Cardiac safety of adjuvant pegylated liposomal doxorubicin with concurrent trastuzumab: a randomized phase II trial.

BACKGROUND: The cardiac safety of trastuzumab concurrent with pegylated liposomal doxorubicin (PLD) in an adjuvant breast cancer treatment regimen is unknown. PATIENTS AND METHODS: Women with resected node-positive or intermediate-risk node-negative HER2 overexpressing breast cancer and baseline left ventricular ejection fraction (LVEF)≥55% were randomized (1:2) to doxorubicin 60 mg/m2 (A)+cyclophosphamide 600 mg/m2 (C) every 21 days (q21d) for four cycles or PLD 35 mg/m2+C q21d+trastuzumab 2 mg/kg weekly (H) for 12 weeks. Both groups then received paclitaxel (Taxol, T) 80 mg/m2 with H for 12 weeks followed by H to complete 1 year. The primary end point was cardiac event rate or inability to administer 1 year of trastuzumab. RESULTS: Of 181 randomized patients, 179 underwent cardiac analysis. The incidence of cardiac toxicity or inability to administer trastuzumab due to cardiotoxicity was 18.6% [n=11; 95% confidence interval (CI) 9.7% to 30.9%] with A+C→T+H and 4.2% (n=5; 95% CI 1.4% to 9.5%) with PLD+C+H→T+H (P=0.0036). All events, except one, were asymptomatic systolic dysfunction or mildly symptomatic heart failure. Mean absolute LVEF reduction at cycle 8 was greater with doxorubicin (5.6% versus 2.1%; P=0.0014). CONCLUSION: PLD+C+H→T+H is feasible and results in lower early cardiotoxicity rates compared with A+C→T+H.

Whipple's disease: easily diagnosed, if considered.

Patients present with arthralgia, abdominal pain, diarrhoea and weight loss. The disease is commonly diagnosed by histological examination of small bowel biopsies, especially after staining with periodic acid-Schiff. Because of the rarity of the disease, its diagnosis is not often considered. Therefore the necessary investigations might be omitted. This case report might serve as a reminder for internists or gastroenterologists to consider Whipple's disease in patients with abdominal, articular or other symptoms after having excluded common differentials. We also review the current literature on Whipple's disease. Whipple's disease is an infectious disorder caused by Tropheryma whipplei.

Anthracycline-trastuzumab regimens for HER2/neu-overexpressing breast cancer: current experience and future strategies.

Anthracycline-trastuzumab-containing regimens demonstrate significant clinical activity in human epidermal growth factor receptor 2 (HER2)-positive breast cancer; however, the utility of this strategy is limited by unacceptably high rates of significant cardiotoxicity, particularly with concurrent administration. Anthracycline-induced cardiotoxicity is thought to be mediated primarily through increased myocardial oxidative stress, modified partly by the activity of neuregulins. Trastuzumab-induced cardiotoxicity is thought to be mediated by the ErbB/neuregulin system, with exposure to trastuzumab partly blocking the protective effect of neuregulins on the myocardium. As a result, trastuzumab increases the risk of anthracycline-induced cardiotoxicity. Several strategies have been adopted in attempts to minimize cardiotoxicity, including patient selection on the basis of preexisting cardiac risk, monitoring of cardiac function during treatment, and early management of cardiac dysfunction. The use of less cardiotoxic anthracyclines may be one strategy to lessen the risk of cardiotoxicity. Liposomal doxorubicin products offer similar efficacy compared with conventional doxorubicin, with significantly less cardiotoxicity, and have been successfully used in combination with trastuzumab in the metastatic and neo-adjuvant setting. Clinical trials are currently underway to assess the safety of pegylated liposomal doxorubicin during concurrent administration with trastuzumab compared with standard sequential treatment using conventional doxorubicin in the adjuvant setting.

The red cell revisited--matters of life and death.

