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Graft-versus-host-disease-free, relapse-free survival (GRFS) is a useful composite endpoint that measures survival without relapse or significant morbidity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aimed to develop a novel analytical method that appropriately handles right-censored data and competing risks to understand the risk for GRFS and each component of GRFS. This study was a retrospective data-mining study on a cohort of 2207 adult patients who underwent their first allo-HSCT at the Kyoto Stem Cell Transplantation Group (KSCTG), a multi-institutional joint research group of 17 transplantation centers in Japan. The primary endpoint was GRFS. A stacked ensemble of Cox proportional hazard regression and seven machine learning algorithms was applied to develop a prediction model. The median age of patients was 48 years. For GRFS, the stacked ensemble model achieved better predictive accuracy evaluated by C-index than other top-of-the-art competing risk models (ensemble model: 0.670, Cox-PH: 0.668, Random Survival Forest: 0.660, Dynamic DeepHit: 0.646). The probability of GRFS after 2 years was 30.54% for the high-risk and 40.69% for the low-risk group, respectively (hazard ratio [HR] compared to the low-risk group: 2.127; 95% CI: 1.19-3.80). We developed a novel predictive model for survival analysis that showed superior risk stratification to existing methods using a stacked ensemble of multiple machine learning algorithms., アンサンブル学習を用いた造血幹細胞移植予後予測モデルの開発 --機械学習を用いた新規生存時間解析手法の実装--. 京都大学プレスリリース. 2021-12-28.

Since the introduction of leukemia-type induction therapies for T-cell lymphoblastic lymphoma (T-LBL), improvements in the long-term outcomes of T-LBL have been reported. However, indications for and the appropriate timing of hematopoietic stem cell transplantation (HSCT) have not yet been established. Therefore, we performed a multicenter retrospective cohort study of patients with T-LBL treated using leukemia-type initial therapies to compare the outcomes after HSCT at different disease stages. We enrolled 21 patients with T-LBL from a total of 11 centers, and all patients received hyper-CVAD as a leukemia-type initial regimen. HSCT was performed during the CR1/PR1 (standard disease) stage in 11 patients, while it was completed at a later or non-remission (advanced disease) stage in 10 patients. Following HSCT, the overall survival rate was significantly greater in standard disease than in advanced-disease patients (79.5% vs. 30.0% at 5 years; hazard ratio (HR) 5.97; p = 0.03), with trend to the lower incidence of relapse in the former group (27.3% vs. 60.0% at 5 years; HR 2.29; p = 0.19). A prognostic difference was not detected between cases treated with allogeneic and autologous HSCTs. Our study suggests that frontline HSCT may be a feasible treatment option for T-LBL, even in the era of leukemia-type initial therapy.

[Objectives:] We conducted a phase II trial to prospectively evaluate the efficacy and safety of bortezomib-cyclophosphamide-dexamethasone (VCD) induction, autologous stem cell transplantation (ASCT), VCD consolidation, and bortezomib maintenance in transplant-eligible newly diagnosed multiple myeloma (NDMM) patients in Japan (UMIN000010542). [Methods:] From 2013 to 2016, 42 patients with a median age of 58 (range 42–65) years with NDMM were enrolled in 15 centers. The primary endpoint was the complete response (CR) /stringent CR (sCR) rate after transplantation, and overall/progression-free survival rates were also evaluated. [Results:] Following induction therapy, the overall response rate was obtained in 71% of patients, including a CR/sCR of 10% and a very good partial response (VGPR) of 26%. Twenty-six of the 42 patients completed ASCT following the protocol and CR/sCR and VGPR rate 100 days after ASCT was 26% and 17%, respectively. During consolidation therapy, 3 of the 24 patients achieved deeper responses. Eight of the 18 patients completed 2-year bortezomib maintenance without disease progression and grade 3/4 toxicities. Five patients were VGPR or partial response after ASCT but maintained response with 2-year bortezomib maintenance. Two-year overall and progression-free survival rates were 92.5% (95% confidence interval [CI]: 78.5%−97.5%) and 62.6% (95% CI: 45.8%−75.5%), respectively. Grade 3/4 toxicities (≥ 10%) included neutropenia (19%) and anemia (17%) in induction, and thrombocytopenia (29%) in consolidation. [Conclusion:] VCD induction/consolidation and bortezomib maintenance with ASCT for NDMM resulted in a high CR/sCR rate and provided good overall/progression-free survival in Japan.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive inherited disorder characterized by bone marrow failure, exocrine pancreatic dysfunction, and skeletal abnormalities. SDS is typically caused by a pathogenic mutation in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. Patients with SDS have an increased risk of developing acute myeloid leukemia (AML) and myelodysplastic syndromes. We identified germline biallelic SBDS mutations (p.K62X and p.I167M) in a 50-year-old AML patient who had never experienced the typical symptoms of SDS. The K62X mutation is one of the most common pathogenic mutations, whereas the significance of the I167M mutation was unclear. Based on cellular experiments, we concluded that the I167M mutation contributed to the development of AML, and chemotherapy including topoisomerase inhibitors, which induce DNA double-strand breaks, may have been toxic to this patient. Our experience indicates that some asymptomatic Shwachman-Bodian-Diamond syndrome mutations contribute to the development of leukemia, and that careful treatment selection may be warranted for patients harboring these mutations.

