Biomedical subjects

Donato Nitti

Publications and source records attributed to Donato Nitti.

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

The potential of restaging in the prediction of pathologic response after preoperative chemoradiotherapy for rectal cancer.

BACKGROUND: We performed this study to prospectively evaluate the postchemoradiotherapy performance of transrectal ultrasonography (TRUS), pelvic computed tomography (CT) scan and magnetic resonance imaging (MRI), and endoscopic biopsies for predicting the pathologic complete response of rectal cancer patients. METHODS: Four weeks after completion of preoperative chemoradiotherapy, 46 consecutive patients with mid to low rectal cancer were prospectively evaluated by proctoscopy, TRUS, and pelvic CT scan and MRI. On the basis of T and N status, patients were classified as T0 or T1-4 and N-negative or N-positive. For each staging modality used, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated. Findings were compared with the pathologic tumor-node-metastasis stage. RESULTS: On histopathologic analysis, 12 patients had pT0 and 34 had pT1-4 lesions; out of 45 assessable patients, 9 were N-positive. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy in predicting T status (T0 vs. T >or=1) were 77%, 33%, 74%, 36%, and 64%, respectively, for TRUS; 100%, 0%, 74%, not assessable, and 74% for CT; and 100%, 0%, 77%, not assessable, and 77% for MRI. The corresponding figures in predicting N status (N-negative vs. N-positive) were, respectively, 37%, 67%, 21%, 81%, and 61% for TRUS; 78%, 58%, 32%, 91%, and 62% for CT; and 33%, 74%, 25%, 81%, and 65% for MRI. CONCLUSIONS: Current rectal cancer staging modalities after chemoradiotherapy allow good prediction of node-negative cases, although none of them is able to predict the pathologic complete response on the rectal wall.

Adenocarcinoma↗

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

Sentinel lymph node metastasis from mammary ductal carcinoma in situ with microinvasion.

Axillary lymph node dissection (ALND) in patients with ductal carcinoma in situ with microinvasion (DCISM) of the breast was controversial, because of the relevant morbidity incurred by the procedure and the low incidence of axillary involvement. The introduction of the sentinel lymph node (SLN) biopsy as a minimally invasive procedure for axillary staging has prompted new interest in this issue. However, as DCISM is a rare type of cancer, data on the incidence of SLN metastasis are scarce. The aim of the present paper was therefore to assess the prevalence of SLN metastasis in a multi-institutional series of DCISM patients, in order to ascertain whether SLN biopsy might be justified as a standard procedure in the presence of microinvasive cancer. Between 1999 and 2004, 43 patients with a diagnosis of DCISM underwent SLN biopsy. Microinvasion was defined as one or more foci of invasion beyond the basal membrane, none exceeding 1mm. SLNs were examined following haematoxylin-eosin and immunohistochemical staining. SLN metastases were found in four out of 43 cases (9.3%). In one patient, SLN contained only micrometastasis. All four patients with positive SLN underwent complete ALND and in all these cases further metastatic axillary nodes were found. In conclusion, given the relevant incidence of nodal metastases and the low morbidity of the procedure, we believe that SLN biopsy should be considered in all patients with a diagnosis of DCISM. In cases of SLN involvement, even if micrometastatic, our policy is to perform a complete ALND.

Adult↗

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

Association between MDM2-SNP309 and age at colorectal cancer diagnosis according to p53 mutation status.

A single-nucleotide polymorphism (SNP) in the promoter of the MDM2 gene, SNP309 (a T-->G change), was recently implicated in the early onset of cancer in individuals with Li-Fraumeni syndrome and of sporadic soft-tissue sarcoma. SNP309 induces an increase in the level of Mdm2 protein, which causes attenuation of the p53 pathway. To investigate the effect of this polymorphism in colorectal cancer pathogenesis, we genotyped 153 colorectal cancer patients who were randomly selected from among 330 consecutive patients stratified according to p53 mutation status and age at diagnosis, for alleles of MDM2-SNP309. Among the 77 patients with p53 wild-type tumors, the median age at colorectal cancer diagnosis was 71.5 years for patients with the T/T genotype and 61.0 years for patients with SNP309 (T/G or G/G genotype) (estimated difference between medians [Hodges-Lehmann method] = 8.0 years, 95% confidence interval = 1.0 to 16.0 years; P = .03 [two-sided Wilcoxon rank sum test]). Our data indicate that MDM2-SNP309 is a modifier of the age at colorectal cancer onset for patients whose tumors have a wild-type p53 gene.