An erythrocyte-fractionating method combining volume and subsequent density separation is described. Iron isotope (59Fe)-validation proved this combination of methods to be complementary. By deploying HbA1c as cell age marker, obtained fractions demonstrated that circulating erythrocytes lose 20% of hemoglobin and membrane by shedding vesicles. Vesiculation from older cells proved to be facilitated by the spleen. Animal studies revealed that such vesicles are rapidly removed from the circulation by scavenger receptors on Kupffer cells with phosphatidylserine acting as the principal ligand. These studies reveal the existence of an alternative pathway of erythrocyte breakdown. This means that the premortal substrate of 20% of any erythrocyte is at our disposal. As this kind of vesiculation takes place during the entire erythrocyte lifespan, loss and sometimes reutilisation of marker substances limits the usefulness of isotope studies to the first half of the erythrocyte lifespan, thereby putting the dogmatic lifespan of 120 days into question. Furthermore, these studies add to the understanding of hemoglobin A1c (HbA1c) metabolism and the origin of the wide variation of erythrocyte parameters in peripheral blood. Removal of old erythrocytes from the circulation and from donor blood may open new ways into the treatment of both bilirubin and secondary iron overload.

Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron.

BACKGROUND: Although all first-generation 5-HT(3) receptor antagonists demonstrate efficacy in preventing acute chemotherapy-induced nausea and vomiting (CINV), effective prevention of delayed CINV has not yet been achieved. This study compared the efficacy and tolerability of palonosetron, a novel, second-generation 5-HT(3) receptor antagonist, with ondansetron. PATIENTS AND METHODS: In this multicenter, randomized, double-blind, stratified, phase III study, 570 adult cancer patients were randomized to receive a single i.v. dose of palonosetron 0.25 mg, palonosetron 0.75 mg or ondansetron 32 mg, each administered 30 min before initiation of moderately emetogenic chemotherapy. The primary end point was the proportion of patients with no emetic episodes and no rescue medication [complete response (CR)] during the 24 h after chemotherapy administration (acute period). Secondary end points included efficacy in treatment of delayed CINV (

Serious allergic reaction to administration of epirubicin.

A 47-year old woman was admitted for adjuvant treatment with chemotherapy consisting of epirubicin and cyclophosphamide. During the second course of chemotherapy an allergic reaction occurred after administration of epirubicin. Treatment with clemastine 2 mg iv caused a quick recovery and after 24 hours there was only a slight redness of the face. A discussion follows on allergic reactions to antracyclines and the literature is updated.

An exploratory study into the effect of group psychotherapy on cardiovascular and immunoreactivity to acute stress in breast cancer patients.

BACKGROUND: : Previous studies of cancer patients investigated the effect of psychological treatment on basal endocrine and immune values. Using a randomized experiment, we explored the effect of a 13-week experiential-existential group psychotherapy (EEGP) program on the reactivity to a speech task in breast cancer patients. We explored whether changes in cardiovascular and immune reactivity to a speech task over the 3-month period correlated with changes in psychological distress and emotional expression. METHODS: Patients who had been treated for early-stage breast cancer and who were diagnosed as having either positive axillary lymph nodes or distant metastases were randomly assigned to either EEGP or a waiting list control (WLC) condition. We continuously recorded heart rate (HR), diastolic (DBP) and systolic blood pressure (SBP) in response to the speech task before and after treatment. We also measured lymphocyte proliferation to pokeweed (PWM) and phytohemagglutinin (PHA), and natural killer cell activity (NKCA) as well as peripheral blood lymphocyte distributions in blood samples that were drawn before, during and after the speech task. RESULTS: Patients in EEGP had smaller increases in natural killer (NK) cells induced by the speech task after treatment versus task-induced values observed at study entry and greater than pre-/posttreatment changes seen in patients randomized to the WLC. A similar pattern emerged with respect to NKCA over the intervention period, which was independent of the changes in NK cells. There were no differences between patients assigned to EEGP and WLC in HR, DBP and SBP responses as well as in changes in PWM- and PHA-induced lymphocyte proliferation in response to the speech task measured before and after the 3-month intervention period. Individual differences in pre-/posttreatment increases in emotional expression but not in psychological distress were significantly associated with smaller changes in the number and function of NK cells over the 3-month period. CONCLUSIONS: These findings may indicate that emotional expression during EEGP may render breast cancer patients more comfortable expressing their emotional responses to the speech challenge, which, in turn, results in smaller stress-induced changes in NK cells and function.

