Enzymatic detection of α-hydroxybutyrate, an important marker of insulin resistance, and comparison with LC-MS/MS detection.

Aim: The metabolite α-hydroxybutyrate (α-HB) is an important marker of insulin resistance and impaired glucose tolerance allowing to identify patients at risk of developing diabetes and related metabolic disorders before any symptoms become apparent. At present, its exact quantification requires mass spectrometry (LC-MS), which is not compatible with routine laboratory use. Accordingly, a simple enzymatic-based method was assessed and its applicability and measuring accuracy compared with LC-MS was investigated. Methods: Standards, serum, and plasma samples containing α-HB were prepared with routine procedures and their α-HB contents measured with the XpressGT® enzymatic test kit photometrically or with LC-MS and multiple reaction monitoring. Results: α-HB detection with XpressGT® yielded highly linear calibration curves and 102 % recovery of stocks added to commercial samples. Stability of the analyte in serum and plasma samples prepared with various anti-coagulants was >90 % after 46 h for several widely used preparations and recovery after 3 freeze-thaw cycles was ≥95 % with these anti-coagulants. A direct comparison of 75 samples indicated very good agreement of α-HB levels determined by both methods, 86 % of XpressGT® samples being within ±20 % of LC-MS values and even 93 % within ±20 % considering only samples above 30 µM concentration. Conclusion: XpressGT®-based detection of α-HB is an easily applicable method which can be used for accurate and reliable quantification of the metabolite in clinical practice. Routine α-HB determination in patients at risk of developing diabetes would allow early establishment of preventive measures or pharmacological intervention reducing the risk for the onset of serious diabetes-related health problems.

Perioperative hemostasis management in patients with von Willebrand disease: an institutional experience.

OBJECTIVES: Patients with von Willebrand disease (vWD) undergoing surgery are routinely treated with von Willebrand factor (vWF)/factor VIII (FVIII) concentrate to control bleeding risk, but consensus is lacking on optimal dosing. This study aimed to evaluate the efficacy and safety of tailored doses of vWF/FVIII concentrate according to intervention-associated bleeding risk in vWD patients undergoing surgery. METHODS: This was a retrospective analysis of vWD patients who underwent surgical procedures at a haemophilia centre. Patients received vWF/FVIII concentrate with dosage and duration of treatment dependent on intervention type (dental, gynaecological, abdominal or orthopaedic/traumatic) and bleeding risk (moderate/high). RESULTS: Eighty-three surgical procedures (42 patients) were included. Median preoperative loading doses of vWF/FVIII concentrate were 29.9 IU/kg and 35.7 IU/kg for interventions with moderate ( n  = 16) or high ( n  = 67) bleeding risk, respectively. The median perioperative dose was highest in orthopaedic or trauma-related surgery (140 IU/kg) and lowest in dental or gynaecological interventions (76.4 IU/kg and 80.0 IU/kg, respectively). During follow-up, no bleeding or other complications were observed in 95% of patients. CONCLUSIONS: Individually tailored doses of vWF/FVIII concentrate according to intervention-associated bleeding risk were effective in preventing postoperative bleeding, with few complications observed. These doses may be used as guidance in routine clinical care.

Radiation and Dose-densification of R-CHOP in Primary Mediastinal B-cell Lymphoma: Subgroup Analysis of the UNFOLDER Trial.

