Bi-weekly docetaxel and gemcitabine regimen in her-2-negative and anthracycline-pretreated metastatic breast cancer patients: a multicenter phase II trial.

PURPOSE: Bi-weekly gemcitabine (G) in combination with docetaxel (D) is an effective treatment for metastatic breast cancer (MBC) previously treated with adjuvant/neoadjuvant anthracyclines containing regimens with a good toxicity profile. In the present phase II study, we investigated the activity of the same regimen as first-line treatment. METHODS: Women with breast cancer pretreated in adjuvant/neoadjuvant setting with anthracyclines received bi-weekly G (1,250 mg/m² days 1, 15) and D (50 mg/m² days 1, 15) every 28 days with restaging after 3 and 6 cycles. RESULTS: Overall 42 patients were enrolled. Median age is 48 years (range, 31-71 years). Eight patients (19%) achieved complete responses, 18 (43%) partial responses for an overall response rate (ORR) of 62%; five patients (12%) obtained stable disease (SD), and 8 (19%) patients had progressive disease (PD). After a median 17-month follow-up, the median time to disease progression was 12 months (95% CI, 3-26 months) and the median survival time was 27 months (95% CI, 4-57 months). No grade 4 toxicity was seen except in one patient who developed a grade 4 neutropenia. Grade 3 toxicities were leukopenia (2%), neutropenia (14%), anemia (2%), nausea and vomiting (2%), diarrhea (2%), asthenia (2%), and skin toxicity (12%). CONCLUSION: The GD bi-weekly regimen is well tolerated and active as first line in anthracyclines-pretreated women with MBC. It appears as an interesting alternative compared to a 3-week schedule whenever hematological toxicity is the main clinical concern.

Preliminary results of phase II study of capecitabine and gemcitabine (CAP-GEM) in patients with metastatic pretreated thymic epithelial tumors (TETs).

BACKGROUND: No previous prospective trials have been reported with capecitabine and gemcitabine (CAP-GEM) in patients with metastatic thymic epithelial tumors (TETs). We conducted a multicenter study to determine the activity and tolerability of this regimen in pretreated TETs. PATIENTS AND METHODS: A total of 15 patients were enrolled in the first stage of phase II study. All patients received CAP-GEM every 3 weeks. The primary end point was objective response rate (RR); secondary end points were toxicity, progression-free survival (PFS) and overall survival. RESULTS: Complete responses (CR) and partial responses were observed in three (20%) and three (20%) patients for a 40% RR, respectively. Grade 1-2 neutropenia, anemia and thrombocytopenia were the most common side-effects, noted in seven (46.7%), five (33.3%) and five (33.3%) patients, respectively. The most common grade 3 toxicity was neutropenia in three patients (20%). Median PFS was 11 months (95% confidence interval 4-17). The 1- and 2-year survival rates were 80% and 67%, respectively. CONCLUSION: We have decided to publish the preliminary results because this regimen was more active than that expected. Although our results are preliminary, CAP-GEM shows activity and safety in pretreated TETs. Furthermore, multicenter trials, also in first-line setting, are necessary to confirm our results.

Maintenance therapy with gefitinib after first-line chemotherapy in patients affected by advanced non-small cell lung cancer.

BACKGROUND: Chemotherapy extends life for patients with advanced non-small cell lung cancer (NSCLC). Second-line treatment of NSCLC includes the use of cytotoxic drugs; however, toxicity is of concern. One molecular target for lung cancer is the epidermal growth factor receptor (EGFR). Gefitinib (Iressa) is an EGFR inhibitor. The aim of our study was to evaluate time to progression (TTP), overall survival (OS) and toxicities in a population affected by NSCLC using Iressa as maintenance therapy after first-line chemotherapy. PATIENTS AND METHODS: Thirty patients were enrolled with stable disease or partial response. Six cycles of a platinum-based first-line chemotherapy were administered. Iressa was administered at the dose of 250 mg/d. RESULTS: Median TTP was 5 months; median overall survival was 8 months. TTP for adenocarcinoma and non-adenocarcinoma patients was 10 months and 3.2 months, respectively. No toxic effects were seen in 80% of the patients; 17% of the patients had grade 1 follicolitis. OS for adenocarcinoma and non-adenocarcinoma patients were 15 and 5.9 months, respectively. CONCLUSION: Gefitinib could be an ideal second-line therapy for adenocarcinoma patients responding to first-line chemotherapy.

