Biomedical subjects
Publications and source records attributed to R Miceli.
We report the results of a family-based study of LRRK2 G2019S penetrance in Parkinson disease. We studied 19 families identified through the analysis of unrelated consecutive patients. The cumulative incidence of the disease was 15% at 60 years, 21% at 70 years, and 32% at 80 years. This study provides accurate estimates of G2019S penetrance by minimizing the selection bias.
PURPOSE: The synthetic retinoid fenretinide administered for 5 years for prevention of second breast cancer showed no difference after a median of 8 years, but a possible reduction in premenopausal women. We conducted a long-term analysis in a subgroup of women who were regularly followed up in a single center. PATIENTS AND METHODS: We analyzed data after a median follow-up of 14.6 years (IQ range, 12.3-16.3 years) from 1739 women aged 30-70 (872 in the fenretinide arm and 867 in the observation arm), representing 60% of the initial cohort of 2867 women. The main efficacy endpoint was second primary breast cancer (contralateral or ipsilateral). RESULTS: The number of second breast cancers was 168 in the fenretinide arm and 190 in the control arm (hazard ratio = 0.83, 95% CI, 0.67-1.03). There were 83 events in the fenretinide arm and 126 in the observation arm in premenopausal women (HR = 0.62, 95% CI, 0.46-0.83), and 85 and 64 events in postmenopausal women (HR = 1.23, 95% CI, 0.63-2.40). The younger were the women, the greater was the risk reduction associated with fenretinide, which attained 50% in women aged 40 years or younger and disappeared after age 55 (P-age*treatment interaction = 0.023). There was no difference in cancers in other organs, distant metastases or survival. CONCLUSIONS: Fenretinide induces a significant risk reduction of second breast cancer in premenopausal women, which is remarkable at younger ages, and persists several years after treatment cessation. Since adverse events are limited, a trial in young women at high-risk is warranted.
BACKGROUND: The aim of this study was to investigate the pattern and timing of recurrence and to determine associated risk factors after radical resection of gastric cancer including D2 dissection. METHODS: A total of 274 patients who had undergone radical resection of gastric cancer with nodal involvement or T3-4 tumour were randomized to receive chemotherapy or no further treatment (control group). Locoregional recurrence and distant metastasis were analysed in a competing risks framework, by estimating the crude cumulative incidence in each group. Multiple regression models were used to investigate the influence of treatment and pathological features on the risk of recurrence. RESULTS: Overall, the 7 year rate of locoregional relapse was 15.8 per cent and that of distant recurrence was 34.5 per cent. There was a significant association between pathological node (pN) stage and distant relapse (P < 0.001), and between pathological tumour (pT) stage and locoregional recurrence (P = 0.024). Chemotherapy had no significant effect on either locoregional or distant recurrence. CONCLUSION: The rate of locoregional recurrence after radical surgery for gastric cancer was lower than that in studies based on more conservative surgery. The pT stage was related to the rate of locoregional recurrence whereas pN stage had an impact on distant recurrence.
PURPOSE: The aim of this study was to better understand human breast cancer biology by studying how the timing of metastasis following primary resection is affected by adjuvant CMF (cyclophoshamide, methotrexate, 5-fluorouracil) chemotherapy. PATIENTS AND METHODS: Discrete hazards of recurrence and recurrence risk reductions for treated patients relative to controls were analyzed for all patients enrolled in two separate randomized clinical trials [study 1 (386 women): no further treatment versus 12 cycles of CMF; study 2 (459 women): six versus 12 cycles of CMF] and a historical group (396 women: surgery alone) of axillary node-positive patients undergoing mastectomy. RESULTS: (i) Nearly all CMF benefit occurs during the first 4 years following resection/chemotherapy. (ii) The CMF recurrence rate reduction is largely restricted to two specific spans. These temporally separate recurrence clusters occur during the first and third year of follow-up, while the second-year recurrences are weakly affected. (iii) Prolonging adjuvant treatment from 6 to 12 months partially alters this recurrence timing, without appreciably affecting the overall recurrence rate. (iv) These effects upon the dynamics of post-resection occurrence are menopausal status-independent. CONCLUSIONS: At least two different therapeutically vulnerable proliferative events, resulting in clinical appearance of two metastasis temporally distinct clusters of post-resection cancer recurrence, apparently occur during the administration of adjuvant chemotherapy. Metastases that transpire outside of these temporal windows are refractory to adjuvant therapy. The dynamics of both post-treatment recurrence risk and CMF effectiveness are similar for both pre- and postmenopausal women, suggesting that post-resection mechanisms by which chemotherapy prevents metastases are similar, but of different magnitude in pre- and postmenopausal women. These findings are consistent with a metastasis model that includes tumor dormancy in specific micrometastatic phases (single cells and avascular foci) and with the acceleration of the metastatic process by the surgical resection of the primary breast cancer.
