Humoral immune response to p53 correlates with clinical course in colorectal cancer patients during adjuvant chemotherapy

Background and aims Overexpression of p53 protein in malignancies induces an immune response in some cancer patients. We investigated whether production of serum antibodies against p53 (p53-Ab) is associated with pathohistological parameters of colorectal carcinoma and whether p53-Ab can serve as a tumor marker during cancer treatment.Patients and methods Serum samples from 220 colorectal cancer patients during surgery and adjuvant chemotherapy and 42 healthy controls were tested for the presence of p53-Ab by ELISA. Expression of p53 protein in tumors was determined using mouse anti-human p53-Ab.Results Serum p53-Ab were detected in 18% of patients while all controls were negative. A strong correlation between p53-Ab production and p53 protein expression was observed: 70% of p53-Ab positive cases had tumors positive for p53 vs. 52% of p53-Ab negative cases. There was also a significant predominance of p53-Ab positive cases in Dukes stages B and C over stage A. Although surgery alone reduced p53-Ab levels, decreases in p53-Ab titer became significant midterm through chemotherapy compared to both pre- and postoperative values and remained decreased until the completion of treatment.Conclusion The presence of p53-Ab in sera of patients with colorectal cancer indicates tumors in more advanced histopathologic stages (Dukes B, C). Due to low sensitivity (18%) p53-Ab are not recommendable as a preoperative marker for colorectal cancer. However, due to high specificity (100%), their monitoring after surgery and adjuvant chemotherapy has potential for early diagnosis of tumor relapse in p53-Ab positive cases.     

Insulin and GLP-1 analog combinations in type 2 diabetes mellitus: a critical review

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists have been used in clinical management of type 2 diabetes since 2005. Currently approved agents were initially developed and approved for combination therapy with oral antidiabetic drugs (OADs). The potential for combined use with insulin has garnered increasing attention due to the potential to reduce side effects associated with insulin therapy and improve glycemic control. Areas covered: We reviewed published and other publicly released data from controlled and uncontrolled studies that included subjects treated with insulin/GLP-1 analog combination therapy. The currently available guidance for clinical practice when combining insulin and GLP-1 analogs was also summarized. Expert opinion: Limited data currently available from placebo-controlled trials support the use of exenatide twice daily or liraglutide once daily in combination with basal insulin and metformin in subjects with type 2 diabetes unable to attain treatment goals. Several randomized controlled trials are currently studying combinations of insulin with various GLP-1 analogs. Additional guidance on the clinical use of these combinations will likely be forthcoming once these studies are reported. Insulin/GLP-1 analog combinations will require optimization of blood glucose monitoring strategies and delivery systems to decrease the risk of administration errors and reduce the potential complexity of these regimens.     

Phase 2 study of neoadjuvant treatment with NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with HER-2 negative clinical stage II-IIIc breast cancer

NOV-002 (a formulation of disodium glutathione disulfide) modulates signaling pathways involved in tumor cell proliferation and metastasis and enhances anti-tumor immune responsiveness in tumor models. The addition of NOV-002 to chemotherapy has been shown to increase anti-tumor efficacy in animal models and some early phase oncology trials. We evaluated the clinical effects of NOV-002 in primary breast cancer, whether adding NOV-002 to standard preoperative chemotherapy increased pathologic complete response rates (pCR) at surgery, and determined whether NOV-002 mitigated hematologic toxicities of chemotherapy and whether levels of myeloid derived suppressor cells (MDSC) were predictive of response. Forty-one women with newly diagnosed stages II-IIIc HER-2 negative breast cancer received doxorubicin-cyclophosphamide followed by docetaxel (AC?→?T) every 3?weeks and concurrent daily NOV-002 injections. The trial was powered to detect a doubling of pCR rate from 16 to 32% with NOV-002 plus AC?→?T (α?=?0.05, β?=?80%). Weekly complete blood counts were obtained as well as circulating MDSC levels on day 1 of each cycle were quantified. Of 39 patients with 40 evaluable tumors, 15 achieved a pCR (38%), meeting the primary endpoint of the trial. Concurrent NOV-002 resulted in pCR rates for AC?→?T chemotherapy higher than previously reported. Patients with lower levels of circulating MDSCs at baseline and on the last cycle of chemotherapy had significantly higher probability of a pCR (P?=?0.02). Further evaluation of NOV-002 in a randomized study is warranted.     

Epigenetics: A New Link Between Nutrition and Cancer

Emerging studies suggest that dietary components can affect gene expression through epigenetic mechanisms. Epigenetic modifications are heritable and potentially reversible changes in gene expression that do not require changes in the DNA sequence. The main mechanisms of epigenetic control in mammals are DNA methylation, histone modifications, and RNA silencing. The potential reversibility of epigenetic changes suggests that they could be modulated by nutrition and bioactive food compounds. Thus, epigenetic modifications could mediate environmental signals and provide a link between susceptibility genes and environmental factors in the etiology of cancer. Elucidating the impact of nutrition on epigenetic mechanisms may serve as a tool to predict an individuals’ susceptibility to cancer, provide dietary recommendations, or provide therapeutic applications of natural compounds against cancer. The optimal duration and the dose necessary for a chemopreventive effect require further studies. There is limited information about tissue specificity and temporal aspects of dietary treatments. Species differences need to be considered when interpreting results from various models. Importantly, molecular mechanisms of bioactive dietary components should be investigated in greater detail in human intervention studies. Although some of these issues remain controversial, this review mainly focuses on promising data that support the developing field of Nutritional Epigenetics.     

p53 mutations and human papillomavirus infection in oral squamous cell carcinomas: correlation with overall survival.

PURPOSE: The study investigated the pattern of p53 gene mutations and human papillomavirus (HPV) infection concerning their relation to overall survival in patients with oral squamous cell carcinomas of the tongue and floor of the mouth. PATIENTS AND METHODS: The presence of HPV infection in 50 patients, and p53 gene mutations (42 patients from the same group) in the tumour specimens were analysed by polymerase chain reaction and single-stranded conformational polymorphism method. The follow-up period ranged from 12 to 48 (median 29) months. RESULTS: p53 mutations were identified in 11/42 tumours. HPV infection was detected in 32/50 cases, mostly HPV16 (10/32), HPV18 and HPV31 (6/32). A significantly higher incidence of HPV infection was found among smokers (p<0.05) and among patients with poor oral hygiene (p<0.01). The highest incidence of p53 mutations was detected in tumours of histological grade I and nuclear grade III. Patients with p53 mutation or with HPV infection had significantly shorter overall survival when compared with those that were without p53 mutations (p<0.01) or HPV infection (p<0.05). HPV-infected patients with p53 mutation had the worst prognosis when compared with patients with HPV infection only (p<0.01) or with patients negative for both HPV and p53 (p<0.01). CONCLUSION: The results stress once more the importance of HPV for the prognosis of survival of patients with squamous cell carcinoma of lower parts of the oral cavity. The presence of p53 mutations in HPV-infected tumours was associated with an even poorer prognosis for the patients.