Effect of chemotherapy on somatostatin receptor detection with octreotide scintigraphy in hormone-refractory prostate cancer patients.

BACKGROUND: Neuroendocrine cells have been found in all stages of prostate cancer. Neuroendocrine differentiation of prostate adenocarcinoma is a possible target for therapeutic strategies, such as administration of GH analogs (e.g., somatostatin), especially in patients with hormone-refractory prostate cancer (HRPC). The presence of receptors for these drugs in tumor cells and tissues is essential and is assessed with 111In-octreotide scintigraphy (Octreoscan). The relationship between these receptors and chemotherapy, the new standard therapy for HRPC, is unknown. PATIENTS AND METHODS: 111In-octreotide scintigraphy was performed on 20 patients affected by HRPC, all with metastatic disease. Chemotherapy with a single agent was also administered to all patients. RESULTS: In 63% of the patients, all metastases were negative to Octreoscan. Several metastases were positive in 37% of patients only, compared to 94% previously described in a chemotherapy-naive population. CONCLUSION: Chemotherapy seemed to reduce the cellular receptors for somatostatin analogs.

Concurrent radio-chemotherapy with docetaxel and cisplatinum in inoperable or relapsed head and neck cancer.

Usually head and neck cancer is treated with combined therapy, applying surgery, if possible, and then radiotherapy and chemotherapy in a sequential or concomitant way. Sequential approach seems to be preferred, because of the high toxicity rate of concomitant therapy. Platinum compounds and 5-fluorouracil are the standard drugs, but new drugs are entering therapeutic arena: gemcitabine and taxanes are the most promising ones. The efficacy of these drugs, especially in association with radiotherapy, must be assessed; moreover it is essential to ascertain how to associate these drugs to radiotherapy and to evaluate drug toxicity when combined with the latter. End point of the study here presented is a preliminar assessment of toxicity and feasibility of concurrent radio-chemoterapy with docetaxel and cisplatinum in patients with head and neck cancer. The number of enrolled patients and the relatively short time of follow up do not allow to evaluate treatment efficacy.

Intramuscular depot medroxyprogesterone versus oral megestrol for the control of postmenopausal hot flashes in breast cancer patients: a randomized study.

BACKGROUND: Hot flashes are frequent in postmenopausal breast cancer patients, especially when treated with tamoxifen. Estrogen replacement therapy is the most effective treatment for hot flashes, but its use is controversial in breast cancer survivors. Progestins may offer a good alternative for the control of hot flashes in this setting; in particular, oral megestrol acetate has been proven effective in a randomized, placebo-controlled clinical trial. With the aim of further improving these results, we have designed a randomized study comparing oral megestrol acetate with depot intramuscular (i.m.) medroxyprogesterone acetate (MPA) for the control of hot flashes in postmenopausal patients with a history of breast cancer. PATIENTS AND METHODS: Seventy-one postmenopausal patients were randomized to receive an i.m. injection of depot MPA 500 mg on days 1, 14 and 28, or oral megestrol acetate 40 mg daily for 6 weeks. Patients recorded daily the number and severity of their hot flashes; response was defined as a > or =50% decrease in the number and severity of hot flashes. RESULTS: At week 6, hot flashes were reduced by 86% on average in the whole group of patients, without significant differences between the two progestins. Response was obtained by 75 and 67% of patients receiving MPA or megestrol, respectively (P = 0.5). Responders were followed to assess maintenance of response (without further treatment), which was significantly better with i.m. MPA: in this group, 89% of responders still showed a benefit at week 24, compared with 45% in the megestrol group (P = 0.03). CONCLUSIONS: Our study shows that a short cycle of i.m. depot MPA injections provides significant and long-lasting relief from postmenopausal hot flashes in patients with a history of breast cancer, offering an alternative to estrogen replacement therapy or prolonged administration of oral megestrol.

