Ciro Romano

DETERMINATION OF MOLECULAR MARKER EXPRESSION CAN PREDICT CLINICAL OUTCOME IN COLON CARCINOMAS

Purpose: Conventional staging procedures are often unable to precisely predict prognosis in colorectal cancer (CRC). In this study, we set out to investigate the possible role of molecular/structural indicators involved in cell cycle regulation (p27 and p53), apoptosis (p53 and p27), and tumor neoangiogenesis [p53, vascular endothelial growth factor (VEGF), and microvessel count] in predicting tumor behavior and clinical outcome in CRC patients Experimental Design: Analysis of the above indicators was performed by immunohistochemistry on 104 CRC patient samples and 25 normal colon mucosa specimens. Results: Intense p27 nuclear staining was found in normal colon mucosa, with p53 nuclear staining and VEGF cytoplasmic accumulation <10%, and low microvessel count. In contrast, in CRC samples, p27 was down-regulated in 53.8%, p53 protein was overexpressed in 52%, and VEGF stained positive in 67.3% of the cases, respectively. Multiple regression analysis showed that molecular markers were strongly correlated. In patients treated with curative surgery, a significant relationship was seen between p27 down-regulation and Dukes’ stage, nodal status, and the presence of distant metastases. VEGF overexpression correlated significantly with Dukes’ stage, tumor (t) and metastasis (m) parameters, and left site. Stepwise regression selected p27, p53, VEGF, and Dukes’ stage as the best combination of variables capable of predicting both disease-specific and disease-free survival. Conclusions: The investigated indicators may be useful for the prediction of outcome and recurrence rate in curatively treated CRC patients. In conjunction with clinical and pathological staging, they may provide a stronger indication of clinical outcome than staging alone and help better select therapeutic options in CRC patients.

Chronic HCV infection and inflammation: Clinical impact on hepatic and extra-hepatic manifestations

The liver has a central role in regulating inflammation by its capacity to secrete a number of proteins that control both local and systemic inflammatory responses. Chronic inflammation or an exaggerated inflammatory response can produce detrimental effects on target organs. Chronic hepatitis C virus (HCV) infection causes liver inflammation by complex and not yet well-understood molecular pathways, including direct viral effects and indirect mechanisms involving cytokine pathways, oxidative stress and steatosis induction. An increasing body of evidence recognizes the inflammatory response in chronic hepatitis C as pathogenically linked to the development of both liver-limited injury (fibrosis, cirrhosis and hepatocellular carcinoma) and extrahepatic HCV-related diseases (lymphoproliferative disease, atherosclerosis, cardiovascular and brain disease). Defining the complex mechanisms of HCV-induced inflammation could be crucial to determine the global impact of infection, to estimate progression of the disease, and to explore novel therapeutic approaches to avert HCV-related diseases. This review focuses on HCV-related clinical conditions as a result of chronic liver and systemic inflammatory states.

Serum interleukin-10 levels in patients with advanced gastrointestinal malignancies

Interleukin‐10 (IL‐10) is a cytokine with immunosuppressive properties. In this study, the authors investigated the prognostic significance of IL‐10 levels in the sera of 58 patients with advanced gastric or colorectal carcinoma.

Interleukin-6 Serum Level Correlates with Survival in Advanced Gastrointestinal Cancer Patients but Is Not an Independent Prognostic Indicator

Interleukin-6 (IL-6) is a pleiotropic cytokine that has been shown to regulate immune defense mechanisms and hematopoiesis. In addition, IL-6 may also be involved in malignant transformation and tumor progression. A poor prognosis in patients with multiple myeloma, renal cell carcinoma, ovarian cancer, or prostate cancer has been associated consistently with elevated IL-6 serum levels. The aim of this study was, therefore, to assess IL-6 serum levels in 68 advanced gastrointestinal cancer patients and to correlate them with prognosis. IL-6 serum levels were found to be significantly elevated in cancer patients with respect to controls. Moreover, patients with disseminated cancer displayed significantly higher IL-6 serum levels than patients without apparent metastases. On univariate analysis, both overall survival (OS) and time to disease progression (TTP) were shown to be affected by IL-6 serum levels. However, multivariate analysis failed to demonstrate an independent prognostic significance for IL-6 serum levels while confirming the role of previously established variables, such as performance status, carcinoembryonic antigen (CEA) serum levels, and distant metastases. In conclusion, this study showed that IL-6 serum levels were elevated in advanced gastrointestinal cancer patients and correlated with both OS and TTP. However, they were shown not to be an independent prognostic factor.

