A randomized placebo-controlled phase II study of a Pseudomonas vaccine in ventilated ICU patients.

BACKGROUND: Currently, no vaccine against Pseudomonas is available. IC43 is a new, recombinant, protein (OprF/I)-based vaccine against the opportunistic pathogen, Pseudomonas aeruginosa, a major cause of serious hospital-acquired infections. IC43 has proven immunogenicity and tolerability in healthy volunteers, patients with burns, and patients with chronic lung diseases. In order to assess the immunogenicity and safety of IC43 in patients who are most at risk of acquiring Pseudomonas infections, it was evaluated in mechanically ventilated ICU patients. METHODS: We conducted a randomized, placebo-controlled, partially blinded study in mechanically ventilated ICU patients. The immunogenicity of IC43 at day 14 was determined as the primary endpoint, and safety, efficacy against P. aeruginosa infections, and all-cause mortality were evaluated as secondary endpoints. Vaccinations (100 µg or 200 µg IC43 with adjuvant, or 100 µg IC43 without adjuvant, or placebo) were given twice in a 7-day interval and patients were followed up for 90 days. RESULTS: Higher OprF/I IgG antibody titers were seen at day 14 for all IC43 groups versus placebo (P < 0.0001). Seroconversion (≥4-fold increase in OprF/I IgG titer from days 0 to 14) was highest with 100 µg IC43 without adjuvant (80.6%). There were no significant differences in P. aeruginosa infection rates, with a low rate of invasive infections (pneumonia or bacteremia) in the IC43 groups (11.2-14.0%). Serious adverse events (SAEs) considered possibly related to therapy were reported by 2 patients (1.9%) in the group of 100 µg IC43 with adjuvant. Both SAEs resolved and no deaths were related to study treatment. Local tolerability symptoms were mild and rare (<5% of patients), a low rate of treatment-related treatment-emergent adverse events (3.1-10.6%) was observed in the IC43 groups. CONCLUSION: This phase II study has shown that IC43 vaccination of ventilated ICU patients produced a significant immunogenic effect. P. aeruginosa infection rates did not differ significantly between groups. In the absence of any difference in immune response following administration of 100 µg IC43 without adjuvant compared with 200 µg IC43 with adjuvant, the 100 µg dose without adjuvant was considered for further testing of its possible benefit of improved outcomes. There were no safety or mortality concerns. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00876252 . Registered on 3 April 2009.

Prognostic factors, long-term survival, and outcome of cancer patients receiving chemotherapy in the intensive care unit.

Prognostic factors and outcomes of cancer patients with acute organ failure receiving chemotherapy (CT) in the intensive care unit (ICU) are still incompletely described. We therefore retrospectively studied all patients who received CT in any ICU of our institution between October 2006 and November 2013. Fifty-six patients with hematologic (n = 49; 87.5 %) or solid (n = 7; 12.5 %) malignancies, of which 20 (36 %) were diagnosed in the ICU, were analyzed [m/f ratio, 33:23; median age, 47 years (IQR 32 to 62); Charlson Comorbidity Index (CCI), 3 (2 to 5); Simplified Acute Physiology Score II (SAPS II), 50 (39 to 61)]. The main reasons for admission were acute respiratory failure, acute kidney failure, and septic shock. Mechanical ventilation and vasopressors were employed in 34 patients (61 %) respectively, hemofiltration in 22 (39 %), and extracorporeal life support in 7 (13 %). Twenty-seven patients (48 %) received their first CT in the ICU. Intention of therapy was cure in 46 patients (82 %). Tumor lysis syndrome (TLS) developed in 20 patients (36 %). ICU and hospital survival was 75 and 59 %. Hospital survivors were significantly younger; had lower CCI, SAPS II, and TLS risk scores; presented less often with septic shock; were less likely to develop TLS; and received vasopressors, hemofiltration, and thrombocyte transfusions in lower proportions. After discharge, 88 % continued CT and 69 % of 1-year survivors were in complete remission. Probability of 1- and 2-year survival was 41 and 38 %, respectively. Conclusively, administration of CT in selected ICU cancer patients was feasible and associated with considerable long-term survival as well as long-term disease-free survival.

Extracorporeal membrane oxygenation in adult patients with hematologic malignancies and severe acute respiratory failure.

