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Purpose Outcome for relapsed acute myeloid leukemia (AML) is poor. Cladribine has activity in AML, and an enhancing effect on other cytostatic drugs thus may help overcome resistance. Here, we present the final analysis of our phase II trial evaluating safety and efficacy of cladribine, cytarabine, and idarubicin (CAI) in relapsed AML. Methods Patients with relapsed AML after at least 6 months remission received two courses of CAI. After 9 patients, prolonged neutropenia prompted protocol change (omission of idarubicin in 2nd course and dose-reduction of cytarabine). Primary endpoints were remission rate and safety. Results Twenty patients received treatment, fourteen one, and six two courses CAI/CA. After first course, complete remission (CR/CRi) was achieved in 60%. Most frequent toxicity was infection. Median OS was 8.8 months in all patients and 21.1 months in those with CR. Nine patients (48%) proceeded to allogeneic stem cell transplantation (allo-SCT), four of those are still alive and in CR, accounting for a 5-year survival rate of 55% of transplanted patients. Conclusion Cladribine, cytarabine, and idarubicin in relapsed AML is feasible and induces good response rates. As expected, infections are the most important complication. However, combined with allo-SCT, long-term survival can be achieved in a substantial number of patients.

This study developed and explored a novel composite endpoint to assess the overall impact that treatment can have on patients living with paroxysmal nocturnal hemoglobinuria (PNH). Candidate composite endpoint variables were selected by a group of experts and included: lactate dehydrogenase levels as a measure of intravascular hemolysis; complete terminal complement inhibition; absence of major adverse vascular events, including thrombosis; absence of any adverse events leading to death or discontinuation of study treatment; transfusion avoidance; and improvements in fatigue-related quality of life as determined by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. From these variables, a novel composite endpoint was constructed and explored using data collected in the ravulizumab PNH Study 301 (NCT02946463). Thresholds were defined and reported for each candidate variable. Five of the six candidate variables were included in the final composite endpoint; the FACIT-Fatigue score was excluded. Composite endpoint criterion was defined as patients meeting all five selected individual component thresholds. All patients in the ravulizumab arm achieved complete terminal complement inhibition and a reduction in lactate dehydrogenase levels; 51.2% and 41.3% of patients in the ravulizumab arm and eculizumab arm, respectively, achieved all composite endpoint component thresholds (treatment difference: 9.4%; 95% confidence interval: -3.0, 21.5). The composite endpoint provided a single and simultaneous measurement of overall benefit for patients receiving treatment for PNH. Use of the composite endpoint in future PNH research is recommended to determine clinical benefit, and its use in health technology assessments should be evaluated.

Background: CDK8 and its paralog CDK19 have central roles in maintenance of cancer cell viability and undifferentiated state for a variety of tumor types. (Dannappel et al. 2019; Rzymski et al. 2015; Philip et al. 2018). CDK8 and CDK19 work by incorporating in a mutually exclusive manner, into a Mediator kinase module, that reversibly associates with a protein complex regulator of RNA Polymerase II, to mediate gene transcription. Targeting cancer-specific gene transcription via CDK8/19 inhibition has potential for treatment of solid tumors. RVU120 (SEL120) is a selective CDK8/19 inhibitor with preclinical efficacy in hematologic malignancies and a variety of solid tumor types (Rzymski et al. 2017). RVU120 showed strong anticancer activity in preclinical triple-negative breast cancer (TNBC) models, especially in the mesenchymal stem-like (MSL) molecular subtype (Rzymski et al SABCS 2021). Methods: SOL-021 is a Phase I/II clinical trial of RVU120 in Patients with metastatic or advanced solid tumors, who have exhausted available treatments, currently ongoing in Poland and Spain under NCT05052255 clinical trial register number. RVU120 is administered as single oral dose every other day (QOD) for a total of 7 doses on Days 1, 3, 5, 7, 9, 11 and 13, in a 3-week treatment cycle until progression or unacceptable toxicity. The study is designed in 2 parts: Part 1 follows a 3+3 dose escalation design and has primary objectives to characterize the safety and tolerability of RVU120 (SEL120) as single agent in patients with different tumors types and determination of the RP2D. Secondary objectives include objective response rate (ORR) according to RECIST criteria v1.1, duration of response (DoR), disease-control rate, progression-free survival (PFS), overall survival (OS) and pharmacokinetic profile of RVU120.Part 2 will primarily explore the anti-tumor activity of RVU120 as single agent in different patient populations. Based on strong preclinical evidence of anticancer activity of RVU120 on TNBC cells (Tomasz Rzymski SABCS #1766), patients with relapsed/refractory TNBC will be enrolled. Additionally, relapsed/refractory patients agnostic of their solid tumor type and selected based on their biomarker profile will be enrolled. The total duration of the study is approximately 27 months (12 and 15 for part 1 and 2, respectively). Results: At 11 Feb 2022 data cut off, 5 patients have been enrolled in part 1 of the study and no SAE have been observed: First cohort, 75 mg, was closed on 24 Nov 2021 with no DLT observed; current ongoing cohort, 100 mg dose level, is expected to be closed in the upcoming week, and subsequent cohort, 125 mg, to be opened mid-March. Conclusion: The trial is continuing as planned; the next data analysis will occur first week of March 2022. Citation Format: Rafal Dziadziuszko, Elena Garralda, Noemi Angelosanto, Tomasz Rzymski, Renata Dudziak, Krzysztof Brzózka, Peter Littlewood, Hendrik Nogai, Axel Glasmacher, Iwona Lugowska. RVU120 SOL-021: An open-label, single agent, phase I/II trial of RVU120 (SEL120) in patients with relapsed/refractory metastatic or advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT131.

Background The gut microbiome has emerged as a promising innovative therapeutic target for immune-stimulation treatment of solid tumours. MRx0518 is a novel, gut microbiome-derived oral live biotherapeutic. It has potent anti-tumorigenic efficacy in the preclinical setting including murine models of lung (LLC1), kidney (Renca) and breast (EMT6) cancer.1 In these models, a significant reduction in tumour growth has been demonstrated, including induction of immunostimulatory responses with tumour infiltration of NK cells, CD8+ and CD4+ T-cells. MRx0518 is under investigation in various oncological settings, including in combination with immune checkpoint inhibitors (NCT03637803) and radiotherapy (NCT04193904). Methods Treatment naive patients were recruited from April 2019 to February 2020. Patients were eligible if they received a histologically confirmed diagnosis of cancer (solid tumours) scheduled for surgical resection. Patients received 1 capsule of MRx0518 (1x1010 to 1x1011 CFU) twice daily from inclusion until the day preceding surgery (maximum 28 days therapy). The primary study outcome is to evaluate safety and tolerability of MRx0518 monotherapy in treatment naive patients. Additional exploratory outcomes including identifying surrogate biomarkers of efficacy, microbiome analysis, effect on metabonomic markers and identification of histological and genomic alterations in paired pre-treatment (diagnostic biopsy) and post-treatment (surgical specimen) samples. Results In part A, 17 patients received treatment, across tumour groups including breast (n=8), prostate (n=4), uterine (n=3), melanoma (n=1) and bladder (n=1). MRx0518 was well tolerated by all, with no grade 3/4 CTCAE toxicity reported, no severe adverse effects or treatment discontinuations. All patients proceeded to surgery, however the COVID-19 pandemic delayed surgery in 3 cases. Analysis of the first 5* patient paired samples utilising the NanoString Pan Cancer IO 360TM Gene Expression panel has demonstrated significant changes in gene expression profiles in 48 genes (p Conclusions This study has demonstrated the safety and tolerability of the live biotherapeutic MRx0518 in treatment naive cancer patients. Exploratory analyses of post-treatment samples has echoed preclinical observations of increased infiltration of immune cells following treatment and will undergo further validation. Part B will focus on investigating efficacy in a further 100 treatment naive patients with a placebo-controlled arm. Trial Registration NCT03934827 Ethics Approval The study was approved by East of England - Cambridge East Research Ethics Committee approval number 18/EE/0091 Reference Laute-Caly DL, Raftis EJ, Cowie P, et al. The flagellin of candidate live biotherapeutic Enterococcus gallinarum MRx0518 is a potent immunostimulant. Scientific Reports 2019;9(1):1-14. doi:10.1038/s41598-018-36926-8 *Data analysis has been censored at 18/9/2020, further samples analysis is ongoing and will be updated.

