Salvatore Andreola

Liver Transplantation for the Treatment of Small Hepatocellular Carcinomas in Patients with Cirrhosis

BACKGROUND The role of orthotopic liver transplantation in the treatment of patients with cirrhosis and hepatocellular carcinoma is controversial, and determining which patients are likely to have a good outcome after liver transplantation is difficult. METHODS We studied 48 patients with cirrhosis who had small, unresectable hepatocellular carcinomas and who underwent liver transplantation. In 94 percent of the patients, the cirrhosis was related to infection with hepatitis B virus, hepatitis C virus, or both. The presence of tumor was confirmed by biopsy or serum alpha-fetoprotein assay. The criteria for eligibility for transplantation were the presence of a tumor 5 cm or less in diameter in patients with single hepatocellular carcinomas and no more than three tumor nodules, each 3 cm or less in diameter, in patients with multiple tumors. Thirty-three patients with sufficient hepatic function underwent treatment for the tumor, mainly chemoembolization, before transplantation. After liver transplantation, the patients were followed prospectively for a median of 26 months (range, 9 to 54). No anticancer treatment was given after transplantation. RESULTS The overall mortality rate was 17 percent. After four years, the actuarial survival rate was 75 percent and the rate of recurrence-free survival was 83 percent. Hepatocellular carcinoma recurred in four patients (8 percent). The overall and recurrence-free survival rates at four years among the 35 patients (73 percent of the total) who met the predetermined criteria for the selection of small hepatocellular carcinomas at pathological review of small hepatocellular carcinomas at pathological review of the explanted liver wer 85 percent and 92 percent, respectively, whereas the rates in the 13 patients (27 percent) whose tumors exceeded these limits were 50 percent and 59 percent, respectively (P=0.01 for overall survival; P=0.002 for recurrence-free survival). In this group of 48 patients with early-stage tumors, tumor-node-metastasis status, the number of tumors, the serum alphafetoprotein concentration, treatment received before transplantation, and 10 other variables were not significantly correlated with survival. CONCLUSIONS Liver transplantation is an effective treatment for small, unresectable hepatocellular carcinomas in patients with cirrhosis.

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.

PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients

BACKGROUND It has been reported that KRAS mutations (and to a lesser extent KRAS mutations with the BRAF V600E mutation) negatively affect response to anti-epidermal growth factor receptor (EGFR) mAbs in metastatic colorectal cancer (mCRC) patients, while the biological impact of the EGFR pathway represented by PI3K/PTEN/AKT on anti-EGFR treatment is still not clear. PATIENTS AND METHODS We analysed formalin-fixed samples from a cohort of 32 mCRC patients treated with cetuximab by means of EGFR immunohistochemistry, EGFR and PTEN FISH analysis, and KRAS, BRAF, PI3KCA, and PTEN genomic sequencing. RESULTS Ten (31%) of 32 patients showed a partial response to cetuximab and 22 (69%) did not [nonresponder (NR)]. EGFR immunophenotype and FISH-based gene status did not predict an anti-EGFR mAb response, whereas KRAS mutations (24%) and PI3K pathway activation, by means of PI3KCA mutations (13%) or PTEN mutation (10%)/loss (13%), were significantly restricted to, respectively, 41% and 37% of NRs. CONCLUSION These findings suggested that KRAS mutations and PI3KCA/PTEN deregulation significantly correlate with resistance to cetuximab. In line with this, patients carrying KRAS mutations or with activated PI3K profiles can benefit from targeted treatments only by switching off molecules belonging to the downstream signalling of activated EGFR, such as mammalian target of rapamycin.

Immunocytochemical markers in stage I lung cancer: relevance to prognosis.

PURPOSE This study investigated the frequency of the expression and prognostic significance of a panel of immunocytochemical markers in resected non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS A total of 515 cases of pathologic stage I NSCLC were analyzed. The median follow-up time of surviving patients was 102 months. The following immunocytochemical markers were tested: blood group A and precursors of blood antigens; laminin receptor; c-erbB1/epidermal growth factor receptor (EGFR) and c-erbB2/Neu; BCl2; p53; and angiogenesis. Kaplan-Meier estimates of survival and time to recurrence were calculated for clinical variables and biologic markers using the Cox model for multivariate analysis. RESULTS The pathologic tumor extension (pT) represented the most powerful prognostic factor for survival (P = .0008) and time to recurrence (P = .0007). None of the immunocytochemical markers emerged as an independent predictive factor for survival. Bcl2-positive tumors showed a better time to recurrence (P = .03), but the difference lost statistical significance in the multivariate analysis. Of interest, in the group of 137 patients classified as pT1N0, both EGFR expression and nonangiogenic type of vascular pattern were associated with a poorer survival (P = .02). However, data derived from subset analysis must be interpreted cautiously. CONCLUSION Our findings do not support a relevant prognostic role of immunocytochemical markers in NSCLC. The evidence is not sufficient to alter clinical practice or even to restrict clinical trials of adjuvant treatments to predefined biologic subsets of patients.

