Alfonso Marchianò

Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation: A prospective study

Objective:Determine the histologic response-rate (complete versus partial tumor extinction) after single radiofrequency ablation (RFA) of small hepatocellular carcinoma (HCC) arising in cirrhosis. Investigate possible predictors of response and assess efficacy and safety of RFA as a bridge to liver transplantation (OLT). Background:RFA has become the elective treatment of local control of HCC, although histologic data supporting radiologic assessment of response are rare and prospective studies are lacking. Prognostic impact of repeated RFA for HCC persistence is also undetermined. Methods:Percentage of RFA-induced necrosis and tumor persistence-rate at various intervals from treatment was studied in 60 HCC (median: 3 cm; Milan-Criteria IN: 80%) isolated in 50 consecutive cirrhotic patients undergoing OLT. Single-session RFA was the only treatment planned before OLT. Histologic response determined on explanted livers was related to 28 variables and to pre-OLT CT scan. Results:Mean interval RFA→OLT was 9.5 months. Post-RFA complete response rate was 55%, rising to 63% for HCC ≤3 cm. Tumor size was the only prognostic factor significantly related to response (P = 0.007). Tumor satellites and/or new HCC foci (56 nodules) were unaffected by RFA and significantly correlated with HCC >3 cm (P = 0.05). Post-RFA tumor persistence probability increased with time (12 months: 59%; 18 months: 70%). Radiologic response rate was 70%, not significantly different from histology. Major post-RFA morbidity was 8%. No mortality, Child deterioration, patient withdrawal because of tumor progression was observed. Post-OLT 3-year patient/graft survival was 83%. Conclusions:RFA is a safe and effective treatment of small HCC in cirrhotics awaiting OLT, although tumor size (>3 cm) and time from treatment (>1 year) predict a high risk of tumor persistence in the targeted nodule. RFA should not be considered an independent therapy for HCC.

Vaccination of Metastatic Melanoma Patients With Autologous Tumor-Derived Heat Shock Protein gp96-Peptide Complexes: Clinical and Immunologic Findings

PURPOSE To determine the immunogenicity and antitumor activity of a vaccine consisting of autologous, tumor-derived heat shock protein gp96-peptide complexes (HSPPC-96, Oncophage; Antigenics, Inc, Woburn, MA) in metastatic (American Joint Committee on Cancer stage IV) melanoma patients. PATIENTS AND METHODS Sixty-four patients had surgical resection of metastatic tissue required for vaccine production, 42 patients were able to receive the vaccine, and 39 were assessable after one cycle of vaccination (four weekly injections). In 21 patients, a second cycle (four biweekly injections) was given because no progression occurred. Antigen-specific antimelanoma T-cell response was assessed by enzyme-linked immunospot (ELISPOT) assay on peripheral blood mononuclear cells (PBMCs) obtained before and after vaccination. Immunohistochemical analyses of tumor tissues were also performed. RESULTS No treatment-related toxicity was observed. Of 28 patients with measurable disease, two had a complete response (CR) and three had stable disease (SD) at the end of follow-up. Duration of CR was 559+ and 703+ days, whereas SD lasted for 153, 191, and 272 days, respectively. ELISPOT assay with PBMCs of 23 subjects showed a significantly increased number of postvaccination melanoma-specific T-cell spots in 11 patients, with clinical responders displaying a high frequency of increased T-cell activity. Immunohistochemical staining of melanoma tissues from which vaccine was produced revealed high expression of both HLA class I and melanoma antigens in seven of eight clinical responders (two with CR, three with SD, and the three with long-term disease-free survival) and in four of 12 nonresponders. CONCLUSION Vaccination of metastatic melanoma patients with autologous HSPPC-96 is feasible and devoid of significant toxicity. This vaccine induced clinical and tumor-specific T-cell responses in a significant minority of patients.

Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study.