Background MRx0518 is a novel, human gut microbiome-derived, single-strain, live biotherapeutic in clinical development for treatment of solid tumours. Preclinically, MRx0518 induced broad immunostimulatory activity and demonstrated anti-tumorigenic effects in a range of murine tumor models. MRx0518 increased CD4+ and CD8+ T cell and NK cell tumor infiltration and decreased Tregs. Activation of tumour TLR5 was observed and linked to the bacterial flagellin moiety, which was shown to strongly induce NFκB, cytokine responses and IFNγ+ CD4+ and CD8+ T cells. Methods Heavily pre-treated patients refractory to ICIs were enrolled from March 2019 to March 2020. Patients had experienced at least SD from previous ICI (monotherapy or combination) but eventually progressed as confirmed by two radiological scans ≥4 weeks apart in the absence of rapid clinical progression and within 12 weeks of last dose of ICI. Patients were treated with 1 capsule of MRx0518 (1 × 1010 to 1 × 1011 CFU) BID and pembrolizumab (200 mg every 3 weeks) for up to 35 cycles or disease progression. Tumour response was assessed every 9 weeks per RECIST 1.1. The primary objective was to evaluate safety of the combination by monitoring toxicities in the first cycle of treatment. Secondary objectives were to evaluate efficacy via ORR, DOR, DCR and PFS. Results In Part A, patients with mRCC (n=9) and mNSCLC (n=3) were recruited. At data cut-off (21 Aug 20), 5 patients remain on study treatment. 83% of patients were male and 17% were female. Median number of prior lines of therapy was 3. 10 patients received nivolumab previously (83%), one received avelumab (8%) and one received pembrolizumab and nivolumab (8%). 83% of patients had experienced SD as best response to prior ICI and 17% had PR as best response. Of 6 patients with available PD-L1 results, 5 had a positive CPS/TPS (≥1) and 1 negative ( Conclusions This data represents first-in-class proof of concept for a live biotherapeutic in an oncology setting. The combination was tolerable and there were preliminary signals of efficacy. Part B (phase II) in NSCLC, RCC and bladder cancer is ongoing. Trial Registration www.clinicaltrials.gov NCT03637803 Ethics Approval This study was approved by University of Texas MD Anderson’s Institutional Review Board; approval ref. 2018-0290

Tigecycline (TGC) is a first-in-class glycylcycline with an expanded spectrum of activity. Although TGC has not been prospectively studied in febrile neutropenia (FN), we observed that occasionally critically ill neutropenic patients unresponsive to other antibiotics were treated with TGC in our departments. The aim of our study was to analyse effectiveness and toxicity of TGC in FN.Data of infectious episodes treated with TGC were retrospectively collected. Baseline data of patients, haematological malignancy, infection and adverse events were documented. Success was defined as defervescence (≥7 days) in the absence of any sign of persistent infection.Data of 35 patients with haematological malignancies and FN were evaluated. Median duration of neutropenia was 25 days (range 6-69 days). The type of infection was pneumonia in 24 patients, four microbiologically documented infections, three clinically documented infections and four with fever of unknown origin. The TGC was administered after a median of two (range 1-5) prior antibiotic regimens. Treatment was successful in 15 (43 %) patients. In patients with prolonged neutropenia (≥28 days), response was significantly lower (13 vs. 79 %; p =0.001). Eight (23 %) patients died during the fever episode. Grade 3-4 toxicity occurred in five (14 %) patients.Our results showed promising response rates to TGC and very low toxicity rates compared to the generally low response rate of third-line antibiotic therapies, indicating that TGC may be a successful alternative for salvage treatment of febrile neutropenia, but further study is needed.

Data comparing long-term outcomes in lenalidomide-treated and untreated patients with myelodysplastic syndromes (MDS) with del(5q) are limited. We evaluated clinical outcomes of 295 lenalidomide-treated patients from two clinical trials (MDS-003 and MDS-004) and 125 untreated red blood cell (RBC) transfusion-dependent patients with del(5q) Low- or Intermediate-1 (Int-1)-risk MDS from a large multicenter registry. Risk factors for acute myeloid leukemia (AML) progression and mortality were assessed using Cox proportional hazards models with left truncation to adjust for study entry differences between cohorts. Baseline characteristics were well balanced across cohorts, except for a higher RBC transfusion burden in lenalidomide-treated patients (median, 6 vs 2 units/8 weeks). Median follow-up was 4.3 years from first dose for lenalidomide-treated patients and 4.6 years from diagnosis for untreated patients. Two-year cumulative AML progression incidences were 6.9% (95% confidence interval (CI): 3.3-13.9) and 12.1% (95% CI: 7.0-20.3) and 2-year overall survival (OS) probabilities were 89.9% (95% CI: 84.1-96.0) and 74.4% (95% CI: 66.1-83.7), respectively. AML progression risk was similar in both cohorts (hazard ratio (HR) 0.969, P=0.930); however, lenalidomide treatment was associated with significant improvement in survival (HR 0.597, P=0.012), after adjusting for all other covariates. In conclusion, lenalidomide treatment does not increase AML progression risk, but instead confers a possible survival benefit in RBC transfusion-dependent patients with del(5q) Low- or Int-1-risk MDS.

