Prostate cancer (PCa) ranges from indolent to aggressive tumors that may rapidly progress and met... more Prostate cancer (PCa) ranges from indolent to aggressive tumors that may rapidly progress and metastasize. The switch to aggressive PCa is fostered by reactive stroma infiltrating tumor foci. Therefore, reactive stroma-based biomarkers may potentially improve the early detection of aggressive PCa, ameliorating disease classification. Gene expression profiles of PCa reactive fibroblasts highlighted the up-regulation of genes related to stroma deposition, including periostin and sparc. Here, the potential of periostin as a stromal biomarker has been investigated on PCa prostatectomies by immunohistochemistry. Moreover, circulating levels of periostin and sparc have been assessed in a low-risk PCa patient cohort enrolled in active surveillance (AS) by ELISA. We found that periostin is mainly expressed in the peritumoral stroma of prostatectomies, and its stromal expression correlates with PCa grade and aggressive disease features, such as the cribriform growth. Moreover, stromal perios...
The aim of this cross-sectional study is to evaluate the factors associated with patient-reported... more The aim of this cross-sectional study is to evaluate the factors associated with patient-reported dysphagia in patients affected by locally advanced oropharyngeal cancer (OPC) treated with definitive intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy (CHT), with or without induction CHT. We evaluated 148 OPC patients treated with IMRT and concurrent CHT, without evidence of disease and who had completed their treatment since at least 6 months. At their planned follow-up visit, patients underwent clinical evaluation and completed the M.D. Anderson dysphagia inventory (MDADI) questionnaire. The association between questionnaire composite score (MDADI-CS) and different patients' and tumor's characteristics and treatments (covariates) was investigated by univariable and multivariable analyses, the latter including only covariates significant at univariable analysis. With a median time from treatment end of 30 months [range 6-74 months, interquartile range (...
TAS-102 is indicated for patients with metastatic colorectal cancer (mCRC) previously treated wit... more TAS-102 is indicated for patients with metastatic colorectal cancer (mCRC) previously treated with, or not considered candidates for, available therapies. Given the complete inefficacy in half of patients, the lack of predictive factors, the palliative setting, and the financial and clinical toxicity, optimizing the cost-benefit ratio is crucial. The "ColonLife" nomogram allows an estimate of the 12-week life expectancy of patients with refractory mCRC. We collected data from patients treated at eight Italian centers in the compassionate use program. Baseline characteristics of patients who were or were not progression free at 6 months were compared. The discriminative ability of the ColonLife nomogram was assessed. Among patients who received both TAS-102 and regorafenib, clinical outcomes of the two sequences were compared. This study included 341 patients. Six (2%) and 93 (27%) patients achieved response and disease stabilization, respectively. The median progression-fr...
No validated prognostic tool is available for predicting overall survival (OS) of patients with w... more No validated prognostic tool is available for predicting overall survival (OS) of patients with well-differentiated neuroendocrine tumors (WDNETs). This study, conducted in three independent cohorts of patients from five different European countries, aimed to develop and validate a classification prognostic score for OS in patients with stage IV WDNETs. We retrospectively collected data on 1387 patients: (i) patients treated at the Istituto Nazionale Tumori (Milan, Italy; n=515); (ii) European cohort of rare NET patients included in the European RARECAREnet database (n=457); (iii) Italian multicentric cohort of pancreatic NET (pNETs) patients treated at 24 Italian institutions (n=415). The score was developed using data from patients included in cohort (i) (training set); external validation was performed by applying the score to the data of the two independent cohorts (ii) and (iii) evaluating both calibration and discriminative ability (Harrell C statistic). We used data on age, p...