We report a case of acquired hypofibrinogenemia with multiple myeloma presenting λ-type IgG monoclonal protein. The patient had anemia and renal deficiency, and also developed bleeding tendency due to severe coagulopathy. Her fibrinogen level was under the detectable limits in a functional assay. Enzyme-linked immunosorbent assay (ELISA) and immunoblotting analysis results were consistent with functional assay results, and deficiency patterns observed in cross-mixing tests for PT and aPTT confirmed the diagnosis of hypofibrinogenemia. To determine the cause of hypofibrinogenemia, we purified the patient’s immunoglobulin via protein A agarose, and confirmed that fibrinogen was included in the bound fraction, strongly indicating paraprotein interference with fibrinogen. As accelerated removal of fibrinogen was indicated, we incubated the patient’s plasma up to 48 h, but did not observe significant loss of fibrinogen. In sharp contrast, fibrinogen returned to below the detection level 12 h after infusion of fresh frozen plasma. These findings support leukocyte-mediated fibrinogen removal, rather than paraprotein-triggered fibrinogen instability. Surprisingly, the patient’s paraprotein was IgG2, but we speculate the amount of paraprotein (IgG 5346 mg/dL) compensated for lower affinity to Fcγ receptors.

Autologous stem cell transplantation (ASCT) with high-dose thiotepa and busulfan is a treatment option for patients with central nervous system (CNS) lymphoma. We report here the occurrence of secondary failure of platelet recovery (SFPR) in three out of 24 patients who received high-dose thiotepa and busulfan followed by ASCT. Although there was no obvious abnormality in the primary platelet engraftment as well as the recovery of other blood cells, they developed SFPR with a median time to onset of day 38, and the platelets gradually recovered over several months with steroid therapy. During the same period, there was no development of SFPR among 50 patients who received ASCT with a conditioning regimen of MEAM (ranimustine, etoposide, cytarabine, and melphalan) or high-dose melphalan. However, one of the two patients who received a conditioning regimen of busulfan and melphalan developed SFPR, suggesting that the use of a busulfan-based conditioning regimen may be one of the risk factors for SFPR. It is important to be aware of this possible adverse effect of ASCT with high-dose thiotepa and busulfan to ensure timely diagnosis and prevention of subsequent serious complications.

The intestinal microbiota plays an important role in the pathogenesis of acute graft-versus-host disease (aGVHD). During the course of hematopoietic stem cell transplantation (HSCT), the intestinal microbiota is influenced by the use of broad-spectrum antibiotics. However, the impact of the use and type of antibiotics on the microbiota composition and, subsequently, the onset of aGVHD remain poorly understood. We hypothesized that the use and type of antibiotics had an impact on the occurrence of aGVHD. We assessed 275 patients who underwent their first allogeneic HSCT between January 2005 and June 2015 at Kyoto University Hospital. We monitored the 6 most frequently administered antibiotics (fourth-generation cephalosporins, glycopeptides, piperacillin-tazobactam, carbapenems, aminoglycosides, and quinolones) administered between days –14 and +14 relative to HSCT and its duration. The primary endpoint was the cumulative incidence of grades II to IV aGVHD. The cumulative incidence of aGVHD was significantly higher in patients administered fourth-generation cephalosporins than in patients not receiving fourth-generation cephalosporins (grades II to IV: hazard ratio, 1.98; 95% confidence interval, 1.19 to 3.29; P = .0087; grades III to IV: hazard ratio, 8.03; 95% confidence interval, 1.07 to 60.51; P = .043). In contrast, there was no significant association between administration of other antibiotics and aGVHD incidence. As for organ-specific aGVHD, the cumulative incidence of gut aGVHD was significantly higher in patients who received fourth-generation cephalosporins than in those who did not (31% versus 16%, P = .018). In conclusion, we demonstrated that the administration of fourth-generation cephalosporins had a strong impact on the development of aGVHD.

In 2003, a 60-year-old man presenting with thrombocytosis was referred to our hospital. Laboratory tests revealed normal white blood cell count and hemoglobin level. Bone marrow examination showed an increased number of megakaryocytes with dysplasia. G-banded karyotype analysis revealed del (5q). Initially, the patient was diagnosed with myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and it was treated with aspirin and hydroxyurea. During the treatment course, fluorescence in situ hybridization for CSF1R and EGR1 was performed to detect del (5q), which showed negative results. In 2017, the patient had increased platelet count despite receiving treatment. A comprehensive genomic profiling revealed that the deleted region in this case was present in 5q14-5q23, which was different from the common deleted region of 5q- syndrome (5q32-5q33, where CSF1R was present) and that of high-risk MDS or acute myeloid leukemia (5q31, where EGR1 was present). Moreover, a CALR mutation was also detected. This case met the diagnostic criteria of essential thrombocythemia. The platelet count decreased with the administration of anagrelide. In conclusion, comprehensive genetic profiling is very important, and it leads to accurate diagnosis and therapy.

A 61-year-old man was admitted to our hospital with fever and massive leukocytosis. A bone marrow smear revealed an increased density of myeloid cells in various stages of maturation as well as dysplasia in the neutrophils. There was no proliferation of blasts, eosinophils, or basophils. Genomic analysis of the bone marrow cells revealed no detectable abnormalities associated with myeloproliferative neoplasms, including BCR-ABL1. Therefore, the patient was diagnosed with atypical chronic myeloid leukemia (aCML). Chromosomal analysis revealed the presence of 1-17 double minute chromosomes (dmin) in 20 of 20 tumor cells examined. Multiple MYC signals were detected via interphase fluorescence in situ hybridization, indicating MYC gene amplification in the dmins. Three months after the oral administration of hydroxyurea, leukocytosis reoccurred. Therefore, induction therapy followed with umbilical cord blood transplantation was performed. However, MYC signals remained detectable in the bone marrow sample obtained immediately after neutrophil engraftment, indicating the presence of residual tumor cells. To the best of our knowledge, this is the first case report of aCML with dmin gene amplification, suggesting that the dmin MYC amplification exacerbated the patient's disease.

