Biomedical subjects

Simone Mocellin

Publications and source records attributed to Simone Mocellin.

At least 19 recordsLinked to original sources

PubMed2007

Nitric oxide, a double edged sword in cancer biology: searching for therapeutic opportunities.

Nitric oxide (NO) is a pleiotropic molecule critical to a number of physiological and pathological processes. The last decade has witnessed major advances in dissecting NO biology and its role in cancer pathogenesis. However, the complexity of the interactions between different levels of NO and several aspects of tumor development/progression has led to apparently conflicting findings. Furthermore, both anti-NO and NO-based anticancer strategies appear effective in several preclinical models. This paradoxical dichotomy is leaving investigators with a double challenge: to determine the net impact of NO on cancer behavior and to define the therapeutic role of NO-centered anticancer strategies. Only a comprehensive and dynamic view of the cascade of molecular and cellular events underlying tumor biology and affected by NO will allow investigators to exploit the potential antitumor properties of drugs interfering with NO metabolism. Available data suggest that NO should be considered neither a universal target nor a magic bullet, but rather a signal transducer to be modulated according to the molecular makeup of each individual cancer and the interplay with conventional antineoplastic agents.

Animals↗

PubMed2006

A gene expression signature associated with survival in metastatic melanoma.

BACKGROUND: Current clinical and histopathological criteria used to define the prognosis of melanoma patients are inadequate for accurate prediction of clinical outcome. We investigated whether genome screening by means of high-throughput gene microarray might provide clinically useful information on patient survival. METHODS: Forty-three tumor tissues from 38 patients with stage III and stage IV melanoma were profiled with a 17,500 element cDNA microarray. Expression data were analyzed using significance analysis of microarrays (SAM) to identify genes associated with patient survival, and supervised principal components (SPC) to determine survival prediction. RESULTS: SAM analysis revealed a set of 80 probes, corresponding to 70 genes, associated with survival, i.e. 45 probes characterizing longer and 35 shorter survival times, respectively. These transcripts were included in a survival prediction model designed using SPC and cross-validation which allowed identifying 30 predicting probes out of the 80 associated with survival. CONCLUSION: The longer-survival group of genes included those expressed in immune cells, both innate and acquired, confirming the interplay between immunological mechanisms and the natural history of melanoma. Genes linked to immune cells were totally lacking in the poor-survival group, which was instead associated with a number of genes related to highly proliferative and invasive tumor cells.

Journal Article↗

PubMed2006

Correlation between melphalan pharmacokinetics and hepatic toxicity following hyperthermic isolated liver perfusion for unresectable metastatic disease.

BACKGROUND: In the present work, we report on the results of our pilot study of hyperthermic isolated hepatic perfusion (IHP) with melphalan alone for patients with unresectable metastatic liver tumors refractory to conventional treatments, with particular regard to the correlation between pharmacokinetic findings and hepatic toxicity. PATIENTS AND METHODS: Inclusion criteria were unresectable liver metastases, hepatic parenchyma replacement <or=50%, normal liver function, and previous failure of at least one conventional treatment. IHP was performed under hyperthermic conditions with melphalan (1.5 mg/kg body weight). Completeness of vascular isolation of the liver and drug distribution volumes of the perfusion circuit were assessed by a radiolabeled albumin-based method. Drug concentrations in perfusate and plasma were measured by means of high-performance liquid chromatography (HPLC). RESULTS: Twenty patients with unresectable liver metastases underwent IHP. No intraoperative mortality occurred. Treatment-related systemic toxicity was minimal and reversible. Three patients (15%) experienced grade 4 hepatic toxicity and died due to liver failure and subsequent multiorgan failure. Other six patients had significant (grade 3-4) but transitory hepatic toxicity. Complete and partial responses were observed in three and nine out of 17 evaluable patients, respectively (overall response rate = 70%). The pharmacokinetics study showed a 3% mean perfusate-to-plasma drug leakage (range 1-6%). Logistic regression analysis showed that drug concentration in the perfusate circuit, but not preoperative tests, significantly and independently correlated with hepatic toxicity (P = 0.028). CONCLUSIONS: Following melphalan-based IHP, objective tumor regression could be observed in a remarkable percentage of patients refractory to standard treatments. However, hepatic toxicity and related mortality were significant. Our findings suggest that drug dosage personalization based on the measurement of drug distribution volumes might minimize hepatic toxicity.

Adult↗

PubMed2006

Gene expression profile of primary gastric cancer: towards the prediction of lymph node status.

