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Vincristine (VCR) is a key drug for treating various malignancies. However, few data are available on the pharmacokinetics of VCR, especially in adult patients. The objective of this study was to clarify the population pharmacokinetics and exposure–response relationships of VCR in adult malignant lymphoma patients. Blood samples were collected from patients who were administered R-CHOP-like regimens, and the VCR plasma concentration was determined using liquid chromatography–mass spectrometry. Using NONMEM software, population pharmacokinetic parameters were estimated, and covariates were evaluated. The relationships between the individual parameters and adverse events or therapeutic effects were also investigated. Plasma concentrations were measured in 30 patients. In the final population pharmacokinetics model, body surface area and age were incorporated into clearance as significant covariates. The inter-individual variations in clearance and volume of distribution in the central and third compartments were 17.0, 26.6, and 66.3%, respectively, and the residual variability in the plasma concentration was 23.8%. Although the variability observed in the volume of distribution was large, good predictability was obtained in the individual estimation. The severity of anemia and peripheral neuropathy was correlated with clearance and peak concentration, respectively (adjusted P = 0.040 and 0.024, respectively). In diffuse large B cell lymphoma patients, those with higher area under the curve and dose experienced longer progression-free survival (P = 0.023 and 0.013, respectively). The population pharmacokinetics of VCR were evaluated in adult malignant lymphoma patients. VCR pharmacokinetic data could explain in part the adverse events and prognosis of these patients.

Background Gastrobronchial fistulas are rare, but life-threatening, complications of esophagectomy. They are caused by anastomotic leakage and mainly occur around anastomotic sites. In the present paper, we report a rare case of leakage from the staple line of a gastric tube after esophagectomy for esophageal cancer, which was successfully treated using an intercostal muscle flap and lung resection. Case presentation A 61-year-old male underwent subtotal esophagectomy with regional lymphadenectomy for esophageal cancer. The sutures along the staple line of the gastric tube failed 11 days after surgery, and a pulmonary abscess was also found on imaging. The abscess did not heal after conservative treatment; therefore, right lower lobectomy, gastrobronchial fistula resection, primary closure, and patching of the leaking portion of the gastric tube with an intercostal muscle flap were performed 9 months after the first operation. The patient’s postoperative course was uneventful, and he was discharged on the 354th day. Conclusions We experienced a case involving a gastrobronchial fistula caused by leakage from the staple line of a gastric tube and successfully treated it by performing right lower lobectomy and patching the leak with an intercostal muscle flap.

Patient: Male, 78 Final Diagnosis: Giant cell tumor of soft tissue Symptoms: Fatigue • weight loss Medication: — Clinical Procedure: Surgical resection Specialty: Surgery Objective: Rare disease Background: Giant cell tumor of soft tissue (GCT-ST) is a rare disease generally generated from superficial tissue. We report an extremely rare case of giant cell tumor of soft tissue arising from retroperitoneal tissue. Case Report: A 78-year-old man visited our medical center with the chief complaint of fatigue and weight loss for 1 month. He had a hard and immobilized mass without pain in the left upper quadrant. Contrast-enhanced CT showed a huge tumor (22×20×16 cm) in the retroperitoneal space, and it invaded into the stomach, colon, pancreas, spleen, and left kidney. MRI demonstrated the tumor had a serous cystic component as T1 was low, T2 was high, and DWI was slightly high. We diagnosed the retroperitoneal malignant tumor, and tumor resection was performed with total gastrectomy, partial colectomy, distal pancreatectomy, left nephrectomy, and left adrenal-ectomy for complete resection, without any postoperative complications. The tumor predominantly consisted of a solid mass, and had necrotic lesions, cystic lesions, and calcification. The histological exam showed it was composed of spindle and multinucleated giant cells; however, there was no cellular atypia or pleomorphism. Immunohistochemical staining characterized the tumor with CD68+, SMA+, CD34–, Desmin–, and S-100–. We finally diagnosed it as GCT-ST with the intermediate group of malignancy, according to WHO criteria. Thereafter, the patient had no recurrence at 1 year after resection. Conclusions: The huge GCT-ST arising from the retroperitoneal space, which has never before been reported, was successfully resected. We report it with pathological findings to add to the relevant literature.

YM155, a novel small molecule inhibitor of survivin, shows broad anticancer activity. Here, we have focused on the cytotoxic activity of YM155 against multiple myeloma (MM) including cytokinetically quiescent (G0/G1) cells and bortezomib resistant cells. YM155 strongly inhibited the growth of MM cell lines with the IC50 value of below 10 nM. YM155 also showed potent anti-myeloma activity in mouse xenograft model. YM155 suppressed the expression of survivin and rapidly directed Mcl-1 protein for proteasome degradation. YM155 abrogated the interleukin-6-induced STAT3 phosphorylation, subsequently blocked Mcl-1 expression and induced apoptosis in MM cells. Triple-color flow cytometric analysis revealed that YM155 potently induced cell death of MM cells in G0 phase. Quiescent primary MM cells were also sensitive to YM155. We established bortezomib-resistant MM cell line, U266/BTZR1, which possess a point mutation G322A. YM155 exhibited similar cytotoxic potency against U266/BTZR1 compared with parental cells. Interestingly, survivin expression was markedly elevated in U266/BTZR1 cells. Treatment with YM155 significantly down-regulated this increased survivin and Mcl-1 expression in U266/BTZR1 cells. In conclusion, our data indicate that YM155 exhibits potent cytotoxicity against quiescent (G0/G1) MM cells and bortezomib-resistant cells. These unique features of YM155 may be beneficial for the development of new therapeutic strategies to eliminate quiescent MM cells and overcome bortezomib resistance.

