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A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60-87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45-64)) and the study group arms (53% (95%CI: 47-60) and 59% (95%CI: 58-63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7-14.0) in the CSA, 7.6% (95%CI: 4.5-12.8) in study group A and 11.1% (95%CI: 9.0-13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0-26.9), 17.0% (95%CI: 2.0-23.9), and 19.5% (95%CI: 16.7-22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA., (© 2023. The Author(s).)

Relapse of acute leukemia is a frequent complication with uncertain outcome and poorly defined risk factors. From 1621 patients entered into two prospective clinical trials (AML02; n = 740 and AML04; n = 881), 74.2% reached complete remission (CR) 1 after induction(s) and 59 patients after additional induction ± hematopoietic cell transplantation (HCT). Of the non-refractory patients, 48.4% with a median age of 63 (range 17-85) years relapsed. Relapses occurred within 6 months after CR in 46.5%, between 7 and 18 months in 38.7%, and after 18 months in 14.8% of patients. Relapse treatment resulted in CR2 in 39% of patients depending upon age (54.5% of ≤ 60 and 28.6% of > 60 years), duration of CR1, and treatment of relapse. Overall survival (OS) was 10.9 (7.4-16.2) %, but OS after HCT ± intensive chemotherapy (ICT) was 39.3% (31.8-48.6) at 5 years and not different in younger and older patients. Donor lymphocyte infusion ± chemotherapy and ICT alone resulted only in OS of 15.4% and of 5%, respectively. Independent favorable factors for OS were long CR1 duration, and HCT, while non-monosomal disease was beneficial for OS in elderly patients. Leukemia-free survival [LFS; 24.9 (19.5-31.7) % at 10 years] was affected by similar risk factors. In a competing risk model, the relapse incidence at 5 years was 53.5 ± 3.5% and the non-relapse mortality rate 21.7 ± 2.9%. Lower relapse incidence was observed in patents with HCT, long CR1 duration, and female gender. Risk factors for non-relapse mortality were HCT in younger and type of AML in elderly patients. In conclusion, allogeneic HCT ± IC improved the results in relapsed AML in younger and elderly patients. Increasing CR2 rates and HCT frequency will be the challenge for the next years. Relapse of the disease remains the major problem., (© 2021. The Author(s).)

Hematologic and oncologic patients with chemo- or immunotherapy-related immunosuppression are at substantial risk for bacterial infections and Pneumocystis jirovecii pneumonia (PcP). As bacterial resistances are increasing worldwide and new research reshapes our understanding of the interactions between the human host and bacterial commensals, administration of antibacterial prophylaxis has become a matter of discussion. This guideline constitutes an update of the 2013 published guideline of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO). It gives an overview about current strategies for antibacterial prophylaxis in cancer patients while taking into account the impact of antibacterial prophylaxis on the human microbiome and resistance development. Current literature published from January 2012 to August 2020 was searched and evidence-based recommendations were developed by an expert panel. All recommendations were discussed and approved in a consensus conference of the AGIHO prior to publication. As a result, we present a comprehensive update and extension of our guideline for antibacterial and PcP prophylaxis in cancer patients.

Cancer patients frequently require central venous catheters for therapy and parenteral nutrition and are at high risk of central venous catheter-related infections (CRIs). Moreover, CRIs prolong hospitalization, cause an excess in resource utilization and treatment cost, often delay anti-cancer treatment, and are associated with a significant increase in mortality in cancer patients. We therefore summoned a panel of experts by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) and updated our previous guideline on CRIs in cancer patients. After conducting systematic literature searches on PubMed, Medline, and Cochrane databases, video- and meeting-based consensus discussions were held. In the presented guideline, we summarize recommendations on definition, diagnosis, management, and prevention of CRIs in cancer patients including the grading of strength of recommendations and the respective levels of evidence. This guideline supports clinicians and researchers alike in the evidence-based decision-making in the management of CRIs in cancer patients.

This phase 3 trial compared tandem autologous stem cell transplantation (autoSCT) versus autoSCT followed by reduced-intensity conditioning allogeneic stem cell transplantation (auto/alloSCT) in patients with newly diagnosed multiple myeloma (MM) with deletion of (del) chromosome 13q (del13q). The availability/absence of a human leukocyte antigen-matched-related or matched-unrelated donor (MUD) determined the nature of the second SCT. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population (n = 199). Auto/alloSCT was performed in 126 patients; 74 received MUD allografts. After 91 months median follow-up, median PFS with auto/allo versus tandem autoSCT was 34.5 versus 21.8 months (P = 0.003; adjusted hazard ratio 0.55, 95% confidence interval 0.36-0.84). Median overall survival (OS) was 70.2 versus 71.8 months (P = 0.856). Two-year non-relapse mortality with auto/allo versus tandem autoSCT was 14.3% versus 4.1% (P = 0.008). In patients harboring both del13q and del17p, median PFS and OS were 37.5 and 61.5 months with auto/allo (n = 19) versus 6.1 and 23.4 months with tandem autoSCT (n = 6) (P = 0.0002 and 0.032). Our findings suggest that auto/alloSCT significantly extends PFS versus tandem autoSCT in del13q MM, and indicate some survival benefit for first-line alloSCT in high-risk MM.