Adult↗

PubMed2006

Multivariate analysis approach to the plasma protein profile of patients with advanced colorectal cancer.

The aim of the present study was to identify the pattern of plasma protein species of interest as markers of colorectal cancer (CRC). Using matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS), the plasma protein profile was determined in nine stage IV CRC patients (study group) and nine clean-colon healthy subjects (control group). Multivariate analysis methods were employed to identify distinctive disease patterns at protein spectrum. In the study and control groups, cluster analysis (CA) on the complete MALDI-MS spectra plasma protein profile showed a distinction between CRC patients and healthy subjects, thus allowing the identification of the most discriminating ionic species. Principal component analysis (PCA) and linear discriminant analysis (LDA) yielded similar grouping results. LDA with leave-one-out cross validation achieved a correct classification rate of 89% in both the patients and the healthy subjects.

Adenocarcinoma↗

PubMed2006

Does resection line involvement affect prognosis in early gastric cancer patients? An Italian multicentric study.

BACKGROUND: Resection line involvement has been indicated as an important prognostic factor for gastric cancer. Its late detection renders the choice of treatment difficult for surgeons. MATERIALS AND METHODS: We describe the multicenter experience of a group of 11 patients with early gastric carcinoma (EGC) and positive resection confirmed at histological examination who did not undergo surgical retreatment for reasons of associated disease, surgical considerations on duodenal stump, or patient refusal. RESULTS: The gastric margin was involved in 4 patients, and 7 patients had duodenal resection line involvement. No surgical complications or postoperative deaths were observed. Five and 8-year survival was 100% and 86%, respectively. The only patient who relapsed did not have lymph node involvement and died from liver metastases, without local recurrence. CONCLUSIONS: It is sometimes difficult to accurately define the resection line in gastric cancer surgery, especially in the early stages of disease, but because of the strongly negative prognostic value of an infiltrated margin, frozen sections are recommended if neoplastic invasion is suspected and a new resection is always recommended if possible. Nevertheless, the good prognosis of resected EGC patients with resection line involvement must be considered before submitting patients with associated diseases to radical surgical retreatment.

Adult↗

PubMed2006

5-fluorouracil and weekly oxaliplatin combined with radiotherapy for locally advanced rectal cancer: surgical complications and long-term results.

BACKGROUND: We undertook this study to evaluate early surgical complications and long-term results after preoperative radiotherapy and chemotherapy (RCT) using 5-fluorouracil (5-FU) and oxaliplatin (OXA) for rectal cancer. METHODS: Forty six TNM stage II-III rectal cancer patients were studied, who were given preoperative RT (50.4 Gy/28 fractions) combined with 5-FU (200-225 mg/m(2)/day by continuous venous infusion) and weekly OXA (25-60 mg/m(2)). Major complications and reoperations were recorded overall, whereas outcome analyses were performed only for patients who received the recommended regimen dosage. RESULTS: Forty three patients (M:F, 25:18; median age 59 years) were available for analysis. All patients received the planned RT dose. There were no postoperative deaths; seven patients had early major surgical complications, four requiring re-operation. One additional patient had a second surgical procedure due to a duodenal fistula complicating the resection of an aortic aneurysm performed concomitantly with rectal cancer surgery. At a median follow-up of 49 months, two of the 23 patients treated at the recommended doses developed recurrence (one local, and one local and distant), and two died of cancer progression. Following the Kaplan-Meier method, the estimated 5-year overall and disease-free survival rates were 92 and 89%, respectively. CONCLUSIONS: The preoperative RCT regimen used in the present study incurs a low rate of recurrence with an acceptable surgical morbidity.

Adult↗

PubMed2006

A haplotype of the methylenetetrahydrofolate reductase gene predicts poor tumor response in rectal cancer patients receiving preoperative chemoradiation.