BACKGROUND: The identification of gastric tumors associated with a higher risk of lymph node metastasis could help surgeons select patients who may benefit from extended lymph node dissection. The aim of this study was to screen the genome in the search of primary gastric cancer gene expression profiles that might predict lymph node status. METHODS: The gene expression profile was evaluated in frozen tumor samples obtained from 32 patients with primary gastric adenocarcinomas. The array consisted of a duplicated spot panel of 5,541 human genes. To classify node-positive (N+) and node-negative (N-) cases, a logistic regression model was fitted optimizing the Akaike Information Criteria after a stepwise gene selection. The accuracy was evaluated by means of leave-one-out cross validation. RESULTS: All patients underwent radical gastrectomy and extended lymphadenectomy. Of all the cases, 21 were N+ and 11 demonstrated no lymph node involvement (N-). After quality filtering, the analysis of variance selected a set of 136 genes potentially correlated with nodal involvement (P value <.05). Of these 136 genes, 5 were differentially expressed (adjusted P value <.05). After a stepwise gene selection, only three genes (Bik, aurora kinase B, eIF5A2) were retained in the logistic model, which could correctly predict lymph node status in 30 of 32 cases. CONCLUSIONS: If our findings were confirmed, the identified gene pattern might be used to tailor the extent of lymph node dissection on a single patient basis.

Biomarkers, Tumor↗

PubMed2006

MHC-peptide specificity and T-cell epitope mapping: where immunotherapy starts.

The evaluation and characterization of epitope-specific human leukocyte antigen (HLA)-restricted memory T-cell reactivity is an important step for the development of preventive vaccines and peptide-based immunotherapies for viral and tumor diseases. The past decade has witnessed the use of HLA-restricted peptides as tools to activate strong immune responses of naïve or memory T cells specifically. This has fuelled an active search for methodological approaches focusing on HLA and peptide associations. Here, we outline new perspective on the emerging opportunity of evaluating HLA and peptide restriction by using novel approaches, such as quantitative real-time PCR, that can identify epitope specificities that are potentially useful in clinical settings.

Animals↗

PubMed2006

The prognostic value of circulating tumor cells in patients with melanoma: a systematic review and meta-analysis.

BACKGROUND: The detection of circulating tumor cells (CTC) in patients with melanoma represents an appealing prognostic tool, but no consensus exists on this topic. We aimed to comprehensively and quantitatively summarize the evidence for the use of CTC to predict patients' clinical outcome. METHODS: Fifty-three studies enrolling 5,433 patients were reviewed. Correlation of CTC status with tumor-node-metastasis disease stage and patients' overall (OS) and progression-free (PFS) survival was assessed by means of association statistics and meta-analysis, respectively. RESULTS: CTC status correlated with both tumor-node-metastasis stage (stage I, 32%; stage II, 41.7%; stage III, 41.1%; stage IV, 47.4%; P(trend) < 0.0001) and survival (OS: hazard ratio, 2.42; 95% confidence interval, 1.7-3.45, P < 0.0001; PFS: hazard ratio, 2.45; 95% confidence interval, 1.78-3.38; P < 0.0001). However, statistical heterogeneity was significant for both OS and PFS, likely underscoring the wide variability in study design. Furthermore, CTC positivity rates in early stages were higher and in the metastatic setting were lower than expected, which indicates an unsatisfactory accuracy of currently available CTC detection assays. CONCLUSIONS: Our findings suggest that CTC might have a clinically valuable prognostic power in patients with melanoma. However, the heterogeneity of the studies thus far published warrants caution not to overestimate the favorable results of pooled data.

Adult↗

PubMed2006

Support vector machine learning model for the prediction of sentinel node status in patients with cutaneous melanoma.

BACKGROUND: Currently, approximately 80% of melanoma patients undergoing sentinel node biopsy (SNB) have negative sentinel lymph nodes (SLNs), and no prediction system is reliable enough to be implemented in the clinical setting to reduce the number of SNB procedures. In this study, the predictive power of support vector machine (SVM)-based statistical analysis was tested. METHODS: The clinical records of 246 patients who underwent SNB at our institution were used for this analysis. The following clinicopathologic variables were considered: the patient's age and sex and the tumor's histological subtype, Breslow thickness, Clark level, ulceration, mitotic index, lymphocyte infiltration, regression, angiolymphatic invasion, microsatellitosis, and growth phase. The results of SVM-based prediction of SLN status were compared with those achieved with logistic regression. RESULTS: The SLN positivity rate was 22% (52 of 234). When the accuracy was > or = 80%, the negative predictive value, positive predictive value, specificity, and sensitivity were 98%, 54%, 94%, and 77% and 82%, 41%, 69%, and 93% by using SVM and logistic regression, respectively. Moreover, SVM and logistic regression were associated with a diagnostic error and an SNB percentage reduction of (1) 1% and 60% and (2) 15% and 73%, respectively. CONCLUSIONS: The results from this pilot study suggest that SVM-based prediction of SLN status might be evaluated as a prognostic method to avoid the SNB procedure in 60% of patients currently eligible, with a very low error rate. If validated in larger series, this strategy would lead to obvious advantages in terms of both patient quality of life and costs for the health care system.

