Clinical, histological and high-frequency ultrasonographic evaluation (50 MHz) of morphoea treated with ultraviolet A1 phototherapy.

BACKGROUND: There are few studies in the literature correlating the ultrasonographic findings, clinical scoring systems or histological findings in morphoea after ultraviolet (UV)A1 phototherapy. AIMS: To evaluate the quantitative and morphological aspects of high-frequency ultrasonography in the treatment of plaque morphoea in response to UVA1 phototherapy, and to correlate these with clinical and histological scores. METHODS: In total, 17 patients with morphoea were studied. Initially and at study end, high-frequency ultrasonography (50 MHz) was performed on the edge of a morphoea lesion treated with UVA1 phototherapy. A quantitative and qualitative analysis of dermal features was performed and compared with the features of healthy skin. Skin biopsy specimens were obtained from lesions analysed at the beginning and end of the study, assessing dermal sclerosis and dermal inflammatory infiltrate and their distribution. RESULTS: All affected skin showed a statistically significant increase in dermal thickness and hypoechogenicity, corresponding to a reduction in dermal density by ultrasonography compared with healthy skin. Morphological evaluation identified undulations of the dermis in 11 of 17 lesions (64.7%) and in 5 healthy skin areas (29.4%) (P = 0.08), while 'yoyo' figures were identified in 8 lesions (47%) but only 1 healthy skin area (5.9%) (P = 0.02). Ultrasonographic morphological analysis highlighted an improvement in dermal hyperechogenic bands and disappearance of yoyo figures after UVA1 treatment. Histology revealed a reduction in dermal sclerosis and inflammation, although this was not statistically significant. CONCLUSIONS: Ultrasonographic pattern analysis of morphoea is a suitable technique for monitoring UVA1 phototherapy response.

Synergism between narrowband ultraviolet B phototherapy and etanercept for the treatment of plaque-type psoriasis.

BACKGROUND: Previous investigations have demonstrated that a combination of etanercept (ETN) and narrowband ultraviolet B (NB-UVB) phototherapy is more effective than ETN alone. However, it is unclear if this combination is more effective than NB-UVB phototherapy alone. OBJECTIVES: To evaluate whether the combination of NB-UVB phototherapy with ETN improves the efficacy of ETN alone in the treatment of moderate-to-severe psoriasis. METHODS: We enrolled 322 consecutive patients with moderate-to-severe plaque-type psoriasis, who were treated with NB-UVB phototherapy as the first-line treatment option. Patients who did not achieve a 75% improvement in Psoriasis Area and Severity Index (PASI 75) were treated with conventional systemic therapies for psoriasis. If they were ineligible for these, they were treated with ETN 50 mg twice weekly. If they did not achieve PASI 75 within 12 weeks, NB-UVB phototherapy was added. RESULTS: PASI 75 was achieved in 262 patients (81.4%) treated with NB-UVB phototherapy. Sixteen patients (5.0%) dropped out for personal reasons and 24 (7.5%) were treated with at least one of the conventional systemic treatments for psoriasis. Twenty patients (6.2%) were treated with ETN. The combination regimen was needed in eight patients (2.5%) with poor response to both phototherapy and ETN alone. All of these patients achieved PASI 75 and three of them had a complete remission after 14.6 ± 3.3 NB-UVB exposures. The combined treatment was well tolerated without acute adverse events. Unfortunately, all of these patients relapsed, with PASI > 10 within 2.8 ± 1.7 months. CONCLUSIONS: The combined treatment has a synergistic effect for clearing plaque-type psoriasis previously unresponsive to ETN and NB-UVB phototherapy alone. The clearance rate is very high in a very short time without short-term adverse effects. However, concerns regarding potential cocarcinogenicity remain. Therefore the number of patients who require, and could benefit from, the combined treatment is likely to be small.

Postmarketing study for assessment of tolerability of a grass allergen immunotherapy tablet (GRAZAX) in patients with rhinitis or rhinoconjunctivitis.

