Enhancement of the efficacy of weekly low-dose taxotere by the long acting anti-prolactinemic drug cabergoline in pretreated metastatic breast cancer

In view of its potential action as a growth factor, the evidence of abnormally high blood levels of prolactin (PRL) is associated with a poor prognosis in metastatic breast cancer. Moreover, metastatic breast cancer-related hyperprolactinemia has proven to counteract the efficacy of cancer chemotherapy. The negative influence of high blood levels of PRL on the efficacy of chemotherapy in metastatic breast cancer has been confirmed by previous preliminary studies, showing that the concomitant administration of the anti-prolactinemic dopaminergic agent bromocriptine may enhance the therapeutic effect of chemotherapy. However, the clinical use of bromocriptine is limited by its short duration and gastrointestinal toxicity. Therefore, new anti-prolactinemic drugs, characterized by less toxicity and a longer duration of activity, such as Cabergoline (CBG), could be more appropriated to control PRL secretion in breast cancer. On this basis, a study was planned to evaluate the efficacy and tolerability of a concomitant administration of CBG with weekly low-dose Taxotere (TXT) in pretreated metastatic breast cancer under chemotherapy. The study group comprised 70 metastatic breast cancer patients (females), pretreated with at least one previous chemotherapeutic line containing anthracyclines, who were randomized to be treated with TXT alone or TXT plus CBG. TXT 25 mg/m2 was given i.v. at weekly intervals for at least 9 consecutive cycles. CBG was given orally at 0.5 mg once per week. Abnormally high pre-treatment levels of PRL were seen in 24/70 (34%) patients, 11 of whom were treated with TXT plus CBG, whereas the other 13 received TXT alone. CBG induced a complete normalization of the PRL levels in all patients within the first two weeks of therapy, whereas no normalization of PRL occurred spontaneously in patients treated with chemotherapy alone. The objective tumor regression rate was significantly higher in patients concomitantly treated with CBG than in those who received chemotherapy alone (31/34 vs 13/36, p < 0.05), and this difference was particularly evident in patients with high PRL levels prior to therapy (6/11 vs 2/13). No CBG-related toxicity occurred. On the contrary, chemotherapy-induced asthenia was significantly lower in patients concomitantly treated with CBG (5/34 vs 11/36, p < 0.05). This study shows that the chemoneuroendocrine therapy of weekly low-dose TXT plus the anti-prolactinemic drug CBG is a new, effective and well-tolerated therapy for metastatic breast cancer. It may also be recommended in heavily pretreated patients or in those with poor clinical status.     

Clinical and biological effects of interleukin-2 with or without a concomitant administration of granulocyte-macrophage colony-stimulating factor in metastatic cancer patients

GM-CSF has been shown to modulate the anticancer activity of IL-2 with, however, controversial results depending on the great variety of biological effects induced by GM-CSF itself. The activation of dendritic cells and the generation of suppressive cells would constitute the main favourable and unfavourable biological effects of GM-CSF, respectively. The present study was performed in an attempt to evaluate the clinical and biological effects of a concomitant GM-CSF administration of the immunotherapy of metastatic renal cell carcinoma with IL-2. The study included 25 patients, who were randomized to be treated with IL-2 alone or IL-2 plus GM-CSF. IL-2 was injected subcutaneously at 6 MIU/day for 6 days/week for 4 consecutive weeks, coressponding to one complete cycle. GM-CSF was injected subcutaneously at 0.3 micrograms/kg b.w. for 3 consecutive days for the first 3 days of each week of IL-2 administration. Two immunotherapeutic cycles at 21-day intervals were planned. No significant difference was observed in the percent of non-progressive disease between the two groups of patients. The increase in leukocyte mean number was significantly higher in patients concomitantly treated with GM-CSF, whereas no difference was observed in that of lymphocytes. This preliminary study suggests that the concomitant administration of GM-CSF does not enhance the therapeutic efficacy of IL-2 immunotherapy of metastatic renal cell cancer.     

Effects of IL-2 preoperative immunotherapy on surgery-induced changes in angiogenic regulation and its prevention of VEGF increase and IL-12 decline