Phase I, dose-finding study of capecitabine in combination with docetaxel and epirubicin as first-line chemotherapy for advanced breast cancer.

PURPOSE: Capecitabine is an oral fluoropyrimidine with considerable activity and minimal myelosuppression and alopecia. This phase I study evaluated the addition of capecitabine to epirubicin/docetaxel combination therapy as first-line treatment for advanced breast cancer. PATIENTS AND METHODS: Twenty-three female patients with advanced breast cancer received capecitabine (765-1060 mg/m2 twice daily on days 1-14 of a 3-week treatment cycle) in combination with epirubicin and docetaxel (75 mg/m2 i.v. on day 1). RESULTS: The maximum tolerated dose of capecitabine was 985 mg/m2 and the principal dose-limiting toxicity was febrile neutropenia. No grade 3/4 anemia or thrombocytopenia occurred. There were no grade 4 non-hematological events and grade 3 events other than alopecia were rare. Alopecia occurred in all patients and treatment cycles, and asthenia occurred in all patients and in 84% of treatment cycles. Other frequent adverse events included nausea, vomiting, fever, paresthesia and elevated transaminase levels. An objective response to treatment was observed in 91% (95% confidence interval 72% to 99%) of patients. CONCLUSIONS: The addition of capecitabine to docetaxel/epirubicin combination therapy provides a well-tolerated and active first-line chemotherapy regimen in patients with advanced breast cancer, and merits phase II/III evaluation.

Impact of two different dose-intensity chemotherapy regimens on psychological distress in early breast cancer patients.

In order to improve outcome, new, often more toxic chemotherapy regimens are continuously investigated in early breast cancer patients. Because the expected survival improvement is small, the possible increase in the negative effects of the new treatments should be carefully evaluated. Negative effects are represented not only by acute and chronic toxicity, but also by the adverse psychological impact of chemotherapy. The aim of this study was to evaluate the effect on patient-reported psychological distress of an increase in the dose-intensity of adjuvant chemotherapy compared with a standard regimen. Psychological distress was evaluated at baseline, during chemotherapy and after 6 and 12 months in breast cancer patients enrolled in a phase III multicentre study comparing the standard adjuvant chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil every 21 days (CEF21) with the same chemotherapy given every 14 days (CEF14). 392 patients were randomised in participating centres, and 363 were evaluable for this study. Overall, 1095 out of 1446 expected questionnaires (75.7%) were collected and evaluable. At baseline, the mean scores of psychological distress were similar in the two arms. During chemotherapy, a significantly higher psychological distress was observed in the CEF14 compared with the CEF21 arm (32.3 +/- 1.3 versus 27.6 +/- 1.3; P=0.009), as well as a higher cumulative incidence of anaemia, mucositis, diarrhoea, alopecia, bone pain and fatigue was observed in the CEF14 arm. In multivariate analyses, mucositis (P=0.01), asthenia (P=0.059), and CEF14 treatment (P=0.054) were independently associated with a higher psychological distress. After 6 months, psychological distress was again similar in the two arms and significantly lower when compared with baseline within each arm. A dose-intensive adjuvant regimen induces a higher, although transient, psychological distress in early breast cancer patients. Final results of the randomised trial will indicate whether such higher adverse effects of the dose-intensive regimen are counterbalanced by a higher efficacy of the experimental treatment in terms of survival.

Identification of the highest dose of docetaxel associable with active doses of epirubicin. Results from a dose-finding study in advanced breast cancer patients.