Surgical treatment of phyllodes tumors of the breast

Eighty‐one female patients with phyllodes tumors of the breast, surgically treated from 1974 to 1983, were studied. Their age ranged from 9 to 88 years. According to histology, the series was divided into three groups, of 28 (34.5%) benign tumors, 32 (39.5%) border‐line tumors, and 21 (25.9%) malignant tumors. Because ten patients were lost to follow‐up, only 71 women could be evaluated. All the patients had received surgical treatment: 51 women had been treated conservatively (11 enucleations, 40 wide resections), and 20 had undergone radical operations (13 underwent total and five underwent subcutaneous mastectomies, whereas one underwent modified and one underwent radical mastectomy). The mean follow‐up, for the three groups, was 106 months for benign, 84 months for borderline, and 82 months for malignant tumors; in no case was radical surgery followed by local recurrence: of 51 women conservatively treated, 14 experienced local relapse, i.e., one of 24 women with benign, ten of 22 with borderline, and three of 8 with malignant lesions. Only two of 47 patients (4.2%) with borderline or malignant tumors developed distant metastasis and died from disease. No relationship between tumor size and risk of local recurrence could be demonstrated, and no difference could be identified between borderline and malignant lesions, in terms both of local and distant relapse. Local recurrences do not appear to affect survival: as a consequence, wide resection should be the primary treatment. Enucleation is to be proscribed. Total mastectomy has been indicated for very large tumors and for local recurrences of borderline and malignant lesions. Axillary dissection is not worthwhile.

Extinction and absorption coefficients and scattering phase functions of human tissues in vitro

Optical properties of different human tissues in vitro have been evaluated by measuring extinction and absorption coefficients at 635- and 515-nm wavelengths and a scattering angular dependence at 635 nm. Extinction was determined by the on-axis attenuation of light transmitted through sliced specimens of various thicknesses. The absorption coefficient was determined by placing samples into an integrating sphere. The Henyey-Greenstein function was used for fitting experimental data of the scattering pattern. The purpose of this work was to contribute to the study of light propagation in mammalian tissues. The results show that, for the investigated tissues, extinction coefficients range from ~200 to 500 cm(-1) whereas absorption coefficients, depending on wavelength, vary from 0.2 to 25 cm(-1). Scattering is forward peaked with an average cosine of ~0.7.

Peritonectomy and Intraperitoneal Hyperthermic Perfusion (IPHP): A Strategy That Has Confirmed its Efficacy in Patients with Pseudomyxoma Peritonei

Background: Pseudomyxoma peritonei (PMP) is a rare disease with a poor prognosis characterized by a complete redistribution of mucin within the peritoneal cavity. The aim of this multicentric study was to evaluate the survival, morbidity, toxicity, and mortality of patients with PMP treated by cytoreductive surgery (CRS) with intraperitoneal hyperthermic perfusion (IPHP).Methods: Thirty-three patients with PMP (21 males and 12 females) were enrolled in a phase II clinical trial. One patient underwent surgery twice because of disease recurrence. CRS was performed with peritonectomy procedures. The closed abdomen technique was employed for IPHP with use of cisplatin (25 mg/m2/L) plus mitomycin-C (3.3 mg/m2/L) for 60 minutes under hyperthermic conditions (42.5°C).Results: Thirty-one patients (92%) were optimally cytoreduced. Five-year overall survival, progression-free survival, and locoregional progression-free survival rates were 97%, 43%, and 59%, respectively. Grade II and grade III morbidity was observed in 5 patient (15%) and 6 patients (18%), respectively. There was one treatment-related death (3%), 21 days after treatment.Conclusions: CRS associated with IPHP permitted complete tumor removal with an acceptable morbidity and mortality for patients with PMP. This study confirms the efficacy of the combined treatment in terms of long-term survival and local disease control.

Breast carcinoma presenting as axillary metastases without evidence of a primary tumor

Background. Sixty cases of axillary metastases from clinically occult breast cancer were analyzed. All cases had histologic evidence of metastatic nodes compatible with breast carcinoma.

Monoclonal antibody detection of carcinoma cells in bone marrow biopsy specimens from breast cancer patients

The possibility of using immunologic methods for detecting metastatic cells in bone marrow samples from breast cancer patients was investigated. The MBr1 monoclonal antibody, which recognizes a membrane antigen on breast carcinoma cells and is unreactive on normal bone marrow cells, seemed to be an adequate reagent for this kind of approach. When human leukocyte suspensions artificially contaminated with mammary tumor cells were tested by MBr1 immunofluorescence, it was demonstrated that the added tumor cells could be specifically discriminated from normal cells and that as little as one tumor cell in 200,000 could be detected. With the same methodology we screened bone marrow biopsies from breast cancer patients with apparently uninvolved lymph nodes at the moment of surgery. Immunoreactive tumor cells were detected by the MBr1 antibody in 17% of N‐ patients. None of the bone marrow samples showed any evidence of tumor involvement by conventional histologic analysis.

Biologic and clinicopathologic factors as indicators of specific relapse types in node-negative breast cancer.

PURPOSE AND METHODS We evaluated, in 1,800 patients with node-negative tumors treated with locoregional therapy until relapse, the competitive risks for different types of metastasis by cell proliferation (3H-thymidine labeling index [3H-dT LI]), estrogen receptors (ERs), and progesterone receptors (PgRs), and by the integration of biologic and clinicopathologic information. RESULTS Hormone receptor status and proliferative activity of the primary tumor were not indicative of contralateral failures. Hormone receptors failed to predict the 8-year incidence of locoregional recurrence, but they were significant indicators of distant metastasis and overall survival. The latter finding was confirmed even in multivariate analysis. Conversely, cell proliferation predicted both locoregional and distant metastases and survival, regardless of patient age, tumor size, and ER and PgR status. Recursive partitioning and amalgamation analysis ascribed to cell proliferation an important prognostic role for locoregional recurrence together with patient age and tumor size. CONCLUSION Biologic markers, in particular cell proliferation, provide information for the different types of relapse and could complement the predictive role of pathologic staging.