Prevalence of chromosome 8p11.2 translocations and correlation with myeloid and lymphoid neoplasms associated with FGFR1 abnormalities in a consecutive cohort from nine institutions in Japan.

Myeloid and lymphoid neoplasms associated with FGFR1 abnormalities (MLN-FGFR1 abnormalities) are rare hematologic malignancies associated with chromosome 8p11.2 abnormalities. Translocations of 8p11.2 were detected in 10 of 17,039 (0.06%) unique patient cytogenetic studies performed at nine institutions in Japan. No inversions or insertions of 8p11.2 were detected. Among the 10 patients with 8p11.2 translocations, three patients were diagnosed with MLN-FGFR1 abnormalities, which were confirmed by FISH analysis. Peripheral blood eosinophilia was observed in all three patients, and all progressed to AML or T-lymphoblastic lymphoma/leukemia. The prevalence of 8p11.2 translocations in clinical practice and the proportion of MLN-FGFR1 abnormalities in patients with 8p11.2 translocations in Japan were consistent with those in previous reports from Western countries.

Integrated genetic and clinical prognostic factors for aggressive adult T-cell leukemia/lymphoma.

The prognosis of aggressive adult T-cell leukemia/lymphoma (ATL) is poor, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment. In order to identify favorable prognostic patients after intensive chemotherapy, and who therefore might not require upfront allo-HSCT, we aimed to improve risk stratification of aggressive ATL patients aged <70 years. The clinical risk factors and genetic mutations were incorporated into risk modeling for overall survival (OS). We generated the m7-ATLPI, a clinicogenetic risk model for OS, that included the ATL prognostic index (PI) (ATL-PI) risk category, and non-silent mutations in seven genes, namely TP53, IRF4, RHOA, PRKCB, CARD11, CCR7, and GATA3. In the training cohort of 99 patients, the m7-ATLPI identified a low-, intermediate-, and highrisk group with 2-year OS of 100%, 43%, and 19%, respectively (hazard ratio [HR] =5.46; P<0.0001). The m7-ATLPI achieved superior risk stratification compared to the current ATL-PI (C-index 0.92 vs. 0.85, respectively). In the validation cohort of 84 patients, the m7-ATLPI defined low-, intermediate-, and high-risk groups with a 2-year OS of 81%, 30%, and 0%, respectively (HR=2.33; P=0.0094), and the model again outperformed the ATL-PI (C-index 0.72 vs. 0.70, respectively). The simplified m7-ATLPI, which is easier to use in clinical practice, achieved superior risk stratification compared to the ATLPI, as did the original m7-ATLPI; the simplified version was calculated by summing the following: high-risk ATL-PI category (+10), low-risk ATL-PI category (-4), and non-silent mutations in TP53 (+4), IRF4 (+3), RHOA (+1), PRKCB (+1), CARD11 (+0.5), CCR7 (-2), and GATA3 (-3).

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.

Clinical significance of soluble CADM1 as a novel marker for adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/leukemia (ATLL) is an aggressive peripheral T-cell malignancy, caused by infection with the human T-cell leukemia virus type 1 (HTLV-1). We have recently shown that cell adhesion molecule 1 (CADM1), a member of the immunoglobulin superfamily, is specifically and consistently overexpressed in ATLL cells, and functions as a novel cell surface marker. In this study, we first show that a soluble form of CADM1 (sCADM1) is secreted from ATLL cells by mainly alternative splicing. After developing the Alpha linked immunosorbent assay (AlphaLISA) for sCADM1, we showed that plasma sCADM1 concentrations gradually increased during disease progression from indolent to aggressive ATLL. Although other known biomarkers of tumor burden such as soluble interleukin-2 receptor α (sIL-2Rα) also increased with sCADM1 during ATLL progression, multivariate statistical analysis of biomarkers revealed that only plasma sCADM1 was selected as a specific biomarker for aggressive ATLL, suggesting that plasma sCADM1 may be a potential risk factor for aggressive ATLL. In addition, plasma sCADM1 is a useful marker for monitoring response to chemotherapy as well as for predicting relapse of ATLL. Furthermore, the change in sCADM1 concentration between indolent and aggressive type ATLL was more prominent than the change in the percentage of CD4+CADM1+ ATLL cells. As plasma sCADM1 values fell within normal ranges in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients with higher levels of serum sIL-2Rα, a measurement of sCADM1 may become a useful tool to discriminate between ATLL and other inflammatory diseases, including HAM/TSP.

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.

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).

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.

Higher reliability and validity of Baba classification with computerised tomography imaging and implant information for periprosthetic femoral fractures.