UNFOLDER (NCT00278408, EUDRACT 2005-005218-19) is a phase-3 trial in patients with aggressive B-cell lymphoma and intermediate prognosis, including primary mediastinal B-cell lymphoma (PMBCL). In a 2 × 2 factorial design, patients were randomized to 6× R-CHOP-14 or R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prediso(lo)ne) and to consolidation radiotherapy to extralymphatic/bulky disease or observation. Response was assessed according to the standardized criteria from 1999, which did not include F-18 fluordesoxyglucose positron emission tomography/computed tomography (FDG-PET) scans. Primary end point was event-free survival (EFS). A subgroup of 131 patients with PMBCLs was included (median age, 34 y; 54% female, 79% elevated lactate dehydrogenase (LDH), 20% LDH >2× upper limit of normal [ULN], and 24% extralymphatic involvement). Eighty-two (R-CHOP-21: 43 and R-CHOP-14: 39) patients were assigned to radiotherapy and 49 (R-CHOP-21: 27, R-CHOP-14: 22) to observation. The 3-year EFS was superior in radiotherapy arm (94% [95% confidence interval (CI), 89-99] versus 78% [95% CI, 66-89]; P = 0.0069), due to a lower rate of partial responses (PRs) (2% versus 10%). PR triggered additional treatment, mostly radiotherapy (n = 5; PR: 4; complete response/unconfirmed complete response: 1). No significant differences were observed in progression-free survival (PFS) (95% [95% CI, 90-100] versus 90% [95% CI, 81-98]; P = 0.25) nor in overall survival (OS) (98% [95% CI, 94-100] versus 96% [95% CI, 90-100]; P = 0.64). Comparing R-CHOP-14 and R-CHOP-21, EFS, PFS, and OS were not different. A prognostic marker for adverse outcome was elevated LDH >2× ULN (EFS: P = 0.016; PFS: P = 0.0049; OS: P = 0.0014). With the limitation of a pre-PET-era trial, the results suggest a benefit of radiotherapy only for patients responding to R-CHOP with PR. PMBCL treated with R-CHOP have a favorable prognosis with a 3-year OS of 97%.

Radiation and Dose-densification of R-CHOP in Aggressive B-cell Lymphoma With Intermediate Prognosis: The UNFOLDER Study.

UNFOLDER (Unfavorable Young Low-Risk Densification of R-Chemo Regimens) is an international phase-3 trial in patients 18-60 years with aggressive B-cell lymphoma and intermediate prognosis defined by age-adjusted International Prognostic Index (aaIPI) of 0 and bulky disease (≥7.5 cm) or aaIPI of 1. In a 2 × 2 factorial design patients were randomized to 6× R-CHOP-14 or 6× R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prediso[lo]ne) and to consolidation radiotherapy to extralymphatic and bulky disease or observation. Response was assessed according to the standardized response criteria published in 1999, not including F-18 fluordesoxyglucose positron emission tomography/computed tomography (FDG-PET). Primary endpoint was event-free survival (EFS). A total of 695 of 700 patients were eligible for the intention-to-treat analysis. Totally 467 patients qualified for radiotherapy of whom 305 patients were randomized to receive radiotherapy (R-CHOP-21: 155; R-CHOP-14: 150) and 162 to observation (R-CHOP-21: 81, R-CHOP-14: 81). Two hundred twenty-eight patients not qualifying for radiotherapy were randomized for R-CHOP-14 versus R-CHOP-21. After a median observation of 66 months 3-year EFS was superior in the radiotherapy-arm versus observation-arm (84% versus 68%; P = 0.0012), due to a lower rate of partial responses (PR) (2% versus 11%). PR often triggered additional treatment, mostly radiotherapy. No significant difference was observed in progression-free survival (PFS) (89% versus 81%; P = 0.22) and overall survival (OS) (93% versus 93%; P = 0.51). Comparing R-CHOP-14 and R-CHOP-21 EFS, PFS and OS were not different. Patients randomized to radiotherapy had a superior EFS, largely due to a lower PR rate requiring less additional treatment (NCT00278408, EUDRACT 2005-005218-19).

FOLFOXIRI Plus Cetuximab or Bevacizumab as First-Line Treatment of BRAFV600E-Mutant Metastatic Colorectal Cancer: The Randomized Phase II FIRE-4.5 (AIO KRK0116) Study.