PURPOSE: To determine the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of docetaxel in combination with fixed doses of epirubicin. PATIENTS AND METHODS: Women with locally advanced or metastatic breast cancer were given docetaxel, 60 mg/m2 in escalated doses by steps of 10 mg/m2, in association with two fixed doses of epirubicin (90 mg/m2, and 75 mg/m2). Since neutropenia was foreseen to be the most likely DLT, a third group with prophylactic G-CSF support was planned to define the MTD of docetaxel with 90 mg/m2 of epirubicin. Selected patients underwent pharmacokinetic evaluation of docetaxel. RESULTS: Fifty-eight patients entered the study. At the first step (90 mg/m2 of epirubicin) the MTD was obtained at 60 mg/m2 of docetaxel. At the second step (75 mg/m2 of epirubicin) the MTD of docetaxel was 80 mg/m2. At the third step (epirubicin 90 mg/m2) G-CSF allowed a safe escalation of docetaxel up to 90 mg/m2. Neutropenia was the most common hematological adverse event. Without G-CSF, grade 4 neutropenia occurred in 69% of cycles, of which 11% was complicated by fever. In G-CSF group, grade 4 neutropenia and neutropenic fever occurred in 31% and 3%, respectively. Most frequent non-hematological adverse effects were asthenia (45%), nausea (39%) and mucositis (36%). No patient developed congestive heart failure. Two toxic deaths occurred. Overall response rate was 73% in 42 out of 58 patients, with no apparent epirubicin dose-related effect. No statistically significant effect of the two doses of epirubicin was observed in docetaxel pharmacokinetics. CONCLUSIONS: On the basis of the toxicity profile, the docetaxel pharmacokinetics and the response rate observed, epirubicin 75 mg/m2 combined with docetaxel 80 mg/m2 can be recommended for further studies.

Intensified chemotherapy supported by DMSO-free peripheral blood progenitor cells in breast cancer patients.

BACKGROUND: The majority of high-dose chemotherapy (HDC)-related complications results from bone marrow aplasia, but the graft infusion per se may cause adverse reactions due to the injection of both dimethyl sulfoxide (DMSO) and cell lysis products. We evaluated the feasibility of a two-step chemotherapy regimen with peripheral blood progenitor cell (PBPC) support in association with a novel procedure to remove DMSO and products of cell lysis from the cryopreserved cells. PATIENTS AND METHODS: Stage III and IV breast cancer patients received induction chemotherapy with three cycles of CEF (cyclophosphamide 600 mg/m2, epirubicin 100 mg/m2, 5-fluorouracil 600 mg/m2) followed by three cycles of HDC consisting of escalating doses of cyclophosphamide (dose range 1200 3000 mg/m2) and carboplatin (dose range 600-1000 mg/m2), supported by DMSO-free PBPC reinfusion. DMSO was removed by a washing/enzymatic digestion procedure. RESULTS: Twenty patients received induction chemotherapy and eighteen completed the entire chemotherapy program; a total of fifty-four cycles of HDC were administered. Dose limiting toxicity of HDC was long-lasting grade 4 neutropenia associated with documented infection. The maximum tolerated dose (MTD) was cyclophosphamide 3000 mg/m2 and carboplatin 600 mg/m2. No side effects related to PBPC reinfusion were observed. CONCLUSIONS: The proposed two-step chemotherapy regimen, associated with a novel washing/enzymatic digestion procedure, is feasible in advanced breast cancer patients in the absence of complications related to the specific toxicity of PBPC reinfusion.

Accelerated-intensified cyclophosphamide, epirubicin, and fluorouracil (CEF) compared with standard CEF in metastatic breast cancer patients: results of a multicenter, randomized phase III study of the Italian Gruppo Oncologico Nord-Ouest-Mammella Inter Gruppo Group.