Circulating levels of interleukin-10 and interleukin-6 in gastric and colon cancer patients before and after surgery: relationship with radicality and outcome

Elevated interleukin-10 (IL-10) and IL-6 serum levels in advanced gastrointestinal cancer patients have been shown previously. To investigate the behavior and the prognostic role of IL-10 and IL-6 serum levels in gastric and colon cancer patients undergoing surgery, we studied the relationship between these cytokine levels and surgical radicality and outcome. Seventy-eight patients with gastric or colon cancer were admitted to the study, and 50 underwent radical surgery. Cytokine serum levels were measured by ELISA the day before surgery and 16 days after surgery. Circulating levels of IL-10 and IL-6 were found to be higher in cancer patients than in controls. Both IL-10 and IL-6 serum levels were demonstrated to be able to predict likelihood to perform radical surgery. IL-10 serum levels returned to normal in all but 8 radically resected patients. These 8 patients had tumor recurrence. In contrast, IL-6 serum levels were shown to significantly decrease in all patients but not to normalize regardless of the radicality of the operation. On multivariate analysis, basal IL-10 serum levels were found to be among the variables significantly affecting the disease-free survival rate. Stepwise regression selected tumor stage, number of metastatic resected nodes, and basal IL-10 serum level as the best combination of variables for prediction of likelihood of tumor recurrence. Preoperative IL-10 serum levels may be a useful marker to predict likelihood of performing radical surgery. Abnormally high postoperative IL-10 values negatively affected disease-free survival and tumor recurrence. IL-6 serum levels were found to have a more limited prognostic role.

Behaviour of interleukin-2 serum levels in advanced non-small-cell lung cancer patients: relationship with response to therapy and survival.

Abstract Interleukin(IL)-2 is a T helper (Th) 1 type cytokine that has been shown to play an important role in antitumour immune responses. In this study, the prognostic significance of serum IL-2 levels was investigated in 60 advanced non-small-cell lung cancer (NSCLC) patients. IL-2 serum levels were determined before chemotherapy, at the end of chemotherapy and during follow-up, using a commercially available enzyme-linked immunoadsorbent assay kit. The results were analysed according to the response to therapy and were used to generate a model predicting overall survival and time to treatment failure. All 60 patients were shown to have higher IL-2 serum levels than controls (P < 0.0001). Stage IV patients had significantly lower IL-2 levels than stage III patients (P < 0.0001), although they were still significantly higher than controls (P < 0.0001). It is interesting that, when patients were divided into responders and non-responders according to the response to therapy, the former were shown to have significantly higher pre-chemotherapy levels than the latter (P < 0.0001). Moreover, a further significant increase in IL-2 serum levels (P=0.004) and a significant decrease (P < 0.0001) were shown in responders and non-responders, respectively at the end of the therapy. Using univariate and multivariate analyses, both overall survival and time to treatment failure were shown to be affected by the mean pathological levels of IL-2. Furthermore, the prognostic significance of the serum level of IL-2 was confirmed by the stepwise regression analysis. In conclusion, determination of pre-treatment IL-2 serum levels was shown to be of independent prognostic utility in patients with advanced NSCLC; therefore, its possible use for prediction of outcome is proposed.

Prognostic Value of p27, p53, and Vascular Endothelial Growth Factor in Dukes A and B Colon Cancer Patients Undergoing Potentially Curative Surgery