INTRODUCTION: Acute respiratory failure (ARF) is the main reason for intensive care unit (ICU) admissions in patients with hematologic malignancies (HMs). We report the first series of adult patients with ARF and HMs treated with extracorporeal membrane oxygenation (ECMO). METHODS: This is a retrospective cohort study of 14 patients with HMs (aggressive non-Hodgkin lymphoma (NHL) n = 5; highly aggressive NHL, that is acute lymphoblastic leukemia or Burkitt lymphoma, n = 5; Hodgkin lymphoma, n = 2; acute myeloid leukemia, n = 1; multiple myeloma, n = 1) receiving ECMO support because of ARF (all data as medians and interquartile ranges; age, 32 years (22 to 51 years); simplified acute physiology score II (SAPS II): 51 (42 to 65)). Etiology of ARF was pneumonia (n = 10), thoracic manifestation of NHL (n = 2), sepsis of nonpulmonary origin (n = 1), and transfusion-related acute lung injury (n = 1). Diagnosis of HM was established during ECMO in four patients, and five first received (immuno-) chemotherapy on ECMO. RESULTS: Before ECMO, the PaO2/FiO2 ratio was 60 (53 to 65), (3.3 to 3.7). Three patients received venoarterial ECMO because of acute circulatory failure in addition to ARF; all other patients received venovenous ECMO. All patients needed vasopressors, and five needed hemofiltration. Thrombocytopenia occurred in all patients (lowest platelet count was 20 (11 to 21) G/L). Five major bleeding events were noted. ECMO duration was 8.5 (4 to 16) days. ICU and hospital survival was 50%. All survivors were alive at follow-up (36 (10 to 58) months); five patients were in complete remission, one in partial remission, and one had relapsed. CONCLUSIONS: ECMO therapy is feasible in selected patients with HMs and ARF and can be associated with long-term disease-free survival.

Automated red blood cell exchange as an adjunctive treatment for severe Plasmodium falciparum malaria at the Vienna General Hospital in Austria: a retrospective cohort study.

BACKGROUND: Severe falciparum malaria is associated with considerable rates of mortality, despite the administration of appropriate anti-malarial treatment. Since overall survival is associated with total parasite biomass, blood exchange transfusion has been proposed as a potential method to rapidly reduce peripheral parasitaemia. However, current evidence suggests that this treatment modality may not improve outcome. Automated red blood cell exchange (also referred to as "erythrocytapheresis") has been advocated as an alternative method to rapidly remove parasites from circulating blood without affecting patients' volume and electrolyte status. However, only limited evidence from case reports and case series is available for this adjunctive treatment. This retrospective cohort study describes the use of automated red blood cell exchange for the treatment of severe malaria at the Medical University of Vienna. METHODS: Epidemiologic data for imported malaria cases in Austria are reported and data of patients treated for malaria at the General Hospital/Medical University of Vienna were extracted from electronic hospital records. RESULTS: Between 2000 and 2010, 146 patients were hospitalized at the Medical University of Vienna due to malaria and 16 of those were classified as severe malaria cases. Eleven patients of this cohort were potentially eligible for an adjunctive treatment with automated red blood cell exchange. Five patients eventually underwent this procedure within a period of seven hours (range: 3-19 hours) after hospital admission. Six patients did not undergo this adjunctive treatment following the decision of the treating physician. The procedure was well tolerated in all cases and rapid reduction in parasite counts was achieved without occurrence of haemodynamic complications. One patient died within seven days, whereas four patients survived without any sequelae. DISCUSSION AND CONCLUSION: Automated red blood cell exchange was a safe and efficient procedure to rapidly clear peripheral parasitaemia. Whether the fast reduction in parasite biomass may ultimately improve patient survival remains however unclear. Randomized controlled trials are needed to conclusively appreciate the value of this adjunctive treatment.