PURPOSE: To evaluate whether an accelerated-intensified cyclophosphamide, epirubicin, and fluorouracil (CEF) chemotherapy regimen with the support of granulocyte colony-stimulating factor (G-CSF) induces a higher activity and efficacy compared with standard CEF in metastatic breast cancer patients. PATIENTS AND METHODS: Stage IV breast cancer patients were randomized to receive as first-line chemotherapy either standard CEF (cyclophosphamide 600 mg/m(2), epirubicin 60 mg/m(2), and fluorouracil 600 mg/m(2)) administered every 21 days (CEF21) or accelerated-intensified CEF (cyclophosphamide 1,000 mg/m(2), epirubicin 80 mg/m(2), and fluorouracil 600 mg/m(2)) administered every 14 days (HD-CEF14) with the support of G-CSF. Treatment was administered for eight cycles. RESULTS: A total of 151 patients were randomized (74 patients on the CEF21 arm and 77 on the HD-CEF14 arm). In both arms, the median number of administered cycles was eight. The dose-intensity actually administered was 93% and 86% of that planned, in CEF21- and HD-CEF14-treated patients, respectively. Compared with the CEF21 arm, the dose-intensity increase in the HD-CEF14 arm was 80%. Both nonhematologic and hematologic toxicities were higher in the HD-CEF14 arm than in the CEF21 arm. During chemotherapy, four deaths occurred in the HD-CEF14 arm. No difference in overall response rate (complete plus partial responses) was observed: 49% and 51% in the CEF21 and HD-CEF14 arms, respectively (P =.94). A slightly non-statistically significant higher percentage of complete response was observed in the HD-CEF14 arm (20% v 15%). No difference in efficacy was observed. The median time to progression was 14.3 and 12.8 months in the CEF21 and HD-CEF14 arms, respectively (P =.69). Median overall survival was 32.7 and 27.2 months in the CEF21 and HD-CEF14 arms, respectively (P =.16). CONCLUSION: In metastatic breast cancer patients, an 80% increase in dose-intensity of the CEF regimen, obtained by both acceleration and dose intensification, does not improve the activity and the efficacy compared with a standard dose-intensity CEF regimen.

Toremifene as a substitute for adjuvant tamoxifen in breast cancer patients.

BACKGROUND: Toremifene is a new antiestrogen, which in nonclinical studies appears less carcinogenic than tamoxifen. Clinical trials of adjuvant toremifene vs. tamoxifen in breast cancer patients are ongoing. This study aimed to evaluate the short-term effects of changing from adjuvant tamoxifen to toremifene. PATIENTS AND METHODS: Twenty postmenopausal breast cancer patients receiving adjuvant tamoxifen, 20 mg/day, were switched to toremifene 60 mg/day. The effects on the uterus were evaluated prospectively by transvaginal ultrasound; tolerability was assessed clinically. RESULTS: In 14 patients who had uterine abnormalities (endometrial thickening or polyps) under tamoxifen, no significant changes occurred during a median of 18 months (range 7-24) of toremifene treatment. Out of six patients who had entered the study due to intolerance to tamoxifen, however, 3 tolerated toremifene well. CONCLUSION: Toremifene does not modify previous uterine changes induced by tamoxifen. For some patients who do not tolerate tamoxifen, however, switching to toremifene may allow the continuation of adjuvant antiestrogenic therapy.

Comparative effects of paclitaxel and docetaxel on the metabolism and pharmacokinetics of epirubicin in breast cancer patients.

PURPOSE: To investigate whether paclitaxel and docetaxel influence the pharmacokinetics and metabolism of epirubicin. PATIENTS AND METHODS: We studied the pharmacokinetics and biotransformation patterns of epirubicin in 27 cycles and 20 breast cancer patients. Four patients received epirubicin alone 90 mg/m(2) by intravenous (IV) bolus; eight patients received the same dose of epirubicin followed immediately by paclitaxel 175 mg/m(2) in a 3-hour infusion; the other eight patients received epirubicin 90 mg/m(2) followed immediately by docetaxel 70 mg/m(2) in a 1-hour infusion. Epirubicin and its metabolites, epirubicinol (EOL) and 7-deoxydoxorubicinone (7d-Aone), were identified by high-pressure liquid chromatography. RESULTS: No pharmacokinetic interaction between the parent compound epirubicin and taxanes was detected. Conversely, a significant effect on epirubicin metabolism by both paclitaxel and docetaxel was found. Epirubicin given with paclitaxel or docetaxel yielded areas under the plasma concentration-time curves (AUC) for 7d-Aone 1. 7-fold and 1.9-fold higher (P <.05), respectively, than epirubicin alone. The appearance of two polar metabolites sensitive to glucuronidase was also significantly greater in both taxane groups. Quantitatively different metabolic rates and patterns for EOL were observed in the paclitaxel and docetaxel combinations. The EOL AUC after paclitaxel treatment (1,521 +/- 150 ng/mL*h) was significantly higher (P <.01) than the corresponding values after epirubicin administered either as a single agent (692 +/- 46 ng/mL*h) or in combination with docetaxel (848 +/- 237 ng/mL*h). CONCLUSION: There is no apparent pharmacokinetic interaction between the parent compound epirubicin and paclitaxel or docetaxel. A different pattern of interaction between these taxanes and epirubicin metabolism is clearly evident.

