Role of neoadjuvant therapy for nonmetastatic pancreatic cancer: Current evidence and future perspectives

Pancreatic adenocarcinoma (PDAC) is one of the most common and lethal human cancers worldwide. Surgery followed by adjuvant chemotherapy offers the best chance of a long-term survival for patients with PDAC, although only approximately 20% of the patients have resectable tumors when diagnosed. Neoadjuvant chemotherapy (NACT) is recommended for borderline resectable pancreatic cancer. Several studies have investigated the role of NACT in treating resectable tumors based on the recent advances in PDAC biology, as NACT provides the potential benefit of selecting patients with favorable tumor biology and controls potential micro-metastases in high-risk patients with resectable PDAC. In such challenging cases, new potential tools, such as ct-DNA and molecular targeted therapy, are emerging as novel therapeutic options that may improve old paradigms. This review aims to summarize the current evidence regarding the role of NACT in treating non-metastatic pancreatic cancer while focusing on future perspectives in light of recent evidence.     

Participation of CYP2C8 and CYP3A4 in the N-demethylation of imatinib in human hepatic microsomes

The receptor activity-modifying proteins (RAMPs) are a family of three single transmembrane proteins that have been identified as accessory proteins to some G-protein-coupled receptors (GPCRs). They can regulate their pharmacology, forward trafficking and recycling, depending on the GPCR. The best characterized receptor complexes formed by RAMPs and GPCRs are the calcitonin peptide family receptors. The association of RAMP1 with the calcitonin receptor-like receptor (CL) constitutes the calcitonin gene-related peptide receptor, whereas RAMP2 or 3 with CL generates adrenomedullin receptors. In this case, the RAMPs substantially alter the pharmacology and trafficking properties of this GPCR. Amylin receptor subtypes are formed from calcitonin receptor (CTR) interactions with RAMPs. Although the RAMPs themselves are not responsive to calcitonin peptide family ligands, there is clear evidence that they participate in ligand binding, although it is still unclear whether this is by directly participating in binding or through allosteric modulation of CL or CTR. A considerable amount of mutagenesis data have now been generated on RAMPs to try and identify the residues that play a role in ligand interactions, and to also identify which residues in RAMPs interact with CL and CTR. This review will focus on RAMP mutagenesis studies with CL, summarizing and discussing the available data in association with current RAMP models and structures. The data reveal key regions in RAMPs that are important for ligand binding and receptor interactions.This article is part of a themed section on Molecular Pharmacology of GPCR. To view the editorial for this themed section visit http://dx.doi.org/10.1111/j.1476-5381.2010.00695.x     

Molecular aspects of insulin therapy in critically ill patients

PURPOSE OF REVIEW: This review provides an overview of molecular mechanisms involved in beneficial effects of insulin in insulin resistant critically ill patients. RECENT FINDINGS: Intense insulin therapy reduced morbidity in critically ill patients. Insulin acts by two major molecular pathways: reduction of the inflammation process induced by free fatty acid excess in tissues and decrease of reactive oxygen species production induced by hyperglycemia. By these actions, insulin preserves mitochondrial function, enhances adiponectin secretion and probably modulates AMP-activated protein kinase activity, which in turn depletes lipid depots in tissues and restores glucose uptake and oxidation. Furthermore, it was recently established that insulin prevents microcirculation alteration and subsequent cellular hypoxia by reducing inducible nitric oxide synthase expression and activity in the endothelium. So, insulin beneficial effects in critically ill patients are dependent on metabolic and non-metabolic molecular pathways. SUMMARY: Critically ill patients requiring intensive care for more than a few days have a high risk of death. A tight control of glucose levels by intense insulin therapy reduced morbidity in critically ill patients. Unraveling the molecular mechanisms of insulin will provide new insights into the pathogenesis of multiple organ failure and will allow novel therapeutic strategies to manage patients needing intensive care.     

In utero exposure to di-(2-ethylhexyl) phthalate affects liver morphology and metabolism in post-natal CD-1 mice

The plasticizer di-(2-ethylhexyl)phthalate (DEHP) affects reproductive development, glycogen and lipid metabolism. Whereas liver is a main DEHP target in adult rodents, the potential impact on metabolic programming is unknown. Effects of in utero DEHP exposure on liver development were investigated upon treatment of pregnant CD-1 mice on gestational days (GD)11–19. F1 mice were examined at post-natal days 21 (weaning) and 35 (start of puberty): parameters included liver histopathological, immunocytochemical and α-fetoprotein (AFP) gene expression analyses. In utero DEHP exposure altered post-natal liver development in weanling mice causing significant, dose-related (i) increased hepatosteatosis, (ii) decreased glycogen storage, (iii) increased β-catenin intracytoplasmic localization (females only). At puberty, significantly decreased glycogen storage was still present in males. A treatment-induced phenotype was identified with lack of glycogen accumulation and intracytoplasmic localization of β-catenin which was associated with increased AFP gene expression. Our findings suggested that DEHP alters post-natal liver development delaying the programming of glycogen metabolism.     