PURPOSE: To explore the prognostic effect of microscopic marginal status after surgery for extremity soft tissue sarcomas. PATIENTS AND METHODS: We analyzed 911 consecutive patients surgically treated throughout a 20-year span at a single referral center. Six hundred forty-two were first seen with a primary tumor, and 269, with a locally recurrent tumor. All patients underwent macroscopically complete resection. Microscopic marginal status was negative (tumor size > 1 mm) in 748 patients and positive (</= 1 mm) in 163 patients. Median follow-up was 107 months. RESULTS: Patients with primary disease had a lower disease-specific mortality in comparison to those first examined for recurrence (25% v 37%, respectively, at 10 years). Size, malignancy grade, depth, histotype, and local recurrence had a statistically significant prognostic effect at multivariable analysis, while microscopically positive surgical margins had not, though a trend in favor of negative margins was observed. However, an extra risk was observed for patients with positive margins after 3 to 5 years (hazard ratio, 1.8 after 5 years v 0.8 before 5 years). In patients treated for a local recurrence, the prognostic impact of positive margins was higher (hazard ratio, 1.6). CONCLUSION: Positive surgical margins had a weak adverse prognostic effect, which was more pronounced for those patients escaping an early relapse. This would seem to justify a policy of surgical adequacy in adult soft tissue sarcomas, though clinical decision making in borderline presentations for conservative surgery might be reasonably flexible and shared with the patient. Once a local relapse has occurred, the impact of local treatments seems more critical.
The calibration factor variation for a PTW natural diamond detector and a Scanditronix p-type stereotactic silicon diode (designed for use in photon beams) was studied in the 10-59 MeV range. Irradiations were performed in a water phantom with the 60 MeV ocular therapy beam at the CCO (UK). The diamond detector showed a sensitivity increase with energy, underestimating the dose by about 18% at the Bragg peak, by 7% at the centre and by 17% at the distal end of the SOBP region. The silicon diode did not show any significant sensitivity change with energy. However, a decrease in response of 24% was observed for an accumulated dose of 300 Gy.
To investigate whether c-erbB 2 serum levels may be predictive of clinical response, progression-free and overall survival in postmenopausal women with advanced breast cancer hormonally treated, 265 patients enrolled in previous clinical trials were evaluated. C-erbB 2 serum levels were assessed before the start of treatment and in a subgroup of patients also at the first response evaluation. In addition, serum CA 15.3 levels were determined. The role of c-erbB 2 was investigated by means of multiple regression models in which both c-erbB 2 and CA 15.3 values were modelled as continuous variables together with other known prognostic factors. The failure probability tended to be higher in the presence of high c-erbB 2 levels, but the trend was not statistically significant; in contrast, significant results were obtained for progression-free survival (PFS,P <0.001) and overall survival (OS, P=0.014). The within-patient c-erbB 2 variation significantly predicted PFS (P=0.006) and OS (P=0.040). It is worth noting that c-erbB 2 and CA 15.3 baseline levels were significantly correlated and that the prognostic effect of c-erbB 2 tended to disappear in the presence of high CA 15.3 levels for PFS and OS.
