Impact of Metformin Use and Diabetic Status During Adjuvant Fluoropyrimidine-Oxaliplatin Chemotherapy on the Outcome of Patients with Resected Colon Cancer: A TOSCA Study Subanalysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with increased risk of colon cancer (CC), whereas metformin use seems to be protective. However, the impact of metformin use on the risk of death or disease recurrence after radical surgery for CC remains uncertain. MATERIALS AND METHODS: This is a substudy conducted in patients with high-risk stage II or stage III CC randomized in the TOSCA trial, which compared 3 versus 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy. Objective of the study was to investigate the impact of metformin exposure during adjuvant chemotherapy on overall survival (OS) and relapse-free survival (RFS). We also evaluated the impact of T2DM or metformin dosage on clinical outcomes. RESULTS: Out of 3,759 patients enrolled in the TOSCA trial, 133 patients with diabetes (9.2%) and 1,319 without diabetes (90.8%) were recruited in this study. After excluding 13 patients with diabetes without information on metformin exposure, 76 patients with T2DM (63.3%) were defined as metformin users and 44 (36.7%) as metformin nonusers. After a median follow-up of 60.4 months, 26 (21.7%) patients relapsed and 16 (13.3%) died. Metformin use was neither associated with OS (adjusted hazard ratio [HR], 1.51; 95% confidence interval [CI], 0.48-4.77; p = .4781) nor with RFS (HR, 1.56; 95% CI, 0.69-3.54; p = .2881). Similarly, we found no association between T2DM or metformin dosage and OS or RFS. CONCLUSIONS: Metformin use and T2DM did not impact on OS or RFS in patients with resected CC treated with adjuvant fluoropyrimidine-oxaliplatin chemotherapy. Larger studies and longer follow-up are required to clarify the potential efficacy of metformin in improving the prognosis of patients with CC. IMPLICATIONS FOR PRACTICE: The role of the antidiabetic drug metformin in colon cancer prevention and treatment is highly debated. While low-dose metformin reduced the incidence of colorectal adenomas in two prospective studies, its effect in patients with already established colon cancer remains unclear. In this study, the potential impact of metformin on the survival of resected colon cancer patients who received adjuvant chemotherapy was investigated in the context of the TOSCA study. We did not find any association between metformin use or dosages and patient survival. Prospective studies are required to draw definitive conclusions about metformin impact on colon cancer recurrence and survival.

Novel nanohydrogel of hyaluronic acid loaded with quercetin alone and in combination with temozolomide as new therapeutic tool, CD44 targeted based, of glioblastoma multiforme.

Glioblastoma multiforme is the most common and aggressive primary brain cancer with only ∼3% of patients surviving more than 3 years from diagnosis. Several mechanisms are involved in drug and radiation resistance to anticancer treatments and among them one of the most important factors is the tumor microenvironment status, characterized by cancer cell hypersecretion of interleukins and cytokines. The aim of our research was the synthesis of a nanocarrier of quercetin combined with temozolomide, to enhance the specificity and efficacy of this anticancer drug commonly used in glioblastoma treatment. The nanohydrogel increased the internalization and cytotoxicity of quercetin in human glioblastoma cells and, when co-delivered with temozolomide, contribute to an improved anticancer effect. The nanohydrogel loaded with quercetin had the ability to recognize CD44 receptor, a brain cancer cell marker, through an energy and caveolae dependent mechanism of internalization. Moreover, nanohydrogel of quercetin was able to reduce significantly IL-8, IL-6, and VEGF production in pro-inflammatory conditions with interesting implications on the mechanism of glioblastoma cells drug resistance. In summary, novel CD44 targeted polymeric based nanocarriers appear to be proficient in mediating site-specific delivery of quercetin via CD44 receptor in glioblastoma cells. This targeted therapy lead to an improved therapeutic efficacy of temozolomide by modulating the brain tumor microenvironment.

Enhanced Drug Delivery into Cell Cytosol via Glycoprotein H-Derived Peptide Conjugated Nanoemulsions.