BACKGROUND AND OBJECTIVE: Many patients with grass pollen allergy in Spain have concomitant sensitization to other allergens such as profilin. Since this type of sensitization is more common in Mediterranean countries than in countries where most patients were enrolled in clinical trials on GRAZAX (Phleum pratense 75,000 SQ-T/2, 800 BAU, ALK), the aim of this study was to analyze tolerability to GRAZAX under clinical practice conditions in patients with grass pollen allergy. METHODS: A total of 155 patients were enrolled consecutively in a prospective, open-label, observational study. Adverse reactions were recorded during the first month of treatment at 3 different timepoints: after the first dose, when patients were kept under observation for 30 minutes, and on days 15 and 30 after starting treatment RESULTS: With the first dose, 117 adverse reactions were recorded in 63 patients (40.7%). The commonest reactions (>10% patients) were oral pruritus (25.2%) and throat irritation (24.5%). Ear pruritus was recorded in 7.7%. All reactions but 1 occurred within 30 minutes of administration and all were mild-to-moderate. At the end of treatment, the percentage of patients with adverse reactions had decreased significantly (21.3%). Most adverse reactions (95.2%) were mild-to-moderate and only 3 (1.4%) were severe. No serious adverse reactions were recorded. CONCLUSION: GRAZAX seems to be well tolerated, and most reactions were mild-to-moderate. Many of these reactions occur with the first dose. Therefore, according to the Summary of Product Characteristics, the first dose has to be administered under medical supervision.

Antioxidants and narrow band-UVB in the treatment of vitiligo: a double-blind placebo controlled trial.

BACKGROUND: Vitiligo is an acquired depigmenting disease with uncertain aetiopathogenesis, possibly associated with oxidative stress. Narrowband ultraviolet B phototherapy (NB-UVB) is the most widely used and effective treatment. AIM: To evaluate the clinical effectiveness of NB-UVB and the repairing of oxidative stress-induced damage, using oral supplementation with an antioxidant pool (AP). METHODS: Patients (n = 35) with nonsegmental vitiligo were enrolled in a randomized, double-blind, placebo-controlled multicentre trial. The treatment group received, for 2 months before and for 6 months during the NB-UVB treatment, a balanced AP containing alpha-lipoic acid, vitamins C and E, and polyunsaturated fatty acids. The area and number of lesions, as well as some parameters of the oxidation-reduction (redox) status of the peripheral blood mononuclear cells (PBMCs) were estimated at the beginning, after 2 months, and at the end of the trial. RESULTS: In total, 28 patients completed the study. After 2 months of AP supplementation, the catalase activity and the production of reactive oxygen species (ROS) were 121% and 57% of the basal values (P < 0.05 and P < 0.02 vs. placebo, respectively). The AP increased the therapeutic success of NB-UVB, with 47% of the patients obtaining > 75% repigmentation vs. 18% in the placebo group (P < 0.05). An increase in catalase activity to 114% (P < 0.05 vs. placebo) and decrease in ROS level of up to 60% (P < 0.02 vs. placebo) of the basal value was observed in PBMCs. Finally, the AP intake maintained the membrane lipid ratio (saturated : unsaturated fatty acids 1.8 : 3.1; P < 0.05), counteracting phototherapy-induced saturation. CONCLUSIONS: Oral supplementation with AP containing alpha-lipoic acid before and during NB-UVB significantly improves the clinical effectiveness of NB-UVB, reducing vitiligo-associated oxidative stress.

Immune response to Neospora caninum in naturally infected heifers and heifers vaccinated with inactivated antigen during the second trimester of gestation.

