Central venous catheters (CVCs) are essential for the intensive care of patients with haematological illness. Catheter-related infections (CRI) are an important problem in modern medicine, which may ...lead to life-threatening situations, to prolonged hospitalisation and increased cost. In immunocompromised patients suffering from haemato-oncological diseases, CRI is a significant factor for adverse outcome. Several clinical studies have shown that CVCs coated with antiseptics such as chlorhexidine and silver-sulfadiazine (CHSS) reduce the risk of catheter-related bacteraemia. Most studies, however, were performed on intensive care patients not suffering from chemotherapy-induced immunosuppression.
A prospective double-blind, randomised, controlled trial was performed to investigate the effectiveness of CHSS-coated catheters in haemato-oncological patients. A total number of 184 catheters (median duration of placement, 11 days) were inserted into 184 patients (male 115, female 69), of which 90 were antiseptically coated. After removal, all catheters were investigated for bacterial growth.
Catheters coated with CHSS were effective in reducing the rate of significant bacterial growth on either the tip or subcutaneous segment (26%) compared to control catheters (49%). The incidence of catheter colonisation was also significantly reduced (12% coated vs 33% uncoated). Data obtained show a significant reduction of catheter colonisation in CHSS catheters. There was no significant difference in the incidence of catheter-related bacteraemia (3% coated vs 7% uncoated). However, due to the overall low rate of CRI, we could not observe a significant reduction in the incidence of catheter-related bacteraemia.
Our data show that the use of CHSS catheters in patients with haematological malignancy reduces the overall risk of catheter colonisation and CRI, although the incidence of catheter-related bacteremia was similar in both groups.
Introduction: Early mortality is up to 10% in newly diagnosed multiple myeloma (MM) with no improvement in subsequent study generations until 2002 (Augustson et al., JCO, 2005). Recent data on the ...causes of early mortality in transplant-eligible (te) MM patients during induction therapy (IT) and associated risk factors are not available.
Patients and Methods: This retrospective multi-cohort analysis included 1515 patients from three subsequently conducted phase III multicenter trials for teMM (HD3, HD4, MM5) from the German-speaking Myeloma Multicenter Group (GMMG).
The analyzed IT period was defined from the first dose of IT until the last dose of IT plus 30 days or until start of stem cell mobilization. Patients were analyzed as treated if they received at least one dose of trial medication and no more than three IT cycles. Early deaths were defined as any deaths in the defined period. Severe infections (SI) were defined as any infection ≥ grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE). Three cycles of a three-drug IT were applied in each trial: vincristine, doxorubicin (DOX), dexamethasone (DEX; VAD) vs. thalidomide, DOX, DEX (TAD) in the HD3 trial (09/2001-09/2004, Breitkreutz et al., Leukemia, 2007; n=529); VAD vs. bortezomib (BTZ), DOX, DEX (PAD) in the HD4 trial (05/2005-05/2008, Sonneveld et al., JCO, 2012; n=388); and PAd vs. BTZ, cyclophosphamide (CYC), DEX (VCD) in the MM5 trial (07/2010-11/2013, Mai et al., Leukemia, 2015; n=598). Major inclusion / exclusion criteria were similar between the trials, except for the maximum age for inclusion: 65 years (HD3, HD4) vs. 70 years (MM5).
Uni- and multivariate logistic regression models were built to assess risk factors. Trial effect was accounted for. Based on the risk factors for SI during IT, a predictive score for SI-related / overall mortality during IT was developed. Data from the Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON) -50 (VAD and TAD IT, 11/2001-05/2005, Lokhorst et al., Blood, 2010, n=528) and HOVON-65 (VAD and PAD IT, 05/2005-05/2008, Sonneveld et al., JCO, 2012; n=430) multicenter phase III trials for teMM were used to validate the prognostic score for mortality during IT.