Antifungal prophylaxis for allogeneic haematopoietic stem-cell transplant (alloHCT) recipients should prevent invasive mould and yeast infections (IFIs) and be well tolerated. This prospective, randomized, open-label, multicentre study compared the efficacy and safety of voriconazole (234 patients) versus itraconazole (255 patients) in alloHCT recipients. The primary composite endpoint, success of prophylaxis, incorporated ability to tolerate study drug for ≥100 d (with ≤14 d interruption) with survival to day 180 without proven/probable IFI. Success of prophylaxis was significantly higher with voriconazole than itraconazole (48·7% vs. 33·2%, P 10%) treatment-related adverse events were vomiting (16·6%), nausea (15·8%) and diarrhoea (10·4%) for itraconazole, and hepatotoxicity/liver function abnormality (12·9%) for voriconazole. More itraconazole patients received other systemic antifungals (41·9% vs. 29·9%, P

Summary Invasive Candida infections are important causes of morbidity and mortality in immunocompromised and hospitalised patients. This article provides the joint recommendations of the German-speaking Mycological Society (Deutschsprachige Mykologische Gesellschaft, DMyKG) and the Paul-Ehrlich-Society for Chemotherapy (PEG) for diagnosis and treatment of invasive and superficial Candida infections. The recommendations are based on published results of clinical trials, case-series and expert opinion using the evidence criteria set forth by the Infectious Diseases Society of America (IDSA). Key recommendations are summarised here: The cornerstone of diagnosis remains the detection of the organism by culture with identification of the isolate at the species level; in vitro susceptibility testing is mandatory for invasive isolates. Options for initial therapy of candidaemia and other invasive Candida infections in non-granulocytopenic patients include fluconazole or one of the three approved echinocandin compounds; liposomal amphotericin B and voriconazole are secondary alternatives because of their less favourable pharmacological properties. In granulocytopenic patients, an echinocandin or liposomal amphotericin B is recommended as initial therapy based on the fungicidal mode of action. Indwelling central venous catheters serve as a main source of infection independent of the pathogenesis of candidaemia in the individual patients and should be removed whenever feasible. Pre-existing immunosuppressive treatment, particularly by glucocorticosteroids, ought to be discontinued, if feasible, or reduced. The duration of treatment for uncomplicated candidaemia is 14 days following the first negative blood culture and resolution of all associated symptoms and findings. Ophthalmoscopy is recommended prior to the discontinuation of antifungal chemotherapy to rule out endophthalmitis or chorioretinitis. Beyond these key recommendations, this article provides detailed recommendations for specific disease entities, for antifungal treatment in paediatric patients as well as a comprehensive discussion of epidemiology, clinical presentation and emerging diagnostic options of invasive and superficial Candida infections.

In primary central nervous system lymphoma (PCNSL), 2 international prognostic scores have been developed to estimate the outcome according to certain “prognostic groups”. However, these scores do not predict the individual course of a single patient under therapy. In this analysis, we addressed the question of whether early tumor remission in patients still under therapy, according to magnetic resonance imaging (MRI) criteria, helps to predict long-term outcome. Eighty-eight patients treated with 6 polychemotherapy cycles within a pilot/phase II trial underwent MRI scanning within 72 hours prior to initiation of therapy, after the second chemotherapy cycle, and after completion of chemotherapy. Response was assessed by contrast-enhanced MRI of the brain according to the Macdonald criteria. Median follow-up was 42 months (range, 0–124 months). Patients achieving a complete radiographic response after 2 courses of chemotherapy (n = 18) had a significantly longer median overall survival (OS) (not reached) and median time-to-treatment failure (TTF) (not reached) than patients with complete response (CR) after termination of treatment but with only a partial response after the second cycle (n = 24) (OS: 55 months; TTF: 32 months) (P < .01). Early complete tumor response assessed by MRI after the second of sixth scheduled chemotherapy cycles was highly predictive for both OS and TTF in patients with PCNSL treated in this series.

Objectives Invasive fungal infections (IFIs) contribute significantly to mortality and morbidity in patients receiving myelosuppressive chemotherapy for haematological malignancies. The present study investigates the overall survival (OS), infection-related mortality and changes in treatment of IFIs in our department from 1995 until 2006. Methods Outcomes of all chemotherapy courses were retrospectively evaluated using a standard questionnaire. Modified EORTC/MSG criteria for IFIs were applied: a positive PCR result for Aspergillus spp. in bronchoalveolar lavage was also defined as probable IFI. Results In total, 1693 chemotherapy courses in 592 patients were evaluated. Sixty-three percent of chemotherapy courses were given to treat acute myeloid leukaemia, with the rest for acute lymphoblastic leukaemia or aggressive lymphoma. IFIs were observed in 139/592 patients [23.5%, 95% confidence interval (CI) 20%–27%] and in 149/1693 courses (8.8%, 95% CI 8%–10%). IFI-related mortality was 56.9% in 1995–2001 and 28.6% in 2002–06, P

Infection is the main treatment-related cause of mortality in cancer patients. Rapid and accurate diagnosis to facilitate specific therapy of febrile neutropenia is therefore urgently warranted. Here, we evaluated a commercial PCR-based kit to detect the DNA of 20 different pathogens (SeptiFast) in the setting of febrile neutropenia after chemotherapy. Seven hundred eighty-four serum samples of 119 febrile neutropenic episodes (FNEs) in 70 patients with hematological malignancies were analyzed and compared with clinical, microbiological, and biochemical findings. In the antibiotic-naïve setting, bacteremia was diagnosed in 34 FNEs and 11 of them yielded the same result in the PCR. Seventy-three FNEs were negative in both systems, leading to an overall agreement in 84 of 119 FNEs (71%). During antibiotic therapy, positivity in blood culture occurred only in 3% of cases, but the PCR yielded a positive result in 15% of cases. In six cases the PCR during antibiotic treatment detected a new pathogen repetitively; this was accompanied by a significant rise in procalcitonin levels, suggestive of a true detection of infection. All patients with probable invasive fungal infection (IFI; n = 3) according to the standards of the European Organization for Research and Treatment of Cancer had a positive PCR result for Aspergillus fumigatus ; in contrast there was only one positive result for Aspergillus fumigatus in an episode without signs and symptoms of IFI. Our results demonstrate that the SeptiFast kit cannot replace blood cultures in the diagnostic workup of FNEs. However, it might be helpful in situations where blood cultures remain negative (e.g., during antimicrobial therapy or in IFI).

We conducted a phase 1/2 trial combining lenalidomide (R) with adriamycin (A) and dexamethasone (D) for relapsed and relapsed-refractory myeloma to determine tolerability and efficacy of this novel regimen, RAD, delivered for six 28-day cycles. A total of 69 intensively pretreated patients with a median age of 65 years (range, 46-77 years) were enrolled. Using pegfilgrastim (G), the maximum tolerated dose (MTD) was formally not reached at the highest dose level (R, 25 mg on days 1-21; A, 9 mg/m2 intravenously on days 1-4; and D, 40 mg on days 1-4 and 17-20; dose level 5+G), which was then used to determine efficacy. Grades 3/4 neutropenia and thrombocytopenia were seen in 48% and 38% of patients, respectively. Thromboembolic events occurred in 4.5% and severe infections in 10.5% of patients. On an intent-to treat analysis, overall response rate (ORR) was 73% for the whole study and 77% including 74% complete response (CR) plus very good partial response (VGPR) for dose level 5+G. Response rates and progression-free survival did not differ between relapsed and relapsed-refractory patients. Deletion of chromosome 17p and elevated β2-microglobulin were associated with significantly inferior response and shortened time to progression. In conclusion, RAD induces substantial and durable remission with an acceptable toxicity profile in patients with relapsed and relapsed-refractory myeloma. This trial was registered at www.ClinicalTrials.gov as no. NCT00306813.

