Key Issues in Hymenoptera Venom Allergy: An Update.

In this review, the Hymenoptera Allergy Committee of the SEAIC analyzes the most recent scientific literature addressing problems related to the diagnosis of hymenoptera allergy and to management of venom immunotherapy. Molecular diagnosis and molecular risk profiles are the key areas addressed. The appearance of new species of hymenoptera that are potentially allergenic in Spain and the associated diagnostic and therapeutic problems are also described. Finally, we analyze the issue of mast cell activation syndrome closely related to hymenoptera allergy, which has become a new diagnostic challenge for allergists given its high prevalence in patients with venom anaphylaxis.

Key issues in hymenoptera venom allergy: an update

In this review, the Hymenoptera Allergy Committee of the SEAIC analyzes the most recent scientific literature addressing problems related to the diagnosis of hymenoptera allergy and to management of venom immunotherapy. Molecular diagnosis and molecular risk profiles are the key areas addressed. The appearance of new species of hymenoptera that are potentially allergenic in Spain and the associated diagnostic and therapeutic problems are also described. Finally, we analyze the issue of mast cell activation syndrome closely related to hymenoptera allergy, which has become a new diagnostic challenge for allergists given its high prevalence in patients with venom anaphylaxis (AU)

En esta revisión el Comité de Alergia a Himenópteros de la SEAIC ha analizado la literatura científica más reciente sobre los principales problemas diagnósticos de la alergia a himenópteros, así como sobre las dificultades que pueden surgir durante la inmunoterapia con venenos. Se revisan especialmente las novedades relacionadas con el diagnóstico molecular y los perfiles moleculares de riesgo. También se describe la alergia a himenópteros poco habituales y los problemas diagnósticos y terapéuticos que esta conlleva. Por último, se tratan los síndromes de activación mastocitaria clonal, íntimamente relacionados con la alergia a himenópteros, que se han convertido en un nuevo reto diagnóstico para el alergólogo (AU)

Use of bevacizumab as a first-line treatment for metastatic breast cancer.

OBJECTIVE: During clinical practice, it can be challenging, given the lack of response biomarkers, to identify the patients with metastatic breast cancer (mbca) who would benefit most from the addition of bevacizumab to first-line standard chemotherapy. The aim of the present review was to summarize the relevant scientific evidence and to discuss the experience of a group of experts in using bevacizumab to treat mbca. METHODS: A panel of 17 Spanish oncology experts met to discuss the literature and their experience in the use of bevacizumab as first-line treatment for mbca. During the meeting, discussions focused on three main issues: the profile of the patients who could benefit most from bevacizumab, the optimal bevacizumab treatment duration, and the safety profile of bevacizumab. RESULTS: The subset of mbca patients who would benefit the most from the addition of bevacizumab to first-line standard chemotherapy are those with clinically defined aggressive disease. Treatment with bevacizumab should be maintained until disease progression or the appearance of unacceptable toxicity. In the mbca setting, the toxicity profile of bevacizumab is well known and can be managed in clinical practice after adequate training. CONCLUSIONS: This expert group recommends administering bevacizumab as first-line treatment in patients with clinically aggressive disease.

Randomized study of cefepime versus ceftazidime plus amikacin in patients with solid tumors treated with high dose chemotherapy (HDC) and peripheral blood stem cell support (PBSCS) with febrile neutropenia.

OBJECTIVE: This randomized clinical trial evaluated the efficacy and safety of monotherapy with cefepime for patients with solid tumors treated with high dose chemotherapy (HDC) and peripheral blood stem cell support (PBSCS) with febrile neutropenia. SUBJECTS: Patients with solid tumors treated with HDC and PBSCS, that developed fever and neutropenia (absolute neutrophil count < 500 cells/microL) were eligible, and randomly assigned to receive ceftazidime plus amikacin or cefepime. RESULTS: Fifty-one episodes were randomized, and all were evaluable (27 received ceftazidime plus amikacin arm, and 24 cefepime). Major efficacy endpoints did not show significant differences, with success rates of 44.4% and 54.2% (p = 0.481) for the combination arm and the monotherapy arm, respectively. The proportion of patients that became afebrile in the first 24 hours was significantly higher in the cefepime group (41.7% vs 11.1%, respectively; p = 0.012). However, due to its premature closure and small sample size, this study lacks the adequate power to definitely address this question. CONCLUSIONS: Cefepime monotherapy appeared to have an equivalent efficacy and safety as empiric treatment in febrile neutropenia episodes in a highrisk population compared with ceftazidime and amikacin. Nevertheless, this study is not adequately powered to answer this question. Given the small number of patients randomized and the single-center nature of this study, these results must be cautiously interpreted.