The accurate prediction of prognosis in patients with soft tissue sarcoma (STS) is a challenging ... more The accurate prediction of prognosis in patients with soft tissue sarcoma (STS) is a challenging issue. Extreme variability in the clinical and pathological characteristics of this family of tumors hinders the simple stratification of patients into meaningful prognostic cohorts. Precision medicine tools for the prediction of prognosis, such as nomograms, enable personalized computation of outcome based on clinical and pathological characteristics of both patient and tumor. The eighth edition of the American Joint Committee on Cancer staging manual moved from a "population-based" to a "personalized" approach endorsing high-quality nomograms to improve clinician prediction ability in definite patient subgroups. The first nomogram for STS was published in 2002, and this was followed by several prognostic predictors offered to clinicians. Focusing on a specific STS subgroup or site, nomograms can take into consideration highly specific factors relevant only in that p...
Despite a radical surgical approach to primary retroperitoneal sarcoma (RPS), many patients exper... more Despite a radical surgical approach to primary retroperitoneal sarcoma (RPS), many patients experience locoregional and/or distant recurrence. The objective of this study was to analyze post-relapse outcomes for patients with RPS who had initially undergone surgical resection of their primary tumor at a specialist center. All consecutive patients who underwent macroscopically complete resection for primary RPS at 8 high volume centers from January 2002 to December 2011 were identified, and those who developed local recurrence (LR) only, distant metastasis (DM) only, or synchronous local recurrence and distant metastasis (LR+DM) during the follow-up period were included. Overall survival (OS) was calculated for all groups, as was the crude cumulative incidence of a second recurrence after the first LR. Multivariate analyses for OS were performed. In an initial series of 1007 patients with primary RPS, 408 patients developed recurrent disease during the follow-up period. The median fo...
Background. This prospective study stratified patients by surgical resection (complete ¼ NED vs i... more Background. This prospective study stratified patients by surgical resection (complete ¼ NED vs incomplete ¼ ED) and centrally reviewed histology (World Health Organization [WHO] grade II vs III). Methods. WHO grade II/NED patients received focal radiotherapy (RT) up to 59.4 Gy with 1.8 Gy/day. Grade III/NED received 4 courses of VEC (vincristine, etoposide, cyclophosphamide) after RT. ED patients received 1-4 VEC courses, second-look surgery, and 59.4 Gy followed by an 8-Gy boost in 2 fractions on still measurable residue. NED children aged 1-3 years with grade II tumors could receive 6 VEC courses alone. Results. From January 2002 to December 2014, one hundred sixty consecutive children entered the protocol (median age, 4.9 y; males, 100). Follow-up was a median of 67 months. An infratentorial origin was identified in 110 cases. After surgery, 110 patients were NED, and 84 had grade III disease. Multiple resections were performed in 46/160 children (28.8%). A boost was given to 24/ 40 ED patients achieving progression-free survival (PFS) and overall survival (OS) rates of 58.1% and 68.7%, respectively, in this poor prognosis subgroup. For the whole series, 5-year PFS and OS rates were 65.4% and 81.1%, with no toxic deaths. On multivariable analysis, NED status and grade II were favorable for OS, and for PFS grade II remained favorable.
Metastasis is the main reason for lung cancer related mortality but little is known about specifi... more Metastasis is the main reason for lung cancer related mortality but little is known about specific determinants of successful dissemination from primary tumors and metastasis initiation. Here we show that CD133+/CXCR4+ cancer initiating cells (CICs) directly isolated from patient-derived xenografts (PDX) of non-small cell lung cancer (NSCLC) are endowed with superior ability to seed and initiate metastasis at distant organs. We additionally report that CXCR4 inhibition successfully prevents the increase of cisplatin-resistant CD133+/CXCR4+ cells in residual tumors and their metastatization. Immunophenotypic analysis of lung tumor cells intravenously injected or spontaneously disseminated to murine lungs, demonstrates the survival advantage and increased colonization ability of a specific subset of CD133+/CXCR4+ with reduced expression of epithelial cell adhesion molecule (EpCAM-), that also shows the greatest in vitro invasive potential. We next prove that recovered disseminated cel...
