Cetuximab, irinotecan and fluorouracile in fiRst-line treatment of immunologically-selected advanced colorectal cancer patients: the CIFRA study protocol.

BACKGROUND: Combination of chemotherapies (fluoropirimidines, oxaliplatin and irinotecan) with biologic drugs (bevacizumab, panitumumab, cetuximab) have improved clinical responses and survival of metastatic colorectal cancer (mCRC). However, patients' selection thorough the identification of predictive factors still represent a challange. Cetuximab (Erbitux®), a chimeric monoclonal antibody binding to the Epidermal Growth Factor Receptor (EGFR), belongs to the Immunoglobulins (Ig) grade 1 subclass able to elicite both in vitro and in vivo the Antibody-Dependent Cell-mediated Cytotoxicity (ADCC). ADCC is the cytotoxic killing of antibody-coated target cells by immunologic effectors. The effector cells express a receptor for the Fc portion of these antibodies (FcγR); genetic polymorphisms of FcγR modify the binding affinity with the Fc of IgG1. Interestingly, the high-affinity FcγRIIIa V/V is associated with increased ADCC in vitro and in vivo. Thus, ADCC could partially account for cetuximab activity. METHODS/DESIGN: CIFRA is a single arm, open-label, phase II study assessing the activity of cetuximab in combination with irinotecan and fluorouracile in FcγRIIIa V/V patients with KRAS, NRAS, BRAF wild type mCRC. The study is designed with a two-stage Simon model based on a hypothetical higher response rate (+ 10%) of FcγRIIIa V/V patients as compared to previous trials (about 60%) assuming ADCC as one of the possible mechanisms of cetuximab action. The test power is 95%, the alpha value of the I-type error is 5%. With these assumptions the sample for passing the first stage is 14 patients with > 6 responses and the final sample is 34 patients with > 18 responses to draw positive conclusions. Secondary objectives include toxicity, responses' duration, progression-free and overall survival. Furthermore, an associated translational study will assess the patients' cetuximab-mediated ADCC and characterize the tumor microenvironment. DISCUSSION: The CIFRA study will determine whether ADCC contributes to cetuximab activity in mCRC patients selected on an innovative immunological screening. Data from the translational study will support results' interpretation as well as provide new insights in host-tumor interactions and cetuximab activity. TRIAL REGISTRATION: The CIFRA trial (version 0.0, June 21, 2018) has been registered into the NIH-US National Library of Medicine, ClinicalTrials.gov database with the identifier number ( NCT03874062 ).

Risk of thyroid cancer and high prevalence of hepatitis C virus.

Some studies report an increased risk of autoimmune thyroid disease in hepatitis C and B as well as in interferon therapy. Recently a new link between HCV and papillary thyroid cancer has been published. The mechanism responsible for the oncogenetic role of HCV is not well understood, but it involves immunity system and autoimmunity disorders. We designed a case-control study on HCV exposure. To assess the positivity to HCV ELISA test and polymerize chain reaction technique (PCR) were used. For statistical analysis an odds ratio and corresponding 95% confidence intervals were computed using unconditional multiple-logistic-regression models. Our findings show a statistically significant association between HCV and papillary thyroid cancer (OR = 3.3, 95% CI 1.5-7.4, p=0.003), overall in female gender (OR = 3.3, 95% CI 1.2-8.7, p=0.01) and in the > or =50 years age category the risk for thyroid cancer was confirmed by the OR = 3.2 (95% CI 1.3-7.9, p=0.01). Based on our study there is an association between HCV and thyroid cancer and it is more readily detectable in countries with a high prevalence of HCV.

Risk factors for classical Kaposi's sarcoma.

BACKGROUND: Classical Kaposi's sarcoma (KS) is a malignancy of lymphatic endothelial skin cells. Although all forms of KS are associated with the KS-associated herpesvirus (KSHV), classical KS occurs in a small fraction of KSHV-infected people. We sought to identify risk factors for classical KS in KSHV-infected individuals. METHODS: Lifestyle and medical history data from case patients with biopsy-proven non-AIDS (non-acquired immunodeficiency syndrome) KS in Italy were compared by logistic regression analysis with data from population-based KSHV-seropositive control subjects of comparable age and sex. After KSHV immunofluorescence testing, randomly selected patients on the rosters of local physicians were identified as control subjects. Risk of KS was estimated by odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: From April 13, 1998, through October 8, 2001, we enrolled 141 classical KS case patients and 192 KSHV-seropositive control subjects of similar age (mean = 72 years for case patients and 73 years for control subjects) and sex (30% female case patients and 35% female control subjects). The strongest association was a reduced risk of KS with cigarette smoking (OR = 0.25, 95% CI = 0.14 to 0.45). Cigarette smoking intensity and duration could be evaluated for men, among whom the risk for KS was inversely related to the amount of cumulative smoking (P(trend)<.001). KS risk decreased approximately 20% (OR = 0.81, 95% CI = 0.74 to 0.89) for each 10 pack-years reported, and it was decreased sevenfold (OR = 0.14, 95% CI = 0.07 to 0.30) with more than 40 pack-years. In multivariable analysis, a decreased KS risk was associated with smoking (OR = 0.23, 95% CI = 0.12 to 0.44); but an increased KS risk was associated with topical corticosteroid use (OR = 2.73, 95% CI = 1.35 to 5.51), infrequent bathing (OR = 1.85, 95% CI = 1.04 to 3.33), and a history of asthma (OR = 2.18, 95% CI = 0.95 to 4.97) or of allergy among men (OR = 2.59, 95% CI = 1.15 to 5.83) but not among women (OR = 0.09, 95% CI = 0.003 to 2.76). KS was not related to other exposures or illnesses examined. CONCLUSION: Risk for classical KS was approximately fourfold lower in cigarette smokers, a result that requires confirmation by other studies. Identification of how smoking affects KS risk may lead to a better understanding of the pathogenesis of this malignancy and interventions for its prevention.