Artificial Intelligence↗

PubMed2006

Circulating tumor cells: the 'leukemic phase' of solid cancers.

It is well known that malignant cells circulate in the bloodstream of patients with solid tumors. However, the biological significance of circulating tumor cells (CTCs) and the clinical relevance of their detection are still debated. Besides technical issues regarding CTC-detection methods, discontinuous shedding of CTCs from established cancer deposits, genomic instability and metastatic inefficiency might underlie the conflicting results currently available. Nevertheless, technological advances and recent clinical findings are prompting researchers to dissect CTC biology further. Here, we review these recent findings, and discuss the prospects for the identification and molecular characterization of the CTC subset that is responsible for metastasis development. This would provide a formidable tool for prognosis evaluation, anticancer-drug development and, ultimately, cancer-therapy personalization.

DNA, Neoplasm↗

PubMed2006

Intravenous and isolated limb perfusion delivery of wild type and a tumor-selective replicating mutant vaccinia virus in nonhuman primates.

In this study we examine the safety, feasibility, and biodistribution of a tumor-selective mutant vaccinia (vvDD) and wild-type WR (vF13) vaccinia after delivery via intradermal or intravenous infection or isolated limb perfusion (ILP) in rhesus macaques. By intradermal inoculation, 10(6) PFU of vvDD caused a minimal skin reaction whereas vF13 caused marked erythema and necrosis with a peak indurated area of 108 cm2. By intravenous delivery, vvDD caused no clinical symptoms of viremia and no viral recovery from tissues, serum, saliva, urine, or feces. In contrast, vF13 caused symptoms of lethargy, anorexia, fever, and signs of viremia. Delivery of vF13 via ILP resulted in numerous cutaneous pox lesions localized solely to the perfused limb with high viral recovery in the perfused skin and muscle. ILP with vvDD resulted in no visible pox lesions and no clinical signs or symptoms of viremia. No long-term toxicity was identified after ILP with 10(9) PFU of vvDD, and no virus was recovered from any tissue, serum, saliva, urine, or fecal sample. These results suggest that vvDD appears to be safe in primates, and thus vvDD should be further investigated for clinical trial in human cancer patients.

Animals↗

PubMed2006

The impact of lymphoscintigraphy technique on the outcome of sentinel node biopsy in 1,313 patients with cutaneous melanoma: an Italian Multicentric Study (SOLISM-IMI).

UNLABELLED: An observational multicentric Italian trial on sentinel node biopsy (SNB) in melanoma patients was performed to diffuse a common SNB protocol nationwide (Italy). We report herein the results of this trial. The influence of some technical aspects on the outcome of SNB was also investigated, because a certain degree of variability was accepted in performing lymphoscintigraphy. METHODS: From January 2000 to December 2002, 1,313 consecutive patients with primary cutaneous melanoma (Breslow thickness, >1.0 mm or <1.0 mm but with ulceration, Clark level IV-V, presence of regression) were enrolled by 23 centers. One half to 1 mL of 99mTc-labeled human albumin colloid, at a suggested dosage of 5-15 or 30-70 MBq, was injected intradermally, closely around the scar, the same day or the day before SNB. Intraoperatively, Patent blue was associated when a definitive wide excision of the primary was required. A positive sentinel node (SN) was defined when containing melanoma cells detected by either hematoxylin-eosin or immunohistochemistry (S100 and HMB45 antibodies). All patients underwent regular follow-up. False-negative cases were considered when lymph node metastases occurred in the same lymphatic basin of SN biopsy (SNB) during follow-up. A quality control program has been performed for the surgical procedure and for the histologic diagnosis. RESULTS: The SN identification rate was 99.3%. The axilla was the site of the SN in 52.5% of the cases. The mean number of SNs was 2.0 (range, 1-17) and only 1 node was removed in 45.4%. The positivity and false-negative rates were 16.9% and 14.7%, respectively (median follow-up, 31 mo). On multivariate analysis (logistic and linear regression) only the number of peritumor injections was inversely associated with the number of excised SNs (P = 0.002), whereas none of the technical variables showed an independent impact on SN status when Breslow thickness was included as a control variable. CONCLUSION: The number of peritumor injections seems to influence the outcome of lymphoscintigrapy in melanoma patients undergoing SNB. If these results are confirmed in a controlled trial, 3 injections at least should be recommended.