A correlation between osteopontin, E-cadherin, b-catenin, and cyclooxygenase 2 overexpression and... more A correlation between osteopontin, E-cadherin, b-catenin, and cyclooxygenase 2 overexpression and poor clinicopathological features and prognosis has been previously suggested in gastric cancer. This translational study was aimed at assessing the correlation of these immunohistochemical biomarkers with outcome in patients with radically resected gastric cancer. We analyzed osteopontin, E-cadherin, b-catenin, and cyclooxygenase 2 expression by immunohistochemistry in 346 primary gastric tumor tissue samples from patients enrolled in the ITACA-S trial. This phase III study randomized patients with radically resected gastric cancer to receive adjuvant chemotherapy with either 5-fluorouracil and leucovorin or a sequential regimen of infusional 5-fluorouracil and leucovorin plus irinotecan followed by cisplatin and docetaxel. High expression of osteopontin was correlated with high histological grade, diffuse histotype, and peritoneal relapse, but not with TNM stage. Moreover, osteopontin overexpression was associated with higher risk of tumor recurrence and metastases, and was an independent prognostic factor for both relapsefree and overall survival of gastric cancer patients following adjuvant chemotherapy. Abnormal E-cadherin expression and abnormal b-catenin expression were correlated with more advanced disease stage, and as a consequence, with poor outcome. Our results suggest that osteopontin overexpression is a valuable independent predictor of tumor recurrence and survival in patients with radically resected gastric cancer.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 10, 2014
Cutaneous melanoma incidence is increasing. Most new cases are thin (≤ 1 mm) with favorable progn... more Cutaneous melanoma incidence is increasing. Most new cases are thin (≤ 1 mm) with favorable prognoses, but survival is nonetheless variable. Our aim was to investigate new prognostic factors and construct a nomogram for predicting survival in individual patients. Data from 2,243 patients with thin melanoma were retrieved from prospectively maintained databases at six centers. Kaplan-Meier survival and crude cumulative incidences of recurrence were estimated, and competing risks were taken into account. Multivariable Cox regression was used to investigate survival predictors. Median follow-up was 124 months (interquartile range, 106 to 157 months); 12-year overall survival was 85.3% (95% CI, 83.4% to 87.2%). Median times to local, regional, and distant recurrence were 79, 78, and 107 months, respectively. Relapse was significantly related to age, Breslow thickness, mitotic rate (MR), ulceration, lymphovascular invasion (LVI), and regression; incidence was lower and subgroup differenc...
Background: Fenretinide, a vitamin A analogue, has been shown to inhibit breast carcinogenesis in... more 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 twosided. 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. [
Gastric cancer still represents one of the major causes of cancer mortality worldwide. Patients s... more Gastric cancer still represents one of the major causes of cancer mortality worldwide. Patients survival is mainly related to stage, with a high proportion of patients with metastatic disease at presentation. Thus, the cure rate largely depend upon surgical resection. Despite the additional, albeit small, benefit of adjuvant chemotherapy has been clearly demonstrated, no general consensus has been reached on the best treatment option. Moreover, the narrow therapeutic index of adjuvant chemotherapy (i.e. , limited survival benefit with considerable toxicity) requires a careful assessment of expected risks and benefits for individual patients. Treatment choices vary widely based on the different geographic areas, with chemotherapy alone more often preferred in Europe or Asia and chemoradiotherapy in the United States. In the present review we discuss the current evidence and future challenges regarding adjuvant chemotherapy in curatively resected gastric cancer with particular emphasis on the recently completed landmark studies and meta-analyses. The most recent patient-level meta-analysis demonstrated the benefit of adjuvant chemotherapy over curative surgery; the same Authors also showed that diseasefree survival may be used as a surrogate end-point for overall survival. We finally discuss future research issues such as the need of economic evaluations, development of prognostic or predictive biomarkers, and the unmet clinical need of trials comparing perioperative chemotherapy with adjuvant treatment.
JNCI Journal of the National Cancer Institute, 1999
Background: Fenretinide, a vitamin A analogue, has been shown to inhibit breast carcinogenesis in... more 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 twosided. 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. [
The article by Karrison et al. (1) argues incorrectly that the long, latent period before the rec... more The article by Karrison et al. (1) argues incorrectly that the long, latent period before the recurrence of breast cancer after mastectomy is due to dormant cells. An alternate and better documented explanation is the extreme variation in the actual tumor volume doubling time. How the variation in actual growth rates affects the extremes of disease duration has been well documented in previous publications and has been reviewed recently (2-5).