[Use of erythropoietin in oncology]. / Uso dell'eritropoietina in oncologia.

UNLABELLED: Anemia is a common complication observed in cancer patients. Its etiology is multifactorial and its severity depends on patient characteristics, type and stage of neoplasia, type of used chemotherapy. Erythropoietin can be effective by counteracting two of the main causes of anemia in cancer patients undergoing chemotherapy: 1. Myelosuppression induced by chemotherapy. Almost all cytotoxic drugs induce this effect. In this circumstance erythropoietin can be effective by accelerating the recovery of the erythroid compartment spared by chemotherapy. For this effect, higher than physiologically normal levels of erythropoietin are required. 2. Endogenous erythropoietin deficiency secondary to renal impairment. Renal impairment is primarily induced by cisplatin and leads to a deficient renal production of erythropoietin. In this case, erythropoietin administration can be considered as a hormone replacement therapy. Possible indications for the use of erythropoietin in cancer patients are the following: 1. Prevention of anemia; 2. Treatment of anemia induced by either high dose chemotherapy and bone marrow transplantation (BMT) or standard dose chemotherapy. The preventive use of erythropoietin is still under investigation. Two randomized studies reported the erythropoietin ability to prevent the anemia development. Further trials are required to identify subsets of patients in which the preventive use of the drug could be cost-effective. One of the causes of anemia after allogeneic BMT is the endogenous production of erythropoietin inappropriately low for the degree of anemia. On the contrary, after autologous BMT the erythropoietin response to anemia is appropriate. Phase III randomized studies showed the efficacy of erythropoietin in the treatment of anemia after allogeneic but not after autologous BMT. After standard dose chemotherapy, phase III randomized studies showed that erythropoietin is able to correct anemia in 60-80% of patients receiving platinum-based chemotherapy and in nearly 40% of patients receiving chemotherapy without platinum. The correction of anemia leads to a significant reduction in transfusion requirement. In solid tumors erythropoietin is commonly administered at the schedule of 150 U/Kg subcutaneously three times per week. Normal levels of current iron supply should be guaranteed by oral iron support during erythropoietin treatment. Because the response to erythropoietin occurs after a median time of 5 weeks, it is necessary to start erythropoietin therapy at an hemoglobin level higher that that triggering transfusion. Various parameters, at baseline or after 2-4 weeks of erythropoietin therapy, have been evaluated as predictors of response. However, other parameters should be studied to identify stronger predictors. CONCLUSIONS: Erythropoietin treatment is recommended after allogeneic BMT. Erythropoietin is effective in 60-80% of anemic patients receiving platinum-containing chemotherapy and in approximately 40% of patients receiving chemotherapy without platinum. The preventive use of erythropoietin is still under investigation. Further studies should identify subsets of patients and types of chemotherapy in which the prevention of anemia could be cost/effective.

[Mobilization of peripheral blood stem cells with conventional chemotherapy]. / Mobilizzazione di progenitori emopoietici nel sangue periferico con chemioterapia convenzionale.