Therapeutic antibodies have heterogeneities in their structures, although its structural alteration in the body is unclear. Here, we analyzed the change of amino acid modifications and carbohydrate chains of rituximab after administration to patients. Twenty B cell non-Hodgkin’s lymphoma patients who were treated with rituximab for the first time or after more than one year’s abstinence were recruited. Structural analysis of rituximab was carried out at 1 h after administration and at the trough by using liquid chromatography/time-of-flight-mass spectrometry. Plasma rituximab concentration and pharmacodynamic markers were also determined. Of recruited twenty, 3 patients exhibited rapid rituximab clearance. Nine types of carbohydrate chains were detected in rituximab isolated from the blood. The composition ratios in some glycoforms were significantly different between at 1 h after administration and at the trough, although consisted amino acids remained unchanged. The patients with high clearance showed extensive alterations of glycoform composition ratios. However, pharmacodynamics makers were not different. Inter-individual variations in plasma concentrations of rituximab were found in some B-NHL patients. We could analyze a change in glycoforms of rituximab in the patients, and this finding may affect the pharmacokinetics of rituximab.

Autoimmune neutropenia (AIN) is a rare disorder that may cause life-threatening infections. In adults, most cases are secondary to other pathological conditions, and primary AIN is extremely rare. We herein report a case involving a 57-year-old woman diagnosed with AIN. A granulocyte immunofluorescence test detected autoantibodies against human neutrophil antigens in her serum, while various examinations revealed no other causes of neutropenia, suggesting her AIN was primary. She was refractory to granulocyte-colony-stimulating factor but responded to prednisolone. Her neutrophil count remained normal after gradual discontinuation of prednisolone. Diagnostic procedures and optimal treatments for this disorder need to be established.

Iron overload is considered a risk factor for mortality in patients with hematopoietic malignancies. Hepcidin is a key regulator of systemic iron balance. We previously reported dynamic changes of serum hepcidin‐25 levels in patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation (allo‐HSCT). In this study, we retrospectively analyzed the association of pretransplant hepcidin‐25 levels with overall survival (OS), engraftment, and other clinical outcomes of allo‐HSCT in patients with hematologic malignancies. A total of 166 patients were divided into two groups depending on their pretransplant serum hepcidin‐25 levels; their median age was 49.5 years, and the median follow‐up time was 46.8 months. At 3 years, the patients in the high‐hepcidin group had a significantly lower OS than those in the low‐hepcidin group (49.2 vs. 69.0%, respectively; P = 0.006). Multivariate analysis revealed that pretransplant serum hepcidin‐25 level, sex, and disease status were independently associated with OS. The incidence of platelet engraftment was significantly lower in the high‐hepcidin group than in the low‐hepcidin group, whereas no significant differences were observed in neutrophil and reticulocyte engraftments between these groups. Hence, pretransplant serum hepcidin levels can be a marker for predicting delayed platelet recovery after allo‐HSCT.

In this multicenter, single-arm, phase II study, the efficacy and safety of ibrutinib were examined in Japanese patients with relapsed or refractory mantle cell lymphoma (MCL). Patients (age ≥20 years) with relapsed or refractory MCL who had progressed after receiving at least one prior treatment regimen, were enrolled. Patients were treated with oral ibrutinib (560 mg once daily; 28-day cycle) until disease progression (or relapse), unacceptable toxicity, or study end. The primary end-point was overall response rate. Secondary end-points included duration of response (DOR), time to response, progression-free survival (PFS), overall survival, and safety. Of the 16 patients who received treatment, 5 patients discontinued the study (progressive disease, 4; sepsis, 1). Median duration of ibrutinib exposure was 6.5 months (range, 2.8-8.3 months). The overall response rate was 87.5% (90% confidence interval, 65.6-97.7; complete response = 2 [12.5%]; partial response = 12 [75.0%]). Median time to response for all responders (n = 14) was 1.8 months (range, 0.7-5.3 months). The median DOR and PFS were not estimable due to censoring (range: DOR, 1.1-6.4+ months; PFS, 2.8-8.0+ months). Overall survival data were immature due to the limited observation period. A total of 8/16 patients (50%) had at least one grade 3 adverse event (AE), and 5 (31.3%) patients reported serious AEs. The most commonly reported AEs were diarrhea and stomatitis (37.5% each), platelet count decrease (31.3%), and anemia (25%). Overall, orally administered single agent ibrutinib was efficacious with an acceptable safety profile in Japanese patients with relapsed or refractory MCL. Clinical trial registration NCT02169180 (ClinicalTrials.gov).

Neurolymphomatosis (NL) is a rare condition involving the infiltration of lymphoma cells into the peripheral nervous system. NL can be primary or secondary in the setting of an unknown or known hematologic malignancy, respectively. Here, we report five cases in which F-18 2-fluoro-2-deoxy-glucose positron emission tomography/computed tomography (F-18 FDG-PET/CT) had great value for diagnosing NL. Two cases were rare primary NL, and the other three were secondary NL. Clinical presentations were asymmetric sensorimotor disturbances in the extremities with or without involvement of cranial nerves. Furthermore, all patients experienced spontaneous pain in the face or affected extremities. Cerebrospinal fluid analysis was cytologically negative in two of five cases. Gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) detected abnormalities in the cranial nerves, nerve roots, and cauda equina in all cases except case 1 and the recurrent stage of case 2. F-18 FDG-PET/CT showed clear visualization of almost all the lymphomatous involvement of peripheral nerves and other tissues in all patients. Furthermore, F-18 FDG-PET/CT detected abnormalities including asymptomatic lesions that were not detected with MRI, and also identified the appropriate lesion for diagnostic biopsy. However, as in case 3, the lesions in the left oculomotor nerve and the cauda equina were detected only with Gd-enhanced MRI, which has superior spatial resolution. In conclusion, F-18 FDG-PET/CT is a sensitive modality that can suggest the presence of malignancy and identify appropriate places for diagnostic biopsies. It is especially useful when combined with Gd-enhanced MRI, even in patients with primary NL that is usually difficult to diagnose.