Purpose In this study on a series of 205 patients with rhabdomyosarcoma, we investigated whether ... more Purpose In this study on a series of 205 patients with rhabdomyosarcoma, we investigated whether the prognostic effect of tumor size, at diagnosis or in terms of tumor response after induction chemotherapy, differed when tumor diameter or tumor volume were considered. Patients and Methods Tumor size was assessed radiologically at diagnosis and, for the 108 patients with measurable disease, after three courses of chemotherapy. The analysis was based on multivariable models (linear for association between size and patient/tumor characteristics, Cox for association with survival). The predictive performance of the Cox model (estimated by V measure) was compared for the tumor's diameter and volume. Results Initial tumor size was significantly larger in male or older patients and in T2 or alveolar tumors, but was not associated with the achievement of complete surgical resection. Initial tumor size significantly influenced overall survival. The risk of death was comparable for tumors...
Purpose Tumor size is a key prognostic variable for soft tissue sarcomas (STS), and a tumor diame... more Purpose Tumor size is a key prognostic variable for soft tissue sarcomas (STS), and a tumor diameter of 5 cm is generally used as a cutoff for risk grouping purposes. This study aimed to investigate the prognostic effect of tumor size on overall survival and whether such an effect was influenced by the patient's size, expressed as body-surface area (BSA), in a series of 553 pediatric patients with localized STS. Patients and Methods Multivariable Cox models were used in which the effect of tumor size was adjusted for patients age, tumor site, histologic subtype, and Intergroup Rhabdomyosarcoma Study grouping, and the interaction between size and BSA was included. Results Tumor size was confirmed as a significant prognostic factor. Interaction between size and BSA meant that, for a given tumor size, the mortality increased from the larger to the smaller BSA. Conversely, the mortality risk associated with a patient with a BSA of 1.75 m2 and a 5-cm tumor was the same as for a 0.6 m...
Purpose Dermatofibrosarcoma protuberans (DFSP) is a rare, low-grade, cutaneous sarcoma with autoc... more Purpose Dermatofibrosarcoma protuberans (DFSP) is a rare, low-grade, cutaneous sarcoma with autocrine overproduction of the platelet-derived growth factor (PDGF) β-chain from gene rearrangement as a key pathogenetic factor, now susceptible of molecular-targeted therapy. The aim of this retrospective analysis was to explore the outcome of patients with primary or recurrent DFSP. Patients and Methods Two hundred eighteen patients surgically treated at the Istituto Nazionale per lo studio e la cura dei Tumori (Milan, Italy) over 20 years were reviewed. Local relapse, distant metastasis, and survival were studied. Results One hundred thirty-six patients (62.4%) presented with a primary DFSP, while 82 patients (37.6%) had a recurrent disease. In the primary group, margins were microscopically positive in 11.8%, while in the recurrent group they were positive in 14.6% (P =.613). In the primary group, patients undergoing re-excision after inadequate previous surgery had residual disease in...
Purpose Integration of numerous prognostic variables not included in the conventional staging of ... more Purpose Integration of numerous prognostic variables not included in the conventional staging of retroperitoneal soft tissue sarcomas (RPS) is essential in providing effective treatment. The purpose of this study was to build a specific nomogram for predicting postoperative overall survival (OS) and disease-free survival (DFS) in patients with primary RPS. Patients and Methods Data registered in three institutional prospective sarcoma databases were used. We included patients with primary localized RPS resected between 1999 and 2009. Univariate (Kaplan and Meier plots) and multivariate (Cox model) analyses were carried out. The a priori chosen prognostic covariates were age, tumor size, grade, histologic subtype, multifocality, quality of surgery, and radiation therapy. External validation was performed by applying the nomograms to the patients of an external cohort. The model's discriminative ability was estimated by means of the bootstrap-corrected Harrell C statistic. Results...