Results: Severe infections occurred in 22.3% vs. 27.3% vs. 10.0% vs. 18.8% of patients in the HD3, HD4, MM5, and pooled population, respectively. In the HD3, HD4, MM5 and pooled cohort, 6.2% vs. 3.1% vs. 1.3% vs. 3.5% (n=33/12/8/53) of patients died during IT, respectively. Infections were the single largest cause of death during IT (n=26, 49.1%).
Besides trial effects (HD4, odds ratio OR=1.42, p=0.03; MM5, OR=0.37, p>0.001, both vs. HD3), pooled multivariate analyses identified World Health Organization performance status >1 (WHO>1, OR=1.97, p<0.001), age >60 years (age>60, OR=1.42, p=0.01) and lactate dehydrogenase > upper level of normal (LDH>ULN, OR=1.45, p=0.04) as trial-independent significant predictors for SI during IT. Combination of these factors allowed the stratification in three groups according to the risk of SI during IT: high risk (HiR, WHO>1 plus age>60 and/or LDH>ULN, n=95, SI incidence: 37.9%), low risk (LoR, no risk factors or age>60 only, n=1046, SI incidence: 15.8%) and intermediate risk (ImR, neither HiR nor LoR, n=310, SI incidence: 21.6%). In the HiR group, the incidence of death from any cause or SI was 14.7%/8.4% vs. 6.1%/2.6% vs. 1.4%/0.9% in the ImR and LoR groups, respectively. The increased risk of death from any cause or SI in the HiR and ImR group was independent of trial effects (HiR group: OR any cause/SI=11.46/10.19, both p<0.001 and ImR group: OR any cause/SI=4.83/3.23, p<0.001/0.02; vs. LoR group).
To validate the constructed risk score, we analyzed the HOVON-50 and HOVON-65 trials (n=922): 5.8% (n=53) of patients died during IT. Similar to the GMMG cohort, the HiR group included 7.7% of patients with an overall mortality of 18.3% vs. 6.1% and 4.3% in the ImR (21.4% of patients) and LoR groups (70.9% of patients) during IT, respectively. Again, the increased risk for death from any cause during IT was independent of trial effects (HiR group: OR=4.90, p<0.001).
Conclusions: Our validated risk score for early mortality in teMM identifies a subgroup of patients with an excessive mortality during IT. These patients are at risk to miss the benefits of modern anti-MM therapy, thus intensive clinical monitoring and the development of strategies to prevent early mortality are needed.
Mai:Onyx: Other: Travel grants; Mundipharma: Other: Travel grants; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Other: Travel grants; Celgene: Other: Travel grants. Salwender:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Honoraria and travel support: Janssen Cilag, Celgene, BMS.: Honoraria, Other: Travel support. Lokhorst:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; OncoImmune: Research Funding. Zweegman:Takeda: Other: advisory board participation, Research Funding; Janssen: Other: advisory board participation, Research Funding; Celgene: Other: advisory board participation, Research Funding; Amgen: Other: advisory board participation. Hillengass:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; honoraria from Amgen, BMS, Celgene: Honoraria; BMS: Honoraria; Sanofi: Research Funding. Raab:Novartis: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy, Speakers Bureau. Hose:Sanofi: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; EngMab: Research Funding. Merz:Takeda: Honoraria, Research Funding; Celgene: Other: Travel grant; Janssen: Other: Travel grant. Kersten:Millennium/Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Mundipharma: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria; Kite Pharma: Honoraria; Roche: Honoraria, Research Funding; Gilead Sciences: Honoraria; BMS: Honoraria; MSD: Honoraria; Amgen: Honoraria. Scheid:Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Weisel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sonneveld:Celgene Corporation, Amgen, Janssen, Karyopharm, SkylineDx, PharmaMar: Consultancy; Celgene Corporation, Amgen, Janssen, Karyopharm, PharmaMar, SkylineDx: Honoraria; Celgene, Amgen, Janssen, Karyopharm, Takeda: Consultancy, Honoraria, Research Funding. Goldschmidt:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Morphosys: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.