Infectious complications are a significant cause of morbidity and mortality in patients with malignancies specifically when receiving anticancer treatments. Prevention of infection through vaccines is an important aspect of clinical care of cancer patients. Immunocompromising effects of the underlying disease as well as of antineoplastic therapies need to be considered when devising vaccination strategies. This guideline provides clinical recommendations on vaccine use in cancer patients including autologous stem cell transplant recipients, while allogeneic stem cell transplantation is subject of a separate guideline. The document was prepared by the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO) by reviewing currently available data and applying evidence-based medicine criteria.

Introduction: In Brazil, more than 487,450 individuals are currently undergoing antiretroviral treatment. In order to monitor the transmission of drug-resistant strains and HIV subtype distribution in the country, this work aimed to estimate its prevalence and to characterize the nationwide pretreatment drug resistance in individuals recently diagnosed with HIV between 2013 and 2015., Methods: The HIV threshold survey methodology (HIV-THS, WHO) targeting antiretroviral-naive individuals with recent HIV diagnosis was utilized, and subjects were selected from 51 highly populated cities in all five Brazilian macroregions. The HIV pol genotypic test was performed by genomic sequencing., Results: We analysed samples from 1568 antiretroviral-naive individuals recently diagnosed with HIV, and the overall transmitted drug resistance (TDR) prevalence was 9.5% (150 sequences). The regional prevalence of resistance according to Brazilian geographical regions was 9.4% in the northeast, 11.2% in the southeast, 6.8% in the central region, 10.2% in the north and 8.8% in the south. The inhibitor-specific TDR prevalence was 3.6% for nucleoside reverse transcriptase inhibitors (NRTIs), 5.8% for non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 1.6% for protease inhibitors (PIs); 1.0% of individuals presented resistance to more than one class of inhibitors. Overall, subtype B was more prevalent in every region except for the southern, where subtype C prevails., Conclusions: To the best of our knowledge, this is the first TDR study conducted in Brazil with nationwide representative sampling. The TDR prevalence revealed a moderate rate in the five Brazilian geographical regions, although some cities presented higher TDR prevalence rates, reaching 14% in São Paulo, for example. These results further illustrate the importance of surveillance studies for designing future strategies in primary antiretroviral therapy, aiming to mitigate TDR, as well as for predicting future trends in other regions of the globe where mass antiretroviral (ARV) treatment was implemented., (© 2018 The Authors. Journal of the International AIDS Society published by John Wiley & sons Ltd on behalf of the International AIDS Society.)

Immunocompromised patients are at high risk of invasive fungal infections (IFI), in particular those with haematological malignancies undergoing remission-induction chemotherapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) and recipients of allogeneic haematopoietic stem cell transplants (HSCT). Despite the development of new treatment options in the past decades, IFI remains a concern due to substantial morbidity and mortality in these patient populations. In addition, the increasing use of new immune modulating drugs in cancer therapy has opened an entirely new spectrum of at risk periods. Since the last edition of antifungal prophylaxis recommendations of the German Society for Haematology and Medical Oncology in 2014, seven clinical trials regarding antifungal prophylaxis in patients with haematological malignancies have been published, comprising 1227 patients. This update assesses the impact of this additional evidence and effective revisions. Our key recommendations are the following: prophylaxis should be performed with posaconazole delayed release tablets during remission induction chemotherapy for AML and MDS (AI). Posaconazole iv can be used when the oral route is contraindicated or not feasible. Intravenous liposomal amphotericin B did not significantly decrease IFI rates in acute lymphoblastic leukaemia (ALL) patients during induction chemotherapy, and there is poor evidence to recommend it for prophylaxis in these patients (CI). Despite substantial risk of IFI, we cannot provide a stronger recommendation for these patients. There is poor evidence regarding voriconazole prophylaxis in patients with neutropenia (CII). Therapeutic drug monitoring TDM should be performed within 2 to 5 days of initiating voriconazole prophylaxis and should be repeated in case of suspicious adverse events or of dose changes of interacting drugs (BIItu). General TDM during posaconazole prophylaxis is not recommended (CIItu), but may be helpful in cases of clinical failure such as breakthrough IFI for verification of compliance or absorption.