In the present study, the dosage and duration of rasburicase administration were retrospectively evaluated for the ability to control the serum uric acid (S-UA) level in 13 patients diagnosed with hematological malignancies and tumor lysis syndrome (TLS), or those at risk of developing TLS, at the University of Fukui Hospital. At the time of diagnosis, seven patients already exhibited laboratory TLS, and three demonstrated clinical TLS. All patients received rasburicase in addition to chemotherapy agents. The median dose was 0.19 mg/kg (range, 0.13–0.25 mg/kg), and the median duration was four days (range, 1–7 days). Six patients sequentially received a xanthine oxidase inhibitor, allopurinol or febuxostat. The primary estimate was the normalization of the S-UA level at the end of rasburicase treatment and on treatment day seven. The average S-UA level prior to treatment was 10.4±4.5 mg/dl (mean ±standard deviation), and 11 out of 13 patients demonstrated a S-UA level >7 mg/dl. The S-UA level at the end of rasburicase administration was 0.5±1.5 mg/dl and the S-UA level at day seven was 1.4±1.5 mg/dl. All the patients achieved normalization of the S-UA level. On day seven subsequent to the initiation of treatment, the patients receiving rasburicase for a maximum of three days exhibited an S-UA level of 1.9±1.8 mg/dl, while the patients receiving rasburicase for longer than three days demonstrated an S-UA level of 1.0±1.3 mg/dl (P=0.20; Mann-Whitney test). The administration of 0.13 mg/kg and 0.22 mg/kg resulted in comparable UA level reductions. The administration of allopurinol or febuxostat following rasburicase administration suppressed the re-increase in S-UA level. Therefore, it was concluded that reduced administration of rasburicase successfully controlled the S-UA level in TLS.

The objective of this study was to evaluate whether aprepitant in addition to 5-HT3 receptor antagonist is useful for preventing chemotherapy-induced nausea and vomiting (CINV) and anorexia in patients receiving CHOP therapy, and to evaluate the relationship between in vivo kinetics of plasma substance P and these adverse events. Patients with malignant lymphoma who received CHOP chemotherapy or THP (THP-ADR)-COP therapy were investigated for CINV and anorexia for 5 days after the start of chemotherapy. With the first course of chemotherapy, all patients received only granisetron on day1 as an antiemetic. Patients who experienced nausea, vomiting, or anorexia exceeding grade 1 in the first course received aprepitant for 3 days in addition to granisetron with the second course of CHOP chemotherapy. Plasma substance P concentrations at 24 and 72 hours after chemotherapy were measured. Nineteen patients were evaluated. Nausea, vomiting, or anorexia was observed with the first course in 7 of 19 patients. During the second course with aprepitant, no patients experienced vomiting, and the toxicity grade of nausea, vomiting, or anorexia was decreased compared with those in the first course. Substance P concentrations showed no differences after chemotherapy, in patients with nausea, vomiting, or anorexia and in patients without. The addition of aprepitant to 5-HT3 receptor antagonist appears effective for CINV or anorexia for patients who received CHOP chemotherapy.

Objective We retrospectively compared the clinical efficacy and toxicity of rituximab (R)-THP-COP (pirarubicin, cyclophosphamide, vincristine, and prednisolone) with that of R-CHOP (rituximab, adriamicin, cyclophosphamide, vincristine, and prednisolone) in previously untreated old patients with diffuse large B-cell lymphoma (DLBCL). Patients and Methods Patients admitted to our institution between 2004 and 2013 were examined. The patients received either R (375 mg/m2, day 1)-THP-COP (pirarubicin 50 mg/m2 day 1, cyclophosphamide 750 mg/m2 day 1, vincristine 1.4 mg/m2 day 1, and prednisolone 100 mg day 1-5) or R-CHOP (adriamicin 50 mg/m2 day 1, cyclophosphamide 750 mg/m2 day 1, vincristine 1.4 mg/m2 day 1, and prednisolone 100 mg day 1-5). The doses of chemotherapeutic agents were adjusted depending on the patient's age and associated complications. The treatment was performed for 6 to 8 cycles. Results Among 74 patients with DLBCL (median 76, range 65-90 years; male 39, female 35), 29 received R-THP-COP, while 45 received R-CHOP. The overall response rates were 94.6% (complete response 86.4%, partial response 8.1%). The 2-year overall and progression-free survival rates were 77.6% and 68.5% for the R-THP-COP regimen and 79.2% and 78.9% for R-CHOP, respectively. No significant differences were found between these two regimens regarding the clinical efficacies. The most frequent adverse event was neutropenia (72.4% for the R-THP-COP regimen, 88.9% for the R-CHOP regimen). The cardiac function as evaluated by ejection fraction values was not impaired in either regimen. Conclusion R-THP-COP was effective and safe as an alternative to R-CHOP.