Randomized study of cefepime versus ceftazidime plus amikacin in patients with solid tumors treated with high dose chemotherapy (HDC) and peripheral blood stem cell support (PBSCS) with febrile neutropenia

OBJECTIVE: This randomized clinical trial evaluated the efficacy and safety of monotherapy with cefepime for patients with solid tumors treated with high dose chemotherapy (HDC) and peripheral blood stem cell support (PBSCS) with febrile neutropenia. SUBJECTS: Patients with solid tumors treated with HDC and PBSCS, that developed fever and neutropenia (absolute neutrophil count < 500 cells/microL) were eligible, and randomly assigned to receive ceftazidime plus amikacin or cefepime. RESULTS: Fifty-one episodes were randomized, and all were evaluable (27 received ceftazidime plus amikacin arm, and 24 cefepime). Major efficacy endpoints did not show significant differences, with success rates of 44.4% and 54.2% (p = 0.481) for the combination arm and the monotherapy arm, respectively. The proportion of patients that became afebrile in the first 24 hours was significantly higher in the cefepime group (41.7% vs 11.1%, respectively; p = 0.012). However, due to its premature closure and small sample size, this study lacks the adequate power to definitely address this question. CONCLUSIONS: Cefepime monotherapy appeared to have an equivalent efficacy and safety as empiric treatment in febrile neutropenia episodes in a highrisk population compared with ceftazidime and amikacin. Nevertheless, this study is not adequately powered to answer this question. Given the small number of patients randomized and the single-center nature of this study, these results must be cautiously interpreted (AU)

High-dose mitoxantrone and cyclophosphamide without stem cell support in patients with high-risk and advanced breast carcinoma: a Phase II multicentric trial.

BACKGROUND: Currently employed high-dose regimens for patients with breast carcinoma consist mainly of single-cycle combinations of alkylating agents. In a previous Phase I trial, the authors developed a tandem high-dose combination of two cycles of mitoxantrone and cyclophosphamide for the treatment of patients with metastatic breast carcinoma (MBC) and high-risk breast carcinoma (HRBC). Treatment was delivered with granulocyte-colony stimulating factor (G-CSF) but without stem cell support to avoid potential tumor cell reinfusion. The objective was to validate the safety and obtain preliminary efficacy assessment of this combination in a Phase II trial. METHODS: Fifty-three patients were included: 27 patients with MBC and 26 patients with HRBC. After standard induction treatment, patients received two cycles of mitoxantrone 25 mg/m2 and cyclophosphamide 4000 mg/m2 separated by a 4-week interval. Patients received G-CSF and ciprofloxacin until hematologic recovery. Follow-up was performed in an outpatient setting. RESULTS: One hundred one of 106 projected cycles (95%) were delivered. The mean dose intensities achieved were mitoxantrone 5.8 mg/m2 per week and cyclophosphamide 933 mg/m2 per week. Infection developed in 46% of the cycles, and platelet transfusions were required in 42%. Nonhematologic toxicity was mainly Grade 3 emesis. There were no toxic deaths. In 17 evaluable patients with MBC, 13 patients (77%) had response improvements, including 7 complete responses (41%). CONCLUSIONS: Treatment with two cycles of mitoxantrone 25 mg/m2 and cyclophosphamide 4000 mg/m2 with G-CSF but without stem cell support was well tolerated. The dose intensities achieved approach those obtained with conventional high-dose therapy. This combination warrants further investigation as an alternative to conventional high-dose regimens.