Phase II study of edatrexate in chemotherapy-naive patients with metastatic breast cancer.

A phase II trial of the new antifolate edatrexate (10-ethyl-10-deaza-aminopterin) was performed in thirty-eight patients with metastatic breast cancer who had never received chemotherapy. Edatrexate was administered as a weekly intravenous bolus injection at a dose of 80 mg/m2. Sites of metastases included visceral (31%), soft tissue/lymph node/bone (51%), and bone only (18%). Thirty-two patients were evaluable for response; there were 3 complete responses (CR) and 8 partial responses (PR), yielding a response rate (CR plus PR) of 34% (95% confidence limits, 17.9% to 50.9%). Responses were seen in soft tissue metastases, in visceral metastases (liver, lung) and in one patient with bone metastases. Median duration of response was 30 weeks (range 12-66 weeks). Substantial toxicity was observed. The dose-limiting toxicities were mucositis, myelo-suppression and skin toxicity. The general toxicity profile was similar to that usually reported for methotrexate, but mucositis and skin toxicity were more pronounced. Edatrexate appears to be an active drug in the treatment of chemotherapy-native patients with metastatic breast cancer.

Once-daily dosing regimen for aminoglycoside plus beta-lactam combination therapy of serious bacterial infections: comparative trial with netilmicin plus ceftriaxone.

PURPOSE: Once-daily dosing of aminoglycosides has been suggested to improve their efficacy and reduce their toxicity. To test the clinical validity of this suggestion, we conducted a prospective, randomized trial comparing a conventional multiple-daily-dosing regimen of netilmicin with once-daily administration of the same total daily dose of this aminoglycoside. PATIENTS AND METHODS: We enrolled 141 predominantly elderly patients with severe bacterial infections. All patients received once-daily doses of 2 g ceftriaxone, in addition to netilmicin. RESULTS: Patients randomized to either of the two dosing strategies were comparable regarding age, APACHE II score, concomitant diseases, infection site, and rate of culture-proven bacteremia. Netilmicin treatment did not differ significantly in mean daily dose per kg body weight and days of therapy between the two treatment arms. Compared to patients receiving conventional doses, patients treated with a once-daily dose had higher serum peak netilmicin levels and lower trough levels. Outcome of infection and mortality were not influenced by dosing strategy. Although the overall incidence of nephrotoxicity was similar in both groups (16%), the occurrence of nephrotoxicity in patients treated with once-daily doses of netilmicin was significantly shifted to those given prolonged treatment, i.e., beyond 9 days. Auditory toxicity was documented in one patient treated with conventional doses and two patients treated with once-daily doses. CONCLUSION: Once-daily dosing of an aminoglycoside plus a long-acting cephalosporin in these patients constituted cost-effective and safe treatment for severe bacterial infections. Netilmicin-induced toxicity may be reduced by using once-daily dosing regimens and limiting the duration of treatment.

Mitoxantrone, methotrexate, and 5-fluorouracil (MMF) in hormone-refractory advanced breast cancer.

Thirty-nine patients with metastatic breast cancer who had not received prior chemotherapy for metastatic disease were treated in a phase II trial with a combination of mitoxantrone (10 mg/m2), methotrexate (40 mg/m2) and 5-fluorouracil (600 mg/m2) i.v. every 3 weeks (MMF). Thirty-three patients could be evaluated with regard to response and toxicity. Objective response was observed in 33% (3/33 complete responses, 8/33 partial responses). Dominant sites of disease were bone (16 patients), liver (7 patients), skin/lymph node (7 patients), lung (1 patient) and breast (2 patients). Responses occurred in bone (4/16), liver (3/7) and skin/lymph node (4/7). Moderate to severe alopecia (grade 3-4 WHO criteria) occurred in 3/33 (10%) patients; moderate to severe nausea and vomiting in 2/33 (6%) patients. Haematological toxicity consisted of predominantly leukopenia. Leukopenia grade 3-4 (nadir below 2000 x 10(9)/litre) occurred in 22/33 (67%) patients; thrombocytopenia grade 3-4 (nadir below 50,000 X 10(9)/litre) occurred in 3 patients (9%). The MMF regimen appears to be effective. The non-haematological toxicity compares favourably with that of the more commonly used chemotherapy regimens, but the anti-tumour activity may be less.