The primary objective of the present study was to correlate blood cell counts (lymphocyte, monocyte and platelet counts) with early disease relapse following the attainment of complete remission (CR) by the rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP)-like regimen in patients with advanced diffuse large B-cell lymphoma (DLBCL). In total, 30 patients were evaluated, with a median follow-up period of 43 months. All the participating patients attained CR. In total, eight patients experienced relapse within two years of the diagnosis, and the three-year overall survival rate was recorded as 77%. The peripheral counts for lymphocytes, monocytes and platelets, and the lymphocyte-monocyte ratio, all of which have been reported to be prognostic in DLBCL, were assessed. None of these parameters were correlated with the incidence of early relapse or with the prognosis. The lymphocyte count was higher in the patients with durable remission than in those who relapsed, however, no significant differences were identified. Thus, the present study concluded that early disease relapse was not predicted by peripheral blood cell counts in advanced DLBCL that reached CR using the R-CHOP-like regimen.

Background To examine the utility of diffusion-weighted MRI (DW-MRI) for staging and early response to chemotherapy assessment in lymphoma patients as compared with fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). Methods Twenty-eight patients with histologically confirmed malignant lymphoma underwent both MRI and FDG-PET/CT before (pretreatment) and after two courses of chemotherapy (mid-treatment). Staging with MRI (DW-MRI alone and with T2-weighted images) and FDG-PET was compared visually, and the concordance rate (kappa value, κ) was calculated. To evaluate early response to chemotherapy, patients were divided into two groups, lesion-positive (LP) and lesion-negative (LN), based on a proposed original criterion. Progression-free survival (PFS) was compared between the groups using the Kaplan-Meier method. Results The stage diagnosed with DW-MRI alone and with FDG-PET/CT was concordant in 22 patients (κ = 0.71; P

Tumor lysis syndrome (TLS) is a life-threatening oncological emergency, in which control of serum uric acid (S-UA) levels is important. S-UA-lowering efficacy of a new xanthine oxidase inhibitor, febuxostat, was retrospectively evaluated in seven patients with hematological malignancies who were at an intermediate risk of developing TLS. A 10-mg dose of febuxostat was initiated and chemotherapy was started within 24 h of administering the first dose of febuxostat. Febuxostat was continued until at least day 7 of chemotherapy treatment. The UA-lowering treatment was considered effective if febuxostat reduced S-UA levels to ≤7.5 mg/dl by day 5. The mean S-UA level at base line was 6.4±2.6 mg/dl and, on day 5, the mean S-UA level was 4.7±1.8 mg/dl. All the patients achieved S-UA levels ≤7.5 mg/dl. Serum creatinine levels decreased from 0.93±0.25 to 0.85±0.25 mg/dl. The estimated glomerular filtration rate values increased from 69.7±24.5 to 76.9±26.2 ml/min. No adverse reactions were noted during the study period and no patients experienced progressive TLS. Successful control of S-UA and improved renal function were obtained in response to febuxostat treatment in cancer patients at a risk of TLS.

Summary Objectives The rapid diagnosis of bacteremia is crucial for patient management including the choice of antimicrobial therapy, especially in cases of hematological disease, because neutropenia occurs frequently during antineoplastic chemotherapy or disease progression. We describe a rapid detection and identification system that uses universal PCR primers to amplify a variable region of bacterial 16S ribosomal DNA (rDNA), followed by DNA microarray hybridization. Methods Probes for 72 microorganisms including most causal clinical pathogens were spotted onto a microarray plate. The DNA microarray and conventional methods of identification were applied to 335 cultures from patients with hematological diseases. Results Forty-one samples (12.2%) tested positive by conventional blood culture test in a few days, while 40 cases (11.9%) were identified by the new method within 24h. The sensitivity and specificity of this new method were 93% and 99%, respectively, compared with conventional blood culture testing. Conclusions PCR combined with a DNA microarray is useful for the management of febrile patients with hematological diseases.

Background/Aim: Tumor lysis syndrome (TLS) is a life-threatening complication associated with cancer chemotherapy. We retrospectively evaluated the risk of developing TLS in patients with symptomatic multiple myeloma undergoing chemotherapy. Patients and Methods: Sixty-four patients (median age=71 years, range=48-87 years, 35 males/29 females) who were treated at our Institution between April 2006 and December 2015 were evaluated. Results: A total of 124 chemotherapy courses were administered, of which 63 courses were bortezomib-based regimens and 34 courses were immunomodulatory drug (IMiD)-based regimens. TLS occurred in 13 (10.5%) out of 124 chemotherapy courses with five (4.0%) cases of laboratory TLS and eight (6.5%) cases of clinical TLS. The incidences of TLS were 17.5% for bortezomib-containing regimens and 3.2% for non-bortezomib-based regimens. No TLS occurred in the patients treated with IMiD-containing regimens. TLS occurred more frequently in the patients with elevated uric acid, creatinine, or beta-2-microglobulin levels at baseline. The patients with disease classified as advanced International Staging System also developed TLS more frequently. All the patients who developed clinical TLS received bortezomib-containing regimens (8/63, 12.7%). Among them, patients with elevated values of uric acid or creatinine developed clinical TLS more often than those without such elevation. The incidence of clinical TLS was 33.3% if the patients had renal dysfunction at baseline and were subsequently treated with bortezomib-based regimens (8/24 cases). Conclusion: Patients with renal dysfunction or a high uric acid level receiving bortezomib-based chemotherapy have a high risk of developing TLS.