To investigate immuno-chemotherapy for elderly immuno-competent patients (⩾65 years) with newly diagnosed primary central nervous system lymphoma, we conducted a multicentre single-arm trial. One cycle consisted of rituximab (375 mg/m 2 , days 1, 15, 29), high-dose methotrexate (3 g/m 2 days 2, 16, 30), procarbazine (60 mg/m 2 days 2-11) and lomustine (110 mg/m 2 , day 2)-R-MPL protocol. Owing to infectious complications, we omitted lomustine during the study and consecutive patients were treated with the R-MP protocol. Three cycles were scheduled and repeated on day 43. Subsequently, patients commenced 4 weekly maintenance treatment with procarbazine (100 mg for 5 days). Primary end point was complete remission (CR) after 3 cycles. We included 107 patients (69 treated with R-MPL and 38 with R-MP). In all, 38/107 patients achieved CR (35.5%) and 15 (14.0%) achieved partial remission. R-MP was associated with a lower CR rate (31.6%) compared with R-MPL (37.7%), but respective 2-year progression-free survival (All 37.3%; R-MP 34.9%; R-MPL 38.8%) and overall survival (All 47.0%; R-MP 47.7%; R-MPL 46.0%) rates were similar. R-MP was associated with less ⩾grade 3 toxicities compared with R-MPL (71.1% vs 87.0%). R-MP is more feasible while still associated with similar efficacy compared with R-MPL and warrants further improvement in future studies.

Autologous transplantation is controversial for older patients with multiple myeloma. The role of age-adjusted high-dose melphalan and the impact of induction chemotherapy cycles is still unclear. A total of 434 patients aged 60-70 years were randomly assigned to 4 cycles of standard anthracycline-based induction chemotherapy or no induction. For all patients, double autologous transplantation after melphalan 140 mg/m 2 (MEL140) was planned. The primary end point was progression-free survival. Of 420 eligible patients, 85% received a first transplant and 69% completed double transplantation. Treatment duration was short with a median of 7.7 months with induction chemotherapy cycles and 4.6 months without induction. On an intention-to-treat basis, median progression-free survival with induction chemotherapy cycles (207 patients) was 21.4 months versus 20.0 months with no induction cycles (213 patients) (hazard ratio 1.04, 95% confidence interval 0.84-1.28; P=0.36). Per protocol, progression-free survival was 23.7 months versus 23.0 months (P=0.28). Patients aged 65 years or over (55%) did not have an inferior outcome. Patients with low-risk cytogenetics [absence of del17p13, t(4;14) and 1q21 gains] showed a favorable overall survival and included the patients with sustained first remission. MEL140 was associated with a low rate of severe mucositis (10%) and treatment-related deaths (1%). Based on hazard ratio, the short treatment arm consisting of mobilization chemotherapy and tandem MEL140 achieved 96% of the progression-free survival, demonstrating its value as an independent component of therapy in older patients with multiple myeloma who are considered fit for autologous transplantation. (clinicaltrials.gov identifier: 02288741)., (Copyright© Ferrata Storti Foundation.)

Infections of the central nervous system (CNS) are infrequently diagnosed in immunocompetent patients, but they do occur in a significant proportion of patients with hematological disorders. In particular, patients undergoing allogeneic hematopoietic stem-cell transplantation carry a high risk for CNS infections of up to 15%. Fungi and Toxoplasma gondii are the predominant causative agents. The diagnosis of CNS infections is based on neuroimaging, cerebrospinal fluid examination and biopsy of suspicious lesions in selected patients. However, identification of CNS infections in immunocompromised patients could represent a major challenge since metabolic disturbances, side-effects of antineoplastic or immunosuppressive drugs and CNS involvement of the underlying hematological disorder may mimic symptoms of a CNS infection. The prognosis of CNS infections is generally poor in these patients, albeit the introduction of novel substances (e.g. voriconazole) has improved the outcome in distinct patient subgroups. This guideline has been developed by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) with the contribution of a panel of 14 experts certified in internal medicine, hematology/oncology, infectious diseases, intensive care, neurology and neuroradiology. Grades of recommendation and levels of evidence were categorized by using novel criteria, as recently published by the European Society of Clinical Microbiology and Infectious Diseases., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPN) comprise a heterogeneous group of chronic hematologic malignancies. The quality of life, morbidity, and mortality of patients with MPN are primarily affected by disease-related symptoms, thromboembolic and hemorrhagic complications, and progression to myelofibrosis and acute leukemia. Major bleeding represents a common and important complication in MPN, and the incidence of such bleeding events will become even more relevant in the future due to the increasing disease prevalence and survival of MPN patients. This review discusses the causes, differential diagnoses, prevention, and management of bleeding episodes in patients with MPN, aiming at defining updated standards of care in these often challenging situations.