OBJECTIVE: The objective of the present study was to evaluate whether germline methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms as well as polymorphisms in the thymidylate synthase gene promoter, namely the variable number tandem repeat polymorphism (TS VNTR) and the intrarepeat G to C single nucleotide polymorphism (TS SNP), are predictive markers of tumor regression in rectal cancer patients following preoperative chemoradiotherapy. BASIC METHODS: Blood samples from 125 patients with primary adenocarcinoma of the mid-low rectum who received 5-fluorouracil-based chemotherapy and external beam radiotherapy (median dose 48.4 Gy), 125 patients (women n=45, men n=80; median age 60 years, range 31-79 years) were genotyped. Response to preoperative treatment was evaluated employing the Tumor Regression Grade criteria. On the basis of the pathologic response, patients were classified as responders (TRG 1-2, n=48) and non-responders (TRG 3-5, n=74). Three patients were excluded because of insufficient data. MAIN RESULTS: Among the polymorphic variants examined, the MTHFR 677T-1298A haplotype was, upon univariate analysis, the only variable found associated with tumor regression (P=0.004). Moreover, at multivariate analysis, the MTHFR 677T-1298A haplotype was an independent predictor of tumor regression. Patients not carrying the MTHFR 677T-1298A haplotype (odds ratio 0.29, 95% confidence interval 0.13-0.64, P=0.002) displayed a higher response rate than patients with the MTHFR 677T-1298A haplotype. CONCLUSIONS: Unlike TS VNTR and SNP polymorphisms, MTHFR 677T-1298A haplotype in genomic DNA has the potential to be a predictive marker of tumor response in rectal cancer patients submitted to preoperative chemoradiotherapy.

Adenocarcinoma↗

PubMed2006

Feasibility of laparoscopic sleeve gastrectomy as a revision procedure for prior laparoscopic gastric banding.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG), initially described by Gagner's group as the first stage of the laparoscopic duodenal switch in super-obese patients, is now gaining wide diffusion among bariatric surgeons as a new restrictive operation. METHODS: From January 2005 to January 2006, 8 obese patients with BMI 37-74 kg/m(2) underwent LSG for conversion from a prior complicated or failed laparoscopic adjustable gastric banding (LAGB). Three patients had severe symptomatic esophageal dilation, while 5 patients had unsuccessful weight loss with poor "band compliance". After de-banding, LSG was calibrated upon a 34-Fr gastric bougie, and blue and green linear staplers were used. The staple-line was buttressed by placing a sero-serosal running suture in all but one patient, and methylene blue dye was used to test for leaks. All the patients underwent upper GI series with water-soluble contrast medium 2 days after the surgery. RESULTS: The average operating-time for LSG was 90 minutes (range 60-120 min). The average hospital stay was 4 days (range 3-7). There were no perioperative complications, no conversion, and no mortality. No intraoperative or postoperative blood transfusions were required. CONCLUSIONS: LSG proved to be feasible and safe after LAGB. Longer follow-up and larger series are needed to assess weight loss results.

Adult↗

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

A novel 10B-enriched carboranyl-containing phthalocyanine as a radio- and photo-sensitising agent for boron neutron capture therapy and photodynamic therapy of tumours: in vitro and in vivo studies.

The synthesis of a Zn(ii)-phthalocyanine derivative bearing four 10B-enriched o-carboranyl units (10B-ZnB4Pc) and its natural isotopic abundance analogue (ZnB4Pc) in the peripheral positions of the tetraazaisoindole macrocycle is presented. The photophysical properties of ZnB4Pc, as tested against model biological systems, were found to be similar with those typical of other photodynamically active porphyrin-type photosensitisers, including a singlet oxygen quantum yield of 0.67. The carboranyl-carrying phthalocyanine was efficiently accumulated by B16F1 melanotic melanoma cells in vitro, appeared to be partitioned in at least some subcellular organelles and, upon red light irradiation, induced extensive cell mortality. Moreover, ZnB4Pc, once i.v.-injected to C57BL/6 mice bearing a subcutaneously transplanted pigmented melanoma, photosensitised an important tumour response, provided that the irradiation at 600-700 nm was performed 3 h after the phthalocyanine administration, when appreciable concentrations of ZnB4Pc were still present in the serum. Analogously, irradiation of the 10B-ZnB4Pc-loaded pigmented melanoma with thermal neutrons 24 h after injection led to a 4 day delay in tumour growth as compared with control untreated mice. These results open the possibility to use one chemical compound as both a photosensitising and a radiosensitising agent for the treatment of tumours by the combined application of photodynamic therapy and boron neutron capture therapy.

Animals↗

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↗