model was devised to identify different levels of risk. In the validation sample, MSTs were 3.6, 7.3, and 16.2 months for patients at high, intermediate, and low risk, respectively (P < .001; χ(2) = 89.7, 2 df; log-rank test). We also simplified the original ATL-PI according to dichotomizing age at 70 years, serum albumin at 3.5 g/dL, and sIL-2R at 20,000 U/mL and developed an easily calculable PI with prognostic discrimination power (P < .001; χ(2) = 74.2, 2 df; log-rank test). CONCLUSION: The ATL-PI is a promising new tool for identifying patients with acute- and lymphoma-type ATL at different risks.

Clinical features and treatment outcomes of isolated secondary central nervous system lymphomas in Miyazaki Prefecture.

BACKGROUND: Secondary central nervous system lymphoma (SCNSL) without extra-central nervous system (CNS) involvement is characterized by isolated secondary CNS relapse in malignant lymphoma patients. SCNSL is a rare disease, and no standard treatment has yet been established. PATIENTS AND METHODS: To elucidate the clinical characteristics and outcomes of SCNSL, we retrospectively analyzed 12 patients (median age 67 years) in Miyazaki prefecture for the last 5 years. RESULTS: The initial histological diagnoses of the patients were diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma, and adult T-cell lymphoma in 9, 2, and 1 patient, respectively. We focused on analysis of the 9 SCNSL cases originating from DLBCL. The locations of CNS relapse were the cerebral hemisphere, basal ganglia, and cerebellum in 7, 1, and 1 patient, respectively. Three patients were treated with high-dose methotrexate (HD-MTX) therapy; 4 with whole-brain radiation therapy (WBRTX); and 1 with both HD-MTX and WBRTX. The remaining patients were treated with rituximab. Partial remission was achieved in 6 out of 9 patients (67%); the other 3 patients (33%) did not respond to therapy. Median survival of the 9 patients with CNS relapse was 253 days; 6 of the 9 patients survived for more than 6 months. As of March 2011, 2 HD-MTX group patients but none of the WBRTX group patients were alive. CONCLUSIONS: In this retrospective study, 6 of 9 patients with SCNSL originating from DLBCL survived for more than 6 months. Both HD-MTX and WBRTX had clinical benefits in the treatment of SCNSL.

Cavity-resonator-integrated grating input/output coupler for high-efficiency vertical coupling with a small aperture.

A cavity-resonator-integrated grating input/output coupler (CRIGIC) is designed to operate at about 850 nm wavelength for high-efficiency vertical coupling of a guided wave and a free-space wave with a small aperture. The CRIGIC consists of a grating coupler and a waveguide cavity resonator constructed by two distributed Bragg reflectors. A coupling efficiency of 96% with a 3 dB bandwidth of 1.2 nm is predicted by a theoretical calculation. An output coupling efficiency of about 60% is experimentally demonstrated on a 20 microm aperture device, fabricated in a thin-film SiO(2)-based waveguide on a substrate with an Au reflection layer, for what we believe to be the first time.

THP-COP regimen for the treatment of peripheral T-cell lymphoma and adult T-cell leukemia/lymphoma: a multicenter phase II study.

OBJECTIVE: The efficacy of pirarubicin (THP)-COP was previously compared with cyclophophamide + doxorubicin + vincristine + prednisolone (CHOP) in elderly patients with lymphoma. The subset analysis showed that T-cell lymphoma had a significantly better response with THP-COP, whereas no such difference was observed in B-cell lymphoma. The aim of this study is to confirm the efficacy of THP-COP in the treatment of T-cell lymphoma. METHODS: We underwent a multicenter phase II study of THP-COP as a first-line treatment for T-cell lymphoma. The overall response rate, survival period, and toxicity were analyzed. RESULTS: Fifty-three patients were enrolled in this study. Seventeen patients had peripheral T-cell lymphoma (PTCL), including nine of PTCL not otherwise specified (PTCL-NOS) and eight of angioimmunoblastic T-cell lymphoma (AITL). Thirty-six patients had adult T-cell leukemia/lymphoma (ATLL), including 20 of acute type and 16 of lymphoma type. A treatment response was obtained in 35 (66%) patients, including 17 (32%) complete responses. Median overall survival (OS) and progression-free survival (PFS) times were 14.3 months and 5.2 months, respectively. Patients with ATLL showed a tendency to obtain low response rate (61% vs. 77%, P = 0.27) and had a significantly inferior OS (13.3 vs. 28.6 months, P = 0.04) and PFS (4.6 vs. 8.1 months, P = 0.01) in comparison with PTCL. Grade 3 to 4 neutropenia, anemia, and thrombocytopenia occurred in 72%, 34%, and 58% of the patients, respectively. Febrile neutropenia was observed in 51% and grade 3 non-hematological toxicities in 2-9% of the patients. CONCLUSION: The efficacy of THP-COP is equivalent to that of CHOP for the first-line therapy in T-cell lymphoma.