The objective of this study was to compare the immune response to Neospora caninum in naturally infected heifers and heifers inoculated with a killed whole N. caninum tachyzoite preparation during the second trimester of gestation. Nine Holstein heifers were used in this study; three naturally infected heifers were born from seropositive dams, and six seronegative heifers were born from seronegative dams. Four seronegative heifers were subcutaneously vaccinated with a killed whole N. caninum tachyzoite preparation at weeks 13, 15 and 17 of gestation. A killed whole N. caninum tachyzoite preparation containing 45 mg of protein/5 ml dose was formulated with 70% of mineral oil adjuvant (13% consisting of Arlacel C, 85% Marcol 52 and 2% Tween-80). Similarly, two seronegative heifers (negative controls) were inoculated with mock-infected bovine monocytes in oil adjuvant. Humoral immune responses were tested by using an indirect fluorescent antibody test (IFAT) and an indirect enzyme-linked immunosorbent assay (ELISA) for detecting isotype specific antibodies. Cellular immune responses were assessed by lymphocyte proliferation test (LPT) and IFN-gamma production. N. caninum-specific antibody responses increased in immunized cattle by week 15 of gestation (mean reciprocal antibody titers 450+/-252), peaked at week 23 (mean 16,000+/-6400). Maximum antibody response in naturally infected heifers was observed at week 19 of gestation (mean: 3467+/-2810). Mean serum IFAT titers were significantly higher in immunized heifers compared with those in naturally infected heifers from weeks 17 to 25 (P < 0.05). Analysis of isotype specific antibodies in naturally infected heifers revealed a predominant IgG1 response in one heifer and a predominant IgG2 response in the other two. Similar titers of IgG1 and IgG2 occurred in immunized heifers. Control heifers remained seronegative throughout the study by IFAT and ELISA. Significant antigen-specific proliferation responses were only detected in naturally infected heifers in week 19 of gestation. Peripheral mononuclear blood cells (PMBC) from immunized animals produced IFN-gamma in similar concentrations to those of infected animals (P > 0.05). No abortion was seen in any experimental group; however, one calf from a vaccinated heifer died due to dystocia. All calves from vaccinated and control heifers were seronegative by IFAT at 6 months of age; in contrast, calves born from naturally infected heifers remained seropositive with titers > or = 200. Killed vaccine induced similar immune responses to those found in chronically, naturally infected cattle which did not abort; however, different immune pathways may be followed in vaccinated and natural infected heifers with differences in degree of protective immunity.

Correlation between Chenopodiacea/Amaranthacea pollen counts and allergic symptoms in Salsola kali monosensitized patients.

UNLABELLED: We performed a prospective observational study to establish a relationship between pollen counts of Chenopodiacea/Amaranthacea and clinical symptoms of rhinoconjunctivitis and asthma in a group of monosensitised patients. MATERIAL AND METHODS: A total of 60 patients (19 with asthma) were included in the study. All patients collected daily symptom scores during the summer months of 1999, 2000 and 2001. The questionnaire included ocular, nasal and pulmonary symptoms. Pollen counts were expressed as pollen grains/m3. Symptom scores and pollen counts were correlated using correlation coefficients and Log transformed variables. RESULTS: In the 3 seasons studied we identified a peak of pollen and clinical symptoms in the second half of August and first half of September. In 1999, there was a significant positive correlation between total symptoms and daily pollen grains/m3 (p<0.005, r = 0.347). This correlation was not significant for the summers of 2000 and 2001. After further analysis, and by displacing one of both variables between 11 to 17 days, the correlation coefficients for total symptoms, improved for 1999 (r = 0. 744; p < 0.0001) and became significant for 2000 (r = 0. 521; p < 0.0001) and 2001 (r = 0.635; p < 0.0001). CONCLUSION: We identified a significant time lag between pollen counts and symptom scores in S. kali monosensitized patients.

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.

High-dose chemotherapy shows a dose-dependent toxicity to bone marrow osteoprogenitors: a mechanism for post-bone marrow transplantation osteopenia.