The key role of nanocarriers in improving the pharmacological properties of commonly used drugs is recognized worldwide. It is also known that in the development of new effective nanocarriers the use of targeting moieties integrated on their surface is essential. Herein, we propose a nanocarrier based on an oil in water nanoemulsion coated with a membranotropic peptide derived from the glycoprotein H of Herpes simplex virus 1, known as gH625, in order to reduce endolysosomal accumulation and to enhance cytosolic localization. In addition, we show an enhanced anti-inflammatory activity of curcumin, a bioactive compound isolated from the Curcuma longa plant, when loaded into our engineered nanocarriers. This effect is a consequence of a higher uptake combined with a high curcumin preservation exerted by the active nanocapsules compared to control ones. When loaded into our nanocapsules, indeed, curcumin molecules are directly internalized into the cytosol rather than into lysosomes. Further, in order to extend the in vitro experimental setting with a more complex model and to explore the possibility to use our nanocarriers for further biological applications, we tested their performance in a 3D sprouting angiogenesis model. Finally, we show promising preliminary in vivo results by assessing the anti-inflammatory properties of the proposed nanocarrier.

Oil/water nano-emulsion loaded with cobalt ferrite oxide nanocubes for photo-acoustic and magnetic resonance dual imaging in cancer: in vitro and preclinical studies.

Dual imaging dramatically improves detection and early diagnosis of cancer. In this work we present an oil in water (O/W) nano-emulsion stabilized with lecithin and loaded with cobalt ferrite oxide (Co0.5Fe2.5O4) nanocubes for photo-acoustic and magnetic resonance dual imaging. The nanocarrier is responsive in in vitro photo-acoustic and magnetic resonance imaging (MRI) tests. A clear and significant time-dependent accumulation in tumor tissue is shown in in vivo photo-acoustic studies on a murine melanoma xenograft model. The proposed O/W nano-emulsion exhibits also high values of r2/r1 (ranging from 45 to 85, depending on the magnetic field) suggesting a possible use as T2 weighted image contrast agents. In addition, viability and cellular uptake studies show no significant cytotoxicity on the fibroblast cell line. We also tested the O/W nano-emulsion loaded with curcumin against melanoma cancer cells demonstrating a significant cytotoxicity and thus showing possible therapeutic effects in addition to the in vivo imaging.

Intracardiac metastasis originated from chondrosarcoma.

Primary cardiac tumors are extremely rare. By comparison, metastatic involvement of the heart is over 20 times more common and has been reported in autopsy series in up to one in five patients dying of cancer. Cardiac metastasis of chondrosarcoma is absolutely not frequent. In the recent literature, a cardiac metastasis from chondrosarcoma has never been described. We report the case of an 18-year-old man with a diagnosis of cardiac metastasis that originated from a left scapular chondrosarcoma. Chondrosarcoma is a skeletal tumor with various grades of malignancy, rapidly evolving, and with a strong tendency to metastasize, with low responsiveness to chemotherapy. The onset of characteristic systemic symptoms in the late stage of the disease led to the diagnosis of a mass localized in the right atrium. Management and differential diagnosis of infective heart lesions were also very complex in a rapidly evolving life-threatening condition.

The emerging issue of cardiac dysfunction induced by antineoplastic angiogenesis inhibitors.

Left ventricular dysfunction from anticancer drugs has emerged as a relevant problem in the clinical and scientific communities. Anthracycline toxicity has always been the most relevant, but with the increasing use of biological targeted therapies in treatment protocols, with an increasing number of cancer survivors, new toxicities have been increasing in more recent years. Cardiomyopathy after ErbB2 inhibitors has been intensively studied. Another important class of biological anticancer drugs are vascular endothelial growth factor (VEGF) inhibitors. VEGF signalling is crucial for vascular growth, but it also has a major impact on myocardial function. Also, it is important to note that such angiogenesis inhibitors are multitargeted in most cases, and can produce a broad spectrum of cardiovascular side effects. Here we review the mechanisms and pathophysiology of the most significant cardiotoxic effects of antiangiogenic drugs, and particular attention is drawn to LV dysfunction, discussing the assessment and management on the basis of the most recent cardio-oncological findings and heart failure guidelines.

Detection, monitoring, and management of trastuzumab-induced left ventricular dysfunction: an actual challenge.

The antibody trastuzumab, targeted to inhibit the signalling of ErbB2, a tyrosine kinase receptor overexpressed in 20-30% of breast cancers, improves the prognosis in women affected by this tumour, but produces cardiotoxicity, since ErbB2 is also involved in myocardial homeostasis. In this review, we discuss the pathophysiology of trastuzumab cardiomyopathy and the complex interplay between ErbB2 inhibition and anthracyclines, and we focus on the actual challenges of detecting, monitoring, and managing trastuzumab cardiotoxicity: the research of new, sensitive markers of early trastuzumab toxicity, before the ejection fraction is reduced, is an active field of research.

Metronomic administration of zoledronic acid and taxotere combination in castration resistant prostate cancer patients: phase I ZANTE trial.