Adolescent↗

PubMed2006

New strategies to improve the efficacy of colorectal cancer vaccines: from bench to bedside.

By exploiting a naturally occurring defense system, anticancer vaccination embodies an ideal non-toxic treatment capable of evoking tumor-specific immune responses that can ultimately recognize and kill colorectal cancer (CRC) cells. Despite the enormous theoretical potential of active specific immunotherapy, no vaccination regimen has achieved sufficient therapeutic efficacy necessary for clinical implementation. Nevertheless, several immunological advances have opened new avenues of research to decipher the biological code governing tumor immune responsiveness, and this is leading to the design of potentially more effective immunotherapeutic protocols. This review briefly summarizes the principles behind anti-CRC vaccination and describes the most promising immunological strategies that have been developed, which are expected to renew interest in this molecularly targeted anticancer approach.

Animals↗

PubMed2005

Adult soft tissue sarcomas: conventional therapies and molecularly targeted approaches.

The therapeutic approach to soft tissue sarcomas (STS) has evolved over the past two decades based on the results from randomized controlled trials, which are guiding physicians in the treatment decision-making process. Despite significant improvements in the control of local disease, a significant number of patients ultimately die of recurrent/metastatic disease following radical surgery due to a lack of effective adjuvant treatments. In addition, the characteristic chemoresistance of STS has compromised the therapeutic value of conventional antineoplastic agents in cases of unresectable advanced/metastatic disease. Therefore, novel therapeutic strategies are urgently needed to improve the prognosis of patients with STS. Recent advances in STS biology are paving the way to the development of molecularly targeted therapeutic strategies, the efficacy of which relies not only on the knowledge of the molecular mechanisms underlying cancer development/progression but also on the personalization of the therapeutic regimen according to the molecular features of individual tumours. In this work, we review the state-of-the-art of conventional treatments for STS and summarize the most promising findings in the development of molecularly targeted therapeutic approaches.

Adult↗

PubMed2005

RNA interference: ready to silence cancer?

RNA interference (RNAi) is considered the most promising functional genomics tool recently developed. As in other medical fields, this biotechnology might revolutionize the approach to dissecting the biology of cancer, ultimately speeding up the discovery pace of novel targets suitable for molecularly tailored antitumor therapies. In addition, preclinical results suggest that RNAi itself might be used as a therapeutic weapon. With the aim of illustrating not only the potentials but also the current limitations of RNAi as a tool in the fight against cancer, here we summarize the physiology of RNAi, discuss the main technical issues of RNAi-based gene silencing, and review some of the most interesting preclinical results obtained so far with its implementation in the field of oncology.

Animals↗

PubMed2005

Interleukin-10 and the immune response against cancer: a counterpoint.

Although interleukin-10 (IL-10) is commonly regarded as an anti-inflammatory, immunosuppressive cytokine that favors tumor escape from immune surveillance, a wealth of evidence is accumulating that IL-10 also possesses some immunostimulating properties. In fact, IL-10 has the pleiotropic ability of influencing positively and negatively the function of innate and adaptive immunity in different experimental models, which makes it questionable to merely categorize this cytokine as a target of anti-immune escape therapeutic strategies or rather, as an immunological adjuvant in the fight against cancer. Here, we review available data about the immunostimulating anticancer properties of IL-10, and in particular, we focus on the hypothesis that in contrast to what occurs in secondary lymphoid organs, IL-10 overexpression within the tumor microenvironment may catalyze cancer immune rejection.

Adjuvants, Immunologic↗

PubMed2005

Cancer vaccines: the challenge of developing an ideal tumor killing system.

Despite the evidence that the immune system plays a significant role in controlling tumor growth in natural conditions and in response to therapeutic vaccination, cancer cells can survive their attack as the disease progresses and no vaccination regimen should be currently proposed to patients outside experimental clinical trials. Clinical results show that the immune system can be actively polarized against malignant cells by means of a variety of vaccination strategies, and that in some cases this is associated with tumor regression. This implies that under some unique circumstances, the naturally "dormant" immune effectors can actually be put at work and used as endogenous weapons against malignant cells. Consequently, the main challenge of tumor immunologists appears to lie on the ability of reproducing those conditions in a larger set of patients. The complexity of the immune network and the still enigmatic host-tumor interactions make these tasks at the same time challenging and fascinating. Recent tumor immunology findings are giving new impetus to the development of more effective vaccination strategies and might revolutionize the way of designing the next generation of cancer vaccines. In the near future, the implementation of these insights in the clinical setting and the completion/conduction of comparative randomized phase III trials will allow oncologists to define the actual role of cancer vaccines in the fight against malignancy.