BACKGROUND/AIMS: IL-2 preoperative immunotherapy has been proven to abrogate surgery-induced immunosuppression in cancer patients. In contrast, at present there are no data about the possible influence of IL-2 on angiogenesis-related molecular changes determined by the surgical operation. At present, it is known that VEGF (vascular endothelial growth factor) is the main endogenous angiogenic factor, whereas the antitumor cytokine IL-12 has appeared to play an anti-angiogenetic role. On this basis, a study was planned to evaluate the influence of IL-2 presurgical immunotherapy on the perioperative changes in VEGF and IL-12 secretions. METHODOLOGY: The study was performed on 30 colorectal cancer patients undergoing radical surgery, who were randomly chosen to be treated with or without preoperative immunotherapy of IL-2 (12 million IU/day subcutaneously for 3 consecutive days prior to surgery). Serum levels of VEGF and IL-12 were measured by ELISA for blood samples collected before surgery, and at days 3, 7 and 10 of the postoperative period. RESULTS: VEGF mean concentrations progressively and significantly increased during the postoperative period in patients treated with surgery alone. Mean values of VEGF were enhanced also in patients pretreated with IL-2, but VEGF increase observed in the IL-2 group was delayed, more transient and significantly lower with respect to that found in controls. IL-12 mean concentrations significantly decreased during the postoperative period only in the control patients, whereas in the IL-2-treated patients IL-12 postoperative mean values were not significantly lower than those found before surgery. CONCLUSIONS: This preliminary study would suggest that IL-2 preoperative immunotherapy may abrogate surgery decline in IL-12 levels and reduce, although not completely prevent, VEGF increase during the postoperative period in surgically treated cancer patients. These results would suggest that IL-2 presurgical immunotherapy may counteract surgery-induced stimulation of the angiogenesis, by either opposing the decline in blood levels of the anti-angiogenetic cytokine IL-12, or reducing the increase in those of the angiogenic factor VEGF.     

Salvage radiotherapy in postoperative recurrences of rectal and rectosigmoid carcinomas]

One hundred and twenty-five patients, previously operated for rectal or rectosigmoid cancer, have been submitted to external radiation therapy from 1964 to 1985 on pelvic and/or perineal recurrence (50 perineal, 66 pelvic, 9 both). Fifty-seven per cent received more than 50 Gy, but only 14% more than 60 Gy. Overall survival has been poor (66% at 1 year, 20% at 3 years, 15% at 5 years) whereas better results have been achieved for pain relief: complete remission in 49% and partial remission in 26% of 77 symptomatic patients. Among 94 patients, evaluable for tumor size before and after treatment, radiation significantly decreased the size of the recurrence in 63% (27% CR). Among prognostic factors (recurrence site, radiation dose, age, pain relief and disease-free interval since surgery) only perineal recurrence without pelvic involvement, if treated with high doses (greater than 50 Gy), seems to be related to a significantly improved prognosis.     

Prevalence of hepatitis A among drug users in north-eastern Italy. Is vaccination necessary in low prevalence areas?

BACKGROUND: The authors report on the prevalence of, and risk factors for, hepatitis A virus (HAV) in a group of drug users in Italy. METHODS: 404 heroin users were recruited and compared with a control group of 107 subjects in the general population. RESULTS: Drug users born in north-eastern Italy have a prevalence of anti-HAV similar to the control group. A much higher prevalence was found in drug users born in southern Italy. CONCLUSION: The similar prevalence of anti-HAV in drug users born in north-eastern Italy and in the general population, suggests that their lifestyle does not involve a substantial additional risk of HAV. The much higher prevalence found in drug users born in southern Italy is more likely to be related to infection during infancy.     

Endocrine effects of erythropoietin in cancer patients

The recent advances in the knowledge of the psychoneuroimmunological pathogenesis of human neoplasms have demonstrated the existence of feed-back mechanisms operating between interleukins and endocrine secretions, which play an important role in the regulation of the immune responses, including the anticancer immunity. In contrast, few studies only have been performed to investigate the possible relation between endocrine activities and hematopoietic growth factors. The present study was performed to analyze the acute endocrine effects of erythropoietin-alpha (EPO) on the main endocrine secretions. The study was carried out in 10 advanced solid tumor patients. EPO was injected subcutaneously at a dose of 10,000 U, and venous blood samples were collected before and 2, 4 and 6 h after EPO administration. No significant changes in mean serum levels of FSH, LH and TSH were seen in response to EPO. Cortisol and DHEAS concentrations increased after EPO injection, whereas those of PRL decreased, but none of these differences was statistically significant. Finally, mean serum levels of both growth hormone (GH) and somatomedin-C (IGF-1) significantly decreased after EPO administration. This preliminary study shows that EPO may inhibit GH secretion from the pituitary gland and IGF-1 production. Since GH would stimulate EPO release, the results of this study may suggest the existence of feedback mechanism operating between GH secretion and EPO production, with inhibitory effect of EPO on GH secretion, and stimulatory action of GH on EPO production. Therefore, this study would describe the first example of hemato-endocrine feedback mechanisms. Moreover, this study, by showing an inhibitory effect of EPO on IGF-1 secretion, would suggest a possible use of EPO in the medical oncology not only for the treatment of cancer related anemia, but also to counteract tumor growth by blocking IGF-1 production, which has been proven to be a growth factor for several tumor histotypes. Obviously, IGF-1 is not the only tumor growth factor, but it could play a fundamental role in the regulation of production and activity of several other tumor growth factors. In any case, this study describes the only acute endocrine effects of EPO. Therefore, further studies, by evaluating the endocrine effects of a chronic treatment with EPO, will be required to establish which may be its effect on IGF-1 endogenous production, and its consequence on survival time.     