Background: The well-described prognostic impact of tumor characteristics and biology in multiple myeloma (MM), such as the combination of cytogenetics, the International Staging System (ISS) and ...lactate dehydrogenase (LDH, Moreau et. al., JCO, 2014) as well as frailty (Palumbo et al., Blood, 2015) significantly influence patient outcomes. However, only limited data on the impact of infections during therapy exist (Rajkumar et al., Lancet Oncology, 2010). Therefore, we hypothesized that severe infections during induction therapy (IT) in transplant-eligible MM influence dosage of therapies, treatment responses after IT and survival.
Patients and Methods: From 05/2005 until 05/2008, 399 patients were randomly assigned to receive IT with either three cycles of VAD (vincristine, VIN, i.v. 0.4mg, days 1-4; doxorubicine, DOXO, i.v. 9mg/m2, days 1-4; dexamethasone, DEX, p.o. 40mg, days 1-4, 9-12, 17-20; n=201, arm A) or PAD (bortezomib, BTZ, i.v. 1.3mg/m2, days 1, 4, 8, 11; DOXO i.v. 9mg/m2, days 1-4; DEX p.o. 40mg, days 1-4, 9-12, 17-20; n=194, arm B), followed by high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT) and either thalidomide (arm A) or bortezomib (arm B) maintenance within the German part of the joint GMMG-HD4/HOVON65 trial (Sonneveld et al., JCO, 2012). After exclusion of ineligible patients, 395 patients (99.0%) were evaluable for analyses.
Any severe infection (equal or greater grade 3, according to the Common Terminology Criteria for Adverse Events, Version 4.0) during IT (at least once, defined from first until last date of application of IT medication) occurred in 105 patients (VAD n=53/198 and PAD n=52/192, 26.9% of all patients, missing data n=5).
Results: Among patients with a severe infection during IT in the VAD and PAD arms, total DEX and DOXO doses (equal dosage in VAD/PAD group) were significantly lower (median DEX dose (mg/m2): 689.0 77.7, 1014.1 vs. 742.3 0.0, 1324.1, p<0.001 and median DOXO dose (mg/m2): 106.9 33.0, 115.4 vs. 107.6 27.6, 149.5, p<0.001). Accordingly, the BTZ dose during IT in the PAD group was significantly lower in patients with severe infections (median BTZ dose (mg/m2): 15.1 5.1, 16.6 vs. 15.5 1.3, 16.4, p<0.001). Combined PAD and VAD very good partial response rates or better (VGPR+) after IT were 27.6% vs. 19.9% (p=0.12) for patients with or without a severe infection during IT.
Overall survival (OS) was significantly shortened in patients with at least one severe infection during IT (median OS: 81.8 months vs. not reached, p=0.04, Figure 1A). OS plots diverged in the early period of observation (< 3 months), driven by infection-related deaths (n=8). A landmark analysis 3 months after registration demonstrated approximated survival curves without significant differences in OS (median OS: 78.8 months vs. not reached, p=0.30, Figure 1B). Similarly, progression-free survival (PFS) was shortened, though not significantly (median PFS: 30.2 vs. 35.0 months, p=0.08). However, since not just death accounts as PFS event, the impact of infection-related deaths on PFS remains smaller than on OS. Accordingly, landmark analyses after 3 months from registration showed again closer survival curves (median PFS: 28.5 vs. 32.4 months, p=0.36).
Conclusions: Severe infections have a critical impact on the applied doses of IT and outcome in the early, vulnerable phases of MM therapy. OS for transplant-eligible MM patients with severe infections during IT was significantly shortened, mainly driven by early infection-related deaths (< 3 months). A reduction of DEX doses during PAD/PAd IT in the subsequent GMMG study generation (GMMG-HD4/HOVON65: 480mg/cycle to GMMG-MM5: 240mg/cycle) and the recommendation of antibiotic/antiviral prophylaxis throughout the whole IT led to a reduced rate of severe infections of 12% (PAd) in the GMMG-MM5 trial. Further analyses are needed to elucidate how severe infections can be avoided, and whether there is an overlap between the subgroup of patients with severe infections during IT and patients with known adverse prognostic factors or reduced fitness/pre-existing conditions.