BACKGROUND: Osteoporosis is a sequela of hemopoietic cell transplantation with a complex multifactorial pathogenesis in which the relative role of chemotherapy and irradiation is not completely understood. Therefore, the authors investigated the toxicity of chemotherapy-only conditioning regimens on bone homeostasis and bone marrow osteoprogenitors, its dose dependency, and the mechanism of chemotherapy-induced osteopenia. METHODS: Fifty-one patients with high-grade non-Hodgkin lymphoma or breast carcinoma who had been treated previously with high-dose + peripheral blood progenitor cell or conventional chemotherapy or who had not received any treatment (prechemotherapy) were enrolled. The authors measured the bone marrow colony-forming unit fibroblast (CFU-f) and long-term culture-initiating cell frequency, forearm bone mineral density, serum osteotropic hormones and metabolic markers of bone formation (plasma osteocalcin), and resorption (urinary collagen I C-crosslinks). RESULTS: Both high-dose chemotherapy regimens caused a 50% reduction in CFU-f frequency, independently of gonadal function status, whereas conventional chemotherapy and prechemotherapy groups were unaffected. Bone mineral density was measured in 26 non-Hodgkin lymphoma patients and again only high-dose chemotherapy caused a 10% loss in cortical bone and 20% in trabecular bone. No endocrine abnormality was found except for the secondary amenorrhea uniformly induced in the high-dose chemotherapy group. In these patients, plasma osteocalcin unexpectedly failed to increase in response to the menopausal increase in bone resorption rate, showing a selective impairment of the osteoblast compartment to cope with increased functional demand. CONCLUSIONS: Chemotherapy without irradiation shows a dose-dependent toxicity to bone marrow stromal osteoprogenitors and can cause osteopenia by direct damage of the osteoblastic compartment, as a mechanism distinct from and summable to hypogonadism.

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.

Pre-operative chemoembolization of hepatocellular carcinoma in cirrhotic patients.

BACKGROUND/AIMS: The aim of the study was to evaluate clinical and pathological effects of transcatheter arterial chemoembolization (TACE) before surgical resection for hepatocellular carcinoma (HCC) in cirrhosis (55 patients); results were compared with a group of 45 patients undergoing surgical resection without TACE. METHODOLOGY: From March 1989 to December 1997, 55 cirrhotic patients, affected by surgically resectable HCC not larger than 5 cm with unifocal or bifocal tumor lesions, underwent TACE pre-operatively. RESULTS: Massive necrosis was observed in 26%, necrosis > 50% in 38% of lesions. Neoplastic cells were found in 47% of cases within the capsule or in the pericapsular tissue. Satellite nodules showed a low rate of necrosis. Mortality and morbidity in the pre-operative TACE group were 1.8% and 29%, respectively, and 4.4% and 33%, respectively, in the control group. One-, 3- and 5-year patient survival rates were 87%, 70% and 39%, respectively, versus 79%, 38% and 19%, respectively (p<0.02), in the control group. Disease-free survival was 40% and 28% at 3 years and 5 years with pre-operative TACE versus 20% and 11% (p<0.05). CONCLUSIONS: Pre-operative TACE can be performed with low morbidity. TACE can necrotize the main lesion and temporarily arrest portal diffusion of neoplastic cells by acting on microvascular infiltration. No evident effect on satellites and pericapsular neoplastic foci was observed. The long-term patients and disease-free survival rates were improved upon.

[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.

Randomized phase III trial evaluating the role of erythropoietin in the prevention of chemotherapy-induced anemia.

PURPOSE: Although erythropoietin (EPO) is known to be useful in treating chemotherapy-induced anemia, few data are available on its potential preventive role. The aim of this study was to evaluate the ability of EPO in preventing the development of clinically significant anemia in patients treated with chemotherapy. PATIENTS AND METHODS: Sixty-two early-stage breast cancer patients undergoing accelerated adjuvant chemotherapy were randomized to receive EPO 150 U/kg three times a week or no additional treatment. Chemotherapy consisted of six cycles of cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2, and fluorouracil 600 mg/m2 (CEF) intravenously on day 1, every 2 weeks with the support of granulocyte colony-stimulating factor (G-CSF), 5 microg/kg subcutaneously from day 4 to day 11. RESULTS: Throughout the six cycles of chemotherapy, EPO-treated patients maintained stable values of hemoglobin, whereas control patients developed a progressive anemia. At the end of chemotherapy, the mean (+/- SD) hemoglobin decrease in the control group was 3.05 g/dL (+/- 1.0; 95% confidence interval [CI], 2.6 to 3.5), whereas in the EPO group it was 0.8 (+/- 1.4; 95% CI, 0.3 to 1.4). Clinically significant anemia (hemoglobin < or = 10 g/dL) occurred in 16 patients (52%; 95% CI, 33 to 69) in the control arm and in no patient (0%; 95% CI, 0 to 14) in the EPO arm (P = .00001). CONCLUSION: EPO prevents anemia in patients undergoing chemotherapy. Further trials are required to identify subsets of patients in which the preventive use of this drug could be cost-effective.