High insulin-like growth factor-I (IGF-I) levels are associated with an increased risk of breast cancer in premenopausal women. Because the synthetic retinoid fenretinide showed a beneficial effect on second breast cancers in premenopausal women in a Phase III trial, we studied its long-term effects on IGF-I levels. We measured, at yearly intervals for up to 5 years, the circulating levels of IGF-I, IGF binding protein (BP)-3, and their molar ratio in 60 subjects < or = 50 years of age and 60 subjects > 50 years of age allocated either to fenretinide or no treatment. In women < or = 50 years of age, measurements of IGF-II, IGFBP-1, and IGFBP-2 were also performed. The associations between biomarkers and drug or metabolite plasma concentrations were also investigated. All biomarkers were relatively stable over 5 years in the control group. Compared with controls and after adjustment for baseline, treatment with fenretinide for 1 year induced the following changes: IGF-I, -13% [95% confidence interval (CI), -25 to 1%] in women < or = 50 years of age and -3% (95% CI, -16 to 13%) in women > 50 years of age; IGFBP-3, -4% (95% CI, -12 to 6%) in both age groups; IGF-I:IGFBP-3 molar ratio, -11% (95% CI, -22 to 1%) in women < or = 50 years of age and 1% (95% CI, -11 to 16%) in women > 50 years of age. These effects were apparently maintained for up to 5 years, although fewer samples were available as time progressed. No change in other IGF components was observed. Drug and metabolite concentrations were negatively correlated with IGF-I and IGF-I:IGFBP-3 molar ratio in women < or = 50 years of age. Fenretinide induces a moderate decline of IGF-I levels in women < or = 50 years of age. The association between IGF-I change and the reduction of second breast cancers in premenopausal women warrants further study.
BACKGROUND: the combination of a luteinising hormone-releasing hormone (LH-RH) analogue and an aromatase inhibitor (AI) induces greater oestrogen suppression than the analogue alone in premenopausal breast cancer. However, very few data on the biological effects of such a combination are currently available. AIM OF THE STUDY: the short-term effects of treatment with the LH-RH analogue triptorelin alone or in association with the AI formestane on bone metabolism were investigated in premenopausal breast cancer. Circulating levels of the bone formation markers carboxy-terminal and amino-terminal propeptides of type I procollagen (PICP and PINP) and the bone resorption marker cross-linked carboxy-terminal telopeptide of type I collagen (ICTP) were assessed. In addition, serum levels of insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3 and interleukin 6 (IL-6) were evaluated. PATIENTS AND METHODS: twenty-one patients with advanced breast cancer were randomly given triptorelin monthly alone (n=10, arm A) or in combination with formestane fortnightly (n=11, arm B). Blood samples were collected over a 3-month period. RESULTS: serum PICP and PINP levels increased significantly over time (P=0.0065 and 0.0197 in arm A and B, respectively); no change in ICTP levels was observed. A rise in IGF-I and IGFBP-3 levels was seen in each treatment group, but only the increase in IGF-I was significant (P=0.0138, always). The on-treatment levels of the bone turnover markers and IGF-system components were inversely correlated with serum oestrogens. Neither treatment modalities significantly affected serum IL-6 levels over time. No difference in the behaviour of any of the assessed biomarkers was observed between patients with or without skeletal metastases. CONCLUSION: it is worth noting that complete oestrogen depletion, at least in our case series, seems to increase only osteoblastic activity markers. The observed modifications appear to be related to oestrogen depletion per se rather than the degree of oestrogen suppression or the different therapeutic regimen administered.
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The aim of this study was to evaluate the postoperative outcome and occurrence of second primary malignancies in patients who underwent radical resection for early gastric cancer. Altogether 105 patients with early gastric cancer underwent radical resection and were followed up for a median period of 71 months. Overall lethality was analyzed with regard to mortality due to gastric cancer or other causes. Standardized mortality and morbidity ratios were calculated using data from the Tumor Registry of Lombardy. The 5-year survival rate was 82.8% (operative mortality excluded), which was not different from that expected from an age- and sex-matched Italian population. Ten second primary malignancies were identified, giving a standardized mortality ratio of 1.12 and a standardized morbidity ratio of 1.50. Patients undergoing surgery for early gastric cancer (especially the intestinal type) may have a circa 50% higher risk of a second tumor and should be periodically checked for other tumors, mainly in the supramesocolic area.
The dosimetric behaviour of a Scanditronix p-type silicon diode and a PTW natural diamond detector was studied in low-energy proton beams in the 8.3-21.5 MeV range. The properties investigated were linearity, reproducibility, dose rate dependence, energy and linear energy transfer (LET) dependence. The influence of detector thickness on the results of depth dose measurements was also demonstrated. A Markus parallel plate ionization chamber was used for reference dosimetry. Silicon diode and diamond detectors showed linearity at therapeutic dose level, reproducibility better than 1% (1sigma) and sensitivity variation with dose rate and proton energy.