Yttrium‐90 radioembolization (Y90RE) is a novel approach to radiation therapy for hepatocellular carcinoma (HCC), never tested in phase 2 studies. Fifty‐two patients with intermediate (n.17) to advanced (n.35) HCC were prospectively recruited to assess, as the primary endpoint, efficacy of Y90RE on time‐to‐progression (TTP). Secondary endpoints were tumor response, safety, and overall survival (OS). All patients were Eastern Cooperative Oncology Group (ECOG) score 0‐1, Child‐Pugh class A‐B7. Y90RE treatments aimed at a lobar delivery of 120 Gy. Retrospective dosimetric correlations were conducted and related to response. Fifty‐eight treatments were performed on 52 patients. The median follow‐up was 36 months. The median TTP was 11 months with no significant difference between portal vein thrombosis (PVT) versus no PVT (7 versus 13 months). The median OS was 15 months (95% confidence interval [CI], 12‐18 months) with a nonsignificant trend in favor of non‐PVT versus PVT patients (18 versus 13 months). Five complete responses occurred (9.6%), and the 2 year‐progression rate was 62%. Objective response was 40.4%, whereas the disease control rate (78.8%) significantly affected survival (responders versus nonresponders: 18.4% versus 9.1%; P = 0.009). Tumor response significantly correlated with absorbed dose in target lesions (r = 0.60, 95% CI, 0.41‐0.74, P < 0.001) and a threshold of 500 Gy predicted response (area under the curve, 0.78). Mortality at 30‐90 days was 0%‐3.8%. Various grades of reduction in liver function occurred within 6 months in 36.5% of patients, with no differences among stages. On multivariate analysis, tumor response was the sole variable affecting TTP (P < 0.001) and the second affecting survival (after Child‐Pugh class). Conclusion: Y90RE is an effective treatment in intermediate to advanced HCC, particularly in the case of PVT. Further prospective evaluations comparing Y90RE with conventional treatments are warranted. (HEPATOLOGY 2013)

Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial.

The efficacy and cost-effectiveness of low-dose spiral computed tomography (LDCT) screening in heavy smokers is currently under evaluation worldwide. Our screening program started with a pilot study on 1035 volunteers in Milan in 2000 and was followed up in 2005 by a randomized trial comparing annual or biennial LDCT with observation, named Multicentric Italian Lung Detection. This included 4099 participants, 1723 randomized to the control group, 1186 to biennial LDCT screening, and 1190 to annual LDCT screening. Follow-up was stopped in November 2011, with 9901 person-years for the pilot study and 17 621 person-years for Multicentric Italian Lung Detection. Forty-nine lung cancers were detected by LDCT (20 in biennial and 29 in the annual arm), of which 17 were identified at baseline examination; 63% were of stage I and 84% were surgically resectable. Stage distribution and resection rates were similar in the two LDCT arms. The cumulative 5-year lung cancer incidence rate was 311/100 000 in the control group, 457 in the biennial, and 620 in the annual LDCT group (P=0.036); lung cancer mortality rates were 109, 109, and 216/100 000 (P=0.21), and total mortality rates were 310, 363, and 558/100 000, respectively (P=0.13). Total mortality in the pilot study was similar to that observed in the annual LDCT arm at 5 years. There was no evidence of a protective effect of annual or biennial LDCT screening. Furthermore, a meta-analysis of the four published randomized trials showed similar overall mortality in the LDCT arms compared with the control arm.

Clinical Utility of a Plasma-Based miRNA Signature Classifier Within Computed Tomography Lung Cancer Screening: A Correlative MILD Trial Study

PURPOSE Recent screening trial results indicate that low-dose computed tomography (LDCT) reduces lung cancer mortality in high-risk patients. However, high false-positive rates, costs, and potential harms highlight the need for complementary biomarkers. The diagnostic performance of a noninvasive plasma microRNA signature classifier (MSC) was retrospectively evaluated in samples prospectively collected from smokers within the randomized Multicenter Italian Lung Detection (MILD) trial. PATIENTS AND METHODS Plasma samples from 939 participants, including 69 patients with lung cancer and 870 disease-free individuals (n = 652, LDCT arm; n = 287, observation arm) were analyzed by using a quantitative reverse transcriptase polymerase chain reaction-based assay for MSC. Diagnostic performance of MSC was evaluated in a blinded validation study that used prespecified risk groups. RESULTS The diagnostic performance of MSC for lung cancer detection was 87% for sensitivity and 81% for specificity across both arms, and 88% and 80%, respectively, in the LDCT arm. For all patients, MSC had a negative predictive value of 99% and 99.86% for detection and death as a result of disease, respectively. LDCT had sensitivity of 79% and specificity of 81% with a false-positive rate of 19.4%. Diagnostic performance of MSC was confirmed by time dependency analysis. Combination of both MSC and LDCT resulted in a five-fold reduction of LDCT false-positive rate to 3.7%. MSC risk groups were significantly associated with survival (χ1(2) = 49.53; P < .001). CONCLUSION This large validation study indicates that MSC has predictive, diagnostic, and prognostic value and could reduce the false-positive rate of LDCT, thus improving the efficacy of lung cancer screening.