Disseminated intravascular coagulation (DIC) is a life-threatening condition that frequently occurs in patients with hematologic malignancies. Currently, recombinant human soluble thrombomodulin (rTM) is a therapeutic DIC drug that is manufactured and sold in Japan only. We evaluated the efficacy of rTM compared to that of gabexate mesilate (GM), which was previously used routinely for treating DIC in Japan, in patients with acute myeloid leukemia (AML). This retrospective study enrolled 43 AML patients, including 17 with acute promyelocytic leukemia (APL), that was complicated with DIC. DIC resolution rates in non-APL AML and rTM-treated APL patients were 68.4% and 81.8%, respectively. In non-APL AML patients, the duration of rTM administration was significantly shorter than that of GM (7 vs 11 days), suggesting that rTM could improve DIC earlier than GM, although rTM was used in patients with more severe DIC. Moreover, treatment with rTM significantly improved DIC score, fibrinogen, fibrin/fibrinogen degradation product (FDP), and prothrombin time (PT) ratio. Conversely, treatment with GM only improved the DIC score and FDP. In APL patients, the duration of rTM administration was also significantly shorter than that of GM. No severe side effects associated with the progression of bleeding were observed during rTM administration. These findings suggest that rTM is safe, and its anti-DIC effects are more prompt than GM for treating AML patients with DIC.

Glutathione S-transferase mu (GSTM1) is mainly known as a detoxification enzyme but it has also been shown to be a negative regulator of apoptosis-related signaling cascades. Recently GSTM1 has been reported to be a significant risk factor for hematological relapse in childhood acute lymphoblastic leukemia, although the underlying mechanism remains largely unknown. Glucocorticoids play a crucial role in the treatment of childhood acute lymphoblastic leukemia, therefore we hypothesized that GSTM1 plays important roles in glucocorticoid-induced apoptotic pathways. To clarify the relationship between GSTM1 and drug resistance, GSTM1 was transfected into a T-acute lymphoblastic leukemia cell line, CCRF-CEM (CEM), and we established the GSTM1-expressing cell lines CEM/M1-4 and CEM/M1-9. Transduction of GSTM1 into CEM selectively decreased cellular sensitivity to dexamethasone in a manner that was independent of glutathione conjugation, but was due to apoptosis inhibition. Dexamethasone-induced p38-MAPK and Bim activation were concomitantly suppressed. Interestingly, nuclear factor kappa b (NF-kappaB) p50 activity was upregulated in GSTM1-expressing CEM. Inhibition of NF-kappaB by the pharmacological agent BAY11-7082 greatly enhanced the sensitivity of the GSTM1-expressing CEM to dexamethasone and was accompanied by an increase in Bim expression. Thus, we propose that GSTM1, a novel regulator of dexamethasone-induced apoptosis, causes dexamethasone resistance by suppression of Bim through dual mechanisms of both downregulation of p38-MAPK and upregulation of NF-kappaB p50.

Cytarabine (ara-C) is the key agent for treating acute myeloid leukemia (AML). After being transported into leukemic cells by human equilibrative nucleoside transporter 1 (hENT1), ara-C is phosphorylated to ara-C triphosphate (ara-CTP), an active metabolite, and then incorporated into DNA, thereby inhibiting DNA synthesis. Deoxycytidine kinase (dCK) and cytosolic 5'-nucleotidase II (cN-II) are associated with the production of ara-CTP. Because ara-C's cytotoxicity depends on ara-CTP production, parameters that are most related to ara-CTP formation would predict ara-C sensitivity and the clinical outcome of ara-C therapy. The present study focused on finding any correlation between the capacity to produce ara-CTP and ara-C-metabolizing factors. In vitro ara-CTP production, mRNA levels of hENT1, dCK, and cN-II, and ara-C sensitivity were evaluated in 34 blast samples from 33 leukemic patients including 26 with AML. A large degree of heterogeneity was seen in the capacity to produce ara-CTP and in mRNA levels of hENT1, dCK, and cN-II. Despite the lack of any association between each of the transcript levels and ara-CTP production, the ratio of dCK/cN-II transcript levels correlated significantly with the amount of ara-CTP among AML samples. The HL-60 cultured leukemia cell line and its three ara-C-resistant variants (HL-60/R1, HL-60/R2, HL-60/R3), which were 8-, 10-, and 500-fold more resistant than HL-60, respectively, were evaluated similarly. The dCK/cN-II ratio was again proportional to ara-CTP production and to ara-C sensitivity. The dCK/cN-II ratio may thus predict the capacity for ara-CTP production and ultimately, ara-C sensitivity in AML.

