Intact p73 function is shown to be an important determinant of cellular sensitivity to anticancer agents. Inhibition of p73 function by dominant-negative proteins or by mutant p53 abrogates apoptosis and cytotoxicity induced by these agents. A polymorphism encoding either arginine (72R) or proline (72P) at codon 72 of p53 influences inhibition of p73 by a range of p53 mutants identified in squamous cancers. Clinical response following cisplatin-based chemo-radiotherapy for advanced head and neck cancer is influenced by this polymorphism, cancers expressing 72R mutants having lower response rates than those expressing 72P mutants. Polymorphism in p53 may influence individual responsiveness to cancer therapy.
BackgroundIn cancer patients, malnutrition is associated with treatment toxicity, complications, reduced physical functioning, and decreased survival. The Prevalence of Malnutrition in Oncology (PreMiO) study identified malnutrition or its risk among cancer patients making their first medical oncology visit. Innovatively, oncologists, not nutritionists, evaluated the nutritional status of the patients in this study.MethodsPreMiO was a prospective, observational study conducted at 22 medical oncology centers across Italy. For inclusion, adult patients (>18 years) had a solid tumor diagnosis, were treatment-naive, and had a life expectancy >3 months. Malnutrition was identified by the Mini Nutritional Assessment (MNA), appetite status with a visual analog scale (VAS), and appetite loss with a modified version of Anorexia-Cachexia Subscale (AC/S-12) of the Functional Assessment of Anorexia-Cachexia Therapy (FAACT).FindingsOf patients enrolled (N=1,952), 51% had nutritional impairment; 9% were overtly malnourished, and 43% were at risk for malnutrition. Severity of malnutrition was positively correlated with the stage of cancer. Over 40% of patients were experiencing anorexia, as reported in the VAS and FAACT questionnaire. During the prior six months, 64% of patients lost weight (1–10 kg).InterpretationMalnutrition, anorexia, and weight loss are common in cancer patients, even at their first visit to a medical oncology center.
Long noncoding RNAs (lncRNAs) are increasingly known to be important in cancer as they directly interact with the cell cycle, proliferation pathways and microbiome balance. Moreover, lncRNAs regulate the immune system: they do not directly encode proteins of innate or adaptive immunity, but regulate immune cell differentiation and function, such as dendritic cell activity, T cell ratio and metabolism. The result of this complex interaction is that lncRNAs regulate cancer processes through a complex multimodal system involving immunity, metabolism and infection. The possible functions of lncRNAs and their roles in the regulation of cancer immunity will be reported and discussed in the present review. Recent studies showed their function as regulators in the tumour microenvironment (TME), epithelial–mesenchymal transition, microbiota, metabolism and immune cell differentiation. However, there is not much knowledge regarding their roles in cancer immunity regulation. Thus, the main aim of this review is to describe lncRNAs that have specifically been associated with immunity, the immune cycle and the TME.
Immunoglobulin (Ig) G1 antibodies stimulate antibody-dependent cell-mediated cytotoxicity (ADCC). Cetuximab, an IgG1 isotype monoclonal antibody, is a standard-of-care treatment for locally advanced and recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) and metastatic colorectal cancer (CRC). Here we review evidence regarding the clinical relevance of cetuximab-mediated ADCC and other immune functions and provide a biological rationale concerning why this property positions cetuximab as an ideal partner for immune checkpoint inhibitors (ICIs) and other emerging immunotherapies. We performed a nonsystematic review of available preclinical and clinical data involving cetuximab-mediated immune activity and combination approaches of cetuximab with other immunotherapies, including ICIs, in SCCHN and CRC. Indeed, cetuximab mediates ADCC activity in the intratumoral space and primes adaptive and innate cellular immunity. However, counterregulatory mechanisms may lead to immunosuppressive feedback loops. Accordingly, there is a strong rationale for combining ICIs with cetuximab for the treatment of advanced tumors, as targeting CTLA-4, PD-1, and PD-L1 can ostensibly overcome these immunosuppressive counter-mechanisms in the tumor microenvironment. Moreover, combining ICIs (or other immunotherapies) with cetuximab is a promising strategy for boosting immune response and enhancing response rates and durability of response. Cetuximab immune activity-including, but not limited to, ADCC-provides a strong rationale for its combination with ICIs or other immunotherapies to synergistically and fully mobilize the adaptive and innate immunity against tumor cells. Ongoing prospective studies will evaluate the clinical effect of these combination regimens and their immune effect in CRC and SCCHN and in other indications.
BACKGROUNDCancer and cisplatin‐based chemotherapy both are well recognized risk factors for coagulation disorders and thrombosis. However, vascular events (VEs) seldom are considered adverse effects of treatment and may not even be taken into account in reports of chemotherapy trials.METHODSVEs were recorded prospectively in a population of patients with nonsmall‐cell lung carcinoma (NSCLC) who were treated consecutively with cisplatin and gemcitabine using a diagnostic flow chart based on a thorough clinical examination, hematologic and coagulative parameters, and imaging assessments when appropriate.RESULTSFrom January, 2000 to January 2003, 108 patients with Stage III–IV NSCLC underwent chemotherapy and were evaluated. Overall, 22 VEs occurred in 19 patients (17.6%; 95% confidence interval [95% CI], 10.3–24.8%), including 10 arterial VEs (2 myocardial infarctions, 7 lower limb arterial thrombosis, and 1 ischemic stroke) and 12 venous VEs (3 catheter‐related upper limb VEs, 6 venous thrombosis of the lower limb, and 3 pulmonary embolisms). The cumulative proportion of VEs at 1 year after the start of chemotherapy was 22.0% (95% CI, 12.7–31.3%). Four patients died due to the VE (overall mortality, 3.7%), and 3 patients needed surgical revascularization. In the other patients, conservative medical treatment was effective. Baseline patient‐related and disease‐related characteristics of the patients with VEs did not differ significantly from the characteristics of patients without VE; liver and brain metastases were more frequent in patients with VE, although the difference did not reach statistical significance. Response rates were similar in the two groups. A double VE was detected in three patients who were given further chemotherapy after resolution of the first event.CONCLUSIONSVEs were a common finding in chemotherapy‐treated NSCLC patients. Chemotherapy itself seem to be a powerful risk factor for VE. Strategies to predict the occurrence of VEs should be developed to spare this life‐threatening toxicity. Cancer 2005. © 2005 American Cancer Society.
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