A new semi-orthotopic bone defect model for cell and biomaterial testing in regenerative medicine.

In recent decades, an increasing number of tissue engineered bone grafts have been developed. However, expensive and laborious screenings in vivo are necessary to assess the safety and efficacy of their formulations. Rodents are the first choice for initial in vivo screens but their size limits the dimensions and number of the bone grafts that can be tested in orthotopic locations. Here, we report the development of a refined murine subcutaneous model for semi-orthotopic bone formation that allows the testing of up to four grafts per mouse one order of magnitude greater in volume than currently possible in mice. Crucially, these defects are also "critical size" and unable to heal within the timeframe of the study without intervention. The model is based on four bovine bone implants, ring-shaped, where the bone healing potential of distinct grafts can be evaluated in vivo. In this study we demonstrate that promotion and prevention of ossification can be assessed in our model. For this, we used a semi-automatic algorithm for longitudinal micro-CT image registration followed by histological analyses. Taken together, our data supports that this model is suitable as a platform for the real-time screening of bone formation, and provides the possibility to study bone resorption, osseointegration and vascularisation.

Oral idarubicin and cyclophosphamide for metastatic breast cancer in elderly patients.

The authors treated 39 heavily pretreated breast cancer patients, median age 72, with a combined oral regimen featuring idarubicin and cyclophosphamide, administered without hospitalization in cycles repeated every 4 weeks for a total not to exceed idarubicin 400 mg/m2. Treatment was remarkably well tolerated, with generally mild hematological toxicity and only one discontinuation caused by severe neutropenia; non-hematologic toxicity consisted mainly of moderate nausea and vomiting in fewer than half the cycles, and hair loss of various severity in the majority of patients. Therapeutic results were graded as partial responses (13 cases), no change (NC; 11 cases) or progressive disease (11 cases) for a response rate of 37.2% (95% CI: 21.1-53.1%). The authors single out the NC issue as being of special interest, its mere occurrence being rewarding in the circumstance and its duration in excess of 5 months (seen in six cases) almost equivalent to therapeutic success.

Phase II study of the activity and tolerability of a combined regimen of high-dose epirubicin and cisplatin in stage IIIb and IV non-small cell lung cancer.

AIM: To explore the feasibility and activity of a combined regimen of high-dose epirubicin and cisplatin as an alternative to current treatments for non-small cell lung cancer (NSCLC). METHOD: Forty-four patients with stage IIIb or IV NSCLC, median Karnofsky index 90, were enrolled. Epirubicin (60 mg/m2) was administered on days 1 and 2 and cisplatin (100 mg/m2) on day 1. Treatment was repeated every 21 days for a maximum of six cycles. A hematopoietic growth factor (G-CSF) was used only for patients reaching codified nadir count values. RESULTS: A total of 130 cycles were administered with a mean of 2.9 cycles per patient. Of 41 assessable patients one showed a complete response and 15 had partial responses (overall response rate, 39%). Grade 3 or 4 leukopenia and grade 3 hemoglobin toxicity were seen in 40% and 14%, respectively, of the administered cycles. The most common nonhematologic toxic events were nausea and vomiting, mucositis, anorexia, and asthenia. CONCLUSIONS: This epirubicin-cisplatin regimen seemed effective and was generally well tolerated, and therefore suitable for use in an outpatient setting.

Effect of medroxyprogesterone acetate on the quality of life of the oncologic patient: a multicentric cooperative study.

Anorexia and cachexia, major problems in patients with cancer, lead to decreased caloric intake and weight loss. Successful treatment of these conditions has a positive effect on patients' quality of life. Among the pharmacologic treatments, partial effects have been observed following administration of corticosteroids, anabolizing drugs and synthetic progestogens such as megestrol acetate and medroxyprogesterone acetate (MPA). The aim of the present study was to evaluate whether MPA is able to influence the quality of life of neoplastic patients undergoing different chemotherapeutic regimens and/or radiotherapy for different tumor types. A series of 279 cancer patients undergoing either chemotherapy and/or radiotherapy treatment for different tumor types was randomly allocated to receive either MPA or no treatment. We explored the effect of MPA oral suspension at the daily dose of 1000 mg for 12 weeks (group A) or no treatment (group B). Our data show an increase of body weight in group A patients and improvement in performance status. The outcome of the present study strongly demonstrates that therapy with MPA plays a fundamental role in ameliorating the complex symptomatology of cancer patients in intermediate or advanced stage of the disease undergoing casual treatment with chemotherapy and/or radiotherapy.

Weekly epidoxorubicin therapy in hormone-refractory metastatic prostate cancer.

In a pilot trial, we treated thirty-three hormone resistant metastatic prostate cancer patients with a combination of androgen blockade plus weekly cytotoxic therapy and determined both response and toxicity in 32 of them. Their median Karnofsky performance status at the time of entry was 65. We administered Epidoxorubicin (EpiDx) intravenously, at a dose of 35 mg/m2, every week for 4 months. Initially, all patients had only hormonal therapy and chemotherapy was added once they progressed. In terms of W.H.O. criteria, 9 patients (28%) had a partial response, the disease was stable in 14 (44%), and progressive in 9 (28%); even in this last group, 6 patients with bone metastases experienced lasting relief from pain. No patients had to interrupt treatment due to leukopenia or cardiotoxicity. Other toxicities, including nausea and vomiting, mucositis and alopecia, were mild. Pretreatment prostate-specific antigen (PSA) levels decreased significantly (p < 0.05) in 26 patients (81%) after treatment. In our view, weekly EpiDx administration serves as an active regimen in hormone-refractory prostate cancer.