False-positive results of the galactomannan (GM) ELISA caused by concurrent administration of piperacillin/tazobactam have been reported in patients with febrile neutropenia.This prospective study investigated different sampling times in 30 patients receiving piperacillin/tazobactam for febrile neutropenia.Prior to the first piperacillin/tazobactam infusion, a median GM index of 0.2 [interquartile range (IQR) 0.1-0.3] was noted; in two patients (7%) the index was 0.5. Immediately after piperacillin/tazobactam infusion, the median index increased to 0.3 (IQR 0.2-0.4, P = 0.002) leading to 21% (7/30) false-positive results, ifor = 0.5 is assumed as the cut-off level. GM indices before the next piperacillin/tazobactam infusion were not increased (median 0.2, IQR 0.2-0.35, P0.05), but 10% (3/30) were stillor = 0.5. With a cut-off level of0.7, no false-positive results were noted at any sampling time point.We conclude that the clinical relevance of false-positive GM results during piperacillin/tazobactam treatment is small if samples are collected prior to infusion and if a cut-off level of0.7 is used.

Glycopeptides are often used for persistent fever in neutropenic patients. This study compares efficacy and toxicity of teicoplanin and vancomycin. Hundred consecutive neutropenic patients with hematological malignancies and persistent fever after 72 h of first-line antibiotic therapy (91% piperacillin/tazobactam) were treated with teicoplanin (800 mg on day 1, then 400 mg/day) + piperacillin/tazobactam + gentamicin from 08/96 to 09/00 (group T) or with vancomycin (2 g/day) + meropenem + levofloxacin from 10/00 to 04/02 (group V). Success was defervescence (≥ 7 days) in absence of any sign of continuing infection. Nephrotoxicity was monitored daily as increase in serum creatinine. Fifty patients were analyzed in each group. Efficacy was evaluated in patients with piperacillin/tazobactam as first-line therapy only. Treatment was successful in 76% in group T (n = 42) and 59% in group V (n = 49), p = 0.118. Toxicity was evaluated in all patients. The median increase of creatinine was 11% (interquartile range 0%–30%) in group T and 17% (0%–74%) in group V, p = 0.062. In patients who received concomitant amphotericin B (given for 7 days and 6 days, respectively, p = 0.525), median creatinine increased from 0.9 mg/dl (0.8–1.1) to 1.2 mg/dl (0.9–1.5) in group T and from 0.9 mg/dl (0.8–1.08) to 1.55 mg/dl (1.33–2.23) in group V (p < 0.001). This led to a doubling of creatinine in 2/23 (9%) patients of group T and in 9/16 (56%) patients of group V (p = 0.003). A multivariate analysis revealed that concomitant use of amphotericin B (p < 0.001) and treatment with vancomycin (p = 0.002) were independently associated with nephrotoxicity. Teicoplanin and vancomycin were comparably effective in patients with neutropenia and persistent fever, but – if combined with amphotericin B – vancomycin was significantly more nephrotoxic than teicoplanin.

Thalidomide monotherapy in relapsed/refractory multiple myeloma (MM) has a response rate of 30%. The combination of thalidomide with dexamethasone (Thal/Dex) is expected to improve responses, but it is unknown if the combination increases the rate of adverse events. Here, we conducted a systematic review of studies evaluating Thal/Dex in relapsed/refractory MM. Twelve studies were included, comprising 451 patients. The response rate (CR and PR) was 46% (95% CI 42–51%). Therapy-related toxicity was comparable to thalidomide monotherapy and included somnolence (26%, 95% CI 22–31%), constipation (37%, 95% CI 32–42%) and peripheral neuropathy (27%, 95% CI 23–32%). Only venous thromboembolism appeared to occur more often with Thal/Dex (5%, 95% CI 3–8%). Thus, using Thal/Dex results in an improved response rate in relapsed/refractory MM, with a toxicity rate comparable to thalidomide monotherapy.

Observation-based early warning scoring systems (EWSS) have been developed to improve the outcome of critically ill patients by triggering early critical care intervention. To date, none of these scoring systems have been evaluated in cancer patients or stem cell transplant (SCT) recipients. The aim of this study was to validate 3 established EWSS (modified early warning score [MEWS], patient-at-risk score [PARS], and Leed's early warning score [LEWS]) in adult recipients of Allogeneic SCT (Allo-SCT) and to determine their usefulness at predicting survival. We retrospectively analyzed the physiologic observations during the initial admission of 43 Allo-SCT recipients. Respiratory dysfunction was the most common (40 patients, 93%) event. All 3 EWSS revealed high accuracy in predicting in-hospital survival. The cutoff level associated with a high risk of in-hospital mortality was 7. Of 8 patients with a LEWS=7, 6 died during their initial admission, whereas no patient with a lower score died (specificity 95%, sensitivity 100%). Acute clinical deterioration during the initial admission appeared to have an adverse effect on overall survival: in-hospital survivors with a LEWS >3 during their admission had a shorter median survival than patients with LEWS ≤3, P = .018. This is the first study to validate EWSS in Allo-SCT and demonstrate that these systems are highly predictive of in-hospital and overall survival.

The risk for opportunistic infections is correlated with low CD4+ T lymphocyte counts in patients with HIV. We performed a retrospective analysis in 54 patients with multiple myeloma undergoing high-dose melphalan chemotherapy + autologous peripheral blood stem cell transplantation to better define the value of routine control of CD4+ T lymphocyte counts in this important patient group. In 61% of our patients, CD4+ T lymphocyte counts after recovery from neutropenia were200/microl and100/microl in 24% (median = 181/microl). Overall survival, progression-free survival, response to antineoplastic therapy and frequency of post-transplant infections were not significantly different when patients with CD4+ T lymphocyte counts200/microl and200/microl were compared. However, overall survival was significantly shorter in the subgroup of 13 patients with very low CD4+ T lymphocyte counts (100/microl) (P = 0.036). In 79.6% of all patients, at least one infection NCI-CTC grade II - IV developed within 100 days post-transplant. Opportunistic infections were rare. This analysis suggests that patients with CD4+ T lymphocyte counts100/microl may have a poorer prognosis.