Bioactivity of enoxaparin in critically ill patients with normal renal function.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Venous thromboembolism is a frequent complication in critically ill patients that has a negative impact on patient outcomes. Critically ill patients have significantly lower plasma anti-factor-Xa activity levels compared with control patients after administration of subcutaneous heparin. The clinical relevance of the different anti-factor-Xa levels after prophylactic doses of low molecular weight heparin (LMWH) in critically ill patients is not completely understood. WHAT THIS STUDY ADDS: The standard dose of 40 mg enoxaparin led to a significant increase in anti-FXa levels in this selected cohort of ICU patients with normal renal function. This study found only subtle pharmacokinetic differences, but a comparable pharmacodynamic action, after enoxaparin administration in critically ill and normal medical ward patients. Thrombin generation with TGA RC-low and TGARC-high reagents was significantly reduced in ICU and normal ward patients after receiving LMWH. Both readouts appear equally useful for estimating the pharmacodynamics of enoxaparin. The ex vivo model of thrombosis was used for the first time in patients to evaluate the anti-thrombotic activity of LMWH. This method did not show any difference in thrombus formation after administration of enoxaparin in the individual group of patients. AIM: In critically ill patients, reduced anti-FXa plasma activity following subcutaneous administration of enoxaparin or nadroparin has been described. In this study, we aimed to investigate the bioactivity of enoxaparin in critically ill patients and controls. METHODS: A prospective, controlled, open label study was performed on a medical intensive care unit (ICU) and a general medical ward. Fifteen ICU patients (male = 12, median age 52 years [IQR 40-65], with a median Simplified Acute Physiology Score of 30 [IQR 18-52]) and sex- and age-matched medical ward patients were included. The anti-FXa plasma activity was measured after a single subcutaneous dose of40 mg enoxaparin. The thrombus size of a clot formed in an ex vivo perfusion chamber and endogenous thrombin potential (ETP) were measured. RESULTS: The anti-FXa plasma activity increased significantly after enoxaparin administration, with peak levels at 3 h after treatment, but was comparable between the ICU and medical ward groups (median 0.16 IU ml-1 [IQR 0-0.22 IU ml-1] vs. 0.2 IU ml-1 [IQR 0.15-0.27 IU ml-1],respectively, P = 0.13). The area under the anti-FXa activity curve from 0­12 h was similar between the groups (median 0.97 IU ml-1 h [IQR0.59-2.1] and 1.48 IU ml-1 h1 [IQR 0.83-1.62], P = 0.42 for the ICU group compared with the control group, respectively). The ETP was lower in the ICU group (P < 0.05) at baseline, but it was comparable at 3 h between the groups. Thrombus size decreased at 3 h compared with pre-dose (P = 0.029) and was not different between the groups. CONCLUSION: Similar bioactivity was achieved with a standard dose of subcutaneous enoxaparin in this selected cohort of ICU and general ward patients with normal renal function.

Prognostic factors for intensive care unit admission, intensive care outcome, and post-intensive care survival in patients with de novo acute myeloid leukemia: a single center experience.

BACKGROUND: Acute myeloid leukemia is a life-threatening disease associated with high mortality rates. A substantial number of patients require intensive care. This investigation analyzes risk factors predicting admission to the intensive care unit in patients with acute myeloid leukemia eligible for induction chemotherapy, the outcome of these patients, and prognostic factors predicting their survival. DESIGN AND METHODS: A total of 406 consecutive patients with de novo acute myeloid leukemia (15-89 years) were analyzed retrospectively. Markers recorded at the time of diagnosis included karyotype, fibrinogen, C-reactive protein, and Charlson comorbidity index. In patients requiring critical care, the value of the Simplified Acute Physiology Score II, the need for mechanical ventilation, and vasopressor support were recorded at the time of intensive care unit admission. The independent prognostic relevance of the parameters was tested by multivariate analysis. RESULTS: Sixty-two patients (15.3%) required intensive care, primarily due to respiratory failure (50.0%) or life-threatening bleeding (22.6%). Independent risk factors predicting intensive care unit admission were lower fibrinogen concentration, the presence of an infection, and comorbidity. The survival rate was 45%, with the Simplified Acute Physiology Score II being the only independent prognostic parameter (P<0.05). Survival was inferior in intensive care patients compared to patients not admitted to an intensive care unit. However, no difference between intensive care and non-intensive care patients was found concerning continuous complete remission at 6 years or survival at 6 years in patients who survived the first 30 days after diagnosis (non-intensive care patients: 28%; intensive care patients: 20%, P>0.05). CONCLUSIONS: Ongoing infections, low fibrinogen and comorbidity are predictive for intensive care unit admission in acute myeloid leukemia. Although admission was a risk factor for survival, continuous complete remission and survival of patients alive at day 30 were similar in patients who were admitted or not admitted to an intensive care unit.