A phase II trial of vaccination with autologous, tumor-derived heat-shock protein peptide complexes Gp96, in combination with GM-CSF and interferon-α in metastatic melanoma patients

The aim of this study was to determine the immunogenicity and antitumor activity of autologous, tumor-derived heat shock protein gp96-peptide complex vaccine (HSPPC-96; Oncophage®) given with GM-CSF and IFN-α in pre-treated metastatic (AJCC stage IV) melanoma patients. Patients underwent surgical resection of metastatic lesions for HSPPC-96 production. HSPPC-96 was administered subcutaneously (s.c.) in four weekly intervals (first cycle). Patients with more available vaccine and absence of progressive disease received four additional injections in 2-week intervals (second cycle) or more. GM-CSF was given s.c. at the same site at days –1, 0 and +1, while IFN-α (3 MU) was administered s.c. at a different site at days +4 and +6. Antigen-specific anti-melanoma T and NK lymphocyte response was assessed by enzyme-linked immunospot assay on peripheral blood mononuclear cells obtained before and after vaccination. Thirty-eight patients were enrolled, 20 received at least four injections (one cycle) of HSPPC-96 and were considered assessable. Toxicity was mild and most treatment-related adverse events were local erythema and induration at the injection site. Patients receiving at least four injections of HSPPC-96 were considered evaluable for clinical response: of the 18 patients with measurable disease post surgery, 11 showed stable disease (SD). The ELISPOT assay revealed an increased class I HLA-restricted T and NK cell-mediated post-vaccination response in 5 out of 17 and 12 out of the 18 patients tested, respectively. Four of the five class I HLA-restricted T cell responses fall in the group of SD patients. Vaccination with autologous HSPPC-96 together with GM-CSF and IFN-α is feasible and accompanied by mild local and systemic toxicity. Both tumor-specific T cell-mediated and NK cell responses were generated in a proportion of patients. Clinical activity was limited to SD. However, both immunological and clinical responses were not improved as compared with those recorded in a previous study investigating HSPPC-96 monotherapy.

Interstitial lung diseases in a lung cancer screening trial

We assessed the prevalence of interstitial lung disease (ILD) in a cohort of smokers included in a lung cancer screening trial. Two observers independently reviewed, for the presence of findings consistent with ILD, the computed tomography (CT) examinations of 692 heavy smokers recruited by the Multicentric Italian Lung Detection (MILD) trial. Four CT patterns were considered: usual interstitial pneumonia (UIP), other chronic interstitial pneumonia (OCIP), respiratory bronchiolitis (RB) and indeterminate. Subsequently, the evolution of ILD in those subjects who had undergone a repeat CT examination after 3 yrs was assessed. The UIP pattern and the OCIP pattern were identified in two (0.3%) out of 692 and 26 (3.8%) out of 692 patients, respectively; 109 (15.7%) out of 692 patients showed CT abnormalities consistent with RB, while an indeterminate CT pattern was reported in 21 out of 692 (3%) patients. Age, male sex and current smoking status were factors associated with the presence of OCIP and UIP (combined) pattern, although the relationship did not attain statistical significance. A progression of the disease was observed in three (25%) out of 12 subjects with OCIP who underwent repeat CT after 3 yrs. Thin-section CT features of ILD, probably representing smoking-related ILD, are not uncommon in a lung cancer screening population and should not be overlooked.