Safety, tolerability and efficacy of itraconazole and amphotericin B (AMB) were compared for empirical antifungal treatment of febrile neutropenic cancer patients. Patients and Methods: In an open, randomised study, 162 patients with at least 72 h of antimicrobial treatment received either intravenous followed by oral itraconazole suspension or intravenous AMB for a maximum of 28 days. Permanent discontinuation of study medication due to any adverse event was the primary safety parameter. Efficacy parameters included response and success rate for both treatment groups. Results: Significantly fewer itraconazole patients discontinued treatment due to any adverse event (22.2 vs. 56.8% AMB; p < 0.0001). The main reason for discontinuation was a rise in serum creatinine (1.2% itraconazole vs. 23.5% AMB). Renal toxicity was significantly higher and more drug-related adverse events occurred in the AMB group. Intention-to-treat (ITT) analysis showed favourable efficacy for itraconazole: response and success rate were both significantly higher than for AMB (61.7 vs. 42% and 70.4 vs. 49.3%, both p < 0.0001). Treatment failure was markedly reduced in itraconazole patients (25.9 vs. 43.2%), largely due to the better tolerability. Conclusions: Itraconazole was tolerated significantly better than conventional AMB and also showed advantages regarding efficacy. This study confirms the role of itraconazole as a useful and safe agent in empirical antifungal therapy of febrile neutropenic cancer patients. Hintergrund: Es wurden die Sicherheit, Verträglichkeit und Wirksamkeit von Itraconazol und Amphotericin B (AMB) in der antimykotischen Therapie der persistierend febrilen Neutropenie verglichen. Patienten und Methoden: In einer offenen, randomisierten Studie erhielten 162 Patienten mit mindestens 72-stündiger antibiotischer Therapie entweder Itraconazol (erst intravenös, dann oral) oder AMB (intravenös) für maximal 28 Tage. Primärer Sicherheitsparameter war die dauerhafte Unterbrechung der Studienmedikation aufgrund von Nebenwirkungen. Die Wirksamkeitsparameter umfassten die Ansprech- und Erfolgsrate für beide Behandlungsgruppen. Ergebnisse: Signifikant weniger Itraconazol-Patienten brachen die Behandlung wegen Nebenwirkungen ab (22,2 vs. 56,8% AMB; p < 0,0001). Hauptursache für Studienabbrüche war der Anstieg des Serum-Kreatinin-Spiegels (1,2% Itraconazol vs. 23,5% AMB). Nephrotoxische und weitere Nebenwirkungen traten im AMB-Studienarm signifikant häufiger auf. Intention-to-Treat (ITT)-Analysen zeigten eine bessere Wirksamkeit von Itraconazol: Ansprech- und Erfolgsrate waren signifikant höher als unter AMB (61,7 vs. 42% und 70,4 vs. 49,3%, beide p < 0,0001). Behandlungsversagen trat bei Itraconazol-Patienten merklich weniger auf (25,9 vs. 43,2%). Schlussfolgerungen: Die Verträglichkeit von Itraconazol war signifikant höher als beim herkömmlichen AMB. Itraconazol zeigte ebenfalls Vorteile in der Wirksamkeit. Diese Studie bestätigt die Rolle von Itraconazol als sinnvolles und sicheres Medikament in der empirischen antimykotischen Therapie von fiebrigen neutropenischen Tumorpatienten. Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Itraconazole is a triazole broad-spectrum antifungal agent that can be given as capsules, oral solution or intravenous solution. Bioavailability in neutropenic patients is different between capsules ( c. 23%) and oral solution ( c. 55%). A dose–response relationship has been established for the use of itraconazole in antifungal prophylaxis: HPLC-determined trough concentrations of itraconazole need to be above 500 ng/mL for effective prevention of invasive Aspergillus infections. A meta-analysis of 13 randomised clinical trials and 3597 neutropenic patients with haematological malignancies has demonstrated a 53% reduction in the incidence of invasive Aspergillus infections with a sufficient dose of itraconazole. Two randomised clinical trials evaluated itraconazole for empirical antimycotic therapy in neutropenic patients with persisting fever despite broad-spectrum antibiotic therapy in comparison to conventional amphotericin B. Both demonstrated significantly reduced nephrotoxicity and at least comparable efficacy. In conclusion, itraconazole should be regarded as the standard for antifungal prophylaxis in high-risk patients and a valuable therapeutic option for empirical antifungal therapy in these patients.

Objective Effective empirical antimicrobial therapy has led to a better outcome for febrile neutropenic patients. Guidelines are based mainly on expert opinion, current practice and some clinical trials. Clinical study evidence and meta-analyses of treatment options are reviewed and a treatment strategy recommended. Results Piperacillin-tazobactam, meropenem and imipenem have demonstrated significant superiority over ceftazidime and cefepime. Oral ciprofloxacin plus amoxicillin-clavulanic acid is as effective as IV therapy for low risk patients. In high risk patients, additional aminoglycoside does not improve clinical success but increases nephrotoxicity. In clinically stable patients (no CVC, soft tissue, pulmonary, fungal or viral infection), additional glycopeptide is unnecessary. The Bonn treatment strategy is oral combination therapy (fluoroquinolone and amoxicillin-clavulanic acid) in low risk patients. Low risk patients who cannot take oral medication or high risk patients without significant skin, soft tissue or CVC infection receive IV monotherapy with piperacillin-tazobactam. Piperacillin-tazobactam has been used for more than a decade with no increase in bacterial resistance. Conclusion Antimicrobial therapy selection should be based on several factors including the likely pathogen, local antimicrobial susceptibility patterns, patient infection site, risk assessment, clinical stability, organ dysfunction, previous antimicrobial therapy, and cost.

The study described the molecular cytogenetic characterization of myeloma cells in 130 patients via interphase fluorescence in situ hybridization. Nine repetitive DNA probes (for chromosomes 3, 7, 9, 11, 15, 17, 18, X, and Y) as well as seven single-copy DNA probes (for chromosomes 13, 17, 21, and two each for chromosomes 5 and 22) were used for the hybridizations. Using this panel of probes, we were able to show aberrations in 86% of patients. Most of them had one to three aberrations. There was a distinct correlation between the number of aberrations per patient and the tumor stage. Thus, the proportion of patients with 8-12 aberrations increased from 16% in stage II to 26% in stage III. There were marked differences among the chromosomes with respect to the prevalence of genomic losses and gains and deletions of gene loci. Chromosomes 3, 5, 7, 9, 11, 15, and 21 showed a preference for genomic gains. Losses were most often found for chromosomes 13 and 17 (locus specific) as well as for the X and Y chromosomes. The frequency of monosomies and trisomies were approximately the same for chromosomes 15 and 18, which indicates a skewed pattern of distribution. We found two specific aberrations that caused distinct changes in the survival rates of the patients: deletion 13q14 (28% of patients) and translocation of the IGH locus 14q32 (79% of 39 patients who were analyzed separately). The results obtained in this study yielded data of extremely relevant prognostic value.

Abdominal infections are life-threatening complications in neutropenic patients. Among these, neutropenic cholecystitis is relatively rare. Nevertheless, its actual relevance is only investigated by anecdotal reports. We present a consecutive retrospective series of nine patients over a 12-year period. We calculated a frequency of 0.4% among all neutropenic episodes in patients with acute leukemia or aggressive lymphoma undergoing myelosuppressive chemotherapy. Only three of these patients had gallstones. Four patients died during the course of cholecystitis but in none of them cholecystitis was the primary cause of death. Systematic review of the literature revealed 45 patients with neutropenic cholecystitis of whom 26.7% died.

Despite intensive therapy, multiple myeloma (MM) remains an incurable disease, and novel treatment approaches are therefore needed to improve outcome. Bortezomib is the first proteasome inhibitor to be approved by the U.S. Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products for the treatment of refractory or relapsed MM following the failure of at least two prior lines of therapy. Recently, it also received approval from the FDA for use as a second-line agent. An expert panel of hematologists met at the Ninth Congress of the European Hematology Association to review clinical data and experience in the treatment of MM with bortezomib, including bortezomib-based combination therapy. The conclusions of this expert panel, together with updated clinical data from the American Society of Hematology 46th Annual Meeting, provide a practical update on the use of bortezomib in MM. Bortezomib has demonstrated significant antitumor activity as a single agent in refractory and/or relapsed MM, with a significantly longer survival than with dexamethasone (1-year overall survival rate of 80% vs. 66%) and a 78% longer median time to progression. In combination therapy, patient responses suggest the possibility of chemosensitization and synergy. Furthermore, bortezomib does not appear to have an adverse effect on subsequent stem cell therapy. Bortezomib is well tolerated; most side effects are only mild to moderate and are manageable. Information is given on the practical management of the most common adverse events, including peripheral neuropathy and thrombocytopenia, and the use of bortezomib in renal and hepatic impairment.