Short-term effects of combining upright and prone positions in patients with ARDS: a prospective randomized study.

INTRODUCTION: Prone position is known to improve oxygenation in patients with acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). Supine upright (semirecumbent) position also exerts beneficial effects on gas exchange in this group of patients. We evaluated the effect of combining upright and prone position on oxygenation and respiratory mechanics in patients with ALI or ARDS in a prospective randomized cross-over study. METHODS: After turning them prone from a supine position, we randomized the patients to a prone position or combined prone and upright position. After 2 hours, the position was changed to the other one for another 6 hours. The gas exchange and static compliance of the respiratory system, lungs, and chest wall were assessed in the supine position as well as every hour in the prone position. RESULTS: Twenty patients were enrolled in the study. The PaO2/FiO2 ratio improved significantly from the supine to the prone position and further significantly increased with additional upright position. Fourteen (70%) patients were classified as responders to the prone position, whereas 17 (85%) patients responded to the prone plus upright position compared with the supine position (P = n.s.). No statistically significant changes were found with respect to compliance. CONCLUSIONS: Combining the prone position with the upright position in patients with ALI or ARDS leads to further improvement of oxygenation. TRIAL REGISTRATION: Clinical Trials No. NCT00753129.

Continuous lateral rotation therapy to prevent ventilator-associated pneumonia.

OBJECTIVE: To investigate the impact of prophylactic continuous lateral rotation therapy on the prevalence of ventilator-associated pneumonia, duration of mechanical ventilation, length of stay, and mortality in critically ill medical patients. DESIGN: Prospective, randomized, clinical study. SETTING: Three medical intensive care units of an university tertiary care hospital. PATIENTS: Patients were randomized to continuous lateral rotation therapy or standard care if they were mechanically ventilated for <48 hrs and free from pneumonia. Primary study end point was development of ventilator-associated pneumonia. Ventilator-associated pneumonia was defined as infiltrate on the chest radiograph plus newly developed purulent tracheal secretion plus increasing signs of inflammation. The diagnosis had to be confirmed microbiologically and required the growth of a pathogen >10(4) colony-forming units/mL in bronchoalveolar lavage. Radiologists were blinded to randomization whereas clinical outcome assessors were not. INTERVENTIONS: Rotation therapy was performed continuously in a specially designed bed over an arc of 90 degrees. Additional measures to prevent ventilator-associated pneumonia were equally standardized in both groups including semirecumbent position. MEASUREMENTS AND MAIN RESULTS: Ventilator-associated pneumonia frequency during the intensive care unit stay was 11% in the rotation group and 23% in the control group (p = .048), respectively. Duration of ventilation (8 +/- 5 vs. 14 +/- 23 days, p = .02) and length of stay (25 +/- 22 days vs. 39 +/- 45 days, p = .01) were significantly shorter in the rotation group. In a forward stepwise logistic regression model including the continuous lateral rotation therapy, gender, Lung Injury Score, and Simplified Acute Physiology Score II, continuous lateral rotation therapy just failed to reach statistical significance with respect to development of ventilator-associated pneumonia (p = .08). Intolerance to continuous lateral rotation therapy during the weaning phase was observed in 29 patients (39%). Mortality was comparable in both groups. CONCLUSIONS: Ventilator-associated pneumonia prevalence was significantly reduced by continuous lateral rotation therapy. Continuous lateral rotation therapy led to shorter ventilation time and length of stay. Continuous lateral rotation therapy should be considered in ventilated patients at risk for ventilator-associated pneumonia as a feasible method exerting additive effects to other preventive measures.

Thirteen-year analyses of medical oncology outpatient day clinic data: a changing field.

BACKGROUND: Novel treatment modalities like targeted therapy and immunotherapy are currently changing treatment strategies and protocols in the field of medical oncology. METHODS: Numbers of patients and patient contacts admitted to medical oncology day clinics of a large European academic cancer centre in the period from 2006 to 2018 were analysed using our patient administration system. RESULTS: A patient cohort of 9.870 consecutive individual patients with 125.679 patient contacts was descriptively and retrospectively characterised. Mean age was 59.9 years. A substantial increase in both individual patients treated per year (+45.4%; 2006: 1.100; 2018: 1.599) and annual patient contacts (+63.3%; 2006: 8.857; 2018: 14.467) between 2006 and 2018 was detected. Hence and most interestingly, the ratio of visits per patient increased by approximately one visit per patient per year over the last 12 years (+12.4%; 2006: 8.0; 2018: 9.0). Further, a decrease of patient contacts in more prevalent entities like breast cancer was found, while contacts for orphan diseases like myeloma and sarcoma increased substantially. Interestingly, female patients showed more per patient contacts as compared with men (13.5 vs 11.9). Lastly, short-term safety data of outpatient day clinic admissions are reported. CONCLUSIONS: We present a representative and large set of patient contacts over time that indicates an increasing load in routine clinical work of outpatient cancer care. Increases observed were highest for orphan diseases, likely attributed to centralisation effects and increased treatment complexity.