Prostate cancer (PCa) ranges from indolent to aggressive tumors that may rapidly progress and met... more Prostate cancer (PCa) ranges from indolent to aggressive tumors that may rapidly progress and metastasize. The switch to aggressive PCa is fostered by reactive stroma infiltrating tumor foci. Therefore, reactive stroma-based biomarkers may potentially improve the early detection of aggressive PCa, ameliorating disease classification. Gene expression profiles of PCa reactive fibroblasts highlighted the up-regulation of genes related to stroma deposition, including periostin and sparc. Here, the potential of periostin as a stromal biomarker has been investigated on PCa prostatectomies by immunohistochemistry. Moreover, circulating levels of periostin and sparc have been assessed in a low-risk PCa patient cohort enrolled in active surveillance (AS) by ELISA. We found that periostin is mainly expressed in the peritumoral stroma of prostatectomies, and its stromal expression correlates with PCa grade and aggressive disease features, such as the cribriform growth. Moreover, stromal perios...
The aim of this cross-sectional study is to evaluate the factors associated with patient-reported... more The aim of this cross-sectional study is to evaluate the factors associated with patient-reported dysphagia in patients affected by locally advanced oropharyngeal cancer (OPC) treated with definitive intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy (CHT), with or without induction CHT. We evaluated 148 OPC patients treated with IMRT and concurrent CHT, without evidence of disease and who had completed their treatment since at least 6 months. At their planned follow-up visit, patients underwent clinical evaluation and completed the M.D. Anderson dysphagia inventory (MDADI) questionnaire. The association between questionnaire composite score (MDADI-CS) and different patients' and tumor's characteristics and treatments (covariates) was investigated by univariable and multivariable analyses, the latter including only covariates significant at univariable analysis. With a median time from treatment end of 30 months [range 6-74 months, interquartile range (...
TAS-102 is indicated for patients with metastatic colorectal cancer (mCRC) previously treated wit... more TAS-102 is indicated for patients with metastatic colorectal cancer (mCRC) previously treated with, or not considered candidates for, available therapies. Given the complete inefficacy in half of patients, the lack of predictive factors, the palliative setting, and the financial and clinical toxicity, optimizing the cost-benefit ratio is crucial. The "ColonLife" nomogram allows an estimate of the 12-week life expectancy of patients with refractory mCRC. We collected data from patients treated at eight Italian centers in the compassionate use program. Baseline characteristics of patients who were or were not progression free at 6 months were compared. The discriminative ability of the ColonLife nomogram was assessed. Among patients who received both TAS-102 and regorafenib, clinical outcomes of the two sequences were compared. This study included 341 patients. Six (2%) and 93 (27%) patients achieved response and disease stabilization, respectively. The median progression-fr...
No validated prognostic tool is available for predicting overall survival (OS) of patients with w... more No validated prognostic tool is available for predicting overall survival (OS) of patients with well-differentiated neuroendocrine tumors (WDNETs). This study, conducted in three independent cohorts of patients from five different European countries, aimed to develop and validate a classification prognostic score for OS in patients with stage IV WDNETs. We retrospectively collected data on 1387 patients: (i) patients treated at the Istituto Nazionale Tumori (Milan, Italy; n=515); (ii) European cohort of rare NET patients included in the European RARECAREnet database (n=457); (iii) Italian multicentric cohort of pancreatic NET (pNETs) patients treated at 24 Italian institutions (n=415). The score was developed using data from patients included in cohort (i) (training set); external validation was performed by applying the score to the data of the two independent cohorts (ii) and (iii) evaluating both calibration and discriminative ability (Harrell C statistic). We used data on age, p...
The accurate prediction of prognosis in patients with soft tissue sarcoma (STS) is a challenging ... more The accurate prediction of prognosis in patients with soft tissue sarcoma (STS) is a challenging issue. Extreme variability in the clinical and pathological characteristics of this family of tumors hinders the simple stratification of patients into meaningful prognostic cohorts. Precision medicine tools for the prediction of prognosis, such as nomograms, enable personalized computation of outcome based on clinical and pathological characteristics of both patient and tumor. The eighth edition of the American Joint Committee on Cancer staging manual moved from a "population-based" to a "personalized" approach endorsing high-quality nomograms to improve clinician prediction ability in definite patient subgroups. The first nomogram for STS was published in 2002, and this was followed by several prognostic predictors offered to clinicians. Focusing on a specific STS subgroup or site, nomograms can take into consideration highly specific factors relevant only in that p...