Background Staphylococcus epidermidis can cause nosocomial meningitis in the presence of prosthetic devices. We describe a case of Staphylococcus epidermidis meningitis in a patient with neutropenia who had no intracranial foreign body, and we review the literature on meningitis that is caused by coagulase-negative Staphylococcus spp. without a neurosurgical device. Case presentation A 47-year-old Japanese man with acute myeloid leukemia receiving chemotherapy through a totally implantable central venous catheter developed fever and headache. The patient had a history of craniotomy for anaplastic oligodendroglioma without an indwelling neurosurgical device. The results of two blood cultures and a cerebrospinal fluid culture were positive for Staphylococcus epidermidis. Clinical improvement was observed with treatment with vancomycin and removal of the central venous catheter despite prolonged neutropenia. Conclusions To the best of our knowledge, this is the first reported case of Staphylococcus epidermidis meningitis in a patient with neutropenia without a neurosurgical device who was successfully treated.

A 59-year-old woman presented with high serum total protein, detected on a screening examination. Laboratory tests revealed high plasma levels of M-protein (IgG-λ), and FDG-PET/CT revealed systemic lymph node swelling and a large tumorous mass in the abdominal cavity. Bone marrow aspirates contained 8.4% plasma cells and approximately 30% abnormal small lymphocytes. A biopsy of the left supraclavicular lymph node was initially interpreted as lymphoplasmacytic lymphoma (LPL). However, chromosomal analysis of the lymph node demonstrated an unusual karyotype with t (14;18) (q32;q21). FISH analysis for the IgH-BCL2 fusion gene was positive. Furthermore, the MYD88 L265P mutation was not detected in tumor cells. Based on these findings, this case was determined to be a type of follicular lymphoma with plasmacytic differentiation. We considered that this case was an important example emphasizing the importance of karyotypic examination for lymphoma classification.

The number of patients eligible for allogeneic stem cell transplantation (allo-HSCT) has increased because of improvements in transplantation procedures. Among long-term survivors of allo-HSCT, chronic kidney disease (CKD) is a major cause of morbidity. We retrospectively analyzed the clinical data of 106 consecutive patients with a median age of 43 years (range, 17 to 73) who had undergone allo-HSCT at our institution between January 2001 and September 2009. Patients who died within 5 years after transplantation or had CKD at the time of transplantation were excluded from study. CKD was defined as a persistent decrease in the estimated glomerular filtration rate to below 60 mL/min/1.73 m2. CKD occurred in 32 patients (30.2%) at a median time of 55 months after transplantation. Three patients required maintenance hemodialysis. In multivariate analysis older age at the time of transplantation (hazard ratio [HR], 1.07/year; 95% confidence interval [CI], 1.02 to 1.13) and a history of acute kidney injury (AKI) within 100 days after transplantation (HR, 6.30; 95% CI, 2.21 to 17.9) were significant risk factors for CKD. Conditioning regimen, stem cell source, or the presence of acute/chronic GVHD was not significantly associated with CKD in this study. Patients with CKD had a lower overall survival rate (HR, 4.11; 95% CI, 1.3 to 13.0) than patients without CKD. Careful monitoring of renal function is required for long-term survivors after allo-HSCT, especially in patients who have experienced AKI and in older patients.

Late-onset neutropenia after rituximab (RTX) therapy (R-LON) has been widely reported, but clinical studies on a large number of cases are limited. In this study, we aimed to investigate the incidence and risk factors of R-LON.In this study, we retrospectively analyzed data of 213 enrolled B-cell lymphoma patients (male 114; female 99) treated with RTX at a single institution. R-LON was defined as otherwise unexplained grade III-IV neutropenia after RTX. The median age of the patients was 62 years, and 129 of them were initially diagnosed at advanced stages (stage III-IV).R-LON occurred in 19 patients within a median of 121 (range, 49-474) days after the last RTX administration. The 1-year cumulative incidence was 9.0%. On univariate analysis, older age (60 years), advanced stage, and purine analog or methotrexate administration were significant or borderline significant risk factors for R-LON, whereas sex, disease type, bone marrow invasion, combination with cytotoxic chemotherapeutic drugs, intensified therapy (compared with R-CHOP), prior autologous transplantation, and repeated RTX administration were not. On multivariate analysis, older age (hazard ratio (HR), 2.95) and advanced stage (HR, 3.56) were significant risk factors. Treatment with granulocyte colony-stimulating factor was feasible in grade IV R-LON patients with high risk of infection.Careful follow-up is therefore necessary after B-cell lymphoma treatment, especially in high-risk patients with advanced disease or of older age.

Gemcitabine is widely used for chemotherapy in many types of cancers. However, vascular pain frequently occurs during its infusion, which can be serious enough to cause treatment discontinuation. This study was conducted to determine whether dissolution with 5 % glucose solution would relieve vascular pain compared with the approved use of saline as the diluent. Patients with cancer who were treated with weekly gemcitabine were eligible. Vascular pain was assessed during two consecutive administrations in a double-blind, randomized crossover study. One group was scheduled to receive gemcitabine dissolved in saline followed by gemcitabine in 5 % glucose solution. In the other group, 5 % glucose solution was followed by saline. The primary endpoint was frequency of vascular pain for the total infusions of each solvent and the secondary endpoints were intensity, as assessed on a visual analogue scale and duration of vascular pain. Eighty-seven patients were randomly assigned to each treatment schedule. Frequency of vascular pain was significantly lower with 5 % glucose solution compared with saline (40 versus 63 %; p

Paraneoplastic neurological disorders (PND) are neurological effects of malignancy that are recognized as immune-mediated disorders caused by aberrant expression of a tumor antigen that is normally expressed in the nervous system. We report a case of cerebellar ataxia which turned out to be paraneoplastic cerebellar degeneration, a subtype of PND that develops cerebellar symptoms, that was caused by follicular lymphoma. After chemotherapy, the patient attained sufficient improvement of cerebellar symptoms along with complete remission of lymphoma. Paraneoplastic cerebellar degeneration should be recognized as a rare complication of lymphoma as it is important to start proper treatment before the neurological symptoms become irreversible.