PURPOSE: Baba classification for periprosthetic femoral fracture focuses on the positional relationship between the implant design and fracture site. The objective of this study was to investigate whether the addition of CT images and implant information to plain radiograms increases the reliability of Baba classification to a level higher than that of Vancouver classification. METHODS: Twenty patients were randomly selected from 61 patients with periprosthetic femoral fracture between 2009 and 2014. After Vancouver and Baba classifications were fully explained to six orthopedic surgeons (three experts and three non-experts), plain radiograms, CT imaging and implant information at the time of injury were presented, and the inter- and intra-observer reliability based on the Vancouver and Baba classifications and accuracy rates of stem stability were investigated. RESULTS: When interobserver reliability was made based on only radiograms, the mean κ value of Baba classification-based judgments made by the experts was 0.76, and those of Vancouver classification-based judgments made by the experts was 0.41. When interobserver reliability was made based on the radiograms and CT images and implant information, the mean κ value of Baba classification-based judgments made by the experts was 0.94, and those of Vancouver classification-based judgments were 0.48. Intra-observer reliability of Baba classification was 0.81 in the experts. Validity analysis showed 95.0% agreement within all subgroups. CONCLUSIONS: Reliability and validity of Baba classification was improved when additional information was given. We believe that this new classification is useful to establish a therapeutic strategy for femoral fractures around the stem.

Delayed sciatic nerve injury by posterior flange of reinforcement ring after acetabular revision surgery.

Delayed onset of sciatic neuropathy after total hip arthroplasty is uncommon, and late hardware-induced sciatic nerve complications are rarely reported. Here, we report a patient in whom the posterior flange of the reinforcement ring caused severe late sciatic nerve injury. Sciatic nerve radiography was useful for diagnosing flange-related sciatic nerve injury.

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.

Severe subluxation of the femoral head after rotational acetabular osteotomy: a case report.

We encountered a rare case of severe subluxation of the femoral head after the performance of rotational acetabular osteotomy to treat osteoarthritis of the hip, secondary to acetabular dysplasia. The subluxation was corrected by performing varus and flexion osteotomy.

Combined preoperative autologous blood donation and intra-operative cell salvage for hip surgery.

PURPOSE: To review records of 161 consecutive hip surgery patients for whom preoperative autologous blood donation (PABD) was used in combination with intra-operative cell salvage (ICS). METHODS: 114 women and 14 men aged 41 to 86 (mean, 64) years underwent 135 primary total hip arthroplasties (THAs), whereas 19 women and 7 men aged 16 to 52 (mean, 35) years underwent 26 rotational acetabular osteotomies (RAOs). Two or 3 weeks before the operation, patients deposited one unit (400 ml) of blood weekly, so long as their haemoglobin levels exceeded 110 g/l (if they had osteoarthritis) or 100 g/l (if they had rheumatoid arthritis). Patients were given oral ferrous sulphate, lactated Ringer's solution, and recombinant human erythropoietin. 800 and 1200 ml of blood were deposited for patients undergoing THA and RAO, respectively. Intra-operatively, ICS was carried out using a continuous autotransfusion system. The blood from ICS was transfused first, and then the blood from PABD was transfused during the latter half of the operation. RESULTS: By combining PABD and ICS, homologous blood transfusion was avoided in all patients, even in those with unexpected massive bleeding during surgery. In 3 patients, one unit of deposited autologous blood was discarded, because they showed no sign of anaemia. The mean total blood loss was almost 1.5 times higher in RAO than in THA patients (1095 vs 1550 ml). In the THA and RAO patients respectively, the mean amount of ICS was 181 and 210 ml, whereas the mean total blood transfusion volume was 975 and 1394 ml. No complications (including infection) related to autologous blood transfusion were observed during PABD, the surgery or the postoperative period. CONCLUSION: Homologous blood transfusion was avoided with the use of PABD and ICS. Preoperative donation of 800 and 1200 ml of blood (combined with ICS) seemed optimal, as only 3 units of blood were discarded.

Subcapital femoral neck fracture after fixation of an intertrochanteric fracture with a proximal femoral nail: a report of two cases.

Subcapital femoral neck fractures are a rare complication after fixation of an intertrochanteric fracture with a proximal femoral nail. We report 2 such cases where the patients had severe osteoporosis, based on Singh's index and pathological findings. In one case there was a technical error leading to a tip-apex distance of more than 20 mm, but osteoporosis appeared to be a more significant cause than any technical problems.

Influence of living style and situation on the compliance of taking antihypertensive agents in patients with essential hypertension.

BACKGROUND: As the reason for insufficient control of blood pressure (BP), poor compliance of taking antihypertensive agents is an important issue. In Japan, no prospective study on the compliance of antihypertensive agents has been done. In this study we prospectively investigated the details of the relationship between the compliance of taking antihypertensive agents and living style and situation in hypertensive patients. METHODS: We prospectively examined 121 outpatients with essential hypertension treated with antihypertensive agents for 12 months. Using an oral interview based on the questionnaire sheet, the factors about living style and situations which worsen the compliance were assessed. Also we evaluated the relationship of BP control and season, which was compared between patients with poor compliance and those with good compliance. RESULTS: As for the background of the poor compliance, many factors related to the patients' living style and situation were clarified. On average for 12 months the levels of the compliance and BP showed a significant negative correlation and BP was significantly higher in patients with poor compliance than those with good compliance. However, in the summer season BP did not differ between patients with poor and good compliance, CONCLUSION: Many factors regarding the patients' living style and situation were related to poor compliance. The development of strategy that changes these factors is a future task for improving compliance. This study may also imply that unnecessary antihypertensive agents are prescribed in some patients with poor compliance in the summer season. Determination of the suitable prescription by which to attain optimal individual patients' compliance is important in the treatment of hypertensive patients.