(A) Overall survival and (B) landmark analysis on overall survival 3 months after start of induction therapy of patients with or without at least one severe infection (equal or greater grade 3) during induction therapy.
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Mai:Janssen-Cilag: Other: Travel Grant; Onyx: Other: Travel Grant; Mundipharma: Other: Travel Grant; Celgene: Other: Travel Grant. Salwender:Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Pfreundschuh:Roche: Honoraria; Amgen, Roche, Spectrum: Research Funding; Boehringer Ingelheim, Celegene, Roche, Spectrum: Other: Advisory board. Duehrsen:Janssen: Honoraria. Hillengass:Janssen-Cilag: Honoraria, Other: Travel support; Celgene: Honoraria, Other: Travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Other: Travel support; Sanofi: Research Funding. Scheid:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Weisel:BMS: Consultancy, Honoraria, Other: Travel Support; Onyx: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Support; Novartis: Other: Travel Support; Noxxon: Consultancy. Blau:MSD: Honoraria; Celgene: Honoraria, Research Funding; AMGEN: Honoraria; JAZZ pharm: Honoraria; BMS: Honoraria; Shire: Honoraria; Baxalta: Honoraria; Janssen: Honoraria, Research Funding. Goldschmidt:Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Research Funding, Speakers Bureau.
Catheter-related infections cause considerable morbidity in hospitalised patients. The incidence does not seem to be higher in neutropenic patients than in non- neutropenic patients. Gram-positive ...bacteria (coagulase-negative staphylococci, Staphylococcus aureus) are the most frequently cultured pathogens, followed by Candida species. In contrast, Gram-negative bacteria play only a minor role in catheter-related infections. Positive blood cultures are the cornerstone in the diagnosis of catheter-related infections, while local signs of infection are only rarely present. However, a definite diagnosis generally requires the removal of the catheter and its microbiological examination. The role plate method with semiquantitative cultures (Maki) has been established as standard in most laboratories. Other standard procedures use quantitative techniques (Sherertz, Brun-Buisson) and are more sensitive. For therapy of catheter-related infections, antibiotics are administered according to the susceptibility of the cultured organism. Routine administration of gylcopepticed antibiotics is not indicated. Removal of the catheter has to be considered in any case of suspected catheter-related infection and is obligatory in Staphylococcus aureus and Candida infections. Tunnel or pocket infection of long-term catheters is always an indication for removal. In the future, the rate of catheter-related infections in neutropenic patients may be reduced by the use of catheters coated with antimicrobial agents.
Up to 25% of patients with profound neutropenia lasting for >10 days develop lung infiltrates, which frequently do not respond to broad-spectrum antibacterial therapy. While a causative pathogen ...remains undetected in the majority of cases, Aspergillus spp., Pneumocystis jirovecii, multi-resistant Gram-negative pathogens, mycobacteria or respiratory viruses may be involved. In at-risk patients who have received trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis, filamentous fungal pathogens appear to be predominant, yet commonly not proven at the time of treatment initiation. Pathogens isolated from blood cultures, bronchoalveolar lavage (BAL) or respiratory secretions are not always relevant for the etiology of pulmonary infiltrates and should therefore be interpreted critically. Laboratory tests for detecting Aspergillus galactomannan, β-d-glucan or DNA from blood, BAL or tissue samples may facilitate the diagnosis; however, most polymerase chain reaction assays are not yet standardized and validated. Apart from infectious agents, pulmonary side-effects from cytotoxic drugs, radiotherapy or pulmonary involvement by the underlying malignancy should be included into differential diagnosis and eventually be clarified by invasive diagnostic procedures. Pre-emptive treatment with mold-active systemic antifungal agents improves clinical outcome, while other microorganisms are preferably treated only when microbiologically documented. High-dose TMP/SMX is first choice for treatment of Pneumocystis pneumonia, while cytomegalovirus pneumonia is treated primarily with ganciclovir or foscarnet in most patients. In a considerable number of patients, clinical outcome may be favorable despite respiratory failure, so that intensive care should be unrestrictedly provided in patients whose prognosis is not desperate due to other reasons.