原発性アミロイドーシス7例に対して自己末梢血幹細胞移植併用melphalan大量療法を実施した．顆粒球コロニー刺激因子の単独投与で必要な末梢血幹細胞の確保が可能で，7例中2例（29%）に血液学的寛解が得られた．心アミロイドーシスの存在した2例は移植後それぞれ42日目と159日目に治療関連死亡し，安全性確保の観点から本治療の対象外とする必要性が推測された．非寛解の4例にサルベージ治療が行われ3例に血液学的効果が得られた．Melphalan大量療法またはサルベージ治療で血液学的効果の得られた5例中4例（80%）に臨床症状の改善または安定化が得られた．心アミロイドーシスを除外すればmelphalan大量療法は安全に実施可能と推測されたが有効性には限界がある．心アミロイドーシス例やmelphalan大量療法の無効例には新規治療法を組み込んだ更なる臨床研究が必要である．

Background and aim Endotoxin/bacterial translocation (E/BT) plays an important role in systemic complications in severe acute pancreatitis (SAP). The breakdown of intestinal integrity is considered to be implicated in E/BT. We recently demonstrated that accelerated apoptosis of intestinal mucosa may have a part in E/BT. On the other hand, caspase is believed to play a central role in apoptosis. The aim of this study was to investigate the efficacy of caspase inhibitor on intestinal integrity and E/BT in SAP. Methods SAP was induced by retrograde injection of 3% sodium deoxycholate into the biliopancreatic ducts in rats. At the same time, polycaspase inhibitor (Z-VAD-fmk) was administered intraperitoneally. Caspase activation in the intestine was evaluated by immunohistochemical staining and Western blotting. Apoptosis of intestinal mucosa was detected by TdT-mediated dUTP-biotin nick end labeling staining and DNA fragmentation enzyme-linked immunosolvent assay. Intestinal permeability was assayed ex vivo by measuring the leaked amount of FITC-dextran. Blood endotoxin level, bacterial culture of the ascites and mesenteric lymph nodes, and 24-h mortality rate were evaluated. Results Immunoreactivities for activated caspase-10, -9, and -3 were increased 2 h after induction of SAP. Apoptosis and permeability of ileum were significantly increased 6 h after induction of SAP. Caspase inhibitor significantly improved the increasing apoptosis and permeability. It did not prevent the bacterial translocation but improved the disorder of intestinal mucosa and elevation of blood endotoxin 18 h after induction of SAP. Moreover, caspase treatment significantly improved the 24-h mortality rate. Z-VAD-fmk indeed inhibited the caspase-3 activation in intestinal mucosa of SAP. Conclusions These results suggest that caspase activation has a key role in the accelerated apoptosis of intestinal epithelial cells in SAP and that breakdown of intestinal mucosa via accelerated apoptosis causes the increase in intestinal permeability following endotoxin translocation in SAP.

The combination of cytarabine (ara-C) with fludarabine is a common approach to treating resistant acute myeloid leukemia. Success depends on a fludarabine triphosphate (F-ara-ATP)-mediated increase in the active intracellular metabolite of ara-C, ara-C 5'-triphosphate (ara-CTP). Therapy-resistant leukemia may exhibit ara-C resistance, the mechanisms of which might induce cross-resistance to fludarabine with reduced F-ara-ATP formation. The present study evaluated the effect of combining ara-C and fludarabine on ara-C-resistant leukemic cells in vitro. Two variant cell lines (R1 and R2) were 8-fold and 10-fold more ara-C resistant, respectively, than the parental HL-60 cells. Reduced deoxycytidine kinase activity was demonstrated in R1 and R2 cells, and R2 cells also showed an increase in cytosolic 5'-nucleotidase II activity. Compared with HL-60 cells, R1 and R2 cells produced smaller amounts of ara-CTP. Both variants accumulated less F-ara-ATP than HL-60 cells and showed cross-resistance to fludarabine nucleoside (F-ara-A). R2 cells, however, accumulated much smaller amounts of F-ara-ATP and were more F-ara-A resistant than R1 cells. In HL-60 and R1 cells, F-ara-A pretreatment followed by ara-C incubation produced F-ara-ATP concentrations sufficient for augmenting ara-CTP production, thereby enhancing ara-C cytotoxicity. No potentiation was observed in R2 cells. Nucleotidase might preferentially degrade F-ara-A monophosphate over ara-C monophosphate, leading to reduced F-ara-ATP production and thereby compromising the F-ara-A-mediated potentiation of ara-C cytotoxicity in R2 cells. Thus, F-ara-A-mediated enhancement of ara-C cytotoxicity depended on F-ara-ATP accumulation in ara-C-resistant leukemic cells but ultimately was associated with the mechanism of ara-C resistance.