Modulation of systemic and intestinal immune response by interleukin-2 therapy in gastrointestinal surgical oncology. Personal experience in the context of current knowledge and future perspectives

Interactions between host and malignant tumor is currently under intensive investigation. The immune system seems to have a key role in cancer development and spread. Novel strategies to actively modulate the immune system have been proposed to improve the outcome of disease in patients with neoplasms. Our experience with systemic immunomodulation by interleukin-2 (IL-2) focused on both systemic and local immunity in surgical gastrointestinal cancer. Preoperative IL-2 subcutaneous injection was effective in counteracting postoperative immunosuppression, with a reduction of serum levels of IL-6 and the maintenance of preoperative levels of IL-12, a higher number of circulating total lymphocytes, and CD3(+) and CD4(+) T-cells, and a smaller decrease in circulating mature and immature dendritic cells (DCs), as well as a reduction in postoperative serum levels of vascular endothelial growth factor. At the intestinal level, in patients with colorectal cancer, preoperative administration of IL-2 affected both phenotype and function of resident dendritic cells and T-cells, skewing local immunity toward a more immunogenic one. Our data showed that immunomodulation by IL-2 was effective in counteracting the systemic postoperative immune suppression related to surgical stress. IL-2 was also active at a local level on intestinal immunity, affecting both phenotype and function of resident T-cells and DCs. Future studies will encompass the possibility of reaching more adequate intratumoral IL-2 concentrations by direct intralesional injection to maximize immunostimulatory effects and minimize adverse effects.     

Metachronous malignancies in men with previous prostate cancer in Umbria, Italy, 1994-2003

Data about second primary tumors after prostate carcinoma are controversial. Some authors emphasize an increased incidence of some cancer sites, others an overall diminution. With the aim to provide further information to define the issue, we have analyzed the frequency of second metachronous primary malignancies in patients with diagnosed prostate cancer in the Umbria region of Italy. A total of 410 metachronous cancers among 4528 prostate cancer patients were abstracted from incident cases of the RTUP, over the period 1994-2003. This cohort was compared with all cases (except prostate cancers) recorded in the RTUP archive. The expected number of cases was obtained from indirect standardization with regional incidence rates of several sites. The significance of the observed/expected ratios and the corresponding 95% confidence intervals were based on the Poisson distribution. A significant standardized incidence ratio was found for all sites but prostate, with 410/351 observed/expected cases. The significance disappears considering all sites except prostate and skin non-melanomas. Among several sites, significant standardized incidence ratios were found for skin non-melanomas, for bladder, for rectum, but not for colon cancers. Kidney, ureter and urethra showed a nonsignificant standardized incidence ratio. Nasopharynx showed a significant standardized incidence ratio, but the result was based on a very small number of cases. In our data, the increase in urinary bladder and rectal cancers, after prostate cancer diagnosis, seems to be real: it is plausible that the number of second cancers may be due to increased urologist surveillance, which, in our Region, does not seem to be reduced in elderly men.     

Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients.

PURPOSE: The commercial availability of zoledronic acid, a third generation bisphosphonate, prompted us to evaluate the modifications in angiogenic cytokines levels after a single i.v. infusion of this drug. Experimental Design: Thirty consecutive cancer patients with scintigraphic and radiographic evidence of bone metastases were treated with a single infusion of 4 mg of zoledronic acid before any chemotherapy. The patients were prospectively evaluated for circulating levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) just before and at 1, 2, 7, and 21 days after zoledronic acid infusion. RESULTS: Basal serum VEGF median levels were significantly decreased at days 2 (-23%), 7 (-28%), and 21 (-34%) after zoledronic acid infusion (P = 0.0498, 0.0090, and 0.0011, respectively). Serum PDGF levels were significantly decreased by 25% 1 day after zoledronic acid infusion (P = 0.0032). This effect on circulating PDGF levels persisted for 2 days after bisphosphonate infusion (P = 0.0050). PDGF levels had returned to values similar to the median basal value at 7 and 21 days. Moreover, a linear regression model with variance analysis showed a significant positive correlation between basal VEGF and PDGF values but not at the following time points. No significant differences were recorded in platelet levels, WBC count, or hemoglobin concentration before and after zoledronic acid single infusion. CONCLUSIONS: This study confirms that zoledronic acid could have an in vivo antiangiogenic property through a significant and long-lasting reduction in serum VEGF levels.     

Inclusion of rituximab in treatment protocols for non-Hodgkin's lymphomas and risk for progressive multifocal leukoencephalopathy

Objectives. Rituximab is an anti-CD20 monoclonal antibody that promotes better treatment outcomes in patients with non-Hodgkin's lymphoma (NHL). Case series of progressive multifocal leukoencephalopathy (PML) in patients receiving rituximab within polychemotherapy regimens have led to the introduction of a black box warning, but no risk estimation has ever been provided. Methods. We performed a retrospective, monocentric cohort study on 976 NHL patients diagnosed in 1994-2008, including 517 patients who received at least one dose of rituximab. Results. Inclusion of rituximab into standard chemotherapy regimens for NHL caused a significantly higher incidence of PML cases (rate difference, 2.2 every 1,000 patient-years; 95% confidence interval, 0.1-4.3). Interpretation. Based on this finding, clinical surveillance of PML-related symptoms is recommended in NHL patients exposed to rituximab.