BACKGROUND: Docetaxel (DTX) and zoledronic acid (ZOL) are effective in patients with hormone resistant prostate cancer (HRPC) with bone metastases. A phase I clinical trial of metronomic administration of Zoledronic Acid AN d TaxoterE combination (ZANTE trial) in 2 different sequences was conducted in HRPC. RESULTS: The maximum tolerated dose was not achieved with sequence A. Two patients at third level of sequence B developed dose limiting toxicity. A disease control was obtained in six out of nine patients treated with sequence A, where a decrease of biological markers and PSA were also observed. No evidence of anti-tumor activity was observed in patients treated with sequence B. PATIENTS AND METHODS: Twenty-two patients enrolled into the study (median age: 73 years; range: 43-80) received one of three escalated doses of DTX (30, 40 and 50 mg/m(2)) in combination with a fixed dose of ZOL (2 mg), both administered every 14 days in two different sequences: DTX at the day 1 followed by ZOL at the day 2 (sequence A) or the reverse (sequence B). Patients were evaluated for adverse events and serum IL-8, MMP-2 and MMP-9 were evaluated prior and after therapy with the two sequences of administration of DTX and ZOL. CONCLUSIONS: The bi-weekly combination of DTX (50 mg/m(2)) followed by ZOL was feasible and show promising anti-tumor activity.

Target-based agents in neoadjuvant treatment of liver metastases from colorectal cancer: secret weapons in anti-cancer war?

The therapeutic options for liver metastases of colorectal cancer mainly include surgical resection and palliative chemotherapy. More recently, the increased availability of new and more active cytotoxic drugs has increased the appeal of a combined treatment strategy, in which chemotherapy is administered before surgery. However, the efficacy of neoadjuvant chemotherapy of CRC liver metastases is limited by: (1) the persistence of micro metastatic foci that cannot be seen by conventional imaging techniques, placed either in other sites throughout the liver and/or in the site of the previous macroscopic metastasis that has undergone to clinical complete response; (2) the occurrence of escape mechanisms. The molecular basis regulating these processes are described and the first clinical attempts to overcome these mechanisms through the use of target-based agents are also reported. Finally, biological rationales to optimize the activity of these agents in neoadjuvant setting are discussed.

Concomitant occurrence of facial cutaneous and parotid gland metastases from rectal cancer after preoperative chemoradiotherapy.

BACKGROUND: Unusual sites of metastasis to the parotid gland and face are reported in patients with colorectal cancer, but the localization to both sites at the same time has never been described so far. CASE REPORT: Here, we describe the case of a 76-year-old woman with a T3N1M0 G2 rectal adenocarcinoma, treated with preoperative chemoradiotherapy performed at suboptimal dosages due to unacceptable toxicity. At the end of the program, the re-staging demonstrated the presence of metastasis in both the left parotid gland and subcutaneously on the frontal region of her face while the primary locoregional tumour manifestation was radiologically down-staged (reduction in N staging from N1 to N0). The patient did not respond to any other treatment and died due to disease progression 15 months after the diagnosis. CONCLUSIONS: Metastatic tumours in the parotid gland are uncommon with a higher incidence of primary sites of the head and neck. Parotid involvement of rectal adenocarcinoma is also extremely rare, and concomitant involvement of both the parotid gland and the face was not previously described. In this case, we cannot rule out the hypothesis that the delay of surgical removal of the primary tumour and/or a specific action of concomitant chemoradiotherapy on the tumour cell phenotype could promote cancer cell spreading to unusual sites.

Recent advances in the treatment of salivary gland cancers: emphasis on molecular targeted therapy.

Salivary gland cancers include tumors of different histologic characteristics and biological behavior. Radical surgery, followed or not by radiation therapy, represents the main treatment approach for this disease. The role of systemic chemotherapy is less clearly defined since trials of single-agent chemotherapy have consistently shown low response rates. Polychemotherapy is likely to induce a higher response rate, but does not improve survival. The determination of the molecular abnormalities underlying the different subtypes of salivary gland cancers might lead to more active targeted therapies. C-kit is overexpressed in a wide percentage of salivary gland carcinomas, but clinical trials with single-agent imatinib have been negative. ErbB1 and ErbB2 are also frequently overexpressed in salivary gland cancers and this has provided the rationale for clinical trials with trastuzumab, cetuximab, gefitinib, lapatinib. Finally, new pathways, such as vascular endothelial growth factor, might be worth targeting and clinical trials with anti-angiogenic agents are ongoing.