Pulmonary Nodules: Volume Repeatability at Multidetector CT Lung Cancer Screening

PURPOSE To assess in vivo volumetric repeatability of an automated software algorithm in pulmonary nodules detected during a lung cancer screening trial. MATERIALS AND METHODS This study was approved by an institutional review board. Written informed consent was obtained from all participants. Data were collected from the Multicentric Italian Lung Detection project, a randomized controlled lung cancer screening trial. The first 1236 consecutive baseline computed tomographic (CT) studies performed at the Istituto Nazionale Tumori of Milan were evaluated. Among the enrolled participants, those who underwent repeat low-dose CT after 3 months and had at least one indeterminate nodule with a volume of more than 60 mm(3) (diameter of 4.8 mm or greater) were considered. Nonsolid, part-solid, and pleural-based nodules were excluded from this study. A descriptive analysis was performed by calculating means and standard deviations of nodule volumes at three assessment times (at baseline and 3 and 12 months later). The volume measurement repeatability was determined by using the approach described by Bland and Altman. RESULTS One hundred one subjects (70 men, 31 women; mean age, 58 years) with 233 eligible nodules (mean volume, 98.3 mm(3); range, 5-869 mm(3)) were identified. The 95% confidence interval for difference in measured volumes was in the range of +/-27%. About 70% of measurements had a relative difference in nodule volume of less than 10%. No malignant lesions were registered during the follow-up of these subjects. CONCLUSION Semiautomatic volumetry is sufficiently accurate and repeatable and may be useful in assisting with lung nodule management in a lung cancer screening program.

Lung function predicts lung cancer risk in smokers: a tool for targeting screening programmes

The relationship between smoking, lung cancer and airflow obstruction is recognised but it is unclear whether the presence of minimal lung function damage constitutes an independent risk factor for the development of lung cancer. In order to identify those individuals at higher risk of lung cancer on the basis of functional impairment, we evaluated baseline pulmonary function tests of 3,806 heavy smokers undergoing annual chest computed tomography screening, and compared the forced expiratory volume in 1 s (FEV1) % predicted of 57 lung cancer cases and that of 3,749 subjects without cancer. We obtained odds ratios (ORs) of lung cancer and the corresponding 95% confidence intervals (CIs) using unconditional logistic regression, adjusting for age, sex, study and smoking variables. Compared with subjects with FEV1 ≥90% pred, the OR of lung cancer was 2.45 (95% CI 1.39–4.33) for subjects with FEV1 <90% pred and 2.90 (95% CI 1.34–6.27) for subjects with FEV1 <70% pred. These data show that even a relatively small reduction in FEV1 % pred is a significant predictor of increased lung cancer risk. Test screening for lung cancer using airflow obstruction with FEV1 <90% is a strategy worth future consideration.

Relationship and Prognostic Value of Modified Coronary Artery Calcium Score, FEV1, and Emphysema in Lung Cancer Screening Population: The MILD Trial

PURPOSE To assess the relationship between a modified coronary artery calcium (mCAC) score and both forced expiratory volume in 1 second (FEV1) and pulmonary emphysema and the associations of such factors with all-cause mortality and cardiovascular events (CVEs) in a lung cancer computed tomographic (CT) screening trial. MATERIALS AND METHODS In this institutional review board-approved study, both clinical and low-dose CT data were evaluated in a cohort of heavy smokers consecutively recruited by the Multicentric Italian Lung Detection, or MILD, trial. Low-dose CT images were analyzed by using software that allowed quantification of mCAC, mean lung attenuation (MLA), and total extent of emphysema. The correlations between mCAC, percentage predicted FEV1, MLA, and emphysema extent were tested by using the Pearson correlation coefficient. Adjusted multiple logistic regression models were applied to assess the relationships between mCAC, FEV1, MLA, and emphysema extent and all-cause mortality and CVEs. RESULTS The final study cohort consisted of 1159 smokers. There were no significant correlations between mCAC score and FEV1 (r=-0.03, P=.4), MLA (r=-0.01, P=.7), or emphysema extent (r=0.02, P=.6). An mCAC score greater than 400 was the only factor that was independently associated with both all-cause mortality (odds ratio [OR]: 3.73; 95% confidence interval [CI]: 1.05, 13.32; P=.04) and CVEs (OR: 2.87; 95% CI: 1.13, 7.27; P=.03). CONCLUSION mCAC is a better predictor of CVE and all-cause mortality than FEV1 and emphysema extent and may contribute to the identification of high-risk individuals in a lung cancer screening setting.