Our aims were to investigate whether the association between smoking and survival is significant when adjusted for prognostic factors including use of epidermal growth factor tyrosine kinase inhibitors and the Glasgow Prognostic Score, an established score for inflammation, and to explore prognostic factors. We analyzed 244 patients with stage IIIB or IV non-small-cell lung cancer in a registry, including only chemotherapy-receiving outpatients with performance status zero. Of 244 patients, 170 had died and the median follow-up time for the 74 surviving patients was 12.0 months. In multivariate Cox regression, smoker (hazard ratio compared to never-smoker: 1.67, P

Purpose : Although the risk of oxaliplatin-induced neuropathy depends on cumulative oxaliplatin dose, susceptibility to this adverse event differs greatly among patients. In this study, we investigated the associations between oxaliplatin-induced neuropathy and the following polymorphisms: glutathione S -transferase π ( GSTP1 ) Ile 105 Val, and glyoxylate aminotransferase ( AGXT ) Pro 11 Leu and AGXT Ile 340 Met. Experimental design : Eighty-two Japanese patients with histologically confirmed colorectal cancer who received at least six cycles of the modified FOLFOX6 (m-FOLFOX6) regimen were enrolled. To minimize differences in cumulative oxaliplatin dose between patients, oxaliplatin-induced neuropathy was evaluated using an oxaliplatin-specific scale during the 2-week period after completion of the sixth cycle of treatment. Results : Forty-four patients developed grade 2/3 oxaliplatin-induced neuropathy. There were more patients carrying at least one GSTP1 105 Val allele among the group with grade 2/3 neuropathy (18/44, 41%) than among the group with grade 1 neuropathy (9/38, 24%), although the difference was not statistically significant ( P =0.098). There were similar numbers of patients carrying at least one AGXT 105 Met allele in the grade 2/3 neuropathy (7/44, 16%) and grade 1 neuropathy groups (5/38, 13%; P =0.725). The AGXT 11 Leu allele was not found in any of our patients or controls. Conclusions : We found no significant association between oxaliplatin-induced neuropathy and the GSTP1 Ile 105 Val and AGXT Ile 340 Met polymorphisms. Given that no AGXT 11 Leu allele was found among our study population ( n =177), evaluating this polymorphism in Japanese patients in future studies is likely to be uninformative.

Background: Hypersensitivity reaction (HSR) and sensory neuropathy are major complications of oxaliplatin-based chemotherapy. Preplanned withdrawal of oxaliplatin after the first six cycles and reintroduction at the time of disease progression (stop-and-go strategy) may reduce neurotoxicity. However, the effect of an oxaliplatin-free interval on HSR occurrence remains poorly understood. Patients and Methods: Data on patients with colorectal cancer who received FOLFOX (5-fluorouracil, leucovorin and oxaliplatin) treatment between June 2005 and June 2009 were retrieved from the prospective cohort database of the Outpatient Oncology Unit of the Kyoto University Hospital. Factor analysis was performed. Results: Among patients who received six or fewer cycles of FOLFOX, the incidence of HSR was low (7/99, 7.1%). For patients who received more than six cycles, the incidence of HSR was higher among patients treated with stop-and-go FOLFOX than among patients treated with continuous FOLFOX (25/61, 41.0% vs. 13/63, 20.6%; p = 0.019). Interestingly, most cases of HSR during stop-and-go FOLFOX occurred during the second or third cycle of the reintroduction phase (21/25, 84%). Multivariate analysis identified undergoing an oxaliplatin-free interval as an independent risk factor (p = 0.016). Conclusions: An oxaliplatin-free interval may increase the risk of HSR. Special vigilance is needed during the second and third cycles after reintroduction of oxaliplatin.

Graft failure (GF) in allogeneic hematopoietic stem cell transplantation (SCT) is a life-threatening complication because patients are at high risk of severe infection during prolonged neutropenia and also experience organ toxicity due to previous transplantation. Graft rejection is a major cause of graft failure, and is caused by the immune response of the recipient against the immunohematopoietic cells of the donor.1, 2 Cord blood is an important source for salvage transplantation because of its prompt availability and less stringent HLA compatibility. However, cord blood transplantation (CBT) has a risk of prolonged neutropenia and recurrence of GF. Previous studies reported that the rate of neutrophil engraftment of salvage CBT is 58% and the overall survival is 28–33%; the major cause of death was treatment-related mortality (TRM) in 61% cases, especially due to infection (65% of the cases of TRM).3, 4 In cases of immune-associated graft rejection, it is thought that patients should receive reconditioning to efficiently suppress recipient-derived immunity. Considering that fludarabine, melphalan and low-dose TBI conditioning efficiently suppress alloreactive host immunity and ensure engraftment,5 we have performed salvage CBT following this regimen for patients with graft rejection. We carefully assessed infectious complications before salvage CBT because they may be strongly associated with TRM as carryover infections, leading to death after salvage CBT.

Aims To report the changes in survival over 20 years of 775 breast cancer women operated between 1982 and 2003 at the Kyoto University Hospital in Japan, reflecting changes in clinical practice over that period. Results Survival curves have significantly improved between the periods 1982–1989 and 1990–2003. The 5- and 10-year survival rates between these periods were 80.3% and 85.1%, and 67.5% and 75.0%, respectively. Moreover, there was a difference in overall survival curves of patients of stages II and III, of 35–54 ages, or of positive estrogen receptor (ER) status between these periods. Conclusion The present study presented the recent advance of the survival rates might be due to the rational development of breast cancer treatment, and suggested the possibility that the patients of stages II and III, of 35–54 ages, or of positive ER status were received benefits by these treatments.