In this paper the suitability of a PTW natural diamond detector (DD) for relative and reference dosimetry of photon and electron beams, with dose per pulse between 0.068 mGy and 0.472 mGy, was studied and the results were compared with those obtained by a stereotactic silicon detector (SFD). The results show that, in the range of the examined dose per pulse the DD sensitivity changes up to 1.8% while the SFD sensitivity changes up to 4.5%. The fitting parameter, delta, used to correct the dose per pulse dependence of solid state detectors, was delta = 0.993 +/- 0.002 and delta = 1.025 +/- 0.002 for the diamond detector and for the silicon diode, respectively. The delta values were found to be independent of particle type of two conventional beams (a 10 MV x-ray beam and a 21 MeV electron beam). So if delta is determined for a radiotherapy beam, it can be used to correct relative dosimetry for other conventional radiotherapy beams. Moreover the diamond detector shows a calibration factor which is independent of beam quality and particle type, so an empirical dosimetric formalism is proposed here to obtain the reference dosimetry. This formalism is based on a dose-to-water calibration factor and on an empirical coefficient, that takes into account the reading dependence on the dose per pulse.
In this work some dosimetric characteristics of MD-55-2 GafChromic films were studied in a low energy proton beam (21.5 MeV) directly in a water phantom. The nonlinearity of the optical density was quantified by a factor P(lin). A correction factor P(en), that accounts for optical density dependence on the energy, was empirically determined. The effects of detector thickness in depth dose measurements and of the film orientation with respect to beam direction were investigated. The results show that the MD-55-2 films provide dose measurements with the films positioned perpendicularly to the proton beam. A dosimetric formalizm is proposed to determine the dose to water at depth d, with films oriented perpendicularly to the beam axis. This formalism uses a calibration factor of the radiochromic film determined directly on the proton beam at a reference depth in water, and the P(lin) factor, that takes into account the nonlinearity of the calibration curve and the P(en) factor that, in turn takes into account the change of proton beam energy in water. The MD-55-2 films with their high spatial resolution and the quasiwater equivalent material are attractive, positioned perpendicularly along the beam axis, for the absolute dose determination of very small beam sizes and modulated proton beams.
Keratinocyte growth factor-2 (KGF-2, repifermin) is a homolog of KGF-1 with epithelial mitogenic activities. We investigated the therapeutic role of KGF-2 in intestinal ulceration and its mechanisms of protection. KGF-2 (0.3-5 mg/kg) was administered before or after induction of small intestinal ulceration by indomethacin (Indo) in prevention and treatment protocols. In acute studies, KGF-2 was injected for up to 7 days before or daily for 5 days after Indo. In a 15-day chronic study, KGF-2 was injected intravenously daily beginning before or 7 days after Indo. Injury was evaluated by blinded macroscopic and microscopic inflammatory scores, epithelial BrdU staining, tissue IL-1beta, PGE(2), and hydroxyproline concentrations, and collagen type I RNA expression. In vitro effects of KGF-2 were evaluated by epithelial cellular proliferation, restitution of wounded monolayers, PGE(2) secretion, and expression of COX-2 and collagen mRNA. Intravenous KGF-2 significantly decreased acute intestinal injury by all parameters and significantly decreased chronic ulceration. Pretreatment, daily infusion, and delayed treatment were effective. KGF-2 promoted in vitro epithelial restitution with only modest effects on epithelial cell proliferation, stimulated COX-2 expression in cultured epithelial cells, and upregulated in vitro and in vivo PGE(2) production. KGF-2 did not affect in vivo fibrosis, although it induced collagen expression in cultured intestinal myofibroblasts. These results suggest that KGF-2 inhibits intestinal inflammation by stimulating epithelial restitution and protective PGs.