Introduction: Treatment of patients (pts) with acute myelogenous leukaemia (AML) above 60 years remains a challenge. We report long-term follow-up of the AML97 study, where pts were registered at diagnosis and received treatment dependent on their comorbidities: dose-intense cytarabine (AraC) and anthracycline in the curative arm, and low-dose chemotherapy in the palliative arm or best supportive care., Materials and Methods: A total of 618 pts were enrolled in this protocol (curative 471, palliative 115 and supportive 32). In the curative arm, complete remission (CR) was obtained in 66.8 % of pts and the estimated probability of being alive at 2 years was 0.30 (±0.02 SE). In multivariate analysis, gender (p = 0.005), performance status (p = 0.04) and cytogenetics (p = 0.002) were significant factors for CR. With a median follow-up of 10 (range 0.1-11.8) years, the estimated probability of being event-free after 2 and 5 years according to cytogenetics was 0.48 ± 0.11 and 0.48 ± 0.11 for favourable, 0.20 ± 0.03 and 0.09 ± 0.03 for normal, 0.18 ± 0.06 and 0.10 ± 0.05 for other standard risk and 0.10 ± 0.03 and 0.05 ± 0.02 for unfavourable karyotypes, respectively. The median survival time for pts treated with palliative chemotherapy was 54 and 11 days with best supportive care only., Conclusion: In conclusion, treatment of older AML pts with dose-intense AraC is feasible in the majority of pts and induces high rates of CR. Nevertheless, except for favourable karyotype, OS and event-free survival remain low. These results need to be viewed in relation to the new modalities including stem cell transplantation following non-myeloablative conditioning, epigenetic and molecular therapies.

Background: Cancer patients are at increased risk for central venous catheter-related infections (CRIs). Thus, a comprehensive, practical and evidence-based guideline on CRI in patients with malignancies is warranted., Patients and Methods: A panel of experts by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) has developed a guideline on CRI in cancer patients. Literature searches of the PubMed, Medline and Cochrane databases were carried out and consensus discussions were held., Results: Recommendations on diagnosis, management and prevention of CRI in cancer patients are made, and the strength of the recommendation and the level of evidence are presented., Conclusion: This guideline is an evidence-based approach to the diagnosis, management and prevention of CRI in cancer patients.

The Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) here presents its updated recommendations for the treatment of documented fungal infections. Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. In recent years, new antifungal agents have been licensed, and agents already approved have been studied in new indications. The choice of the most appropriate antifungal treatment depends on the fungal species suspected or identified, the patient's risk factors (e.g., length and depth of neutropenia), and the expected side effects. This guideline reviews the clinical studies that served as a basis for the following recommendations. All recommendations including the levels of evidence are summarized in tables to give the reader rapid access to the information.

Although it is a severe complication in immunocompromised patients, diagnosing invasive fungal disease (IFD), especially invasive aspergillosis (IA), remains difficult. In certain clinical scenarios, examining tissue samples for identification of the infectious organism becomes important. As culture-based methods rarely yield results, the performance of an Aspergillus-specific nested PCR in fresh tissue or pleural effusion samples was evaluated. Fresh tissue (n = 59) and effusion (n = 47) specimens from 79 immunocompromised patients were subjected to an Aspergillus-specific PCR assay. Twenty-six patients had proven (n = 20) or probable (n = 6) IFD, according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria, while the remaining patients were classified as having either possible IFD (n = 30) or no IFD (n = 23). IA was identified as the underlying IFD in 21/26 proven/probable cases. PCR positivity was observed for 18/21 proven/probable and 6 possible IA cases; cases classified as no IA did not show positive signals. Patients with proven IFD (n = 5) with cultures positive for non-Aspergillus molds also had negative Aspergillus PCR results. Aspergillus PCR performance analysis yielded sensitivity and specificity values of 86% (95% confidence interval [CI], 65% to 95%) and 100% (95% CI, 86% to 100%), respectively, thus leading to a diagnostic odds ratio of >200. In this analysis, good diagnostic performance of the PCR assay for detection of IA was observed for tissue samples, while effusion samples showed lower sensitivity rates. PCR testing represents a complementary tool; a positive PCR result strengthens the likelihood of IA, whereas IA seems unlikely in cases with negative results but findings could indicate non-Aspergillus IFD. Thus, PCR testing of these specimens enhances the diagnostic capabilities.

Background: We previously reported the results of a phase II study for patients with newly diagnosed primary central nervous system lymphoma treated with autologous peripheral blood stem-cell transplantation (aPBSCT) and response-adapted whole-brain radiotherapy (WBRT). Now, we update the initial results., Patients and Methods: From 1999 to 2004, 23 patients received high-dose methotrexate. In case of at least partial remission, high-dose busulfan/thiotepa (HD-BuTT) followed by aPBSCT was carried out. Patients refractory to induction or without complete remission after HD-BuTT received WBRT. Eight patients still alive in 2011 were contacted and Mini-Mental State Examination (MMSE) and the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire (QLQ)-C30 were carried out., Results: Of eight patients still alive, median follow-up is 116.9 months. Only one of nine irradiated patients is still alive with a severe neurologic deficit. In seven of eight patients treated with HD-BuTT, health condition and quality of life are excellent. MMSE and QLQ-C30 showed remarkably good results in patients who did not receive WBRT. All of them have a Karnofsky score of 90%-100%., Conclusions: Follow-up shows an overall survival of 35%. In six of seven patients where WBRT could be avoided, no long-term neurotoxicity has been observed and all patients have an excellent quality of life.