Amenorrhea induced by adjuvant chemotherapy in early breast cancer patients: prognostic role and clinical implications.

BACKGROUND: The role of amenorrhea induced by chemotherapy in premenopausal women with early breast cancer is very controversial. Analyses by various authors of the effect of drug-induced amenorrhea (DIA) on treatment outcome have yielded conflicting results. In order to gain insight into the role of DIA, we reviewed all published data addressing the issue of DIA as a prognostic factor. METHODS: Computerised and manual searches were conducted of relevant studies published from 1966 to 1995. RESULTS: Thirteen studies involving 3929 patients were selected. In two papers, the prognostic role of DIA was analysed in three and two different groups of patients, respectively. Overall, 16 groups of patients were evaluated. With 12 groups, a higher disease free survival was observed in patients developing DIA compared to those who did not. This difference was statistically significant in eight groups. Data on overall survival, reported in only five studies, indicated that it was always improved in patients who became amenorrheic. CONCLUSIONS: Available data on the role of DIA support its importance as a favorable prognostic factor for early breast cancer patients. However, due to the possible biases of this type of evaluation, this result should be interpreted with caution.

Effect of adjuvant chemotherapy with or without anthracyclines on the activity and efficacy of first-line cyclophosphamide, epidoxorubicin, and fluorouracil in patients with metastatic breast cancer.

PURPOSE: To evaluate the effect of previous adjuvant chemotherapy with or without anthracyclines on overall survival (OS), progression-free survival (PFS), and objective response (OR) rates of metastatic breast cancer patients treated with cyclophosphamide, epidoxorubicin, and fluorouracil (CEF) as first-line chemotherapy. PATIENTS AND METHODS: Three-hundred twenty-six assessable metastatic breast cancer patients entered onto four consecutive randomized trials performed in our Institution and North-West Oncology Group (GONO) cooperative centers from 1983 to 1994. Patients received CEF-based chemotherapy as first-line therapy and were then evaluated. One hundred forty-four patients (44%) did not receive previous adjuvant chemotherapy, and 143 (44%) and 39 (12%) patients received cyclophosphamide, methotrexate, and fluorouracil (CMF)-based and anthracycline-based adjuvant chemotherapy, respectively. RESULTS: ORs to CEF chemotherapy were observed in 161 patients (49.4%). On univariate analysis, patients who had received prior adjuvant chemotherapy had a significantly lower probability of response than patients who did not: 43% versus 58% (P=.02). No difference between CMF-based (OR rate, 43%) and anthracycline-based (OR rate, 44%) adjuvant chemotherapy was observed. Stepwise logistic regression analysis indicated that adjuvant chemotherapy (P=.005), bone as dominant metastatic site (P=.02), and previous hormonotherapy for metastatic disease (P=.005) were the most important factors in predicting a poor OR rate. The median PFS and OS times of the whole group were 9.8 and 17.9 months, respectively. Patients who did not receive adjuvant chemotherapy had a longer survival time (21.1 months) compared with patients previously treated with CMF-based (15.3 months) or anthracycline-based (15.8 months) adjuvant chemotherapy. Multivariate analysis confirmed adjuvant chemotherapy to be among the strongest prognostic factors associated with both a poor PFS and OS. CONCLUSION: Previous adjuvant chemotherapy adversely affects OR, PFS, and OS in metastatic breast cancer patients treated with the CEF regimen as first-line chemotherapy. No difference was observed between patients previously treated with CMF-based or anthracycline-based adjuvant chemotherapy.

Randomized cooperative study of perioperative chemotherapy in breast cancer.