Adjuvant chemotherapy after gastric resection in node-positive cancer patients: a multicentre randomised study.

After curative resection for gastric adenocarcinoma, 103 patients, all with positive nodes, were randomised so that 48 received adjuvant chemotherapy of epidoxorubicin (EPI) 75 mg m-2 on day 1, leucovorin (LV) 200 mg m-2 on days 1-3 and 5-fluorouracil (5-FU) 450 mg m-2 on days 1-3, every 21 days for 7 months, whereas the remaining 55 did not. During the first year of observation, 21 control patients (38%) and five treated patients had recurrences. After a follow-up period of 36 months, 12 of the treated patients (25%) and only seven controls (13%) were still alive. At that point, the median survival was 13.6 months for the 55 untreated patients and 20.4 months for the 48 treated patients, a significant difference. We found a survival advantage for patients treated with the EPI-LV-5-FU regimen and a consistent delay in the appearance of recurrent or metastatic cancer. Acute toxicity was mild and treatment was well accepted by all patients. There was no long-term toxicity or any cardiac toxicity. We conclude that this particular chemotherapy, administered shortly after gastric resection, improves survival rate in node-positive gastric cancer patients, even although final assessment of this particular adjuvant approach must await completion of the trial.

Cyclophosphamide, epidoxorubicin and Carboplatin as treatment for advanced-carcinoma of the bladder - a phase-ii study.

In advanced carcinoma of the bladder, the M-VAC chemotherapy schedule can yield positive results, but at the cost of very high toxicity. Recent studies have shown epidoxorubicin and to a lesser degree, carboplatin to be active against urothelial tumors, with cardiac, haematological and renal toxicity lower than that observed with CISCA or M-VAC chemotherapy regimens. In this study, we determined the toxicity and efficacy of cyclophosphamide 400 mg/m(2), epidoxorubicin 75 mg/m(2) and carboplatin 300 mg/m(2) in a 28-day course. From February 1990 to December 1991, we enrolled 33 advanced bladder cancer patients (25 males, 8 females), mean age 63 years. 31 patients were evaluable for toxicity and response. The major disease localizations were: locoregional 15 (48%), lymph nodes 6 (20%), liver 5 (16%), lung 3 (10%) and bone 2 (6%). A total of 186 cycles of therapy were administered, with a mean of 5.4 per patient. Six patients (19%) had a complete response (CR): 2 locoregional, 3 lymph node and 1 lung. Eleven patients (36%) had a partial response (PR), for an overall response rate of 55%. The median duration of response was 53 weeks and median survival for the entire group of patients was 40 weeks. No delays or interruptions due to sepsis occurred during therapy; haematological, cardiac and renal toxicity were below WHO grade 3. The efficacy of this chemotherapy regimen proved to be comparable to that of more aggressive schedules, while its toxicity was markedly lower.

Cisplatin-VP16 alternating with cyclophosphamide-epirubicin versus cyclophosphamide-epirubicin-vincristine in small cell lung cancer.

In the hope of increasing the incidence of objective remissions and the survival time of patients with small cell lung cancer, we conducted a randomized study designed to compare a treatment scheme of alternating chemotherapy featuring cisplatin+etoposide followed by cyclophosphamide+epirubicin versus conventional chemotherapy with cyclophosphamide+epirubicin+vincristine, in a total of 113 patients (56 treated with the alternating regime and 57 treated conventionally). Patients receiving the alternating drug regimen showed some increase in objective remission rates, and above all increased mean survival time (297 days versus 232). The higher incidence of side effects encountered was effectively controlled by the usual medical therapy.

Tolciclate in the local treatment of skin candidiases: a double-blind controlled multiclinic trial versus clotrimazole.

A controlled double-blind multiclinic trial comparing the activity and tolerability of tolciclate and clotrimazole on skin candidiasis was carried out in twenty-seven dermatological departments throughout Italy. Two hundred and seventy-eight patients were admitted to the trial. Tolciclate and clotrimazole 1% cream and lotion were applied twice a day for a mean time of about 3 weeks. Efficacy was evaluated weekly during the treatment both by clinical and mycological (culture) examinations. Culture baseline findings were positive for Candida sp in about 72% of cases; C. albicans was the most frequent species (41.5%) but also C. krusei and C. stellatoidea were isolated in a high percentage of cases. Tolciclate induced clinical cure or improvement in 89.7% of cases, mycological conversion in 73.6% with an overall efficacy (clinical + mycological) in 72.2%. Clotrimazole gave comparable results with, respectively, 95.7% of clinical cure or improvement, 75.3% of culture conversion and 77.6% of overall efficacy. The differences were small and statistically not significant. Tolerability was good and similar in both experimental groups.

Multicentre clinical study with tolciclate in the local treatment of skin mycoses in 1083 patients.

A multicentre clinical trial with tolciclate was carried out in Italy on 1083 patients suffering from skin mycoses (tinea corporis, tinea cruris, tinea pedis, tinea manuum and pityriasis versicolor). Both preparations (1% cream and lotion) showed a good activity evaluated weekly by clinical examinations and mycological assessments, i.e. culture for tineas and microscopy for pityriasis versicolor. Favourable clinical results ranged from 83% to 97% according to diagnoses. Cultural or microscopic conversions obtained in a mean time of about 2 weeks varied from 70% to 91%. Mycological relapses a month after the end of treatment were seen in 6.5% of cases examined. Adverse reactions were observed in 5.6% of patients but the treatment was discontinued only in 2.6%.