Sepsis is a leading cause of mortality in neutropenic cancer patients. Early initiation of effective causative therapy as well as intensive adjunctive therapy is mandatory to improve outcome. We give recommendations for the management of adults with neutropenia and sepsis. The guidelines are written for clinicians involved in care of cancer patients and focus on pathophysiology, diagnosis and treatment of sepsis during neutropenia.

There is no widely accepted standard for antifungal prophylaxis in patients with hematologic malignancies. The Infectious Diseases Working Party of the German Society for Haematology and Oncology assigned a committee of hematologists and infectious disease specialists to develop recommendations. Literature data bases were systematically searched for clinical trials on antifungal prophylaxis. The studies identified were shared within the committee. Data were extracted by two of the authors (OAC and MSi). The consensus process was conducted by email communication. Finally, a review committee discussed the proposed recommendations. After consensus was established the recommendations were finalized. A total of 86 trials were identified including 16,922 patients. Only a few trials yielded significant differences in efficacy. Fluconazole 400 mg/d improved the incidence rates of invasive fungal infections and attributable mortality in allogeneic stem cell recipients. Posaconazole 600 mg/d reduced the incidence of IFI and attributable mortality in allogeneic stem cell recipients with severe graft versus host disease, and in patients with acute myelogenous leukemia or myelodysplastic syndrome additionally reduced overall mortality. Aerosolized liposomal amphotericin B reduced the incidence rate of invasive pulmonary aspergillosis. Posaconazole 600 mg/d is recommended in patients with acute myelogenous leukemia/myelodysplastic syndrome or undergoing allogeneic stem cell recipients with graft versus host disease for the prevention of invasive fungal infections and attributable mortality (Level A I). Fluconazole 400 mg/d is recommended in allogeneic stem cell recipients until development of graft versus host disease only (Level A I). Aerosolized liposomal amphotericin B is recommended during prolonged neutropenia (Level B II).

Catheter-related infections (CRI) cause considerable morbidity in hospitalized patients. The incidence does not seem to be higher in neutropenic patients than in nonneutropenic patients. Gram-positive bacteria (coagulase-negative staphylococci, Staphylococcus aureus) are the pathogens most frequently cultured, followed by Candida species. Positive blood cultures are the cornerstone in the diagnosis of CRIs, while local signs of infection are not necessarily present. Blood cultures should be taken from peripheral blood and from the venous catheter. A shorter time to positivity of catheter blood cultures as compared with peripheral blood cultures supports the diagnosis of a CRI. In many cases, a definite diagnosis requires catheter removal and microbiological analysis. The role plate method with semiquantitative cultures has been established as standard in most laboratories. Antimicrobial treatment of CRI should be directed by the in vitro susceptibility of the isolated pathogen. Primary removal of the catheter is mandatory in S. aureus and Candida infections, as well as in case of tunnel or pocket infections. Future studies will elucidate whether the rate of CRI in neutropenic patients may be reduced by catheters impregnated with antimicrobial agents.

Purpose: To evaluate the anticonvulsant profile and behavioral toxicity of rufinamide in animal seizure models compared to the established antiepileptic drugs (AEDs): phenytoin, phenobarbital, valproate, and ethosuximide, or vehicle., Methods: In acute studies of anticonvulsant efficacy, the AEDs were administered via oral (CF1 mice and Sprague-Dawley rats) and intraperitoneal (CF1 mice) routes. The AEDs were assessed for their ability to inhibit seizures induced by maximal electroshock (MES) or subcutaneous pentylenetetrazol, and ability to block seizures induced by subcutaneous strychnine, bicuculline, or picrotoxin. Tolerance of oral rufinamide was assessed in rats following 5-day (versus single-dose) treatment with oral rufinamide using the dose equivalent necessary to achieve a 50% decrease in seizure frequency (ED(50)). Metabolic tolerance was also evaluated using an in vitro liver microsomal assay., Results: Oral rufinamide suppressed pentylenetetrazol-induced seizures in mice (ED(50) 45.8 mg/kg) but not rats, and was active against MES-induced tonic seizures in mice (ED(50) 23.9 mg/kg) and rats (ED(50) 6.1 mg/kg). Intraperitoneal rufinamide suppressed pentylenetetrazol-, bicuculline-, and picrotoxin-induced clonus in mice (ED(50) 54.0, 50.5, and 76.3 mg/kg, respectively). Rufinamide was partially effective in the mouse strychnine test. The behavioral toxicity of rufinamide was similar to or better than established AEDs tested in this study. In general, the protective index of rufinamide was greater than that of the other AEDs., Conclusions: The efficacy and behavioral toxicity profiles in these animal models suggest that rufinamide may be effective in the treatment of generalized and partial seizures.