Autologous peripheral blood progenitor cells (PBPC) rescue after high-dose chemotherapy has been used progressively as a form of treatment in some solid and hematologic tumors. This increasing use can be explained by both advantages of PBPC rescue over bone marrow rescue (decrease in the duration of marrow aplasia, reduction of platelet transfusions, earlier discharge from hospital, potential use in patients with inadequate bone marrow reserve) and the low number of aphereses (one or two) needed to collect a sufficient number of progenitor cells for autografting. High-dose chemotherapy is likely to be increasingly used after the results of two recently reported studies in which treatment with high-dose compared with standard-dose chemotherapy increases overall survival in metastatic breast cancer patients and relapsed lymphoma patients. After the initial use of unselected mobilizing regimens regardless of the patient characteristics and the tumor type, now it seems more useful to optimize this approach. Mobilization of PBPC can be obtained by several approaches. Moderate or high doses of single agent alone (e.g. cyclophosphamide 4-7 g/m2) or some hematopoietic growth factors alone (e.g. G-CSF, GM-CSF) have been proven to be adequate mobilizing agents. However, the use of hematopoietic growth factors alone may disadvantageously delay the start of an effective chemotherapy. An efficient mobilizing regimen requires the use of both chemotherapy and hematopoietic growth factors: the efficiency of mobilization was greater and with less side effects than chemotherapy alone. It was postulated that PBPC mobilization could be achieved only at hematopoietic recovery following myeloablative chemotherapy. Recently, it has been demonstrated that some standard-dose chemotherapy regimens associated with hematopoietic growth factors are efficient priming agents. We reported that standard-dose CEF chemotherapy plus filgrastim is a disease specific regimen (breast cancer) allowing PBPC mobilization without any relevant toxicity. The maximum release of PBPC has been observed at day 11. The optimal time for PBPC collection is predictable and aphereses can be guided by WBC counts. In conclusion, both standard and high dose chemotherapy are effective priming regimens. So presently a mobilizing regimen should be an effective disease specific chemotherapy program and should contain a hematopoletic growth factor. The choice between standard and high-dose chemotherapy can be based on patients characteristic and disease status.

Cardiovascular effects of microinjection of ANF and brain natriuretic peptide into ventrolateral medulla.

Cardiovascular effects of microinjection of atrial natriuretic factor (ANF) into 77 sites of the ventrolateral medulla (VLM) were investigated in urethan-anesthetized rats. Changes in mean arterial pressure (MAP) and heart rate (HR) in response to injections of glutamate into these sites were used to determine that they contained cardiovascular neurons. ANF (20 nl of 10(-7) M) decreased MAP [-8.9 +/- 1.5 (SE) mmHg] and HR [-9.0 +/- 2.8 (SE) beats/min] in 5 of 36 vasopressor sites identified by glutamate located in the more rostral and lateral aspect of the rostral VLM (RVLM); no effect was elicited in the other 31 RVLM sites. ANF decreased MAP (-10.4 +/- 2.4 mmHg) and HR (-9.8 +/- 3.0 beats/min) in 25 of 41 depressor sites distributed throughout the caudal VLM (CVLM); no response was observed in the other 16 CVLM sites. Brain natriuretic peptide (BNP) was microinjected (20 nl of 10(-7) M) in 21 VLM sites, before or after microinjection of ANF. BNP and ANF elicited similar results in 17 sites, a decline in MAP and HR in 10 sites, and no effect in 7 sites. In the remaining four cases ANF caused a decline in MAP and in HR, whereas BNP had minimal or no effect. Cardiovascular responses to ANF microinjection into the RVLM and CVLM support the hypothesis that ANF is involved in the transmission of baroreceptor information from the nucleus tractus solitarii to these medullary regions. The similarity of the results obtained with BNP and ANF suggests that these peptides may serve similar roles in medullary pathways involved in the control of the cardiovascular system.

Effects of intraoral mechanoreceptor stimulation on reticular formation neurones, in the rabbit.

The effects of intraoral mechanoreceptor stimulation on the firing rate of single neurones of the brain stem reticular formation (RF) were investigated in rabbits. 30% of RF neurones responded to periodontal mechanoreceptor stimulation; 16% to mucosal mechanoreceptor stimulation and 6% to both types of stimuli. Periodontal stimulation induced mainly inhibitory effects localized within the mesencephalic and rostral pontine RF. Among periodontal afferents incisors were the most widely represented. The effects of mucosal mechanoreceptor stimulation were predominant in the medullary and pontine RF and they were mainly excitatory. The present results support the hypothesis that brain stem RF neurones can be recruited into regulating mastication and biting also by stimulation of intraoral mechanoreceptors.