X-ray diagnosis of malignant breast calcifications. (author's transl)

The authors have taken into consideration the different features of malignant breast tumor calcification. Frequent, rare and extremely rare radiological pictures will be shown and a differential diagnosis with benign micro-calcifications will be considered. A correct mammographic and xerographic technical performance is absolutely necessary to enhance the images of the smallest micro-calcifications. At last we assess the importance of a radiographic control of the surgical blocks, after conservative surgery of the breast, to assure a complete removal of microcalcifications.     

Longitudinal natural history in young boys with Duchenne muscular dystrophy

The aim of this prospective multicentric study was to document disease progression in young boys affected by Duchenne muscular dystrophy (DMD) between age 3 and 6 years (±3 months) using the North Star Ambulatory Assessment scale. One hundred fifty-three DMD boys (573 assessments) younger than 6 years (mean: 4.68, SD: 0.84) with a genetically proven DMD diagnoses were included. Our results showed North Star Ambulatory Assessment scores progressively increased with age. The largest increase was observed between age 3 and 4 years but further increase was steadily observed until age of 6 years. Using a multiple linear regression analysis, we found that both the use of corticosteroids and the site of mutation significantly contributed to the North Star Ambulatory Assessment changes (p < 0.001). At each age point, boys on corticosteroid treatment had higher scores than corticosteroid naïve ones (p < 0.001). Similarly, patients with mutations downstream exon 44, had lower baseline scores and lower magnitude of changes compared to those with mutations located at the 5′ end of the gene (p < 0,001). Very few boys achieved the age appropriate maximum score. These results provide useful information for the assessment and counselling of young DMD boys and for the design of clinical trials in this age group.     

Response to neoadjuvant therapy in locally advanced rectal cancer: assessment with diffusion-weighted MR imaging and 18FDG PET/CT

The aim of this study was to evaluate the correlation between the changes of SUV_max and of apparent diffusion coefficient (ADC) before and after neoadjuvant therapy, to enable us predict the therapy response, in patients with locally advanced rectal cancer (LARC). A total of 30 patients with LARC who underwent CRT were recruited for our study. All the patients underwent a whole body 18F-FDG-PET/CT scan and a pelvic MR examination including DW imaging for staging (PET/CT1 and RM1), and after the chemoradiation therapy (PET/CT2, and RM2). Histopathologic analysis of rectal specimen, according to tumor regression grade (Mandard??s criteria) was used as the standard reference. MR and PET-CT images were analyzed, and measurements of ADC values and SUV_max were taken. Diagnostic performance for selection of complete responders (TRG1?C2) and overall diagnostic accuracy for each item were calculated. After neoadjuvant therapy, all patients were submitted to surgery. According to Mandard??s criteria, 21 tumors showed complete (TRG1) or subtotal regression (TRG2) and were classified as responders; nine tumors were classified as non responders (TRG3, 4, and 5). In all the patients, mean value of SUV_max in PET/CT1 was higher than those in PET/CT2 (P?<?0.001), whereas mean ADC value was lower in RM1 than RM2 (P?<?0.001), with a significant percentage decrease of values after the treatment (P?<?0.005).The best predictors cut-off values for TRG response were SUV_max of 4.4 and ADC of 1.28?×?10³?mm²/s with sensitivity, specificity accuracy, negative predictive value, and positive predictive values of 77.3%, 88.9%, 80.7%, 61.5%, and 94.4%, respectively. We conclude from the overall data of this study that the absolute values of SUV_max and ADC of rectal lesion after CRT were the best parameters to define the response to treatment, by differentiating fibrosis from viable tumor tissue.     

Radiotherapy of local recurrences of surgically treated rectal and rectosigmoidal cancer

Local surgical failures of rectal and rectosigmoidal cancer are often observed and represent a heavy clinical problem from the viewpoint of quality of life. After having referred bad results of radiotherapy in a group of 55 patients locally relapsed after radical surgery, the authors analyse causes of therapeutic failure, underlining that ineffectiveness of radiation treatment comes mainly from late and, frequently, not complete diagnosis. Computed tomography must be currently considered the best way for monitoring these patients in order to get an earlier detection and the most correct radiation treatment plan.