Prolonged lateral steep position impairs respiratory mechanics during continuous lateral rotation therapy in respiratory failure.

OBJECTIVE: To establish whether prolonged lateral steep position during continuous rotation therapy leads to improvement on pulmonary gas exchange, respiratory mechanics and hemodynamics. DESIGN: Prospective observational study. SETTING: Intensive care unit of a university hospital. PATIENTS: Twelve consecutive patients suffering from acute lung injury or adult respiratory distress syndrome undergoing continuous rotation therapy. INTERVENTIONS: Blood gas analysis, static lung compliance, blood pressure, cardiac index and pulmonary shunt fraction were measured in supine as well as in left and right lateral steep position at 62 degrees during continuous rotation therapy (phase I). Rotation was then stopped for 30 min with the patients in supine position, left and right lateral steep position, and the same measurements were performed every 10 min (phase II). MEASUREMENTS AND RESULTS: Phase I and II revealed no significant changes in PaO(2)/FiO(2) ratio, mean arterial blood pressure, pulmonary shunt fraction, or cardiac index. Significantly lower static compliance was observed in lateral steep position than in supine position (p<0.001). Concomitantly, PaCO(2) was significantly lower in supine position than in left and right lateral steep position (p<0.01). CONCLUSIONS: Lateral steep positioning impairs the compliance of the respiratory system. Prolonged lateral steep position does not lead to benefits with respect to oxygenation or hemodynamics. Individual response to the different positions is unpredictable. The pauses in "extreme" positions should be as short as possible.

The European Society for Medical Oncology 'Magnitude of Clinical Benefit Scale' field-tested in infrequent tumour entities: an extended analysis of its feasibility at the Medical University of Vienna.

BACKGROUND: The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a new tool to quantify the clinical benefit that may be anticipated from a novel anticancer treatment. We present here an analysis on the feasibility of the ESMO-MCBS in less frequent tumour entities. METHODS: This study evaluates the practicability of the ESMO-MCBS for metastatic neuroendocrine tumours (NETs), soft tissue sarcomas, glioblastoma, thyroid cancer, pancreatic cancer, head/neck cancer, urothelial cancer and ovarian cancer at the Medical University Vienna. A three-step approach including data acquisition, assessment of ESMO-MCBS scores and evaluation of results with a focus on clinical feasibility was applied. RESULTS: In NET and thyroid cancer, all analysed trials were very comparable in design and efficacy, and the ESMO-MCBS scores appeared to be consistent with the clinical benefit seen in practice. For pancreatic cancer, it was more difficult to compare first-line trials due to diverging populations included in the respective studies. Concerning soft tissue sarcomas, the ESMO-MCBS was applicable for gastrointestinal stromal tumours(GIST) and 'non-GIST' soft tissue sarcoma with respect to data deriving from randomised studies. However, due to the heterogeneity of the disease itself and a limited number of controlled trials, limitations are noted. In ovarian cancer, the ESMO-MCBS supported the use of bevacizumab in high-risk patients. To date, there are only limited data for glioblastoma, head/neck cancer and urothelial cancer but whenever randomised trials were available, the ESMO-MCBS rating supported clinical decisions. Interestingly, nivolumab for salvage treatment of head/neck cancer rated extremely high. CONCLUSION: The ESMO-MCBS scores supported our common treatment strategies and highlight the potential of new immunomodulatory drugs. Our results encourage further development of the ESMO-MCBS.

Analysis of trastuzumab and chemotherapy in advanced breast cancer after the failure of at least one earlier combination: an observational study.