BACKGROUND: Fenretinide, a vitamin A analogue, has been shown to inhibit breast carcinogenesis in preclinical studies. We determined the efficacy of fenretinide in preventing a second breast malignancy in women with breast cancer. METHODS: We randomly assigned 2972 women, aged 30-70 years, with surgically removed stage I breast cancer or ductal carcinoma in situ to receive for 5 years either fenretinide orally (200 mg/day) or no treatment. The primary end point was the incidence of contralateral breast cancer or ipsilateral breast cancer 7 years after randomization. Other end points considered post hoc were the same outcomes stratified by menopausal status, incidence of distant metastases, overall mortality, and tumors in other organs. The hazards of breast cancer occurrence were determined by Cox proportional hazards regression analysis. Statistical tests were two-sided. RESULTS: At a median observation time of 97 months, there were no statistically significant differences in the occurrence of contralateral breast cancer (P =.642) or ipsilateral breast cancer (P =.177) between the two arms. However, an interaction was detected between fenretinide treatment and menopausal status in both outcomes (P for interaction in both outcomes =.045), with a possible beneficial effect in premenopausal women (contralateral breast cancer: adjusted hazard ratio [HR] = 0.66, and 95% confidence interval [CI] = 0.41-1.07; ipsilateral breast cancer: adjusted HR = 0.65, and 95% CI = 0.46-0. 92) and an opposite effect in postmenopausal women (contralateral breast cancer: adjusted HR = 1.32, and 95% CI = 0.82-2.15; ipsilateral breast cancer: adjusted HR = 1.19, and 95% CI = 0.75-1. 89). There were no statistically significant differences between the two arms in tumors in other organs, incidence of distant metastasis, and all-cause mortality. CONCLUSIONS: Fenretinide treatment of women with breast cancer for 5 years appears to have no statistically significant effect on the incidence of second breast malignancies overall, although a possible benefit was detected in premenopausal women. These studies, particularly the post hoc analyses, are considered exploratory and need to be confirmed.
PURPOSE: To comparatively analyse the risk of recurrence at given times after surgery for breast cancer patients receiving or not receiving adjuvant CMF. PATIENTS AND METHODS: A total of 1452 node positive patients, who entered controlled clinical trials carried out at the Milan Cancer Institute and underwent radical or modified radical mastectomy for operable breast cancer, were examined. In 575 cases no further treatment was performed, whereas 877 pts were given 6 or 12 courses of adjuvant Cyclophosphamide, Methotrexate, Fluorouracil (CMF). The recurrence risk was estimated by the event-specific hazard rate for first failure and distant metastases, and, following Efron, hazard rates were fitted by logistic regression models. RESULTS: The hazard rate for first failure and distant metastases showed a double peaked pattern for both treated patients and controls, with a first major peak at about 18-24 months from surgery (early metastases), a second minor peak at the 5th-6th year, and a tapered plateau-like tail extending over 10 years from surgery (late metastases). As expected, the recurrence risk of CMF treated patients was lower than the corresponding risk of patients undergoing surgery only. However, the difference was highly evident for early recurrences, while it declined and disappeared afterwards. CONCLUSION: Our findings confirm previous reports on patients not receiving adjuvant chemotherapy, suggesting that the recurrence risk for operable breast cancer has a multipeak pattern. As far as CMF treated patients are concerned, the unchanged peak timing together with the early recurrence risk reduction in comparison to controls are much more consistent with the real nonappearance of some early recurrences (putatively 'cured' patients) than with the delay in their manifestation. As late relapsing patients seem to have at most marginal benefits from adjuvant CMF, ways to recognize patients doomed to have late recurrence and new ways for treating micrometastases resulting in late recurrences are required.
BACKGROUND: This study aimed to analyse the possibility of surgical rescue of intrabreast tumour recurrence (IBTR) following conservative operation for breast cancer, i.e. quadrantectomy, axillary dissection and radiotherapy. METHODS: Of 2544 patients treated with this approach, 209 presented with an IBTR as the first and only sign of relapse. Some 197 patients were considered suitable for further surgery; 12 were inoperable. Six patients declined operation. RESULTS: Reoperative surgery was total mastectomy in 134 patients (70 per cent) and further local resection in 57 (30 per cent). Median follow-up after second surgery was 73 (range 1-192) months. The overall survival probability at 60 months was 70 per cent after mastectomy and 85 per cent following further local excision. There was no difference in disease-free survival between the two operative groups. Second IBTR was more common at 5 years in the re-excision group (19 versus 4 per cent). CONCLUSION: Since the type of surgery did not seem to affect survival, breast conservation can be considered in selected patients with IBTR.