The aim of this study was to evaluate the efficacy and safety of combination therapy with docetaxel and nedaplatin in advanced esophageal cancer as a second-line regimen in an outpatient setting.Twenty-seven consecutive patients with advanced esophageal cancer who received docetaxel/nedaplatin combination therapy as a second-line regimen were retrospectively evaluated. The combination therapy consisted of intravenous administration of docetaxel 30 mg/m(2) and nedaplatin 40 mg/m(2) every 2 weeks.The patients received a median of 7.4 cycles of treatment (range, 2-25 cycles ). No complete response was observed, and 3 of the 27 patients (11%) achieved partial responses. The disease control rate (partial response + stable disease) was 52%. The median survival time (MST) was 11.4 months. Severe hematological adverse events (grade 3-4) were: neutropenia (n = 10; 37%) and anemia (n = 5; 19%); there was neither febrile neutropenia nor grade 3-4 thrombocytopenia. Furthermore, no severe nonhematological adverse events or treatment-related deaths were observed.Combination therapy of docetaxel with nedaplatin was safe and well tolerated; however, the development of more effective therapy is warranted to improve the prognosis of esophageal cancer.

Recombinant human thrombomodulin (rTM) improves the blood coagulation disorder characteristic of disseminated intravascular coagulation (DIC) as well as, or even better than, other anti-DIC drugs. On post-marketing surveillance, its effectiveness has been recognized for hematologic disorders, sepsis and solid tumor subgroups. However, the effect on hemophagocytic syndrome (HPS) complicated by DIC remains unclear. We treated three HPS patients with rTM in addition to chemotherapy for the underlying diseases including nasal NK/T cell lymphoma, angioimmunoblastic T-cell lymphoma and refractory acute myeloid leukemia post cord blood transplantation. Although being refractory to medical management was suspected in our cases, clinical status rapidly came under control including not only amelioration of the blood coagulation disorder but also inflammatory reactions, such as serum ferritin and lactic acid dehydrogenase abnormalities, which represent HPS activity. These observations suggest that rTM might exert marked synergistic effects on HPS with DIC. Given the results obtained in these three cases, administration of rTM appears to offer a promising method of treating HPS complicated by DIC.

Gastro-intestinal cytomegalovirus infection (GI-CMV), which occurs after allogeneic stem cell transplantation (allo-SCT), is diagnosed by immunostaining of biopsied tissues obtained using a fiberscope. However, the sensitivity of this pathological diagnostic test is poor. We evaluated the suitability of using quantitative polymerase chain reaction (qPCR) to test GI-mucosal tissues for CMV. We analyzed adult patients who had undergone allo-SCT at our institute. Twenty-seven specimens were collected from patients undergoing GI-fibers-copy for upper GI-symptoms after allo-SCT. Of these patients, 9 tested positive for CMV by qPCR; their symptoms resolved soon after receiving antiviral therapies for CMV. Pathological procedures detected GI-CMV in only 3 cases. In contrast, CMV qPCR was positive for 12 of 30 specimens collected from patients with lower GI-symptoms by using colon fibers-copy. Antiviral therapies were effective in all but one case. GI-CMV was diagnosed pathologically in only 5 cases. Therefore, CMV qPCR is effective for early therapeutic intervention in CMV-GI patients after allo-SCT.

Bendamustine is a chemotherapeutic drug that has recently come to be used frequently in the treatment of indolent B cell lymphomas. Skin toxicity is recognized as one of its characteristic side effects, but detailed information on such reactions has not yet been obtained. To clarify the clinical features of skin toxicity associated with bendamustine, we retrospectively analyzed skin reactions that developed in patients treated with bendamustine and rituximab (BR). Of 34 patients treated with 3-6 cycles of BR, 11 developed late-onset, persistent skin eruptions. These patients demonstrated increases in CD8(+) T cell number and CD8(+):CD4(+) cell ratio at the end of chemotherapy. In contrast, peripheral eosinophil count was not associated with such adverse events, whereas eosinophil infiltration was frequently observed in the skin. Patients with skin reactions tended to have higher seropositivity of hepatitis Bcore antibody, and multiplex viral screening PCR of the frozen sera demonstrated cytomegalovirus-DNA in some of the eruption-positive patients. It is speculated that inappropriate activation of CD8(+) T cells by latently infected pathogens may be one of the triggers of late-onset skin reactions caused by bendamustine., First online: 02 April 2015

Objective.Methotrexate-associated lymphoproliferative disorders (MTX-LPD) often regress spontaneously during MTX withdrawal, but the prognostic factors remain unclear. The aim of our study was to clarify the clinical, histological, and genetic factors that predict outcomes in patients with MTX-LPD.Methods.Patients with MTX-LPD diagnosed between 2000 and 2012 were analyzed retrospectively regarding their clinical course, site of biopsy, histological typing, Epstein-Barr virus (EBV)in situhybridization and immunostaining, and HLA type.Results.Twenty-one patients, including 20 with rheumatoid arthritis (RA) and 1 with polymyositis, were analyzed. The mean dose of MTX was 6.1 mg/week and the mean duration of treatment was 71.1 months. Clinically, 5 patients were diagnosed with EBV-positive mucocutaneous ulcer (EBVMCU) and had polymorphic histological findings. The proportion of those patients successfully treated solely by withdrawal of MTX was significantly greater than that of those without EBVMCU (75% vs 7.7%, p = 0.015). The HLA-B15:11 haplotype was more frequent in patients with EBV+ RA with MTX-LPD than in healthy Japanese controls (p = 0.0079, Bonferroni’s method). EBV latency classification and HLA typing were not associated with the prognosis of MTX-LPD in our cohort.Conclusion.Our data demonstrate that patients in the EBVMCU, a specific clinical subgroup of MTX-LPD, had a better clinical outcome when MTX was withdrawn than did other patients with MTX-LPD.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a devastating complication of hematopoietic stem cell transplantation. TA-TMA likely represents the final stage of vascular endothelial injury; however, its pathophysiology is largely unknown, making clinical management difficult. Recently, the association of neutrophil extracellular traps (NETs) with the development of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome has been reported. Thus, we explored whether NETs are also relevant to the occurrence of TA-TMA. We retrospectively analyzed post-transplant trends of serum NET levels in 90 patients, 11 of whom developed TA-TMA. Relative to baseline (before the conditioning regimen), elevated serum NET levels either at 4 weeks after transplantation or as early as the day of transplantation were associated with significantly increased risk of TA-TMA. In contrast, thrombomodulin, a potential marker for TA-TMA, was not helpful to predict the occurrence of TA-TMA in our study. In addition, we directly detected glomerular deposition of NETs in 2 TA-TMA patients. Increased NET levels are a significant risk factor for TA-TMA, suggesting that NET level is a useful biomarker for TA-TMA.