Despite a radical surgical approach to primary retroperitoneal sarcoma (RPS), many patients exper... more Despite a radical surgical approach to primary retroperitoneal sarcoma (RPS), many patients experience locoregional and/or distant recurrence. The objective of this study was to analyze post-relapse outcomes for patients with RPS who had initially undergone surgical resection of their primary tumor at a specialist center. All consecutive patients who underwent macroscopically complete resection for primary RPS at 8 high volume centers from January 2002 to December 2011 were identified, and those who developed local recurrence (LR) only, distant metastasis (DM) only, or synchronous local recurrence and distant metastasis (LR+DM) during the follow-up period were included. Overall survival (OS) was calculated for all groups, as was the crude cumulative incidence of a second recurrence after the first LR. Multivariate analyses for OS were performed. In an initial series of 1007 patients with primary RPS, 408 patients developed recurrent disease during the follow-up period. The median fo...
Background. This prospective study stratified patients by surgical resection (complete ¼ NED vs i... more Background. This prospective study stratified patients by surgical resection (complete ¼ NED vs incomplete ¼ ED) and centrally reviewed histology (World Health Organization [WHO] grade II vs III). Methods. WHO grade II/NED patients received focal radiotherapy (RT) up to 59.4 Gy with 1.8 Gy/day. Grade III/NED received 4 courses of VEC (vincristine, etoposide, cyclophosphamide) after RT. ED patients received 1-4 VEC courses, second-look surgery, and 59.4 Gy followed by an 8-Gy boost in 2 fractions on still measurable residue. NED children aged 1-3 years with grade II tumors could receive 6 VEC courses alone. Results. From January 2002 to December 2014, one hundred sixty consecutive children entered the protocol (median age, 4.9 y; males, 100). Follow-up was a median of 67 months. An infratentorial origin was identified in 110 cases. After surgery, 110 patients were NED, and 84 had grade III disease. Multiple resections were performed in 46/160 children (28.8%). A boost was given to 24/ 40 ED patients achieving progression-free survival (PFS) and overall survival (OS) rates of 58.1% and 68.7%, respectively, in this poor prognosis subgroup. For the whole series, 5-year PFS and OS rates were 65.4% and 81.1%, with no toxic deaths. On multivariable analysis, NED status and grade II were favorable for OS, and for PFS grade II remained favorable.
Metastasis is the main reason for lung cancer related mortality but little is known about specifi... more Metastasis is the main reason for lung cancer related mortality but little is known about specific determinants of successful dissemination from primary tumors and metastasis initiation. Here we show that CD133+/CXCR4+ cancer initiating cells (CICs) directly isolated from patient-derived xenografts (PDX) of non-small cell lung cancer (NSCLC) are endowed with superior ability to seed and initiate metastasis at distant organs. We additionally report that CXCR4 inhibition successfully prevents the increase of cisplatin-resistant CD133+/CXCR4+ cells in residual tumors and their metastatization. Immunophenotypic analysis of lung tumor cells intravenously injected or spontaneously disseminated to murine lungs, demonstrates the survival advantage and increased colonization ability of a specific subset of CD133+/CXCR4+ with reduced expression of epithelial cell adhesion molecule (EpCAM-), that also shows the greatest in vitro invasive potential. We next prove that recovered disseminated cel...