Introduction: Platelet counts exceeding 1.000 x 103/microl are usually considered secondary to another cause, particularly to chronic myeloproliferative disease (CMPD). Reactive thrombocytosis due to iron deficiency rarely exceeds platelet counts of 700 x 103/microl., Case Presentation: Here we report the case of a young woman presenting with clinical signs of severe anemia. Laboratory findings confirmed an iron-deficiency anemia associated with severe thrombocytosis of 1703 x 103/microl. Macroscopic gastrointestinal and genitourinary tract bleeding was excluded. The excessive elevation of platelets, slightly elevated lactate dehydrogenase and slightly elevated leukocytes along with the absence of other inflammation parameters raised the suspicion of an underlying hematological disease. However, bone marrow evaluation could not prove the suspected diagnosis of a CMPD, especially essential thrombocythemia (ET). In the further clinical course the platelet count returned to normal after raising the hemoglobin to a level close to normal range with erythrocyte transfusion, and normalization of serum iron and decline of erythropoietin. Finally, following small bowel biopsy, despite the absence of typical clinical signs, celiac disease was diagnosed. After discharge from hospital the patient was commenced on a gluten-free diet and her hemoglobin almost completely normalized in the further follow-up period., Conclusion: This case illustrates the rare constellation of an extreme thrombocytosis most likely secondary to iron deficiency due to celiac disease. This represents, to the best of the authors' knowledge, the highest reported platelet count coincident with iron deficiency. A potential mechanism for the association of iron-deficiency anemia and thrombocytosis is discussed. Even in the presence of 'atypically' high platelets one should consider the possibility of reactive thrombocytosis. Extreme thrombocytosis could emerge in the case of iron deficiency secondary to celiac disease.

Background: We investigated the efficacy and safety of tandem high-dose methotrexate (HD-MTX) induction followed by high-dose busulfan/thiotepa (HD-BuTT) with autologous peripheral blood stem-cell transplantation (aPBSCT) and response-adapted whole-brain radiation therapy (WBRT) in patients with newly diagnosed primary central nervous system lymphoma., Patients and Methods: Twenty-three patients were treated with HD-MTX on days 1 and 10. In case of at least a partial remission (PR), HD-BuTT followed by aPBSCT was given. Patients without response to induction or without complete remission (CR) after HD-BuTT received WBRT., Results: Sixteen patients received HD-MTX and HD-BuTT achieving a CR/PR rate of 69%/13%. CR/PR rates for all patients (n = 23) were 70%/13%. There were three deaths during therapy. With longer follow-up three neurotoxic deaths occurred in irradiated patients (n = 9), while no persistent neurotoxicity was seen after HD-BuTT without subsequent WBRT. At a median follow-up of 15 months (range 1-69) median event-free survival (EFS) and overall survival (OS) for all patients were 17 and 20 months (Kaplan-Meier), after HD-BuTT 27 months and "not reached", respectively. Estimated 2-year EFS and OS were 45% and 48% for all patients versus 56% and 61% for the HD-BuTT group, respectively., Conclusion: MTX induction followed by HD-BuTT is an effective and very short time-on-treatment regimen. Median survival for patients treated with high-dose chemotherapy is not reached yet. The induction regimen needs optimisation. In this study WBRT was associated with a high incidence of severe neurotoxicity.

These guidelines from the infectious diseases working party (AGIHO) of the German Society of Hematology and Oncology (DGHO) give recommendations for the management of adults with neutropenia and the diagnosis of sepsis. The guidelines are written for clinicians and focus on pathophysiology, diagnosis, and treatment of sepsis. The manuscript contains evidence-based recommendations for the assessment of the quality and strength of the data.

Patients undergoing allogeneic stem cell transplantation are at high risk for infection with a variety of pathogens during different phases of the procedure. Bacteria and fungi predominate the first phase until engraftment. During the second phase, from engraftment to about day 100, major infectious problems are caused by fungi and cytomegalovirus. Both pathogens remain important under continued immunosuppression, however, in the late post-transplantation period infections with encapsulated bacteria may become a problem. In this review the Infectious Diseases Working Party of the DGHO gives recommendations for prophylaxis of infections under allogeneic stem cell transplantation with drugs and other measures. The aim of the group was to do this on an evidence-based-medicine rating, if possible.