BACKGROUND: Combining trastuzumab and chemotherapy is standard in her2/neu overexpressing advanced breast cancer. It is not established however, whether trastuzumab treatment should continue after the failure of one earlier combination. In this trial, we report our experience with continued treatment beyond disease progression. METHODS: Fifty-four patients, median age 46 years, range 25-73 years, were included. We analysed for time to tumour progression (TTP) for first, second and beyond second line treatment, response rates and overall survival. RESULTS: Median time of observation was 24 months, range 7-51. Response rates for first line treatment were 7.4% complete remission (CR), 35.2% partial remissions (PR), 42.6% stable disease > 6 months (SD) and 14.8% of patients experienced disease progression despite treatment (PD). Corresponding numbers for second line were 3.7% CR, 22.2% PR, 42.6% SD and 31.5% PD; numbers for treatment beyond second line (60 therapies, 33 pts 3rd line, 18 pts 4th line, 6 pts 5th line, 2 pts 6th line and 1 patient 7th line) were 1.7% CR, 28.3% PR, 28.3% SD and 41.6% PD respectively. Median TTP was 6 months (m) in the first line setting, and also 6 m for second line and beyond second line. An asymptomatic drop of left ventricular ejection fraction below 50% was observed in one patient. No case of symptomatic congestive heart failure was observed. CONCLUSION: The data presented clearly strengthen evidence that patients do profit from continued trastuzumab treatment. The fact that TTP did not decrease significantly from first line to beyond second line treatment is especially noteworthy. Still, randomized trials are warranted.

Prognostic value of monitoring tumour markers CA 15-3 and CEA during fulvestrant treatment.

BACKGROUND: At many centres tumour markers are used to detect disease recurrence and to monitor response to therapy in patients with advanced disease, although the real value of serial observation of marker levels remains disputed. In this study, we evaluated the prognostic value of tumour markers for predicting response (partial response [PR], stable disease [SD] > or = 6 months), de novo disease progression (PD) and secondary PD in patients receiving fulvestrant ('Faslodex') 250 mg/month for the treatment of metastatic breast cancer (MBC). METHODS: Changes in cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) were prospectively monitored (monthly) and were also evaluated for the 3 months preceding secondary PD. Data from 67 patients with previously treated MBC participating in a Compassionate Use Programme were analysed. RESULTS: In patients with a PR (n = 7 [10.4%]), a non-significant increase in CA 15-3 occurred during the first 6 months of treatment; CEA was significantly reduced (P = 0.0165). In patients with SD >/= 6 months (n = 28 [41.8%]), both CA 15-3 (P < 0.0001) and CEA (P = 0.0399) levels increased significantly after 6 months treatment. In those experiencing de novo PD (n = 32 [47.8%]), CA 15-3 increased significantly (P < 0.0001) after 4 months; CEA also increased significantly (P = 0.0002) during the same time period. Both CA 15-3 (P < 0.0001) and CEA (P < 0.0001) increased significantly in the 3 months preceding secondary PD. CONCLUSION: CA 15-3 increases in patients progressing on fulvestrant but may also increase in those experiencing clinical benefit; this should not be taken as a sign of PD without verification. Overall, both CA 15-3 and CEA appear to be poor prognostic markers for determining progression in patients receiving fulvestrant.

Oral vinorelbine alone or in combination with trastuzumab in advanced breast cancer: results from a pilot trial.

INTRODUCTION: We evaluated the efficacy of oral vinorelbine (OV) (Navelbine oral Boeringer-Ingelheim Austria) in patients with advanced breast cancer as first-line therapy or after progressing under earlier line chemotherapies alone or in combination with trastuzumab (T). PATIENTS AND METHODS: Seventy-eight patients [median age: 63.5 years (y), range (r): 38-84 years] were included into this trial. Patients with her-2/neu positive tumours received a combination of OV and T. Treatment effect was evaluated every three cycles and treatment continued until progression. OV was administered in a dose of 60 mg/m(2) on day 1 and 8, q = 21 days, and no dose escalation to 80 mg/m(2) was performed. RESULTS: We observed a complete response in 5.9% of patients, partial remission in 22.1%, stable disease (SD) > 6 months in 33.8%, SD < 6 months in 2.9%, and progression despite treatment in 35.3%, respectively. Time to progression was 6 months (range 1-23+). The main toxicities consisted of nausea/vomiting (N/V) and neutropenia. Grade IV neutropenia was found in 5 patients (6.4%), grade III in 6 patients (7.7%) and grade I and II in 11.5%. We did not find any grade IV N/V in our patients, however, grade III N/V was observed in 3.8%. No other grade III and IV toxicities were reported. CONCLUSION: OV appears to be effective in the treatment of advanced breast cancer at the dose and schedule chosen. It is well tolerated, effective, and the oral formulation is an advantage for the patients as well as for the nursing staff.