High-dose mitoxantrone and cyclophosphamide without stem cell support in high-risk and advanced solid tumors: a phase I trial.

This phase I study was designed to develop a high-dose combination of two cycles of mitoxantrone and cyclophosphamide in patients with solid tumors, as an alternative to single-cycle high-dose regimens that use only alkylating agents. Treatment was delivered with granulocyte colony-stimulating factor (G-CSF), but without stem cell support, in order to avoid potential tumor cell reinfusion. Thirty-one patients with advanced solid tumors received two cycles of high-dose mitoxantrone (20-30 mg/m2) plus high-dose cyclophosphamide (3000-4000 mg/m2). All patients received G-CSF until hematologic recovery. Dose-escalation was performed when less than 50% of cycles per level had dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) achieved was mitoxantrone 25 mg/m2 and cyclophosphamide 4000 mg/m2. Main dose-limiting toxicities (DLTs) were hematological: grade IV neutropenia lasting more than 7 days and thrombopenia below 20 x 10(9)/l requiring more than one platelet transfusion. Non-hematological DLT consisted predominantly of grade III emesis and asthenia. Follow-up after each cycle was performed in an outpatient setting and there were no toxic deaths. In conclusion, the administration of two cycles of high-dose mitoxantrone and cyclophosphamide with G-CSF support is safe and feasible. MTD was mitoxantrone 25 mg/m2 and cyclophosphamide 4000 mg/m2. Evaluation of this regimen is being done in a phase II trial.

Granulocyte colony-stimulating factor in the treatment of high-risk febrile neutropenia: a multicenter randomized trial.

BACKGROUND: Granulocyte colony-stimulating factors (G-CSFs) have been shown to help prevent febrile neutropenia in certain subgroups of cancer patients undergoing chemotherapy, but their role in treating febrile neutropenia is controversial. The purpose of our study was to evaluate-in a prospective multicenter randomized clinical trial-the efficacy of adding G-CSF to broad-spectrum antibiotic treatment of patients with solid tumors and high-risk febrile neutropenia. METHODS: A total of 210 patients with solid tumors treated with conventional-dose chemotherapy who presented with fever and grade IV neutropenia were considered to be eligible for the trial. They met at least one of the following high-risk criteria: profound neutropenia (absolute neutrophil count <100/mm(3)), short latency from previous chemotherapy cycle (<10 days), sepsis or clinically documented infection at presentation, severe comorbidity, performance status of 3-4 (Eastern Cooperative Oncology Group scale), or prior inpatient status. Eligible patients were randomly assigned to receive the antibiotics ceftazidime and amikacin, with or without G-CSF (5 microg/kg per day). The primary study end point was the duration of hospitalization. All P values were two-sided. RESULTS: Patients randomly assigned to receive G-CSF had a significantly shorter duration of grade IV neutropenia (median, 2 days versus 3 days; P = 0.0004), antibiotic therapy (median, 5 days versus 6 days; P = 0.013), and hospital stay (median, 5 days versus 7 days; P = 0.015) than patients in the control arm. The incidence of serious medical complications not present at the initial clinical evaluation was 10% in the G-CSF group and 17% in the control group (P = 0.12), including five deaths in each study arm. The median cost of hospital stay and the median overall cost per patient admission were reduced by 17% (P = 0.01) and by 11% (P = 0.07), respectively, in the G-CSF arm compared with the control arm. CONCLUSIONS: Adding G-CSF to antibiotic therapy shortens the duration of neutropenia, reduces the duration of antibiotic therapy and hospitalization, and decreases hospital costs in patients with high-risk febrile neutropenia.

Rifampin does not improve the efficacy of quinolone antibacterial prophylaxis in neutropenic cancer patients: results of a randomized clinical trial.