Anaerobiospirillum succiniciproducens is an anaerobic, Gram-negative, spiral shaped bacteria, which is motile by means of bipolar tuffs of flagella. This organism appears to be a rare cause of bacteremia in humans, and it usually affects patients submitted to immunosuppressive therapy. Anaerobiospirillum succiniciproducens resembles Campylobacter spp. in Gram-stained preparations, however, it is considered resistant to most antimicrobial drugs that are used to treat Campylobacter infections. We observed Gram-negative, spiral shaped bacteria in Gram-stained preparations from blood culture flasks. Growth occurred only under anaerobic incubation, and identification to the species level was achieved by PCR amplification of the 16S rRNA gene, followed by direct sequencing and a GenBank homology search. To the best of our knowledge, this is the first reported Brazilian case of Anaerobiospirillum succiniciproducens bacteremia.

Morbidity and mortality in patients with malignancies, especially leukemia and lymphoma, are increased by invasive fungal infections. Since diagnosis of invasive fungal infection is often delayed, antifungal prophylaxis is an attractive approach for patients expecting prolonged neutropenia. Antifungal prophylaxis has obviously attracted much interest resulting in dozens of clinical trials since the late 1970s. The non-absorbable polyenes are probably ineffective in preventing invasive fungal infections, but may reduce superficial mycoses. Intravenous amphotericin B and the newer azoles were used in clinical trials, but their role in antifungal prophylaxis is still not well defined. Allogeneic stem cell transplant recipients are at particularly high risk for invasive fungal infections. Other well described risk factors are neutropenia >10 days, corticosteroid therapy, sustained immunosuppression, graft versus host disease, and concomitant viral infections. The enormous study efforts are contrasted by a scarcity of risk stratified evidence based recommendations for clinical decision making. The objective of this review accumulating information on about 10.000 patients is to assess evidence based criteria primarily regarding the efficacy of antifungal prophylaxis in neutropenic cancer patients.

A Phase I dose escalation and pharmacokinetic study of the alkylating cytotoxic agent treosulfan was conducted to evaluate the maximum tolerated dose and the dose-limiting toxicities in patients with advanced malignancies rescued by autologous peripheral blood stem cell transplantation. Twenty-two patients (15 ovarian and 7 other carcinomas/lymphomas) with a median age of 48 years were treated with 28 high-dose courses. Treosulfan was infused over 2 h at escalating doses from 20 to 56 g/m2, and pharmacokinetic parameters were analyzed. At 56 g/m2, three of six patients experienced dose-limiting toxicities: diarrhea grade III/IV in three patients; mucositis/stomatitis grade III in one patient; toxic epidermal necrolysis in one patient; and grade III acidosis in one patient. Other low-grade side effects, including erythema, pain, fatigue, and nausea/vomiting, were recorded. Two patients died within 4 weeks after treatment because of rapid tumor progression and fungal infection, respectively. Plasma half-life, distribution volume, and renal elimination of treosulfan were independent of dose, whereas the increase in area under the curve was linear up to 56 g/m2 treosulfan. The maximum tolerated dose of high-dose treosulfan is 47 g/m2. A split-dose or continuous infusion regimen is recommended for future high-dose trials. In consideration of antineoplastic activity and limited organ toxicity, inclusion of high-dose treosulfan in combination protocols with autologous peripheral blood stem cell transplantation seems worthwhile.

Purpose: These studies further investigate the ability of topiramate (TPM) to enhance gamma-aminobutyric acid (GABA)-mediated inhibition through a benzodiazepine-insensitive pathway., Methods: Topiramate (30 and 100 microM) enhancement of GABA (1 microM)-evoked currents in primary cultures of mouse cortical neurons was studied by using whole-cell electrophysiologic techniques. Results obtained with TPM (30 microM) were compared with those obtained with clonazepam (CZP; 1 microM)., Results: Topiramate enhanced GABA currents in a subset of cortical neurons tested. In addition, TPM enhanced GABA-evoked currents in CZP-insensitive neurons, and CZP was effective in a subset of TPM-insensitive neurons. Related studies in vivo demonstrated that intraperitoneal (i.p.) administration of either TPM (25 mg/kg) or CZP (0.012 mg/kg) increases pentylenetetrazol (PTZ) seizure threshold. This effect of CZP, but not TPM, was reversed by the benzodiazepine (BZD) antagonist flumazenil (FMZ; 40 mg/kg, i.p.)., Conclusions: These results indicate that GABA(A)-receptor sensitivity to TPM is not dependent on the presence of BZD sensitivity. Enhancement of GABA-mediated inhibition through a BZD-insensitive pathway may represent one mechanism through which TPM exerts its anticonvulsant action.