PURPOSE: The aim of this multicentric randomized trial was to determine whether reducing the interval between surgery and chemotherapy improves the outcome of breast cancer patients. PATIENTS AND METHODS: Between June 1985 and July 1992, 600 breast cancer patients, clinical stages T1-3A,N0-2,M0 were randomly assigned to a perioperative cycle (PC) of cyclophosphamide 600 mg/m2, epidoxorubicin 60 mg/m2, and fluorouracil 600 mg/m2 (CEF). Node-negative (N-) patients did not receive any further treatment. Node positive (N+) patients received 11 cycles if previously given PC, or 12 cycles of CEF alternated with cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 (CMF). In addition, N+ patients received concomitant or sequential 5-year tamoxifen therapy. RESULTS: At a median follow-up duration of 5.7 years, no significant difference in survival (88% v 84%, P = .3) between the two treatment arms was seen. However, a difference of borderline significance in relapse-free survival (RFS; 76% v 70%, P = .053) was evident. A significant survival advantage for the PC arm was detected only in the estrogen receptor-negative (ER-) patients (P = .003). RFS was significantly improved in N- patients, postmenopausal patients, and ER- patients. Multivariate analyses show that pathologic tumor size, nodal status, receptor status, and treatment (only in ER- patients) are significantly correlated with survival and RFS. PC toxicity did not influence wound healing. CONCLUSION: This study provides preliminary evidence that PC positively affects relapse rate and survival in some subgroups, namely, ER- patients.

Alternating chemo-radiotherapy in bladder cancer: a conservative approach.

PURPOSE: The aim of this Phase II study was to determine a bladder-sparing treatment in patients with invasive bladder cancer, allowing a better quality of life. Objectives were to test toxicity and disease-free and overall survival of patients given an alternated chemo-radiotherapy definitive treatment. METHODS AND MATERIALS: Seventy-six patients with bladder cancer Stage T1G3 through T4 N0 M0 were entered in the same chemotherapy regimen (Cisplatin 20 mg/mq and 5-Fluorouracil 200 mg/mq daily for 5 days) alternated with different radiotherapy scheduling, the first 18 patients received two cycles of 20 Gy/10 fractions/12 days each; the second group of 58 patients received two cycles of 25 Gy/10 fractions/12 days each (the last 21 patients received Methotrexate 40 mg/mq instead of 5-Fluorouracil). RESULTS: A clinical complete response was observed in 57 patients (81%), partial response in 7 patients (10%), and a nonresponse in 6 patients (9%). At a median follow-up of 45 months, 33 patients (47%) were alive and free of tumor. The 6-year overall survival and progression-free survival was 42% and 40%, respectively. Systemic side effects were mild, while a moderate or severe local toxicity was observed in 14 patients and 13 patients (about 20%), respectively. CONCLUSION: Our conservative combination treatment allowed bladder-sparing in a high rate of patients and resulted in a survival comparable to that reported after radical cystectomy.

[Role of magnetic resonance in the follow-up o hepatocarcinoma treated with percutaneous ethanol injection (PEI) or transarterial chemoembolization (TACE)]. / Ruolo della Risonanza Magnetica nel follow-up dell'epatocarcinoma trattato con alcolizzazione percutanea (PEI) o chemioembolizzazione (TACE).