Efficacy of intravenous ciprofloxacin in patients with febrile neutropenia refractory to initial therapy.

We previously reported that monotherapy with carbapenem or cefepime exhibited efficacy equivalent to cefepime plus an aminoglycoside as initial therapy for febrile neutropenia (FN), achieving an adequate response in two-thirds of the patients. However, only one-third of the remaining poor responders to monotherapy became afebrile after an aminoglycoside was added to the initial carbapenem or cefepime. The present study was designed to evaluate the benefit of intravenous ciprofloxacin for neutropenic patients with fever who were refractory to initial therapy given for the first 3 days. Patients with FN--as defined by an axillary temperature >or=37.5 degrees C and a neutrophil count <1,000/microL-who had no response to initial therapy with carbapenem or cefepime for 72 hours were to receive additional ciprofloxacin 600 mg/day. They were otherwise managed according to the Japanese guidelines for FN. An adequate response was defined as a decline of temperature to <37.5 degrees C within 7 days after initiation of ciprofloxacin treatment. Thirty-one patients with FN (seventeen male and fourteen female; mean age 53.1 +/- 14.8 years) were entered in the study. The initial antibiotics were cefepime (2 - 4 g/day) in twenty and carbapenem (1 - 2 g/day) in eleven. Three patients were excluded from analysis, leaving 28 patients for evaluation of efficacy. The response rate was 16/31 patients (51.6%),with four patients judged non-assessable due to adverse effects, protocol violation or early change to other agents. Adverse events occurred in seventeen patients, but all were mild and reversible. Only three patients had adverse events (skin rash, hepatic dysfunction and elevation of alkaline phosphatase in one patient, respectively) considered related to ciprofloxacin. These findings indicate that addition of intravenous ciprofloxacin is effective against FN refractory to initial antibiotic therapy and has acceptable toxicity.

Possible involvement of neutrophils in a serum level increase of hepatocyte growth factor in non-Hodgkin's lymphoma.

Serum levels of hepatocyte growth factor (HGF), a potent angiogenic factor, increase during various haematological malignancies. In this study, we examined serum HGF in 59 patients with non-Hodgkin's lymphoma (NHL). Serum HGF levels in NHL patients were increased, as were levels in patients with multiple myeloma, chronic myeloproliferative disorders, and myelodysplastic syndrome. Some 29 patients with T-cell lymphoma, including 20 with adult T-cell leukemia/lymphoma, exhibited a significant increase in serum HGF, as did 23 with B-cell lymphoma. The levels of serum HGF correlated with increased neutrophil counts (r=0.487, p<0.0001), and also paralleled a neutrophil increase in NHL patients who received granulocyte-colony stimulating factor (G-CSF) at the nadir of neutrophil count following chemotherapy. Additionally, in in vitro experiments, HGF secretion from polymorphonuclear neutrophils and its expression in bone marrow myeloid cells were stimulated by G-CSF. Although HGF has been thought to be involved in the pathogenesis of NHL through its angiogenic activities, these results suggest that HGF production by neutrophils and myeloid lineage cells may also contribute to an increase in serum HGF in NHL patients.

Telomerase activity and telomere length as prognostic factors of adult T-cell leukemia.

For the oncogenesis of many malignancies, it is crucial to prevent the shortening of the telomeres by the action of telomerase. In this study, clinical data and disease outcomes were analyzed in conjunction with the telomerase activity (TA) and telomere length (TL) of peripheral blood mononuclear cells. The study was carried out in 22 patients with adult T-cell leukemia (ATL) (7 chronic and 15 acute types) and in 13 asymptomatic human T-lymphotropic virus type 1 (HTLV-1) carriers. The mean values of TA in acute and chronic type patients were 13.8 and 1.6 total product generated (TPG) units, respectively, as determined by telomeric repeat amplification assays. The mean TA values in HTLV-1 carriers and healthy volunteers were 1.8 and 0.7 TPG, respectively. The mean TA value in acute type patients was significantly higher than in the three other subject groups. The mean TL values in patients with acute and chronic types were 5.39 and 4.38 Kb, respectively, while the mean TL values in HTLV-1 carriers and healthy volunteers were 7.69 and 7.06 Kb, respectively. The mean TL values in all ATL patients and in non-ATL subjects were 5.2 and 7.3 Kb, respectively. The former value is significantly shorter than the latter (p < 0.01). Neither TA nor TL of ATL cells showed any significant association with the number of ATL cells, serum soluble interleukin-2 receptor, or serum lactate dehydrogenase in the peripheral blood of acute type patients. This suggests that the levels of TA and TL did not reflect the ATL tumor load. The median survival period of acute ATL patients with high TA and shortened TL was 0.47 years, however, which was significantly shorter than that of acute ATL patients with low TA and normal TL (4.21 years) (p < 0.002). These data suggest that high TA and shortened TL were associated with poorer prognosis, and that TA and TL may be novel markers for the prognosis of ATL patients.