A correlation between osteopontin, E-cadherin, b-catenin, and cyclooxygenase 2 overexpression and... more A correlation between osteopontin, E-cadherin, b-catenin, and cyclooxygenase 2 overexpression and poor clinicopathological features and prognosis has been previously suggested in gastric cancer. This translational study was aimed at assessing the correlation of these immunohistochemical biomarkers with outcome in patients with radically resected gastric cancer. We analyzed osteopontin, E-cadherin, b-catenin, and cyclooxygenase 2 expression by immunohistochemistry in 346 primary gastric tumor tissue samples from patients enrolled in the ITACA-S trial. This phase III study randomized patients with radically resected gastric cancer to receive adjuvant chemotherapy with either 5-fluorouracil and leucovorin or a sequential regimen of infusional 5-fluorouracil and leucovorin plus irinotecan followed by cisplatin and docetaxel. High expression of osteopontin was correlated with high histological grade, diffuse histotype, and peritoneal relapse, but not with TNM stage. Moreover, osteopontin overexpression was associated with higher risk of tumor recurrence and metastases, and was an independent prognostic factor for both relapsefree and overall survival of gastric cancer patients following adjuvant chemotherapy. Abnormal E-cadherin expression and abnormal b-catenin expression were correlated with more advanced disease stage, and as a consequence, with poor outcome. Our results suggest that osteopontin overexpression is a valuable independent predictor of tumor recurrence and survival in patients with radically resected gastric cancer.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 10, 2014
Cutaneous melanoma incidence is increasing. Most new cases are thin (≤ 1 mm) with favorable progn... more Cutaneous melanoma incidence is increasing. Most new cases are thin (≤ 1 mm) with favorable prognoses, but survival is nonetheless variable. Our aim was to investigate new prognostic factors and construct a nomogram for predicting survival in individual patients. Data from 2,243 patients with thin melanoma were retrieved from prospectively maintained databases at six centers. Kaplan-Meier survival and crude cumulative incidences of recurrence were estimated, and competing risks were taken into account. Multivariable Cox regression was used to investigate survival predictors. Median follow-up was 124 months (interquartile range, 106 to 157 months); 12-year overall survival was 85.3% (95% CI, 83.4% to 87.2%). Median times to local, regional, and distant recurrence were 79, 78, and 107 months, respectively. Relapse was significantly related to age, Breslow thickness, mitotic rate (MR), ulceration, lymphovascular invasion (LVI), and regression; incidence was lower and subgroup differenc...
Background: Fenretinide, a vitamin A analogue, has been shown to inhibit breast carcinogenesis in... more 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 twosided. 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. [
Gastric cancer still represents one of the major causes of cancer mortality worldwide. Patients s... more Gastric cancer still represents one of the major causes of cancer mortality worldwide. Patients survival is mainly related to stage, with a high proportion of patients with metastatic disease at presentation. Thus, the cure rate largely depend upon surgical resection. Despite the additional, albeit small, benefit of adjuvant chemotherapy has been clearly demonstrated, no general consensus has been reached on the best treatment option. Moreover, the narrow therapeutic index of adjuvant chemotherapy (i.e. , limited survival benefit with considerable toxicity) requires a careful assessment of expected risks and benefits for individual patients. Treatment choices vary widely based on the different geographic areas, with chemotherapy alone more often preferred in Europe or Asia and chemoradiotherapy in the United States. In the present review we discuss the current evidence and future challenges regarding adjuvant chemotherapy in curatively resected gastric cancer with particular emphasis on the recently completed landmark studies and meta-analyses. The most recent patient-level meta-analysis demonstrated the benefit of adjuvant chemotherapy over curative surgery; the same Authors also showed that diseasefree survival may be used as a surrogate end-point for overall survival. We finally discuss future research issues such as the need of economic evaluations, development of prognostic or predictive biomarkers, and the unmet clinical need of trials comparing perioperative chemotherapy with adjuvant treatment.
JNCI Journal of the National Cancer Institute, 1999
Background: Fenretinide, a vitamin A analogue, has been shown to inhibit breast carcinogenesis in... more 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 twosided. 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. [
The article by Karrison et al. (1) argues incorrectly that the long, latent period before the rec... more The article by Karrison et al. (1) argues incorrectly that the long, latent period before the recurrence of breast cancer after mastectomy is due to dormant cells. An alternate and better documented explanation is the extreme variation in the actual tumor volume doubling time. How the variation in actual growth rates affects the extremes of disease duration has been well documented in previous publications and has been reviewed recently (2-5).