Treatment-related toxicity in acute lymphoblastic leukemia (ALL) can not only be life threatening but may also affect relapse risk. In 240 patients, we determined whether toxicities were related to 16 polymorphisms in genes linked to the pharmacodynamics of ALL chemotherapy, adjusting for age, race (self-reported or via ancestry-informative markers), sex, and disease risk group (lower- vs higher-risk therapy). Toxicities (gastrointestinal, infectious, hepatic, and neurologic) were assessed in each treatment phase. During the induction phase, when drugs subject to the steroid/cytochrome P4503A pathway predominated, genotypes in that pathway were important: vitamin D receptor (odds ratio [OR], 6.85 [95% confidence interval [CI], 1.73-27.0]) and cytochrome P4503A5 (OR, 4.61 [95% CI, 1.11-19.2]) polymorphisms were related to gastrointestinal toxicity and infection, respectively. During the consolidation phase, when antifolates predominated, the reduced folate carrier polymorphism predicted gastrointestinal toxicity (OR, 10.4 [95% CI, 1.35-80.4]) as it also did during continuation (OR, 2.01 [95% CI, 1.06-4.11]). In all 3 treatment phases, a glucuronosyltransferase polymorphism predicted hyperbilirubinemia (P = .017, P < .001, and P < .001) and methotrexate clearance (P = .028), which was also independently associated with hyperbilirubinemia (P = .026). The genotype-phenotype associations were similar whether analyses were adjusted by self-reported race or ancestry-informative genetic markers. Germ-line polymorphisms are significant determinants of toxicity of antileukemic therapy.

われわれは外科手術に対応する電子入力用のテンプレートを作成し, 診療録記載とデータベース作成を一期的に行っている. これを利用した継続的なsurgical site infection (SSI) サーベイランスの有用性につき検討する. 対象 : 2001年1月から2006年6月まで, 当科で施行された腹腔鏡下大腸切除術の待機手術症例611例. 方法 : 当院では各部署に院内local area network (LAN) の端末が設置されているが, ペーパーレスの電子カルテは導入されていない. FileMaker Pro 7.0を用い, すべての端末からサーバーにアクセス可能とした. 術前評価, 手術記録等の診療録用レイアウトを作成し, 選択型式で簡単に入力できるようにした. 診療録記載とデータベースへの入力を可能な限り一元化した. 癌取扱い規約等の一般的な項目に加え, surgical site infection (SSI) に関連する項目を盛り込んだ. 結果 : 腹腔鏡下大腸手術の件数の増加に伴い, 2003年頃より創感染等SSIの発生率が上昇した. SSIおよび創感染の発生率はサーベイランス開始後に有意な低下を認めた. 多変量解析の結果, SSI, 創感染発生の両者でSSIサーベイランスの開始時期が独立した有意な関連因子として抽出された. 結語 : 電子記載に基づくSSIサーベイランスが有用であることが示唆された.

Standardized treatments for indolent B cell lymphoma primarily consisting of follicular lymphoma (FL) and for mantle cell lymphoma (MCL) have yet to be established. Here the Hokuriku Hematology Oncology Study Group conducted a multicenter prospective study to investigate the efficacy and safety of a combination regimen of rituximab, cladribine, mitoxantrone, and dexamethasone (R-CMD) in indolent B cell lymphoma and MCL. A total of 33 CD20-positive patients who received care between January 2008 and August 2011 were investigated. These patients' illnesses were FL (n = 21), nodal marginal zone B cell lymphoma (NMZB, n = 3), MCL (n = 3), splenic marginal zone B cell lymphoma (n = 2), hairy cell leukemia (n = 1), Waldenstrom macroglobulinemia (WM, n = 1), and lymphoplasmacytic lymphoma (LPL, n = 2). Patients received four 21-day cycles of rituximab 375 mg/m(2) (day 1), cladribine 0.10 mg/kg (days 1-3), mitoxantrone 8 mg/m(2) (day 1), and dexamethasone 8 mg/body (days 1-3), with four additional rituximab doses at 4-week intervals. Of the 33 patients, 26 achieved complete response/unconfirmed complete response, and six achieved a partial response (4 with FL, 1 with NMZB, 1 with WM). One had progressive disease (FL), and four relapsed after remission (1 with FL, 2 with MCL, 1 with LPL). R-CMD therapy was relatively convenient and effective in indolent B cell lymphoma and MCL. Nonetheless, to suppress the number and function of both B cells and T cells, comprehensive infection prevention and follow-up are necessary in the future.

We have already shown that the antileukemic activity of daunorubicin that had been reported to be dependent on the area under the concentration - time curve (AUC) was actually peak concentration (Cmax) dependent. The antitumor activity of doxorubicin (DXR) has also been reported to be dependent on AUC, whereas its cumulative cardiotoxicity has been reported to be Cmax dependent. In this study, we evaluated whether the antileukemic and cardiotoxic effects of DXR were AUC or Cmax dependent, and compared their cytotoxic effects, utilizing the computer-controlled in vitro pharmacokinetic simulation system or a conventional culture system for a leukemic cell line and measuring the intracellular ATP amount or the proportion of beating cells for the cardiotoxicity. In leukemic cells, the cytotoxic rate decreased as the simulated infusion time or exposure time increased with the same AUC value in the simulation and conventional culture system (P0.05 and0.01, respectively). The intracellular ATP and proportion of beating cells also increased with prolonged DXR exposure time with the same constant concentration - time product value (P0.05 and0.0001, respectively) in heart cells. These results indicated that both the antileukemic effects and the cardiotoxicity were Cmax dependent. However, a comparison of the two showed that cardiotoxicity was more Cmax dependent than the antileukemic effect. These results suggested that the continuous infusion treatment schedule of DXR may have the clinical advantage of reducing cardiotoxicity more markedly than the antileukemic effect.