Rotational acetabular osteotomy for osteonecrosis of the femoral head after intracapsular fracture of the neck of the femur.

The treatment of osteonecrosis of the femoral head in younger patients varies among orthopaedic surgeons. In particular, the optimal treatment of extensive osteonecrosis associated with femoral head collapse remains controversial. Since 1995, we have performed rotational acetabular osteotomy on 70 hips, including those of 3 patients with extensive osteonecrosis of the femoral head after intracapsular fracture of the neck of the femur. In all 3 patients, adequate coverage of the femoral head by the osteotomized acetabulum was obtained, and their symptoms (especially pain) showed marked improvement at latest follow-up.

Rapid resolution of femoral head osteonecrosis after rotational acetabular osteotomy.

The natural history of osteonecrosis of the femoral head is generally thought to be one of progressive deterioration if no intervention is undertaken. However, it is unknown whether surgical intervention is beneficial for patients with a small region of osteonecrosis. We observed rapid improvement of MRI findings after rotational acetabular osteotomy (RAO) was performed in a young patient with osteonecrosis of the femoral head. The band-like low signal area on T2-weighted images almost resolved by six months after surgery. He returned to work as an electrician by six months after surgery. Early surgical intervention such as RAO that alters the mechanical force acting on the necrotic region of the femoral head may accelerate the recovery of osteonecrosis and the improvement of symptoms.

Phase I study of the combination of irinotecan hydrochloride, carboplatin, and dexamethasone for the treatment of relapsed or refractory malignant lymphoma.

A phase I study of irinotecan hydrochloride (CPT-11), carboplatin, and dexamethasone treatment in 7 patients with relapsed lymphoma and 7 patients with refractory lymphoma was conducted to evaluate the maximal tolerated dose. The 6 female and 8 male patients had a median age of 63 years (range, 45-73 years), a median performance status of 0 (range, 0-2), and a median disease stage of IV. This study included patients with diffuse large B-cell lymphoma (n = 5), adult T-cell leukemia/lymphoma (n = 2), mantle cell lymphoma (n = 2), follicular lymphoma (n = 2), angioimmunoblastic T-cell lymphoma (n = 1), anaplastic large cell lymphoma (n = 1), and Hodgkin's lymphoma (n = 1). All patients had received anthracycline-containing combination chemotherapy prior to this therapy. The starting dosage of CPT-11 was 15 mg/m2 per day (days 1-3 and 8-10), and dosage-escalation increments of 5 mg/m2 per day were planned, with fixed dosages of carboplatin (250 mg/m2 per day, day 1) and dexamethasone (40 mg/body, days 1-3 and days 8-10). Five patients were enrolled at level 1, 3 at level 2, 4 at level 3, and 2 at level 4. Ten patients (71%) and 11 patients (79%) experienced grade 3 or 4 hematologic toxicities of leukocytopenia and neutropenia, respectively. Three patients (29%) and 9 patients (64%) experienced grade 3 or 4 thrombocytopenia and anemia, respectively. Two patients who received 30 mg/m2 (level 4) of CPT-11 developed sepsis. We concluded that the recommended dose of CPT-11 with carboplatin and dexamethasone is 25 mg/m2. No deaths were related to this chemotherapy, and no patient developed liver dysfunction. The overall response rate was 36%. We conclude that the combination therapy of CPT-11, carboplatin, and dexamthasone is effective as salvage therapy but that the duration of response is too short.

[Infection control for the treatment of hematological malignancies: a survey of the Kyushu Hematology Organization for Treatment Study Group (K-HOT)].

The Kyushu Hematology Organization for Treatment Study Group (K-HOT) consisted of 22 institutions specializing in hematology in Kyushu. This study is aimed at reviewing the daily practice of infection control for the treatment of hematological malignancies in our group. Nominal questionnaires were mailed to the hematology department in each institution from November 2001 to April 2002. For the first general surveys, 19 of 22 (86%) institutions responded. The second survey was mailed to the 19 respondents and 17 answered the detailed questionnaires with a response rate of 89%. Prophylactic use of trimethoprim-sulfamethoxazole (ST) against Pneumocystis carinii and anti-mycobacterial drugs in patients who had a history of tuberculosis was routine especially for patients with adult T-cell leukemia/lymphoma (ATL). Furthermore, the neutrophil counts to start a granulocyte-colony stimulating factor appeared to be high in ATL as compared with other hematological malignancies. In the setting of autologous stem cell transplantation (SCT), prophylactic use of acyclovir, immunoglobulin and ST was not routine and was reduced in duration, if used at all, as compared with allogeneic SCT. For allogeneic SCT, the cumulative dose of immunoglobulin significantly varied from institutions to institutions. The benefit of this study is the ability to recognize practical management patterns for infection control.