Glycolytic activity in human red cell populations separated by a combination of density and counterflow centrifugation. Evidence for an improved separation of red cells according to age.

Human red blood cells were separated by a discontinuous Percoll density gradient into fractions of increasing density. Red cells comprising the lowest and highest density fractions, respectively, were subsequently separated according to mean cell volume (MCV) by means of counterflow centrifugation. The activities of 4 red cell age-dependent enzymes (hexokinase (HK), pyruvate kinase (PK), glucose-6-phosphate dehydrogenase (G6PD) and aspartate aminotransferase (ASAT) were highest in the red cell fraction with low density/large MCV, although the difference from red cell enzyme activities in the total low density fraction was not significant. These 4 enzyme activities were lowest in the fraction of red cells with high density/small MCV. The relative activities of the enzymes in the high density/small MCV fraction, as compared to the unseparated cell population, were: HK (58%), PK (49%), G6PD (53%) and ASAT (28%). These activities were all significantly lower than those measured in the total high density red cell fraction. The rates of lactate production in the low density/large MCV cells (0.89 +/- 0.15 mumol X min-1 X 10(-11) cells) is approximately 3-fold higher than in high density/small MCV cells (0.33 +/- 0.03 mumol X min-1 X 10(-11) cells). This latter value is 1.8-fold lower than the rate of lactate production in the total high density red cell fraction (0.59 +/- 0.14 mumol X min-1 X 10(-11) cells) and is, in contrast to lactate production in other density/size fractions, insensitive to phosphate as a metabolic stimulus. It is argued that the combination of density gradient and counter-flow centrifugation offers a greater potential for obtaining an old red cell population than classical red cell density centrifugation alone.

Counterflow centrifugation of red cell populations: a cell age related separation technique.

Red cell populations were fractionated on the basis of differences in density by a centrifugation method described by Murphy and on the basis of differences in mean cell volume (MCV) by counterflow centrifugation. By 59Fe-incorporation and determination of the HbA1c content, both methods were studied for their ability to separate red cell populations into fractions of different mean cell age. It can be concluded that separation on the basis of differences in cell volume results in a linear separation according to age whereas separation on the basis of density only results in an accumulation of very young cells in the top fractions. A gradual decrease in cell volume with age, combined with a constant haemoglobin concentration in the cells, indicates release of haemoglobin from the red cells during their lifespan.

Membrane characteristics and osmotic fragility of red cells, fractionated with anglehead centrifugation and counterflow centrifugation.

Red cell populations were separated on the basis of differences in density using anglehead centrifugation and on the basis of differences in mean cell volume using counterflow centrifugation. In the different fractions, mean surface area was calculated, phospholipid and cholesterol content determined as well as the osmotic behaviour in hypotonic salt solutions. Older red cells appeared to be more resistant to hypotonic salt solutions, due to favourable surface area to volume ratio.

Phase II trial of 5-fluorouracil, adriamycin and cisplatin (FAP) in advanced gastric cancer.

Twenty patients (15 male, 5 female) with nonresectable gastric adenocarcinoma were treated with FAP (5-fluorouracil 300 mg/m2 IV on days 1-5, adriamycin 50 mg/m2 IV on day 1, cisplatin 20 mg/m2 IV on days 1-5). Each course was repeated every 21 days. Eighteen patients were evaluable for response. The median age was 51 years, the range extending from 34 to 68. None had undergone chemotherapy. The median Karnofsky performance score was 80%. Nine (50%) partial responses (PR) and eight (44%) cases of stable disease (SD) were observed. One patient showed progression of the disease and died after 6 months. The median duration of response was 6+ months for PR and 6 months for SD. The median survival was 12 months. FAP toxicity was moderate, with the median WBC nadir 3.2 X 10(9)/l (range 0.7-4.2). One patient in PR died of septicemia. Nausea and vomiting were not dose-limiting. Neuropathy was mild in four and moderate in two patients. This FAP combination appears to be as effective with respect to response rate and duration as reported for 5-fluorouracil, adriamycin and mitomycin C (FAM).