The purpose of this study was to assess Magnetic Resonance Imaging (MRI) patterns of hepatocellular carcinoma (HCC) treated with percutaneous ethanol injection (PEI) or Transarterial Chemoembolization (TACE) and, consequently, the potential role of MR Imaging in the follow-up of these lesions. HCC treated with PEI. Thirty-one patients with a single small HCC lesion underwent MR Imaging at 0.5 T before and after PEI. In all cases before and after treatment contrast enhanced Computed Tomography (CT) and US-guided fine-needle biopsy were performed. Twenty-seven of 31 HCC lesions in which complete tumor necrosis was obtained with PEI showed homogeneous hypointensity on SE T2-weighted MR images. This feature corresponded to an unenhanced and low-attenuation area on follow-up contrast-enhanced CT scans. All these lesions were negative for malignant cells at fine-needle biopsy follow-up. In four HCCs, high-signal areas on SE T2-weighted images and high-attenuation areas on contrast-enhanced CT scans were observed, suggesting the presence of residual tumor tissue; these lesions were positive for malignant cells at 6-month fine-needle biopsy. In each case, incomplete tumor necrosis was confirmed at pathologic examination of the surgical specimen. HCC treated with TACE. Twenty-one patients with a total of 36 HCC lesions underwent plain and Gadolinium-enhanced MR Imaging before and after TACE. 10 HCC lesions were later surgically resected; 26/36 lesions underwent MR, CT and angiographic follow-up. At short-term follow-up exams (15-30 days), hypointensity was present on enhanced SE T1 weighted sequences in those lesions (5/10) in which complete tumor necrosis was histologically confirmed. In the remaining 5/10 HCC lesions, persistent viable tumor portions were found at pathology. These areas corresponded to areas on hyperintensity of Gadolinium-enhanced SE T1-weighted images. Hypointensity on both SE T2-weighted and enhanced SE T1-weighted images was a characteristic pattern on long-term follow-up MR images in 21/26 unresected lesions; this finding was correlated with devascularization at angiography; the presence of hyperintense areas on SE T2 weighted and enhanced SE T1-weighted images corresponded to the persistence of hypervascular (viable) areas at angiography.

Release of peripheral blood progenitor cells during standard dose cyclophosphamide, epidoxorubicin, 5-fluorouracil regimen plus granulocyte colony stimulating factor for breast cancer therapy.

BACKGROUND: High dose chemotherapy with the support of peripheral blood progenitor cells (PBPC) is increasingly used in the treatment of solid tumors. Although the best method of PBPC mobilization is still under investigation, it should be optimized for different tumor types to obtain antitumor effect and mobilizing activity. The authors report these results in terms of the number of PBPC released and the time of maximum mobilization induced by standard dose cyclophosphamide, epidoxorubicin, 5-fluorouracil (CEF) (cyclophosphamide 600 mg/m2, epidoxorubicin 60 mg/m2, 5-fluorouracil 600 mg/m2) plus granulocyte colony stimulating factor (G-CSF) in patients with breast cancer. METHODS: Peripheral blood progenitor cells were studied by clonogenic assay of granulocyte macrophage colony-forming units (CFU-GM), megakaryocyte colony-forming unit (CFU-Meg) and erythrocyte burst-forming unit (BFU-E) and by flow cytometric analysis of CD34+ cells in 12 patients with early breast cancer throughout three cycles of CEF chemotherapy plus G-CSF. RESULTS: Colony assays and CD34+ cell determination were performed on 111 and 151 blood samples, respectively. The peak of CFU-GM and CD34+ cells occurred consistently at day 11 throughout all three cycles. At day 11 of the first cycle, the median peak values were 2223 CFU-GM/mL and 256 CD34+ cells/microL. A progressive decrease in peak value from the first to the third cycle was observed. CONCLUSIONS: Standard dose CEF chemotherapy plus G-CSF is a disease specific regimen allowing PBPC mobilization without any relevant toxicity. Maximum mobilization was recorded at day 11 of the first cycle.

A pilot study of accelerated cyclophosphamide, epirubicin and 5-fluorouracil plus granulocyte colony stimulating factor as adjuvant therapy in early breast cancer.

32 consecutive early breast cancer patients were treated to evaluate the feasibility of an accelerated CEF regimen (cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2 and 5-fluorouracil 600 mg/m2) given intravenously every 2 weeks for six cycles together with granulocyte colony stimulating factor, 5 micrograms/kg/day subcutaneously from day 4 to day 11. One hundred and eighty two out of 192 planned cycles (95%) were administered. Toxicity was mild: no cases of grade IV non-haematological toxicity and only one episode of grade IV granulocytopenia were observed. Delays or dose reductions of anti-neoplastic drugs occurred in 14 cycles (7.7%). The mean duration of six cycles of treatment was 71 days (planned 70) and 93% of average planned dose intensity was actually administered. The short course CEF therapy is a feasible, well tolerated outpatient chemotherapy regimen, allowing a 46% increase in dose intensity compared with a standard CEF regimen given every 3 weeks. A randomised study comparing this regimen to a standard CEF regimen is now in progress in early breast cancer patients.