PURPOSEEarly-stage colon cancer patients (Dukes A or B; pT1–T3 pNO pMO) are excluded from adjuvant chemotherapy following potentially curative surgery because they are expected to have good long-term survival. However, 20 percent to 30 percent of these patients ultimately succumb from recurrent disease. This indicates that the conventional staging procedures may be unable to precisely predict cancer prognosis.METHODSIn 65 early-stage colon cancers, we investigated by immunohistochemistry the role of molecular markers such as p27, p53, and vascular endothelial growth factor in identifying high-risk patients who may benefit from adjuvant treatments.RESULTSNo clinicopathologic factor, namely Dukes stage, t parameter, number of resected nodes, and vascular or lymphatic invasion, was found be an independent significant predictor of disease-specific and disease-free survival. In contrast, each molecular marker predicted survival and recurrence rates much better than the conventional Dukes staging system. The best combination of variables for prediction of long-term outcome and recurrence rate included p27, p53, and vascular endothelial growth factor. Interestingly, the greater the number of molecular alterations, the lower the five-year estimated survival function. Nearly all cancer-related deaths were observed among patients whose colon cancers expressed all three molecular alterations. Regardless of Dukes stage, the recurrence rate was found to increase with the increase in the number of molecular alterations. Early-stage colon cancers expressing p27 down-regulation and high p53 and vascular endothelial growth factor immunoreactivity showed a 100 percent actuarial four-year recurrence rate.CONCLUSIONSAssessment of molecular alterations may be useful to identify a higher-risk group of early-stage colon cancer patients who may benefit from adjuvant chemotherapy.

Neutrophil to lymphocyte ratio is a strong predictor of tumor recurrence in early colon cancers: A propensity score-matched analysis.

BACKGROUND Systemic inflammation and immune response play a crucial role in tumor growth, and the neutrophil to lymphocyte ratio (NLR) may be a simple way to assess the host inflammatory response. The NLR has been shown to be a prognostic indicator in many human tumors; in early colon cancers, it has been evaluated only in a few studies and its role remains controversial. METHODS We analyzed data from 503 colon cancer patients. The best cutoff value for NLR was defined by receiver operating characteristic curve analysis. We grouped 276 Dukes A/B colon cancers, not receiving adjuvant chemotherapy, into low (<2.36) and high (>2.36) NLR and subjected to further analyses related to disease-free survival (DFS). A propensity score-matched analysis and the inverse probability of treatment weighting (IPTW) were performed to avoid confounding bias. RESULTS The NLR correlated with tumor stage and oncologic outcome. The best NLR cutoff value was identical in the whole cohort and in Dukes A/B patients. Low NLR patients had a significantly better DFS rate than high NLR patients (hazard ratio [HR], 0.27; P = .0001); along with elevated carcinoembryonic antigen levels and Dukes B stage, high NLR was an independent prognostic factor of worse prognosis (HR, 2.86; P = .0033). Even in Dukes A patients, NLR discriminated between relapsing and nonrelapsing patients. Propensity score and IPTW analyses confirmed such results, thus excluding possible misinterpretation. CONCLUSION Preoperative NLR, an inexpensive and readily available biomarker, can predict tumor relapse and should be assessed for implementation of tailored therapy in early stage colon cancer.

Primary cardiac T-cell lymphoma

Primary cardiac lymphoma (PCL), defined as a lymphoma clinically mimicking cardiac disease, with the bulk of the tumor located intrapericardially, is extremely rare in immunocompetent patients. Clinical manifestations vary depending on sites of involvement in the heart and include chest pain, arrhythmias, pericardial effusion, and heart failure. Diagnosis is often difficult and may require invasive procedures; in some cases, diagnosis is not made until autopsy. Histologically, nearly all cases of PCL reported thus far have been of B-cell origin. In this report, we describe a case of PCL of T-cell origin in an adult immunocompetent patient, the second reported in the literature to the best of our knowledge, and provide a brief overview of the features of previously published PCL cases.

Behavior of Circulating CD4+CD25+Foxp3+ Regulatory T Cells in Colon Cancer Patients Undergoing Surgery

CD4+CD25+Foxp3+ regulatory T cells (Treg) specialize in suppressing immune responses. In this study, 47 consecutive colon cancer patients were subjected to circulating Treg frequency assessment by flow cytometry before and after cancer resection. Thirty-two healthy subjects served as controls. Circulating Treg frequencies were significantly higher in colon cancer patients with respect to healthy controls. When patients were subgrouped according to Dukes stages, a linear relationship was observed between Dukes stages and Treg frequencies. In radically resected patients, Treg frequencies were shown to have significantly dropped down. Patients with advanced colon cancer were more likely to have significantly higher proportions of circulating Treg frequencies than Dukes A and B patients when compared to healthy subjects. Of note, nonradically resected patients were found to display reductions in—but not normalization of—Treg frequencies. These results suggest that cancer itself may be able to drive Treg recruitment as a strategy of immunoevasion.