PURPOSE: BRAFV600E mutation is associated with a poor outcome in metastatic colorectal cancer (mCRC). This clinical trial investigated the efficacy of triplet chemotherapy (fluorouracil, folinic acid, oxaliplatin, and irinotecan) combined with either cetuximab or bevacizumab in patients with previously untreated BRAFV600E-mutant mCRC. PATIENTS AND METHODS: In this controlled, randomized, open-label phase II trial, 109 patients were randomly assigned, 107 of whom were included into the full analysis set (FAS). Patients were randomly assigned in a 2:1 ratio to receive either FOLFOXIRI plus cetuximab in the experimental arm (n = 72) or FOLFOXIRI plus bevacizumab in the control arm (n = 35). The primary end point was objective response rate (ORR) according to RECIST 1.1., evaluated in patients treated according to protocol (ATP population). Progression-free survival (PFS), overall survival (OS), toxicity, and feasibility were analyzed as secondary end points. RESULTS: Eighteen patients discontinued study treatment before the first tumor assessment, thus resulting in the ATP population of 89 patients. In these patients, ORR was 51% (30/59) in the cetuximab-based experimental arm and 67% (20/30) in the bevacizumab-based control arm (odds ratio, 1.93; 80% CI, 1.06 to 3.52; P = .92 [one-sided]). In the full analysis set, median PFS was significantly inferior in the experimental arm (6.7 months v 10.7 months; hazard ratio [HR], 1.89; P = .006). Median OS analyzed at an event rate of 64.5% showed a trend toward shorter survival in cetuximab-treated patients (12.9 months v 17.1 months; HR, 1.4; P = .20). CONCLUSION: To our knowledge, FIRE-4.5 is the first prospective and randomized study investigating first-line treatment of BRAFV600E-mutant mCRC. FOLFOXIRI plus cetuximab does not induce a higher ORR when compared with FOLFOXIRI plus bevacizumab in first-line treatment of BRAFV600E-mutant mCRC. Bevacizumab-based chemotherapy remains the preferable first-line treatment of patients with BRAFV600E-mutant mCRC.

Flavin Mononucleotide-Dependent l-Lactate Dehydrogenases: Expanding the Toolbox of Enzymes for l-Lactate Biosensors.

The development of L-lactate biosensors has been hampered in recent years by the lack of availability and knowledge about a wider range and diversity of L-lactate-oxidizing enzymes that can be used as bioelements in these sensors. For decades, L-lactate oxidase of Aerococcus viridans (AvLOx) has been used almost exclusively in the field of L-lactate biosensor development and has achieved somewhat like a monopoly status as a biocatalyst for these applications. Studies on other L-lactate-oxidizing enzymes are sparse and are often missing biochemical data. In this work, we made use of the vast amount of sequence information that is currently available on protein databases to investigate the naturally occurring diversity of L-lactate-utilizing enzymes of the flavin mononucleotide (FMN)-dependent α-hydroxy acid oxidoreductase (HAOx) family. We identified the HAOx sequence space specific for L-lactate oxidation and additionally discovered a not-yet described class of soluble and FMN-dependent L-lactate dehydrogenases, which are promising for the construction of second-generation biosensors or other biotechnological applications. Our work paves the way for new studies on α-hydroxy acid biosensors and proves that there is more to the HAOx family than AvLOx.

Neglected geriatric assessment and overtreatment of older patients with pancreatic cancer - Results from a prospective phase IV clinical trial.