PURPOSE: To determine whether the addition of rifampin to a quinolone-based antibacterial prophylactic regimen in patients undergoing high-dose chemotherapy (HDC) with peripheral-blood stem-cell transplantation (PBSCT) decreases the incidence of neutropenia and fever, Gram-positive bacteremia, and infection-related morbidity. PATIENTS AND METHODS: Patients with solid tumors undergoing HDC with PBSCT were randomized to receive prophylactic antibiotics with either ciprofloxacin 500 mg orally every 8 hours or the same ciprofloxacin regimen with rifampin 300 mg orally every 12 hours. Prophylaxis was started 48 hours before stem-cell reinfusion. Patients were monitored to document the occurrence of neutropenia and fever, incidence and cause of bacterial infection, time to onset and duration of fever, requirement for intravenous antimicrobials, and length of hospital admission. RESULTS: Sixty-five patients were randomized to receive ciprofloxacin and 65 to receive ciprofloxacin plus rifampin, and from these groups, 62 and 61 were assessable, respectively. The proportion of patients who developed neutropenia and fever was 87% in the group treated with ciprofloxacin and 78% in the group treated with ciprofloxacin and rifampin (P =.25). Although there was a trend toward a reduction in the overall incidence of bacteremia (12 v 4 patients), and Gram-positive bacteremia (8 v 2 patients) with the addition of rifampin, none of these comparisons was statistically significant (P =.05 and P =.09, respectively). CONCLUSION: The results of this study, which demonstrate that rifampin does not improve ciprofloxacin antibacterial prophylaxis in cancer patients undergoing HDC with PBSCT support but that it does increase the occurrence of undesirable side effects, do not support the routine use of rifampin in this setting.

Incidence and clinical impact of fluoroquinolone-resistant Escherichia coli in the faecal flora of cancer patients treated with high dose chemotherapy and ciprofloxacin prophylaxis.

This study evaluated the susceptibility of Escherichia coli to quinolones in 72 stool samples collected from 31 patients with solid tumours who had undergone high dose chemotherapy (HDC) and peripheral blood stem-cell (PBSC) rescue with ciprofloxacin prophylaxis. Samples were obtained at admission, after completing prophylaxis and three months later. All E. coli strains isolated from baseline samples were susceptible to quinolones. Fluoroquinolone-resistant E. coli strains were isolated in 10 (32%) patients in the second sample. In eight of these patients isolates were susceptible 3 months later. No patient developed infection due to fluorquinolone-resistant E. coli. No differences were observed in outcome between patients with susceptible and resistant flora.

Favorable prognosis after late relapse of Hodgkin's disease.

BACKGROUND: Most relapses of Hodgkin's disease (HD) occur within the first 2 years after diagnosis, but they may develop after a longer observation period. The aim of this study was to define the incidence, clinical course, and prognostic factors for late relapse (LR) of Hodgkin's disease. For this purpose, the authors defined LR as relapse that occurred in patients who achieved a complete remission that lasted a minimum of 24 months. METHODS: During the years 1974-1994, 375 patients with newly diagnosed HD were treated at out institution. Of these patients, 223 remained free of disease for at least 2 years. In addition, 26 patients had been in complete remission for a minimum of 24 months after salvage treatment. Thus, 249 patients were identified as being at risk of LR, and they were the study subjects. The median age was 29 years. Fifty-nine percent of the patients had early stage disease (Stage I/II), and 48% underwent staging laparotomy. Ninety patients presented B symptoms at diagnosis, and 87 had bulky disease. Treatment consisted of radiotherapy for 68 patients, chemotherapy for 68, and combined modality therapy for 113. RESULTS: With a median follow-up of 125 months (range, 22-287 months), the authors observed LR in 25 patients (10%). The estimated relapse rate at 15 years was 13.4%. Relapse occurred after a median disease free interval of 45 months (range, 25-113 months), and it involved sites of previous disease in 70% of the patients. Age > 30 years and treatment with radiotherapy alone were the only significant independent predictors for an increased risk of LR. At a median of 79 months (range, 6-168 months) after therapy for LR, 20 patients were still alive and free of disease (1 of them after rescue treatment for second relapse), and 5 had died (3 of HD, 2 of second tumor). The estimated overall survival (OS) after LR was 82% at 8 years. OS was not significantly different for LR patients than for those who did not relapse. CONCLUSIONS: The actual incidence of LR emphasizes the need for continuous follow-up of patients treated for HD. LR, if properly managed with conventional therapy, does not compromise survival.