The addition of rituximab to chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL) has been shown to improve outcome in first-line therapy. However, in patients with relapsed or refractory disease, the value of adding rituximab to salvage chemotherapy is less clearly defined. This study performed a matched-pair analysis of patients with relapsed or refractory DLBCL by comparing the combination of dexamethasone, high-dose cytarabine and cisplatin (DHAP) with rituximab to DHAP alone. Sixty-seven patients with relapsed or refractory DLBCL were collected from two prospective phase II trials from Germany and Italy. Twenty-three patient pairs treated with either DHAP in combination with rituximab or DHAP alone could be analysed after matching for important prognostic factors. The addition of rituximab to the DHAP regimen led to higher complete and similar overall remission rates. However, differences with regard to complete remission rates failed to reach statistical significance, thereby necessitating further evaluation of the role of combined immunochemotherapy in this patient population.

BACKGROUND Neutropenia is an indicator of poor prognosis in patients with fungal infections. All available clinical trial experience from the caspofungin development program was reviewed to ascertain the efficacy of caspofungin in neutropenic patients with documented invasive aspergillosis (IA) or invasive candidiasis (IC). METHODS The review was limited to neutropenic patients with proven IC or proven/probable IA at caspofungin onset. Data were available from four clinical trials. All patients had an absolute neutrophil count < 500/mm3 at the initiation of caspofungin. In all cases caspofungin was administered as monotherapy at a dose of 50 mg/day, after a 70-mg loading dose. In all patients efficacy was assessed at the completion of caspofungin therapy. Success included complete and partial responses. RESULTS Sixty-eight neutropenic patients were identified with documented invasive infection, including 27 with IC and 41 with IA. Most patients had acute or chronic leukemia. A favorable response was noted in 63% (17 of 27 patients) of patients with IC, including a 58% (14 of 24 patients) response as first-line therapy and a 100% (3 of 3 patients) response as salvage therapy. Success in candidemia was 68% (17 of 25 patients). Outcomes across the different Candida species were similar. Favorable responses were noted in 39% (16 of 41 patients) of patients with IA, including a 42% (5 of 12 patients) response as first-line therapy and 38% (11 of 29 patients) response as salvage therapy. Success by site of IA was 40% for pulmonary (12 of 30 patients), 43% for sinus (3 of 7 patients), and 25% for skin/disseminated site (1 of 4 patients). CONCLUSIONS A review of the caspofungin database demonstrates that this echinocandin is effective in neutropenic patients with documented cases of IC or IA. Cancer 2006. © 2005 American Cancer Society.

Pseudomembranous and obstructive Aspergillus tracheobronchitis (PMATB/OATB) are still considered to be refractory to therapy and to have a fatal outcome. To evaluate the optimal diagnostic strategy and to describe factors affecting the outcome of PMATB and OATB. Retrospective analysis of four new cases of PMATB and OATB combined with 16 previously reported cases over a 10-year period (1995-2004). Among the four new cases reported and the 16 published cases, four patients survived their infection. The mortality rate was significantly higher in the group of ventilated patients [94% (15 of 16 patients)] than in the group of non-ventilated patients [25% (1 of 4 patients), P < 0.05, Fisher's exact test]. In all 20 patients, diagnosis was established by bronchoscopy. Culture examination of mucous plugs was positive in 8 of 10, culture of the tracheobronchial aspirate was positive in 8 of 12, and bronchoalveolar lavage was diagnostic in 7 of 13 patients. All bronchoscopic techniques were complementary in improving the yield of bronchoscopy. However, microscopy of mucous plugs and/or necrotic material was the best diagnostic modality [positive in 94% (17 of 18 patients)]. Prognosis of PMATB and OATB remains poor. Microscopy of respiratory specimens is the most sensitive tool to confirm the diagnosis. The characteristic appearance of the disease makes it possible to start antifungal therapy immediately.

Received 18 May 2005; returned 12 August 2005; revised 7 October 2005; accepted 14 October 2005Background: Caspofungin has shown efficacy in empirical antifungal therapy in neutropenic patients,refractory invasive Aspergillus infections and invasive candidiasis. Here we report the currently largestseries of patients treated with caspofungin outside clinical trials.Methods:CentresinGermanythatwereknowntotreatpatientswithinvasivefungalinfectionswereaskedtofilloutdetailedquestionnairesforallpatientstreatedwithcaspofungin.Noeffortwasmadetoinfluencethe decision to use caspofungin.Results:Atotalof118patientswereevaluable(medianage48years,interquartilerange38–58),outofwhich41(35%)sufferedfromacuteleukaemia,31(26%)hadallogeneicstemcelltransplants,16(14%)lymphomaor myeloma, 8 (7%) autologous stem cell transplants and 22 (19%) other causes for immunosuppression.Onehundredandsixpatientswereevaluableforefficacyoutofwhich68(64%)patientsachievedacompleteor partial remission. A total of 81out of 115 (70%) patients were alive 30 days after the end of caspofungintherapy. Response ratesweresimilar inproven (20/32,63%) andprobable (27/46,59%) infections, inneut-ropenic patients (41/55, 75%) and in patients who were (44/70, 63%) or were not (24/36, 67%) refractoryto antifungal pre-treatment. The response rate in mechanically ventilated patients was 29% (7/24).Caspofungin was well tolerated, even in 14 patients, who were concomitantly treated with ciclosporin A,no drug-related elevations of bilirubin, alanine aminotransferase or creatinine were found.Conclusions: This open case study of severely ill patients with invasive fungal infections demonstratesboth excellent efficacy and very low toxicity of caspofungin.Keywords: fungal infections, candidiasis, aspergillosis, safety

Early anticancer research involving thalidomide was abandoned in the 1960s as the catastrophe surrounding the drug emerged, but research efforts were picked up in the 1990s when thalidomide’s antiangiogenic and anti-tumour necrosis factor properties were explored. More than 50,000 patients with multiple myeloma are estimated to have been treated with thalidomide to date. Research with thalidomide provides clear and convincing evidence that thalidomide monotherapy is efficacious in relapsed and refractory patients with multiple myeloma. Results typically show a consistent 30% (95% confidence interval 27–32%) response rate (partial response + complete response, defined as a reduction of at least 50% in the monoclonal protein). Thalidomide treatment compares favourably with other typical treatments for multiple myeloma. In seven trials that included 332 patients, vincristine, adriamycin and dexamethasone (VAD) had a response rate of 39% (32–45%), while a trial in 193 patients showed a response rate with bortezomib of 27% (21–34%). The use of thalidomide in combination therapy could boost its efficacy further. More studies to look at the toxicity of the drug need to be carried out. Despite thalidomide’s dark past, this drug is of major interest and could be brought back to clinical use in a controlled manner.