[Background]: A blood pressure drop after bevacizumab administration and its clinical significance have not been previously reported. [Methods]: Blood pressure data at 0, 90, and 180 min after a total of 162 bevacizumab administrations in 81 advanced colorectal cancer patients were retrospectively investigated. [Results]: Twenty-five patients (30%) demonstrated an average temporary drop of 20 mm Hg or more in systolic blood pressure. We classified these 25 patients as group A and the others as group B. Median time-to-treatment failure (TTF) was significantly longer in group A than in group B (291 vs 162 days; P=0.02). Furthermore, the proportion of patients who required intervention with antihypertensive drugs during bevacizumab treatment was significantly higher in group A than in group B (36% vs 4%; P

PURPOSE: The purpose of the present phase II study was to evaluate both the efficacy and toxicity of the combination of S-1 and docetaxel in previously treated patients with locally advanced or metastatic non-small cell lung cancer. METHODS: Thirty-eight previously treated patients with non-small cell lung cancer were treated with S-1 (80 mg/m(2), days 1-14, oral) and docetaxel (40 mg/m(2), day 1, intravenous) every 3 weeks. RESULTS: No complete response was observed, and seven patients had a partial response, yielding an overall response rate of 18.4% (95% CI, 7.7-34.3%). The median overall survival time and 1-year overall survival rate were 16.1 months and 60%, respectively. The median progression-free survival time was 4.4 months. Myelosuppression was the main toxicity with grade 3 or 4 neutropenia and leukopenia in 50 and 21%, respectively. There was no irreversible toxicity in this study. CONCLUSIONS: The combination of S-1 and docetaxel is well tolerable and has substantial activity for patients with locally advanced or metastatic non-small cell lung cancer. A phase III trial comparing docetaxel with or without S-1 would warrant further investigation.

We examined the impact of pretreatment neutrophil count on survival in patients with advanced non-small-cell lung cancer (NSCLC). A total of 388 chemo-naive patients with stage IIIB or IV NSCLC from a randomised controlled trial were evaluated. The effects of pretreatment peripheral blood neutrophil, lymphocyte and monocyte counts and neutrophil-lymphocyte ratio on survival were examined using the proportional hazards regression model to estimate hazard ratios after adjustment for covariates. The optimal cut-off value was determined by proportional hazards regression analysis with the minimum P-value approach and shrinkage procedure. After adjustment for prognostic factors, the pretreatment elevated neutrophil count was statistically significantly associated with short overall (P = 0.0008) and progression-free survival (P = 0.024), whereas no association was found between prognosis and lymphocyte or monocyte count. The cut-off value selected for neutrophil count was 4500 mm-3 (corrected hazard ratio, 1.67; 95% confidence interval (CI), 1.09-2.54). The median survival time was 19.3 months (95%CI, 16.5-21.4) for the low-neutrophil group (≥4500 mm-3, n = 204) and was 10.2 months (95%CI, 8.0-12.3) for the high-neutrophil group (≥4500 mm-3, n = 184). We confirmed that pretreatment elevated neutrophil count is an independent prognostic factor in patients with advanced NSCLC receiving modern chemotherapy. Neutrophil count is easily measured at low cost, and it may be a useful indicator of patient prognosis.

Although a variety of FOLFOX regimens (5-fluorouracil and L-leucovorin combined with oxaliplatin) are widely used for the treatment of advanced colorectal cancer, the neurotoxicity caused by oxaliplatin is often problematic. The aim of this observational study was to assess the safety and efficacy of a modified version of the FOLFOX6 regimen (mFOLFOX6) when administered using the 'stop-and-go' strategy.A total of 112 eligible patients treated between June 2005 and July 2007 were identified using the prospective cohort database system of Kyoto University Hospital.The median follow-up was 16.3 months (range 1.6-33.9), and the response rate was 33.3% (95% CI 14.5-52.2), 40.0% (95% CI 22.5-57.5) and 14.0% (95% CI 3.6-24.3) for patients who received mFOLFOX6 as first-line therapy, second-line therapy and third- or later-line therapy, respectively. The estimated median progression-free survival was 8.7 months (95% CI 2.3-15.1) and 8.2 months (95% CI 7.3-9.1) for patients on first-line and second-line therapy, respectively. The median overall survival was not reached as of April 2008 for the patients on first-line therapy, while it was 27.1 months (95% CI 22.0-32.2) for those on second-line therapy. Severe neurotoxicity occurred in only 4 patients (3.6%).mFOLFOX6 administered using the stop-and-go strategy significantly reduced oxaliplatin-induced neurotoxicity relative to conventional FOLFOX treatment, without compromising efficacy.