Single-dose pharmacokinetics of cefodizime in critically ill elderly patients.

Cefodizime is an extended-spectrum third-generation cephalosporin antibiotic that is widely used in the treatment of severe infections of the respiratory and urinary tracts. Pharmacokinetic characteristics of cefodizime were assessed in 13 critically ill elderly patients (median age 73+/-6 years). The mean cefodizime peak serum concentration following a single 2g cefodizime infusion was 219+/-58 mg/L and the mean trough level 12 h after infusion was 29+/-17 mg/L. The elimination half-life was 6.19+/-2.45 h. Total body clearance, area under the plasma concentration-time curve and volume of distribution were 35.8+/-13.2 mL/min, 1089.4+/-505.3 mg h/L and 17.4+/-6.3 L, respectively. Pharmacokinetics of cefodizime in critically ill elderly patients were comparable with those reported previously in healthy volunteers.

Influence of inhaled nitric oxide on plasma nitrate concentrations in patients with adult respiratory distress syndrome and sepsis: results of a pilot study.

STUDY OBJECTIVE: To measure plasma nitrate concentrations after inhalation of nitric oxide for treatment of adult respiratory distress syndrome (ARDS) and sepsis. DESIGN: Prospective pilot study. SETTING: Intensive care unit at a university-affiliated hospital. PATIENTS: Nine consecutive medical intensive care unit patients with ARDS and sepsis. INTERVENTIONS: After diagnosis of ARDS, all patients received a balloon-tipped triple-lumen thermodilution pulmonary artery catheter (Baxter Healthcare Corp, Irvine, CA). Inhaled nitric oxide was initiated starting at a dose of one part per million and titrated according to the maximal achievable increase in arterial oxygenation. Hemodynamic measurements including intrapulmonary shunt fraction and blood as analyses were performed before nitric oxide application, as well as 1 and 24 hours after starting nitric oxide, respectively. Plasma samples for determination of nitrate were taken from the arterial line and from the pulmonary thermodilution catheter and analyzed using high-performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: Eight of 9 patients were nitric oxide responders (intrapulmonary shunt decrease >5%). There was no statistically significant increase in nitrate plasma concentration measured both in peripheral arterial and in mixed venous blood with inhaled nitric oxide up to a concentration of 40 parts per million. CONCLUSION: Inhalation of nitric oxide in patients with ARDS and sepsis does not result in increased plasma nitrate concentrations.

Respiratory failure after stem cell transplantation: improved outcome with non-invasive ventilation.

We retrospectively analyzed the efficacy of non-invasive ventilation in 35 patients with acute hypoxemic respiratory failure after autologous or allogeneic stem cell transplantation (SCT). Non-invasive ventilation was delivered by a standard face mask or helmet. Decisions to intubate were made according to standard criteria. Between 1993 and 2003, 836 patients underwent an autologous or allogeneic bone marrow or SCT. Eighty-two patients developed respiratory failure. Of these, 47 patients were initially intubated and mechanically ventilated. None of these patients survived. Thirty-five patients initially underwent non-invasive ventilation at the bone marrow transplant unit. Seven of these patients survived and were discharged from the hospital (20%). Eleven of the 35 (31%) patients improved within the first 4 h of non-invasive ventilation with respect to oxygenation and were regarded as responders. Seven of these patients survived to hospital discharge (64%), while all non-responders died (P<0.001). In all survivors, the partial pressure of arterial oxygen (PaO2) improved after the initiation of non-invasive ventilation. In non-survivors, PaO2 improved in only 4 of 28 patients (17%) (P<0.0001). Non-invasive ventilation in patients with acute respiratory failure after SCT could improve prognosis in a carefully selected group of patients.

Preoperative second-line chemotherapy induces objective responses in primary breast cancer.