Antigens, Neoplasm↗

PubMed2005

Colorectal liver metastasis: towards the integration of conventional and molecularly targeted therapeutic approaches.

Radical surgery currently represents the only treatment with curative potential for patients with colorectal cancer (CRC) liver metastases. Unfortunately, only a minority of cases is eligible for hepatic resection and many patients still develop recurrent disease, which underscores the need for more effective adjuvant treatments. In case of unresectable disease, locoregional therapeutic strategies can obtain significant tumor regression/local disease control rates, but there is no definitive evidence of their effect on patients' survival. In regards to systemic chemotherapy, the conduction of randomized controlled trials has led to a substantial progress in terms of both tumor response and survival rates. Despite these results, most patients ultimately die of their disease due to hepatic and/or extra-hepatic cancer progression. Therefore, novel therapeutic strategies are urgently needed to improve the prognosis of patients with metastatic CRC. The elucidation of CRC biology is paving the way to the development of molecularly targeted strategies, and results from controlled clinical trials have already demonstrated that some agents targeting tumor-specific molecules can significantly improve the therapeutic efficacy of conventional antineoplastic drugs. The dissection of the molecular mechanisms of CRC metastatization and tumor/host interactions will not only accelerate the development of more effective and less toxic anticancer strategies but also will allow for the personalization of the therapeutic regimen according to the molecular features of individual patients and their tumors. Only the broader clinical implementation of these novel molecular oncology findings and the optimal integration of conventional and molecularly targeted therapeutic approaches will enable clinicians to provide patients with a better chance of cure.

Antineoplastic Agents↗

PubMed2005

Hyperthermic isolated perfusion with low-dose tumor necrosis factor alpha and doxorubicin for the treatment of limb-threatening soft tissue sarcomas.

BACKGROUND: Tumor necrosis factor (TNF)-alpha-based hyperthermic isolated limb perfusion (HILP) is one of the most active available approaches for locally advanced soft tissue sarcomas (STS) of the limbs. The aim of this study was to investigate the anticancer activity of a novel drug regimen including doxorubicin (DXR) and low-dose TNF-alpha. METHODS: HILP with low-dose TNF-alpha (1 mg) and DXR (8.5 mg/L of limb volume) was given to 21 patients with limb-threatening STS: 14 had primary and 7 had recurrent STS, most of which were high grade (grade 1, n = 3; grade 2, n = 6; grade 3, n = 12). Resection of the tumor remnant was performed 6 to 8 weeks after HILP. TNF-alpha concentrations in plasma and perfusate were measured throughout perfusion. RESULTS: A major tumor response was observed at histology and clinical evaluation in 90% and 62% of patients, respectively. After a median follow-up of 30 months, limb salvage and local disease control were achieved in 71% and 81% of cases, respectively. Fourteen patients had moderate regional toxicity, which was resolved in all cases. One patient had severe limb toxicity, which did not require amputation. Systemic side effects were minimal, and there were no postoperative deaths. The perfusate/plasma area under the curve ratio for TNF-alpha was 56. CONCLUSIONS: HILP with low-dose TNF-alpha and DXR seems to be an active neoadjuvant drug regimen against limb-threatening STS. This therapeutic approach can achieve high limb-sparing surgery rates with acceptable local and negligible systemic toxicity.

Adult↗

PubMed2005

Targeted therapy for colorectal cancer: mapping the way.

In spite of the significant advances in conventional therapeutic approaches to colorectal cancer (CRC), most patients ultimately die of their disease. Dissecting the molecular mechanisms underlying CRC progression will not only accelerate the development of novel cancer-selective drugs but will also enable the therapeutic regimen to be personalized according to the molecular features of individual patients and tumors. Here, we report on the novel insights into CRC biology that are paving the way to the development of molecular therapies and summarize the results from recent clinical trials demonstrating that agents targeting tumor-specific molecular derangements can significantly improve the therapeutic efficacy of conventional chemotherapy. Only a broader clinical implementation of these concepts will provide patients with CRC the best chance of a cure.

Angiogenesis Inhibitors↗