Febrile neutropenia is still associated with a high mortality rate, making timely and efficient empirical antibiotic therapy absolutely vital. For these reasons, evidence-based guidelines are urgently needed. The guidelines published so far are mainly based on clinical experience and selective citation. This review summarises studies and meta-analyses concerning empirical antibiotic therapy in high-risk neutropenic patients: (1) No benefit results from the addition of an aminoglycoside to the initial empirical therapy. On the contrary, patients who received an aminoglycoside had a significantly higher rate of adverse events, especially nephrotoxicity. (2) The empirical addition of a glycopeptide after 3–4 days of persistent fever was evaluated in two randomised controlled trials. Combined analysis demonstrates that in clinically stable patients without resistant or skin/soft tissue infections, the use of a glycopeptide can be delayed for another 3–4 days. (3) The choice of drugs for monotherapy is currently being evaluated; preliminary results demonstrate that ceftazidime has a significantly inferior response rate (without modification) to other evaluated antibiotics. In conclusion, guidelines should be based on the systematic evaluation of all relevant clinical trials. The analysis of the existing data leads to the recommendation of monotherapy, without aminoglycoside, using piperacillin–tazobactam, cefepime, meropenem or imipenem–cilastin, any of which may be continued for up to 7 days in persistently febrile, clinically stable patients without skin/soft tissue infections. The choice of drug as standard first-line therapy should depend on drug costs, local resistance rates and the potential for resistance induction.

The purpose of our study was (i) to evaluate the impact of all-trans retinoic acid (ATRA) given as adjunct to chemotherapy and (ii) to compare second consolidation vs maintenance therapy in elderly patients with acute myeloid leukemia (AML). A total of 242 patients agedor=61 years (median, 66.6 years) with AML were randomly assigned to ATRA beginning on day +3 after the initiation of chemotherapy (ATRA-arm, n=122) or no ATRA (standard-arm, n=120) in combination with induction and first consolidation therapy. A total of 61 patients in complete remission (CR) were randomly assigned to second intense consolidation (n=31) or 1-year oral maintenance therapy (n=30). After induction therapy the intention-to-treat analysis revealed a significant difference in CR rates between the ATRA- and the standard-arm (52 vs 39%; P=0.05). Event-free (EFS) and overall survival (OS) were significantly better in the ATRA-compared to the standard-arm (P=0.03 and 0.01, respectively). OS after second randomization was significantly better for patients assigned to intensive consolidation therapy (P0.001). The multivariate model for survival revealed lactate dehydrogenase, cytogenetic risk group, age, and first and second randomization as prognostic variables. In conclusion, the addition of ATRA to induction and consolidation therapy may improve CR rate, EFS and OS in elderly patients with AML.

A group of microbiology and public health experts including regulatory and medical expertise was convened in Geneva, Switzerland, 25–26 April 2002 to consider the utility of heterotrophic plate count (HPC) measurements in addressing drinking water quality and safety. The group was convened following the NSF International/World Health Organization Symposium on HPC Bacteria in Drinking Water—Public Health Implications? The Expert Meeting was attended by 31 participants from Australia, Canada, France, Germany, Italy, Japan, the Netherlands, South Africa, Switzerland, UK and USA.

To assess the prognosis of patients with acute myeloid leukemia (AML) and pulmonary infiltrates requiring mechanical ventilation.A retrospective cohort study.A medical intensive care unit (ICU) in an academic tertiary care center.We identified 30 consecutive patients with acute myeloid leukemia and pulmonary infiltrates who received invasive mechanical ventilation and compared clinical and laboratory parameters between ICU survivors and ICU non-survivors using non-parametric statistics.The overall mortality rate was 87% (26/30). The survival was 40 % (4/10) for patients aged 50 years or less while none (0/20) of the patients older than 50 years survived (P.02). The median time of mechanical ventilation in survivors was 23.5 (3-45) days. No differences between survivors and non-survivors were observed for the APACHE II score, oxygenation quotient, liver function tests, creatinine, blood urea nitrogen, or prognostic parameters of acute myeloid leukemia (presence of blasts on bone marrow aspirate, cytogenetic studies, and intensity of the chemotherapy regimen).Age seems to be an important prognostic parameter in our cohort of 30 consecutive patients with acute myeloid leukemia and pulmonary infiltrates requiring mechanical ventilation. Prolonged ventilation does not preclude survival.

Purpose: Efficacy of antifungal prophylaxis has not yet been convincingly proven in numerous trials of various antifungals. New evidence and the anti-Aspergillus efficacy of itraconazole prompted a new look at the data for the prevention of invasive fungal infections. Patients and Methods: Randomized, controlled studies with itraconazole for antifungal prophylaxis in neutropenic patients with hematologic malignancies were identified from electronic databases and hand searching. Results: Thirteen randomized trials included 3,597 patients who were assessable for invasive fungal infections. Itraconazole reduced the incidence of invasive fungal infection (mean relative risk reduction, 40% ± 13%; P = .002), the incidence of invasive yeast infections (mean, 53% ± 19%; P = .004) and the mortality from invasive fungal infections (mean, 35% ± 17%; P = .04) significantly. The incidence of invasive Aspergillus infections was only reduced in trials using the itraconazole cyclodextrine solution (mean, 48% ± 21%; P = .02) and not itraconazole capsules (mean, 75% ± 73% increase; P = .3). The overall mortality was not changed. Adverse effects were rare, hypokalemia was noted in three studies, and a higher rate of drug discontinuation was found in trials that compared itraconazole cyclodextrine solution to a control without cyclodextrine. The effect of prophylaxis was clearly associated with a higher bioavailable dose of itraconazole. Conclusion: Antifungal prophylaxis with itraconazole effectively prevents proven invasive fungal infections and—shown for the first time for antifungal prophylaxis—reduces mortality from these infections and the rate of invasive Aspergillus infections in neutropenic patients with hematologic malignancies. Adequate doses of the oral cyclodextrine solution (at least 400 mg/d) or IV formulations (200 mg/d) of itraconazole are necessary for these effects.

Purpose: To evaluate response rate, response duration, overall survival (OS), and toxicity in primary CNS lymphoma (PCNSL) after systemic and intraventricular chemotherapy with deferred radiotherapy. Patients and Methods: From September 1995 to July 2001, 65 consecutive patients with PCNSL (median age, 62 years) were enrolled onto a pilot and phase II study evaluating chemotherapy without radiotherapy. A high-dose methotrexate (MTX; cycles 1, 2, 4, and 5) and cytarabine (ARA-C; cycles 3 and 6)–based systemic therapy (including dexamethasone, vinca-alkaloids, ifosfamide, and cyclophosphamide) was combined with intraventricular MTX, prednisolone, and ARA-C. Results: Sixty-one of 65 patients were assessable for response. Of these, 37 patients (61%) achieved complete response, six (10%) achieved partial response, and 12 (19%) progressed under therapy. Six (9%) of 65 patients died because of treatment-related complications. Follow-up is 0 to 87 months (median, 26 months). The Kaplan-Meier estimates for median time to treatment failure (TTF) and median OS were 21 months and 50 months, respectively. For patients older than 60 years, median survival was 34 months, and the median TTF was 15 months. In patients younger than 61 years, median survival and median TTF have not been reached yet; the 5-year survival fraction is 75%. Systemic toxicity was mainly hematologic. Ommaya reservoir infection occurred in 12 patients (19%), and permanent cognitive dysfunction possibly as a result of treatment occurred in only two patients (3%). Conclusion: Primary chemotherapy based on high-dose MTX and ARA-C is highly efficient in PCNSL. Response rate and response duration in this series are comparable to the response rates and durations reported after combined radiotherapy and chemotherapy. Neurotoxicity was infrequent.