Anemia in cancer patients has been under-recognized and little studied in Japan. To gain some insight into cancer-related anemia in Japanese patients undergoing outpatient chemotherapy, we performed a single-center retrospective study of the prevalence and incidence of anemia in 148 patients with solid tumors treated at the Kyoto University Hospital Outpatient Oncology Unit. We classified the cases of anemia in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). Of 148 patients, 65 (44%) were anemic at the start of chemotherapy, 19 (13%) of whom had anemia of grade 2 or higher. Chemotherapy further increased the number of anemic patients, with 125 (84%) being anemic at some point during chemotherapy, and 61 (41%) of these having anemia of grade 2 or higher. Among the 83 patients without anemia at the start of chemotherapy, 60 (72%) developed anemia during chemotherapy, 15 (18%) of whom had anemia of grade 2 or higher. This is the first report showing a high prevalence and incidence of anemia in Japanese patients undergoing outpatient chemotherapy. Better recognition and management of cancer-related anemia are required in Japan. To this end, randomized controlled trials evaluating the effects of erythropoietic agents on patients' survival and quality of life are necessary.

The aim of this study was to investigate the outcomes of gemcitabine-treated patients with inoperable biliary tract cancers.We conducted a retrospective study of consecutively treated 22 inoperable biliary tract cancer patients with gemcitabine (500-1,000 mg/m(2) on days 1, 8, 15 every 4 weeks) as first-line, and 17 patients as second- or third-line treatment.The response rate of patients treated with gemcitabine as first-line and second- or third-line treatment was 5.3 and 28.5%, respectively. The median overall survival time in the first-, and second- or third-line treatment groups was 8.3 and 17.0 months, and the 1-year survival rate was 44.0 and 50.9%, respectively. The present study also suggests the possibility that the prognosis of patients with high levels of C-reactive protein and total bilirubin, or a low level of albumin might be worse.Our results indicate that the treatment of inoperable biliary tract cancers with gemcitabine is feasible. There was no difference in the response rate and overall survival between biliary tract cancer patients in the first- and second- or third-line treatment groups. We also present the systematic review of literature of the recent treatment results of biliary tract cancers treated with gemcitabine.

We investigated the possibility of the proapoptotic lipid ceramide as an indicator of chemoresistance in leukemia. Doxorubicin (DOX) increased the ceramide level and apoptosis in drug-sensitive HL-60 cells but not in drug-resistant HL-60/ADR cells, under the condition that the uptake of DOX was not different between the two cell lines. In addition, exogenous N-acetylsphingosine (C2-ceramide) enhanced DOX-induced apoptosis in HL-60/ADR cells without affecting the expression of multidrug resistant-1 protein (MDR 1) and the uptake of DOX. A lower level of ceramide with higher activities of glucosylceramide synthase (GCS) and sphingomyelin synthase (SMS) was detected in HL-60/ADR cells than in HL-60 cells. In contrast, HL-60/GCS cells, overexpressing GCS, significantly inhibited DOX-induced ceramide increase and apoptosis. These observations suggest the involvement of ceramide regulation in drug resistance of leukemia cells. In vivo, the level of ceramide was lower in chemoresistant leukemia patients (6.4 +/- 1.8 pmol/nmol phosphate; n = 14) than in chemosensitive patients (9.5 +/- 2.7 pmol/nmol phosphate; n = 9), and the activities of GCS and SMS were more than 2-fold higher in chemoresistant leukemia cells than in chemosensitive cells. MDR-1 protein was faintly expressed in one of four chemoresistant patients, but Bcl-2 were clearly detected in four patients. Therefore, it is suggested that a decrease of the ceramide level via activation of GCS and SMS is associated with the chemoresistant condition in leukemia, probably in relation to Bcl-2 but not to MDR-1 expression.

A 57-year-old woman with 6-year history of IgA-k myeloma experienced an increase of serum IgA level from 331 to 683 mg/dl during maintenance therapy with thalidomide after autologous peripheral blood stem cell transplantation followed by allogeneic mini-transplantation. Bone marrow aspiration revealed no sign of relapse of the myeloma. We conducted positron emission tomography/computed tomography (PET/CT) scans using C-methionine (MET) and F-fluorodeoxyglucose (FDG). In MET-PET/CT, there were multiple abnormal hypermetabolic lesions, while FDG uptake in these lesions was faint (Fig. 1). After four courses of bortezomib therapy, MET-PET/CT revealed no abnormal uptake of MET, with decreased serum IgA level (25.3 mg/dl), indicating that MET uptake was correlated with the clinical course, as denoted by IgA level. C-Methionine is a radiolabelled PET tracer that is clinically used for brain tumor. An earlier study reported that MET-PET depicted active myeloma clearly, which might reflect the increased metabolism of amino acids in myeloma cells for producing abundant immunoglobulin [1]. In the present case, MET-PET/CT was very useful for determining the precise localization of the myelomatous lesions and evaluating therapeutic effects. Although FDGPET/CT is reported to have higher sensitivity for localized myelomatous lesions than other imaging modalities, our case suggests the possibility that MET-PET/CT detects myelomatous lesions more clearly than FDG-PET/CT. Considering that in myeloma patients higher FDG uptake or a larger number of FDG-avid lesions is reported to be associated with inferior overall survival and event-free survival, the lower FDG uptake in this patient is possibly related to the slowly progressive nature of her myeloma. In addition, in 30% of myeloma patients, FDG-PET/CT reportedly failed to show the abnormal findings in the spine and pelvis; this may account for the lower FDG uptake in these lesions. Although many imaging modalities, including FDGPET/CT are now widely available, the findings of the present case suggest that MET-PET/CT can provide valuable information for patients with myeloma and has a potential to become an important imaging test. However, further investigation to compare the MET-PET/CT with FDG-PET/CT or other imaging modalities are needed to confirm the diagnostic efficiency and the clinical feasibility of MET-PET/CT for multiple myeloma.