PURPOSE: Preoperative chemotherapy in patients with primary breast cancer results in high response rates, allowing breast-conserving surgery in patients primarily not suitable for this procedure. Tumors of patients with histologically proven breast cancer that fail to respond to preoperative chemotherapy are thought to be chemotherapy resistant. We questioned this hypothesis and treated 13 patients who did not respond to preoperative anthracycline-containing first-line treatment. PATIENTS AND METHODS: Eight patients received a combination therapy consisting of epidoxorubicin and docetaxel as neoadjuvant first-line treatment and were treated with CMF as preoperative second-line chemotherapy. The other five patients did not respond to first-line FEC and were given paclitaxel or docetaxel as second-line treatment. RESULTS: A major response to treatment was observed in 10 of 13 patients (77%) during preoperative second-line therapy: one patient (8%) achieved pathological complete response (pCR) and nine patients (69%) partial response (PR). Three patients (23%) had stable disease (SD), and no patient had progressive disease (PD). Eight patients (62%) could undergo breast-conserving surgery. CONCLUSIONS: We conclude that it is possible to achieve objective responses including pCR with potentially non-cross-resistant neoadjuvant second-line therapy, leading to breast-conserving surgery in a high proportion of patients. Thus, preoperative second-line chemotherapy appears to be justified when breast conservation is an important treatment goal and may have potential in improved tailoring of neoadjuvant treatments.

Sequential Administration of Interferon-gamma, GM-CSF, and Interleukin-2 in Patients With Metastatic Renal Cell Carcinoma: Results of a Phase II Trial.

SUMMARY: Various cytokine combinations have been tested for efficacy in the treatment of metastatic renal cell carcinoma (MRCC). Because several immunologic synergisms between granulocyte-macrophage colony-stimulating-factor (GM-CSF) and interleukin-2 (IL-2) have been demonstrated, this phase II trial was conducted on the efficacy and toxicity of subcutaneous, sequentially administered, interferon-gamma (IFNgamma), GM-CSF, and IL-2. Fifty-five consecutive patients with MRCC were treated with 100 &mgr;g recombinant IFNgamma1b administered thrice weekly during weeks 1 and 4, followed by 400 &mgr;g GM-CSF on 5 consecutive days during weeks 2 and 5. In weeks 3 and 6, patients received 4.5 MU recombinant IL-2 from days 1 to 4. The treatment was repeated every 8 weeks. Five (10%) of patients experienced an objective response (complete response [CR]: 2%, partial response [PR]: 8%). Fourteen (26%) patients had stable disease with a median duration of 19 months (6-47+). The median overall survival was 12 months (range: 0.3-44 months). No toxicity greater than World Health Organization grade II was observed, with fever (43%) and erythema (43%) being the most frequent side effects. Compared with other phase II trials with IFNgamma and IL-2 alone, the addition of GM-CSF failed to improve response or survival in patients with MRCC.

Capecitabine in the treatment of metastatic renal cell carcinoma failing immunotherapy.

Capecitabine is a novel fluoropyrimidine carbamate, orally administered and selectively activated to fluorouracil by a sequential triple-enzyme pathway in liver and tumor cells. This prospective trial aims to evaluate the therapeutic effects and systemic toxicities of capecitabine in patients with metastatic renal cell carcinoma in which immunotherapy failed. Twenty-six patients (median age, 58 years; range, 47 to 76 years) with disease in which first- or second-line immunotherapy treatment failed entered the trial. Median time of observation was 13+ months (range, 3 to 25+ months). Capecitabine was administered in the outpatient setting orally at a dose of 2,500 mg/m2/d divided into two daily doses for 14 days, followed by 7 days of rest. This schedule was repeated in 3-week intervals. Twenty-six patients are now assessable for toxicity, and 23 patients, for response. We observed a partial response to treatment in 2 patients (8.7%), minor response in 5 patients (21.7%), stable disease in 13 patients (56.5%), and continued disease progression despite treatment in only 3 patients (13.1%). Outpatient capecitabine therapy was well tolerated, and World Health Organization (WHO) grade III toxicity in these 26 patients consisted of hand-foot syndrome in 2 patients (7.7%) and anemia in 1 patient (3.8%). We did not observe WHO grade IV toxicity. Oral capecitabine appears to be a promising treatment with a favorable toxicity profile in patients with advanced renal cell carcinoma and should be evaluated in first- and second-line treatment schedules as monotherapy, as well as in combination with immunotherapy agents.