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.

Pancreatic cancer is predominantly diagnosed in advanced stages of the disease. In all, 80–95% of patients are inoperable at diagnosis and only about 1% of patients are still alive 5 years from the time of diagnosis (Ahlgren, 1996). Gemcitabine (2′,2′di-fluorodeoxycytidine), a nucleoside analogue with a mild toxicity profile (Aapro et al, 1998), has been shown to improve both clinical benefit and survival in patients with advanced pancreatic cancer compared to treatment with 5-fluorouracil, although overall survival was poor with a median survival of less than 6 months (Burris et al, 1997). Especially, in pancreatic cancer a common problem with chemotherapeutic approaches consists in the difficulty in determining objective treatment response (Warshaw and Fernandez-del Castillo, 1992; Rothenberg et al, 1996a). This is partly due to the retroperitoneal localisation of the pancreas, and also due to the limited possibilities of differentiating the tumour from the normal surrounding tissue. Moreover, inclusion of desmoplastic tissue into the baseline tumour volume may cause an underestimation of tumour reduction during chemotherapy, while inclusion of surrounding inflammatory tissue may result in an overestimation of response (Rothenberg et al, 1996a). Therefore, great efforts have been undertaken to determine the impact of chemotherapy by methods other than imaging of tumour volume (Rothenberg et al, 1996a; Burris et al, 1997). One approach has been the measurement of clinical benefit that is a composed parameter consisting of factors like performance status, pain, and body weight. While an evaluation of clinical benefit response reflects on the quality of life, this approach is time consuming, in many aspects subjective, and certainly controversial in its validity (Burris et al, 1997). In patients undergoing radiation or resection of pancreatic cancer, the prognostic value of serum carbohydrate antigen 19-9 (CA 19-9) has already been accepted. In search for a parameter reflecting the chemotherapeutic efficacy faster, on a more objective level, and to identify any subgroups of patients in whom chemotherapy with gemcitabine improves survival, prognostic parameters (tumour grading, tumour stage, prior palliative operation, baseline CA 19-9 and CA 19-9 decrease) during the first treatment courses, CA 19-9 was evaluated in patients undergoing chemotherapy with gemcitabine alone (Halm et al, 2000) or in combination with cisplatin (Heinemann et al, 1999). Halm et al (2000) and Heinemann et al (1999) found that kinetics of CA 19-9 concentration may serve as an early indicator of response to gemcitabine/gemcitabine–cisplatin therapy. Serum carbohydrate antigen 19-9, the sialylated Lewis blood group antigen defined by the monoclonal antibody 1116 NS 19-9 (Koprowski et al, 1979), is a tumour-associated antigen synthesised by normal pancreatic and ductular cells occurring in large quantities in normal pancreatic juice (Steinberg, 1990). It is the most sensitive and specific serum marker for pancreatic cancer (Pleskow et al, 1989; Rollhauser and Steinberg, 1998). The prognostic value of CA 19-9 for patients with pancreatic cancer treated by resection or radiotherapy is well established (Glenn et al, 1988; Katz et al, 1998; Rollhauser and Steinberg, 1998), but only few data regarding the prognostic value of CA 19-9 during chemotherapy with gemcitabine have been published so far. No prospective studies comparing clinical benefit response and CA 19-9 response were performed. Although CA 19-9 is not pathognomonic of pancreatic cancer, most patients show elevated serum concentrations of this marker. This study analyses the kinetics and the prognostic value of the tumour marker CA 19-9 as a biochemical response marker before and during chemotherapy in patients with advanced or metastatic pancreatic cancer treated with gemcitabine with special emphasis on objective tumour and clinical benefit response.

Summary We undertook a one-year study to investigate the impact of the NSA model 7100A/B portable air filtration unit on exposure of haematology–oncology patients to airborne Aspergillus fumigatus spores under field conditions. Weekly measurements for airborne A. fumigatus were conducted in indoor and outdoor air, and surveillance for invasive aspergillosis was based on a combination of ward liaison, targeted chart review and consultation with the medical staff. The mean indoor A. fumigatus counts (8.1 cfu/m 3 ; range, ,0.8 to 42 cfu/m 3 ) reflected the fungal load of outdoor air (9.4 cfu/m 3 ; range, ,0.8 to 50 cfu/m 3 ), and were reduced by only about one third in rooms with portable air filtration units (5.3 cfu/m 3 ; range, ,0.8 to 41 cfu/m 3 ). During the study period, a total of five cases (incidence density, 0.8 per 1000 patient-days) of invasive aspergillosis (one proven case, four suspected cases; case fatality rate 40%) were recorded. None of these five patients was allocated to a room with portable air filtration unit, however, the difference between incidence densities in rooms with and without portable air filtration units was non-significant (Fisher’s exact test, P ¼ 0:33). Due to the noise level and thermal discomfort, patient compliance with the air filtration units was poor. We conclude that under field conditions this air filtration unit cannot be recommended for prevention of invasive aspergillosis in neutropenic haematology–oncology patients. Q 2003 The Hospital Infection Society. Published by Elsevier Science Ltd. All rights reserved.

Efficacy and costs of empirical antibacterial therapy in febrile neutropenic patients are important issues. Several strategies have been reported to be similarly effective: monotherapy with cefepime, ceftazidime or a carbapenem or duotherapy with an antipseudomonal beta-lactam antibiotic or ceftriaxone in combination with an aminoglycoside. Piperacillin-tazobactam monotherapy is promising, but its role in this setting still has to be defined.Of 212 consecutive febrile episodes in 130 neutropenic patients with hematological malignancies randomized to receive either piperacillin-tazobactam (4.5 g every 8 h; group A) or ceftriaxone (2 g once daily plus gentamicin 5 mg/kg once daily; group B), 183 episodes (98 group A, 85 group B) were evaluable for response.Defervescence within 72 h without modification of the antibiotic therapy was achieved in 56/98 episodes (57.1%) in group A and in 30/85 (35.3%) in group B (P=0.0047). If fever persisted, teicoplanin plus gentamicin (group A) or teicoplanin plus ciprofloxacin (group B) were added. All patients still febrile then received meropenem, teicoplanin and amphotericin B. With these modifications of antibiotic therapy, 89.8% of patients in group A had responded at 21 days but only 71.8% in group B (P=0.005). The mean total antibiotic drug cost in group A was only 39.4% of that in group B (euro 445 versus euro 1129; P=0.010).Piperacillin-tazobactam monotherapy is significantly more effective and cost-efficient than ceftriaxone plus gentamicin as first-line therapy in febrile neutropenic patients with hematological malignancies.