BACKGROUND: Older patients with metastatic pancreatic cancer may suffer increased toxicity from intensive chemotherapy. Treatment individualization by geriatric assessment (GA) might improve functional outcome. METHODS: We performed a multicenter, phase IV, open label trial in patients ≥70 years with metastatic pancreatic adenocarcinoma. Patients underwent GA and were assigned to one of three categories based on their scores: Go-Go, Slow-Go, or Frail. These categories were intended to guide physician's treatment decisions when choosing to treat patients with nab-paclitaxel/gemcitabine (arm A), gemcitabine (arm B), or best supportive care (arm C). Primary objective was a stable (loss of five points or less) Barthel's Activities of Daily Living (ADL) score during chemotherapy; secondary endpoints included GA scores during therapy, safety, quality of life, response and survival rates. RESULTS: Thirty-two patients were enrolled in the trial in six centers in Germany (out of 135 planned), resulting in termination due to low recruitment. Fifteen patients were allocated to nab-paclitaxel/gemcitabine, fifteen to gemcitabine, and two to best supportive care by their physicians, although according to their GA scores 29 patients (91%) were categorized as Slow-Go and three (9%) as Go-Go. Thus, fifteen of 32 (47%) patients were misclassified and given a course of treatment inconsistent with their GA scores. Median progression-free survival (PFS) were 3.3 months and 9.1 months and median time to quality-of-life deterioration 13 days and 29 days in the nab-paclitaxel/gemcitabine and gemcitabine monotherapy arms, respectively. Serious adverse events were reported in 11 (78.6%) patients in the nab-paclitaxel/gemcitabine and 8 (53.3%) patients in the gemcitabine arm. CONCLUSIONS: Clinical evaluations by investigators differed markedly from geriatric assessments, leading to potential overtreatment. In our modest sample size study, those patients undergoing more intensive therapy had a less favorable course.

Development of Haemophilia Treatment in the Eastern Part of Germany over the Last Decade in the Kompetenznetz Hämorrhagische Diathese Ost (KHDO).

INTRODUCTION: In 2005 the Kompetenznetz Hämorrhagische Diathese Ost published epidemiologic data about patients with haemophilia A (HA) and haemophilia B (HB) in the eastern part of Germany. This study provides data about the development of treatment in these patients over the past 10 years. METHODS: Data from 12 haemophilia centres in eastern Germany were retrospectively collected for the year 2015 from patients' records. RESULTS: We evaluated 413 patients (115 children, 298 adults) with HA or HB. A total of 286 patients (69.2%) had severe haemophilia (patients with severe haemophilia, PWSH). Compared with 2005, the proportion PWSH on prophylaxis increased from 90% to 98.8% in children and from 64% to 80.2% in adults. The use of plasma-derived factor concentrates decreased from >70% to 55.3% in children and to 55.1% in adults. Mean annual factor consumption in PWSH without inhibitor was higher in 2015 compared with 2005 (children with HA: 151,489 vs. 98,894; adults with HA: 217,151 vs. 151,394; children with HB: 105,200 vs. 64,256; adults with HB: 159,185 vs. 85,295). Median annualized bleeding (annualized bleeding rate, ABR) and joint bleeding rates (annualized joint bleeding rate, AJBR) in 2015 were 2 and 0 in children and 3 and 0 in adults, respectively. In 2015 only one child (1.2%) but 101 (53.2%) adults with severe haemophilia were anti-hepatitis C virus (anti-HCV) positive. The rate of anti-HCV positive patients with active hepatitis C dropped from 63.8% to 12.9%. CONCLUSIONS: Within the last decade more patients with severe haemophilia were switched to a prophylactic regimen going along with a moderate increase in factor consumption achieving a low ABR and AJBR.

Frailty impairs the feasibility of induction therapy but not of maintenance therapy in elderly myeloma patients: final results of the German Maintenance Study (GERMAIN).

PURPOSE: The German Maintenance Study (GERMAIN) was designed to evaluate the impact of lenalidomide maintenance after induction therapy with bortezomib, melphalan and prednisolone (VMP) in transplant-ineligible newly diagnosed multiple myeloma (MM) patients. METHODS: Due to poor accrual and high dropout rate, only 85 patients (planned 286) entered the trial and 40 (planned 200) were randomized to lenalidomide maintenance (n = 19) vs. observation (n = 21). RESULTS: The primary endpoint, improved progression-free survival, was not met (p = 0.3572). After a median follow-up of 12.9 months, median progression-free survival in the lenalidomide arm was 14.4 months and 11.4 months with placebo. The hazard ratio 0.621 (95% confidence interval: [0.224, 1.725]) was about the same as expected (0.625). However, with only 40 patients randomized, the actual power to detect a difference was 11%. Of patients receiving at least one dose of induction, 54% were frail according to a modified International Myeloma Working Group frailty score. Discontinuations were high during induction (47%), and affected mainly frail patients (54%). Despite a higher rate of adverse events in the lenalidomide arm (p = 0.0061), only 2 patients discontinued lenalidomide due to toxicity. CONCLUSION: A frailty assessment with appropriate dose modification for induction therapy should be mandatory for all elderly non-transplant-eligible myeloma patients.