Felbamate (2-phenyl-1,3-propanediol dicarbamate, FBM) was subjected to a series of carefully selected in vivo and in vitro tests to provide additional insight into mechanism of action, margin of safety, and clinical potential. FBM was effective against intracerebroventricular (i.c.v.) N-methyl-D-aspartate (NMDA)-induced clonus and i.c.v. NMDA- and quisqualic acid (quis)-induced forelimb tonic extension in mice and ineffective against i.c.v. quis-induced clonus in mice. FBM was also effective in preventing the expression of Stage 5 kindled seizures in corneal-kindled rats. The calculated protective indices (rotorod median toxic dose divided by anticonvulsant median effective dose) ranged from 28 to 146 for those tests in which FBM displayed activity. With the in vitro tests, FBM did not significantly displace [3H]MK-801 from its binding site. In contrast, FBM was effective in blocking sustained repetitive firing in mouse spinal cord neurons grown in tissue culture (median inhibitory concentration 67 micrograms/ml). This effect on repetitive firing suggests indirectly that FBM modulates sodium channel conductance. The results, when compared to similar data for phenytoin, carbamazepine, valproate, and ethosuximide, support the concept that FBM is a relatively nontoxic agent with a unique profile of anticonvulsant action, a broad margin of safety, and a clinical potential that includes at least generalized tonic-clonic and complex partial seizures.

The anticonvulsant profiles of two potent and orally active gamma-aminobutyric acid (GABA) uptake inhibitors, 1-(4,4-diphenyl-3-butenyl)-3-piperidine-carboxylic acid hydrochloride (SK&F 89976-A) and 1-(4,4-diphenyl-3-butenyl)-1,2,5,6-tetrahydro-3-pyridine-carboxylic acid hydrochloride (SK&F 100330-A), were determined with a battery of well-standardized tests in mice and rats and compared with the profiles of phenytoin (PHT), carbamazepine (CBZ), valproate (VPA) and clonazepam (CZP) when subjected to the same tests. ED50 values were calculated and compared with TD50 values for minimal motor impairment to provide protective indexes (PI = TD50/ED50). The anticonvulsant profiles of SK&F 89976-A and SK&F 100330-A were similar and suggest that these compounds raise the threshold for seizure initiation rather than inhibit seizure spread. Like intraperitoneal (i.p.) PHT, CBZ, VPA, and CZP, SK&F 89976-A and SK&F 100330-A inhibited seizures in corneally kindled rats. The profiles of SK&F 89976-A and SK&F 100330-A were most similar to that of CZP and virtually opposite to that of PHT. Intraperitoneal SK&F 100330-A provided complete protection against pentylenetetrazol-induced seizures [subcutaneous (s.c.) PTZ] in mice but was ineffective against seizures induced by maximal electroshock (MES) at doses slightly greater than its TD50. SK&F 100330-A provided complete protection against picrotoxin-induced seizures (s.c. Pic) and against both clonus and forelimb tonic extension induced by NMDA N-methyl-D-aspartate [intracerebral ventricular (i.c.v.)-NMDA] in mice; however, SK&F 100330-A was ineffective against seizures induced by bicuculline (s.c. Bic) and strychnine (s.c. Strych) at doses slightly greater than its TD50. SK&F 89976-A was similar but provided partial protection against NMDA-induced clonus.(ABSTRACT TRUNCATED AT 250 WORDS)

Five clinically available 1,4-benzodiazepines (BDZs) (chlordiazepoxide, diazepam, oxazepam, nitrazepam, and clonazepam) and four investigational 1,4-BDZs (BDZ I, BDZ II, BDZ III, and BDZ IV) were tested in vivo for minimal neurotoxicity (TD50) and for ability to obtund seizures (ED50) induced by a battery of five well-standardized procedures (maximal electroshock, strychnine, pentylenetetrazol, bicuculline, and picrotoxin). In addition, these BDZs were also tested in vitro as inhibitors of [3H]flunitrazepam binding to BDZ receptors. The results with each of the six in vivo tests were compared with those with the in vitro receptor binding test, and the correlation coefficients (r) were calculated. There was a high correlation between the inhibitor constants (Ki) derived from BDZ binding studies and the TD50 values (r = 0.882) and the pentylenetetrazol ED50 values (r = 0.946). There was also good correlation between ED50 values of BDZs effective by the bicuculline and picrotoxin tests and their Ki values in the BDZ receptor binding studies (r = 0.868 and 0.892, respectively). However, BDZ I, BDZ II, and BDZ IV had Ki values of 1.830, 0.075, and 0.015 microM, respectively, but BDZ I was ineffective in nontoxic doses by the bicuculline and picrotoxin tests, BDZ II by the picrotoxin test, and BDZ IV by the bicuculline test. In contrast, there was no correlation between the BDZs' anticonvulsant potency, determined by either the maximal electroshock or strychnine test, and their inhibitory potency on [3H]flunitrazepam binding to receptor sites. The possible methodological and neurochemical bases for these differences are discussed. These studies indicate that BDZ binding studies can be used to screen BDZs for anticonvulsant activity (selectively for antipentylenetetrazol activity and less selectively for antibicuculline and antipicrotoxin activity). More importantly, they complement the conventional in vivo anticonvulsant threshold tests. Therefore, BDZ binding studies can be used in concert with conventional in vivo procedures for the pharmacological differentiation of candidate antiepileptic BDZs.