Multiples Myelom Goldschmidt, H; Salwender, H.-J; Knauf, W
Best practice onkologie,
02/2009, Letnik:
4, Številka:
1
Journal Article
Recenzirano
Das multiple Myelom ist eine maligne lymphoproliferative B-Zell-Erkrankung. Hierbei kommt es im Knochenmark zu einer Akkumulation und Proliferation maligner Plasmazellen. In den letzten Jahren ...konnten die Behandlungsmöglichkeiten durch die Optimierung der Hochdosistherapie und durch die Einführung neuer Substanzen weiter verbessert werden. Die konventionell dosierte Kombination von Melphalan und Prednison (MP-Schema) oder Dexamethason mit neuen Substanzen (Thalidomid, Bortezomib oder Lenalidomid) erhöht die Remissionsrate entscheidend, verlängert die Überlebenszeit und ist der derzeit empfohlene neue Standard der Primärtherapie für Patienten mit Kontraindikationen für eine Hochdosistherapie.
Catheter-related venous thrombosis is one of the most frequent complications of central venous catheters (CVCs). This complication occurs in 4- 40% of patients with hematologic malignancies receiving ...conventional chemotherapy after placement of CVCs.
The objective of this prospective study was to assess whether a silver-coated CVC poses an additional risk in the development of catheter-related thrombosis in hematologic-oncologic patients. Patients were randomized to receive either silver-coated polyurethane catheters (BactiGuard; Metacot, Stockholm, Sweden) or uncoated standard polyurethane catheters (Cavatheter, Fresenius AG, Bad Homburg, Germany) for central venous access. Silver-coated catheters (n = 120) and standard catheters (n = 113) were inserted into the jugular vein in 233 consecutive patients. Variables that may be significant for the development of thrombosis were comparable in the two groups. After removal of the CVC, the patency of both jugularian veins internal as well as external was assessed with real-time ultrasound (Sonolayer-SAL-35A; Toshiba, Tokyo, Japan).
Four of 233 patients (1.5%) were found to have venous thrombosis. Incomplete occlusion of the internal jugular vein occurred in 2 patients (0.75%, parietal thrombosis), and complete thrombosis, although clinically silent, was found in 2 patients (0.75%). There was no difference between patients with silver-coated and uncoated CVCs.
The authors concluded that this novel silver-coated CVC does not cause a higher rate of central venous thrombosis compared with standard CVCs. The low overall incidence of central venous thrombosis might be attributed to the routine application of low-dose heparin in our patients during chemotherapeutic treatment.
Authentic car-to-car side collisions (n = 30) with the main impact area at the B-pillar were analyzed to find technical parameters corresponding with the injury severities of the front seat, ...belt-protected car passengers on the impact side. EES (Energy Equivalent Speed) and delta v (delta v, change in velocity) were highly significant predictors of the severity of thoracic and abdominal injuries and total injury severity coded according to the Abbreviated Injury Scale (AIS). At an EES or delta v greater than or equal to 40 km/h all front-seat car passengers on the impact side sustained a total injury severity of Maximum AIS (MAIS) greater than or equal to 4 and died. Although a passenger could survive the crash without injury to one or more body regions up to the highest EES- and delta v-values, at EES or delta v greater than or equal to 40 km/h fatal injuries were sustained in at least one body region. At an EES greater than or equal to 35 km/h or a delta v greater than or equal to 15 km/h no front-seat car passenger on the impact side remained uninjured.
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