はじめに: 社会の高齢化に伴い急性膵炎患者も高齢化し, 重症急性膵炎の平均年齢はこの15年で10歳増加している. これまでの高齢者急性膵炎に関する報告は, 対象として軽・中等症を多く含み, 重症急性膵炎に焦点を絞った解析はみられない. 今回, 高齢者重症急性膵炎を検討し, その特徴を明らかにした. 方法: 厚生労働省重症度判定基準による重症急性膵炎137例を67歳未満105例と67歳以上 (高齢者群) 32例の2群に分類し, 重症度, 血液検査成績, 治療内容, 治療成績を比較解析した. さらに, 高齢者群における経過の予知因子を検索した. 結果: 高齢者重症急性膵炎は, 女性, 胆石性が多く, 入院時重症度 (Ranson, APACHE II, 厚労省スコア) が高かった. 入院時検査で有意差を認めた因子はBUN, Creatinine, PaO2, CRPであった. リンパ球数は入院後1～3週目に有意な減少を認めた. 高齢者群では, 持続血液濾過透析の施行率が有意に高く, 臓器障害併発率, 死亡率が有意に高かった. 高齢者群における経過予知因子を検索すると, 生命予後予知因子は血糖, Ca, 感染併発予知因子はLDH, CRP, Ca, 臓器障害併発予知因子はCa, 白血球数, IL-6, Base excessであった. 高齢者群において入院時血清Caが7.2mg/dl未満の症例は, 臓器障害併発率, 死亡率が有意に高かった. 結論: 高齢者重症急性膵炎は, 臓器予備能が低いため臓器障害の併発が予後と関連しており, 経過の予知因子として入院時血清Caが有用であると考えられた.

Acquired genetic characteristics of acute lymphoblastic leukemia (ALL) cells are used to individualize therapy, whereas germ line genetic characteristics generally are not. We determined whether ALL outcome was related to 16 genetic polymorphisms affecting the pharmacodynamics of antileukemic agents. Of 246 children, 116 were treated on the lower-risk (LR) and 130 on the higher-risk (HR) arms of a St Jude protocol. Patients in the HR group with the glutathione S-transferase (GSTM1) nonnull genotype had greater risk of hematologic relapse (P = .03), which was further increased by the thymidylate synthetase (TYMS) 3/3 genotype (P = .03). These genotypes remained predictive in multivariate analyses (P < .001 and .003, respectively). No genotypes were predictive in the LR arm. Expression of these 2 genes in ALL blasts was lower in those with low-activity genotypes. For central nervous system relapse, among the HR group, the vitamin D receptor start site (P = .02) and intron 8 genotypes (P = .04) predisposed, whereas for LR patients the TYMS 3/3 genotype predisposed (P = .04). The GSTM1 non-null and TYMS 3/3 genotypes are plausibly linked to drug resistance. Polymorphisms interact to influence antileukemic outcome and represent determinants of response that can be used to optimize therapy. (Blood. 2005;105:4752-4758)

Etoposide is a substrate for P-glycoprotein, CYP3A4, CYP3A5, and UGT1A1. Glucocorticoids modulate CYP3A and P-glycoprotein in preclinical models, but their effect on clinical etoposide disposition is unknown. We studied the pharmacokinetics of etoposide and its catechol metabolite in children with acute lymphoblastic leukemia, along with polymorphisms in CYP3A4, CYP3A5, MDR1, GSTP1, UGT1A1, and VDR. Plasma pharmacokinetics were assessed at day 29, after 1 month of prednisone (n = 102), and at week 54, without prednisone (n = 44). On day 29, etoposide clearance was higher (47.4 versus 29.2 mL/min/m2, P < .0001) than at week 54. The day 29 etoposide or catechol area under the curve (AUC) was correlated with neutropenia (P = .027 and P = .0008, respectively). The relationship between genotype and etoposide disposition differed by race and by prednisone use. The MDR1 exon 26 CC genotype predicted higher day 29 etoposide clearance (P = .002) for all patients, and the CYP3A5 AA and GSTP1 AA genotypes predicted lower clearance in blacks (P = .02 and .03, respectively). The UGT1A1 6/6, VDR intron 8 GG, and VDR Fok 1 CC genotypes predicted higher week 54 clearance in blacks (P = .039, .036, and .052, respectively). The UGT1A1 6/6 genotype predicted lower catechol AUC. Prednisone strongly induces etoposide clearance, genetic polymorphisms may predict the constitutive and induced clearance of etoposide, and the relationship between genotype and phenotype differs by race.