Purpose In this study on a series of 205 patients with rhabdomyosarcoma, we investigated whether ... more Purpose In this study on a series of 205 patients with rhabdomyosarcoma, we investigated whether the prognostic effect of tumor size, at diagnosis or in terms of tumor response after induction chemotherapy, differed when tumor diameter or tumor volume were considered. Patients and Methods Tumor size was assessed radiologically at diagnosis and, for the 108 patients with measurable disease, after three courses of chemotherapy. The analysis was based on multivariable models (linear for association between size and patient/tumor characteristics, Cox for association with survival). The predictive performance of the Cox model (estimated by V measure) was compared for the tumor's diameter and volume. Results Initial tumor size was significantly larger in male or older patients and in T2 or alveolar tumors, but was not associated with the achievement of complete surgical resection. Initial tumor size significantly influenced overall survival. The risk of death was comparable for tumors...
Purpose Tumor size is a key prognostic variable for soft tissue sarcomas (STS), and a tumor diame... more Purpose Tumor size is a key prognostic variable for soft tissue sarcomas (STS), and a tumor diameter of 5 cm is generally used as a cutoff for risk grouping purposes. This study aimed to investigate the prognostic effect of tumor size on overall survival and whether such an effect was influenced by the patient's size, expressed as body-surface area (BSA), in a series of 553 pediatric patients with localized STS. Patients and Methods Multivariable Cox models were used in which the effect of tumor size was adjusted for patients age, tumor site, histologic subtype, and Intergroup Rhabdomyosarcoma Study grouping, and the interaction between size and BSA was included. Results Tumor size was confirmed as a significant prognostic factor. Interaction between size and BSA meant that, for a given tumor size, the mortality increased from the larger to the smaller BSA. Conversely, the mortality risk associated with a patient with a BSA of 1.75 m2 and a 5-cm tumor was the same as for a 0.6 m...
Purpose Dermatofibrosarcoma protuberans (DFSP) is a rare, low-grade, cutaneous sarcoma with autoc... more Purpose Dermatofibrosarcoma protuberans (DFSP) is a rare, low-grade, cutaneous sarcoma with autocrine overproduction of the platelet-derived growth factor (PDGF) β-chain from gene rearrangement as a key pathogenetic factor, now susceptible of molecular-targeted therapy. The aim of this retrospective analysis was to explore the outcome of patients with primary or recurrent DFSP. Patients and Methods Two hundred eighteen patients surgically treated at the Istituto Nazionale per lo studio e la cura dei Tumori (Milan, Italy) over 20 years were reviewed. Local relapse, distant metastasis, and survival were studied. Results One hundred thirty-six patients (62.4%) presented with a primary DFSP, while 82 patients (37.6%) had a recurrent disease. In the primary group, margins were microscopically positive in 11.8%, while in the recurrent group they were positive in 14.6% (P =.613). In the primary group, patients undergoing re-excision after inadequate previous surgery had residual disease in...
Purpose Integration of numerous prognostic variables not included in the conventional staging of ... more Purpose Integration of numerous prognostic variables not included in the conventional staging of retroperitoneal soft tissue sarcomas (RPS) is essential in providing effective treatment. The purpose of this study was to build a specific nomogram for predicting postoperative overall survival (OS) and disease-free survival (DFS) in patients with primary RPS. Patients and Methods Data registered in three institutional prospective sarcoma databases were used. We included patients with primary localized RPS resected between 1999 and 2009. Univariate (Kaplan and Meier plots) and multivariate (Cox model) analyses were carried out. The a priori chosen prognostic covariates were age, tumor size, grade, histologic subtype, multifocality, quality of surgery, and radiation therapy. External validation was performed by applying the nomograms to the patients of an external cohort. The model's discriminative ability was estimated by means of the bootstrap-corrected Harrell C statistic. Results...
Uploads
Papers by Rosalba Miceli