Critical appraisal of ramucirumab (IMC-1121B) for cancer treatment: from benchside to clinical use.

Although antiangiogenic treatments have produced milestone advances in the treatment of several diseases, and have significantly extended the median survival of cancer patients, these agents share some weaknesses, including a limited impact on the overall cure rate, a fleeting effect because of redundant pathways or early appearance of resistance mechanisms, and the lack of predictive factors for treatment selection. Recent data suggest that antibodies targeting the vascular endothelial growth factor axis exert their activity through the inhibition of vascular endothelial growth factor receptor-2 phosphorylation, which has a pivotal role in the neoangiogenic process. Ramucirumab, a fully humanized monoclonal antibody specifically directed against the extracellular domain of the receptor, administered intravenously every 2 or 3 weeks, is emerging as a novel antiangiogenic opportunity. Starting with preclinical data and early clinical results, this concise review focuses on the development of the novel compound across multiple cancers (including gastrointestinal malignancies, breast cancer, lung carcinoma, and genitourinary tumors), and presents available data from randomized phase II and phase III trials. REGARD was the first phase III study to report on the efficacy of single-agent ramucirumab in patients with advanced cancer. Many other ongoing phase III trials are testing the efficacy of this interesting antiangiogenic compound as a single agent or in combination with chemotherapy in different cancer types.

Alteration of hypothalamic-pituitary-thyroid axis function in non-small-cell lung cancer patients.

The aim of this study was to evaluate the hypothalamic-pituitary-thyroid (HPT) axis function in patients suffering from lung cancer. Thyrotropin-releasing hormone (TRH), thyroid-stimulating hormone (TSH), free thyroxine (FT4), interleukin (IL)-2, and melatonin serum levels were measured in blood samples collected every 4 hours for 24 hours from 11 healthy participants (H; ages 35-53 years) and 9 patients suffering from non-small-cell lung cancer (C; ages 43-63 years). Relationships between hormone levels overall and over time of day were evaluated within and among groups. A prominent circadian rhythm with peaks near midnight was present for TSH and melatonin serum levels in both H and C, indicating similar synchronization of the main body clock to the 24-hour environmental light-dark cycle. As regards 24-hour means in H and C, TSH was lower in C, whereas TRH, FT4, and IL-2 were higher in C, with no difference in melatonin levels. Simple linear regression, FT4 versus TRH, showed a positive correlation in H and a negative correlation in C, whereas FT4 versus TSH showed a negative correlation in both groups. For FT4 versus IL-2, a negative correlation was found in C but not for H, whereas TSH versus TRH showed no correlation for either group. Both groups were found to be similarly synchronized to the 24-hour sleep-wake schedule, but HPT axis function was altered in patients suffering from lung cancer. When compared with healthy controls, cancer patients showed modifications of hormone serum levels overall and a negative correlation between individual TRH and FT4 levels.

Comparison of circadian characteristics for cytotoxic lymphocyte subsets in non-small cell lung cancer patients versus controls.

Lymphocyte subsets are major cellular components of the adaptive immune response and in most cases show 24-h (circadian) variations in health. In order to determine overall levels and circadian characteristics of cytotoxic natural killer (NK) and T and B lymphocyte subsets, blood samples were collected every 4 h for 24 h from eleven male controls (C) without neoplastic disease and nine men with untreated non-small cell lung cancer (NSCLC) and analyzed for 3 hormones (melatonin, cortisol, and interleukin 2 [IL2]) and for 11 lymphocyte subpopulations classified by cell surface clusters of differentiation (CD) and antigen receptors. Circadian rhythmicity for each variable was evaluated by ANOVA and 24 h cosine fitting and groups compared. Rhythms in melatonin and cortisol (peaks near 01:30 and 08:00 h) indicated identical synchronization to the light-dark schedule and probable persistent entrainment of rhythms for both groups in metabolism or proliferation of healthy tissues normally tightly coupled to the sleep-wake cycle. Twenty-four hours means were significantly higher in NSCLC for CD16, CD25, cortisol, and IL2 and lower for CD8, CD8bright, and γδTCR. A significant circadian rhythm was found in C with daytime peaks for CD8, CD8dim, CD16, Vδ2TCR, and cortisol and nighttime peaks for CD3, CD4, CD20, and melatonin, and in NSCLC, with daytime peaks for CD16, γδTCR, Vδ2TCR and cortisol, and nighttime peaks for CD4, CD25, and melatonin. Thus, NSCLC was associated with significant increases or decreases in proportions for several lymphocyte subsets that may reflect disease development, but peak times were nevertheless similar between C and NSCLC for each variable, suggesting that timed circadian administration (chronotherapy) of immunotherapy and other cancer treatments may improve efficacy due to persistent circadian entrainment of healthy tissues.

In vitro resistance selection studies of RLP068/Cl, a new Zn(II) phthalocyanine suitable for antimicrobial photodynamic therapy.

Resistance to antimicrobial agents is emerging in a wide variety of nosocomial and community-acquired pathogens. The development of alternative therapies against nosocomial infections caused by clinically relevant pathogens represents a major public health concern. RLP068/Cl is a novel Zn(II) phthalocyanine proposed as a photosensitizer suitable for antimicrobial photodynamic therapy (APDT) for localized infections. Its ability, following activation by light, to induce resistance in three major human pathogens after 20 daily passages was studied. Simultaneously for the same strains, the ability of daily sequential subcultures in subinhibitory concentrations of RLP068/Cl to develop resistant mutants without illumination was evaluated. We demonstrate that 20 consecutive APDT treatments with RLP068/Cl did not result in any resistant mutants and that, in dark conditions, only Staphylococcus aureus strains had increased MICs of RLP068/Cl. However, even in this case, the susceptibility of the mutated bacteria to APDT was not affected by their MIC increase.