Results from the prospective German TPK clinical cohort study: Treatment algorithms and survival of 1,174 patients with locally advanced, inoperable, or metastatic pancreatic ductal adenocarcinoma.

Pancreatic cancer is a highly lethal malignancy. Developments in recent years have broadened our therapeutic armamentarium. Novel drugs such as nab-paclitaxel, liposomal irinotecan and chemotherapy regimens such as FOLFIRINOX have been successfully tested in clinical trials. Data on patients outside of clinical trials are scarce but necessary to assess and improve the standard of care. We present data on treatment and survival of 1,174 patients with locally advanced, inoperable, or metastatic pancreatic ductal adenocarcinoma. Between February 2014 and June 2017, patients were recruited by 104 sites at start of first-line therapy into the ongoing, prospective clinical cohort study TPK (Tumour Registry Pancreatic Cancer). As first-line therapy, 89% of patients received one of the three treatment regimens: gemcitabine monotherapy (23%), nab-paclitaxel plus gemcitabine (42%), or FOLFIRINOX (24%). The corresponding subgroups differed: Patients receiving gemcitabine monotherapy were older and more comorbid (median age 78 years, 73% ECOG ≥ 1) than patients receiving nab-paclitaxel plus gemcitabine (median age 71, 64% ECOG ≥ 1) or patients receiving FOLFIRINOX (median age 60, 52% ECOG ≥ 1). At least 40% of patients died before receiving second-line treatment. First-line progression-free survival was 4.6 months (95% CI: 3.7-5.2) for gemcitabine, 5.6 months (95% CI: 5.0-6.2) for nab-paclitaxel plus gemcitabine, and 6.3 months (95% CI: 5.5-6.9) for FOLFIRINOX. Our data represent the treatment reality in a German community setting. Although there are no stringent inclusion criteria for our cohort study, overall survival is comparable to that reported by randomised clinical trials.

Desmopressin-induced Moschcowitz-like syndrome after treatment of uterine atonic bleeding in a 28-year-old pregnant woman: case report and overview of the literature.

Here we report of a patient who developed a Moschcowitz-like syndrome following a desmopressin treatment of severe postpartum hemorrhage. The patient got an anaphylactic reaction after cervical ripening with dinoproston, leading to an emergency cesarean. A postpartum uterine atony with a blood loss more than 1500 ml resulted in a disseminated intravascular coagulation that was treated with mass transfusion of blood products, including platelets and factor VII. Desmopressin is used as rescue medication in situations of severe bleeding. It was given in this life-threatening situation and presumably triggered a Moschcowitz-like syndrome. Desmopressin exerts its haemostatic effect by releasing von Willebrand factor, which is elevated in pregnancy per se. This results in an increased risk of developing microthrombi, leading to a Moschcowitz-like syndrome. In conclusion, desmopressin should not be administered in pregnant patients owing to its potential risk of triggering the development of thrombotic-thrombocytopenic purpura.

Neurological complications after intrathecal liposomal cytarabine application in patients after allogeneic haematopoietic stem cell transplantation.