Pancreatic stellate cells (PSCs) are thought to be responsible for pancreatic fibrosis. Although fibrosis is a major characteristic of chronic pancreatitis (CP) induced by pancreatic duct obstruction, it is unclear whether pancreatic duct obstruction itself activates PSCs.To test the hypothesis that pancreatic duct obstruction activates PSCs, clinical and experimental analyses were performed using alpha smooth muscle actin (alpha-SMA) as a marker of their activation. In clinical analysis, surgical specimens from the patients with pancreatic cancer or cancer of the papilla Vater were classified into two groups with or without duct obstruction. alpha-SMA expression was examined on these specimens, and the difference between two groups was evaluated. In animal experiment, duct ligation-induced pancreatitis was developed in rats by ligating the secondary pancreatic duct in duodenal segment, and the expression of alpha-SMA was examined.In clinical analysis, the specimens from the pancreas with duct obstruction (14 cases) expressed alpha-SMA significantly stronger than those from the pancreas without duct obstruction (7 cases). All specimens in the former expressed alpha-SMA, but 4 specimens from the latter did not at all (P0.05). In animal experiment, alpha-SMA expression was detected 7 days after the ligation and was increased on the 10th day.We can assume that pancreatic duct obstruction itself activates PSCs. This mechanism may play roles in the development of CP from multiple origins.

Tumor lysis syndrome (TLS) is a life-threatening oncological emergency, and control of serum uric acid level (S-UA) is most important. In this single-institution, short-term and pilot prospective study, the efficacy of a new xanthine oxidase inhibitor, febuxostat, as an alternative to conventional allopurinol, including its effects on hypoxanthine and xanthine, was evaluated in 10 consecutive patients with hematological malignancies at intermediate risk for TLS.Febuxostat at 40 mg (n=7) or 60 mg (n=3) daily was administered according to renal function, and induction chemotherapy was started within 24 h. The primary end-point was the reduction of S-UA to ≤ 7.5 mg/dl by day 5.The median S-UA at base-line was 8.0 mg/dl (range=3.2-10.6 mg/dl). The median S-UA on day 5 after chemotherapy was 3.3 mg/dl (range=1.1-5.8 mg/dl) (p0.0001, by paired t-test), indicating successful control of S-UA during chemotherapy. All patients achieved S-UA ≤ 7.5 mg/dl. A simultaneous decrease in serum creatinine and increase in estimated glomerular filtration rate were seen. Serum hypoxanthine and xanthine levels (as the consequence of inhibition of xanthine oxidase) were elevated along with the decrease in S-UA. Xanthine level was elevated higher compared to hypoxanthine level and reached the level reported to cause xanthine nephropathy, but no advance of renal impairment was observed. Serum febuxostat concentrations at 2 h after administration were 891.8 ± 285.0 ng/ml (mean ± SE) for the 40-mg dose and 770.6 ± 242.7 ng/ml for the 60-mg dose (p=0.80, unpaired t-test), showing no accumulation in patients with renal impairment. No febuxostat-related adverse reactions were noted. No patients experienced progressive TLS.Febuxostat is promising for the management of TLS of an intermediate-risk patient and further observation and reevaluation regarding xanthine nephropathy should be performed.

The prognosis of acute myeloid leukemia (AML) in elderly patients remains poor due to their poor general condition and the intrinsic chemotherapy-resistant nature of their leukemia cells. The present retrospective study evaluated the clinical background as well as the response to treatment, of an unselected group of elderly patients with AML who were admitted to our Institution over a period of six years.Patients aged 65 years or older with AML admitted to our Institution between January 2005 and May 2011 were evaluated retrospectively.Forty-six patients were admitted to our Institution, among whom 41 received remission induction chemotherapy. Twenty-four patients received intensive chemotherapy, while 13 received low-dose cytarabine-based chemotherapy. Other modalities were used in four patients. Complete remission was obtained in 20 patients (48.8%). The complete remission rate (50.0%) tended to be higher in patients receiving intensive chemotherapy than in those receiving low-dose cytarabine-based regimens (30.7%; p=0.25). The median survival time for the whole patient group was 12 months and the 2-year overall survival was 18%. The median survival times for patients with complete remission and for non-responding patients were 14 months and 7 months, respectively. The 2-year overall survival in patients with complete remission was 32%, while that of non-responding patients was 6% (p=0.0025, log-rank test).The present study suggests the necessity of achieving complete remission for obtaining better survival for elderly patients with AML.

To examine the utility of diffusion-weighted MRI (DW-MRI) for staging and early response to chemotherapy assessment in lymphoma patients as compared with fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT).Twenty-eight patients with histologically confirmed malignant lymphoma underwent both MRI and FDG-PET/CT before (pretreatment) and after two courses of chemotherapy (mid-treatment). Staging with MRI (DW-MRI alone and with T2-weighted images) and FDG-PET was compared visually, and the concordance rate (kappa value, κ) was calculated. To evaluate early response to chemotherapy, patients were divided into two groups, lesion-positive (LP) and lesion-negative (LN), based on a proposed original criterion. Progression-free survival (PFS) was compared between the groups using the Kaplan-Meier method.The stage diagnosed with DW-MRI alone and with FDG-PET/CT was concordant in 22 patients (κ = 0.71; P 0.05), and by adding T2-weighted images, the number of concordant patients increased to 26 (κ = 0.90; P 0.05). On mid-treatment imaging, 19 patients were diagnosed as LN from both modalities. PFS differed significantly between LP and LN on both DW-MRI (P = 0.0013) and FDG-PET/CT (P = 0.037).DW-MRI is a promising tool for staging and evaluation of early response to chemotherapy in patients with lymphoma.