Liposomal cytarabine has been proven to be useful for the prevention and intrathecal treatment of neoplastic meningitis. It has no demonstrable myelosuppressive effects and may therefore be an attractive alternative for prophylaxis and treatment of the central nervous system (CNS) relapse after allogeneic haematopoietic stem cell transplantation (HSCT). The use of liposomal cytarabine had not been reported in HSCT recipients. We retrospectively reviewed the feasibility of liposomal cytarabine in the prophylaxis (n=2) and treatment (n=4) of neoplastic meningitis in a cohort of patients after allogeneic HSCT. This report focusses on neurological complications after intrathecal application of liposomal cytarabine. Mild headache was the most commonly reported adverse event. Two patients experienced sacral radiculopathy with irreversible cauda equina syndrome in one patient. Another patient progressed with pre-existing leukencephalopathy. Intrathecal liposomal cytarabine should be used very cautiously in allogeneic HSCT recipients with a history of CNS complications potentially involving cerebral-spinal fluid circulation, since significant neurotoxicity was observed in patients with extensive CNS-directed pre-treatment. The feasibility and safety of liposomal cytarabine in HSCT recipients has to be evaluated in a prospective study.

Methotrexate-albumin and aminopterin-albumin effectively prevent experimental acute graft-versus-host disease.

BACKGROUND: During the last several years, major progress has been made in developing targeted chemotherapy using cytotoxic drugs covalently bound to human serum albumin (HSA). We explored the activity of two antifolates methotrexate (MTX) and aminopterin (AMPT) bound to HSA in prophylaxis and treatment of experimental acute graft-versus-host disease (aGVHD). METHODS: In all, 113 female F1 hybrid BN/Lew-rats were irradiated with 8.2 Gy (n=103) or 9.9 Gy (n=10). One day after irradiation each rat received 4 x 10 bone marrow cells and 1.5 x 10 spleen T-cells from female Lew-rats. GVHD prophylaxis consisted of MTX-HSA 2 mg/kg (n=25), MTX-HSA 0.5 mg/kg (n=8), AMPT-HSA 0.65 mg/kg (n=8), MTX 0.5 mg/kg (n=17), or native HSA (n=39) given intraperitoneally (IP) on days 0, 4, 8, and 12. Treatment of aGVHD consisted of MTX-HSA 2 mg/kg (n=8) or AMPT-HSA 0.5 mg/kg (n=8) given intraperitoneally at the time of onset of aGVHD and subsequently every fourth day (a total of four doses). RESULTS: All animals receiving native HSA developed lethal aGVHD. Prophylactic treatment with MTX-HSA 2 mg/kg prevented aGVHD in 18 of 25 animals and in 6 of 8 receiving AMPT-HSA. In contrast, five out of nine rats receiving free MTX died due to aGVHD. The survival rates in the prophylactic MTX-HSA 2 mg/kg and AMPT-HSA groups were significantly higher compared to the MTX and control groups (P<0.05), while non hematologic toxicity of MTX-HSA was not detectable. AMPT-HSA at a dose of 0.65 mg/kg as well as MTX at a dose of 0.5 mg/kg were associated with temporary weight loss and lethargy. CONCLUSIONS: The albumin conjugates MTX-HSA and AMPT-HSA effectively prevent experimental aGVHD.

Prognostic significance of NOD2/CARD15 variants in HLA-identical sibling hematopoietic stem cell transplantation: effect on long-term outcome is confirmed in 2 independent cohorts and may be modulated by the type of gastrointestinal decontamination.

To assess the role of NOD2/CARD15 variants on the long-term outcome of allogeneic stem cell transplantation in a genetically homogeneous group, we extended our previous study (cohort I, n = 78) and typed DNA for NOD2/CARD15 single nucleotide polymorphisms (SNPs) from an additional 225 recipients and their HLA-identical sibling donors (cohort II) treated at four other European centers. Results of genotyping were compared with clinical outcome. The strong association of NOD2/CARD15 variants with transplantation-related mortality (TRM) was confirmed in univariate and multivariate analysis; TRM increased from 20% in cohort I/22% in cohort II in recipient/donor pairs without any NOD2/CARD15 variants to 47% in cohort I/32% in cohort II in the presence of one variant in either donor or recipient and further to 57% in cohort I/74% in cohort II in the presence of 2 or more variants (P < .002 in both cohorts). NOD2/CARD15 SNPs were not associated with relapse rate but had a strong impact on overall survival. In an analysis of center effects, the type of gastrointestinal decontamination was the only factor interfering with the prognostic significance of NOD2/CARD15 SNPs. Our data further support an interaction between gastrointestinal defense mechanisms, activation of the innate immune system, and specific transplant-related complications.

Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD.

CD4+CD25+ regulatory T cells (Tregs) control immune responses to self- and foreign antigens and play a pivotal role in autoimmune diseases, infectious and noninfectious inflammation, and graft rejection. Since recent experimental studies have indicated that Tregs were able to ameliorate graft-versus-host disease (GvHD), we analyzed the number of infiltrating Tregs in the intestinal mucosa as one site of GvH reactivity using immunoenzymatic labeling to enumerate FOXP3+ T cells in 95 intestinal biopsies from 49 allografted patients in comparison with healthy controls and patients with infectious inflammation. While patients with cytomegalovirus (CMV)-colitis or diverticulitis showed a concomitant increase of CD8+ effectors and Tregs, acute and chronic GvHD were characterized by the complete lack of a counter-regulation indicated by a FOXP3+/CD8+ T-cell ratio identical to healthy controls. In contrast, specimens without histologic signs of GvHD demonstrated increased numbers of FOXP3+ per CD8+ T cells, indicating that the potential for Treg expansion is principally maintained in allografted patients. Our findings provide evidence that GvHD is associated with an insufficient up-regulation of Tregs in intestinal GvHD lesions. The determination of FOXP3+/CD8+ ratio can be a helpful tool to discriminate GvHD from infectious inflammation after allogeneic stem cell transplantation.

Accidental intrathecal administration of bleomycin: favorable outcome after pneumo-encephalus and cerebrospinal fluid exchange: a case report.

Bleomycin is generally used as an antineoplastic drug for the intravenous treatment of germ cell tumors or lymphomas. Due to its toxic effect on epithelial cells bleomycin is also used for the treatment of malignant pleural or pericardial effusions. Inadvertent intrathecal administration of cytotoxic drugs may occur due to increasingly complex therapeutic protocols, even when control mechanisms are applied. We report the case of a 39-year-old man with chronic myeloid leukemia. During the treatment of a lymphoblast crisis 30 mg of bleomycin were inadvertently injected intrathecally. Prompt cerebrospinal fluid exchange, dilution with normal saline, and corticosteroid treatment resulted in a positive outcome without major side effects.

Treosulfan and fludarabine: a new toxicity-reduced conditioning regimen for allogeneic hematopoietic stem cell transplantation.

New conditioning regimens are being explored to reduce toxicity and enable allogeneic bone marrow transplantation in patients not eligible for conventional transplantation. We have investigated treosulfan, an alkylating agent, with the aim of developing an efficient and reliable but less-toxic conditioning regimen. A series of 30 patients who were not eligible for standard conditioning therapy received transplants from HLA-matched related (n = 14) or unrelated (n = 16) donors after administration of treosulfan 10 g/m2 intravenously daily for 3 days and fludarabine 30 mg/m2 intravenously daily for 5 days. Patients receiving grafts from unrelated donors also were given rabbit antithymocyte globulin 10 mg/kg intravenously daily for 3 days. All patients achieved prompt neutrophil and platelet recovery. Extramedullary toxicity was generally mild with Common Toxicity Criteria (CTC) grade 3 or 4 attributable to the conditioning seen only with transaminases. Complete donor chimerism was achieved by 90% of the patients. Acute graft-versus-host disease (GVHD) grade III or IV developed in 14% of the patients and chronic GVHD in 39%. An estimated overall survival rate of 73% and an event-free survival rate of 49% have been reached after a median of 22 months (range, 7.4-33.4 months). In summary, the combination of treosulfan and fludarabine is a safe and efficient conditioning regimen.