Traditional risk factors and nodal yield-still relevant with high-quality risk-adapted adjuvant treatment for locally advanced head and neck cancer?

OBJECTIVE: Patients with locally advanced head and neck cancer (LAHNC) often undergo multimodal therapy including radical resection of the primary tumor and neck dissection (ND) followed by risk-adapted adjuvant radio(chemo)therapy (R(C)T). Quality parameters influencing local control and survival of these patients have been postulated: resection status (R status), extranodal extension (ENE), interval to adjuvant treatment ≤6 weeks, R(C)T given when indicated, and nodal yield (NY) ≥18 lymph nodes per neck. For other solid tumors the trend is towards less extensive lymph node surgery to avoid toxicity such as lymphedema, damage to peripheral nerves, dysesthesia, or paresthesia. The present study aims to investigate whether the number of nodes removed during neck dissection for LAHNC is still predictive for outcome when patients receive risk-adapted adjuvant treatment according to current guidelines. METHODS: Between 2008 and 2015, 468 patients with LAHNC undergoing R(C)T with curative intent were prospectively registered in a database (UICC III/IV). Among them, 359 patients received adjuvant treatment and 295 underwent neck dissection. There were 119 (40%) patients with an oropharyngeal primary, 49 (17%) with cancer of the larynx/hypopharynx, 88 (30%) of the oral cavity, and 39 (13%) of the nasal/paranasal sinuses and cancer of unknown primary (CUP). Median follow-up was 45.6 months. Histopathology revealed an R1 status in 65 (22%) cases and ENE in 93 (31%) cases. 150 (51%) patients received RCT; the median time to adjuvant treatment from the day of tumor resection was 44 days (35-54) and overall treatment time (OTT; time from surgery to the last day of R(C)T) was 90 days (82-101). Factors influencing disease-free survival (DFS) were adjusted and analyzed using CART analysis (removed nodes, number of positive nodes, body mass index (BMI), ENE, T and N classification, R status, and primary site). Local control (LC), distant metastases-free survival (DMFS), and overall survival (OS) were analyzed using Kaplan-Meier statistics and multivariate analysis (MVA) for factors predictive for DFS and OS. RESULTS: CART analysis (Classification and Regression Trees) showed that T classification (T3/4) is the most important predictor for DFS, followed by age (> 61 years) and BMI (< 17.4). Primary site (OPC vs. other) and number of removed nodes (< 17) were shown to be less important for DFS, while ECE, N classification, and R status seem to be of little relevance. MVA revealed number of positive nodes, non-OPC, and T3/4 to be negative predictive factors for DFS. For OS, the number of positive nodes and non-OPC primary were predictive. Five-year rates were 86.1% for LC, 87.9% DMFS, 76.5% DFS, and 67.2% for OS. CONCLUSION: In this patient cohort, the number of removed nodes is not relevant for DFS and OS, while the number of positive nodes and T classification have a negative impact on these endpoints. The high-risk factors positive resection margin and ECE seem to lose their negative impact on DFS and OS. High-quality care in head and oncology is only possible within a close multidisciplinary team and network.

Radio imaging of the very-high-energy gamma-ray emission region in the central engine of a radio galaxy.

The accretion of matter onto a massive black hole is believed to feed the relativistic plasma jets found in many active galactic nuclei (AGN). Although some AGN accelerate particles to energies exceeding 10(12) electron volts and are bright sources of very-high-energy (VHE) gamma-ray emission, it is not yet known where the VHE emission originates. Here we report on radio and VHE observations of the radio galaxy Messier 87, revealing a period of extremely strong VHE gamma-ray flares accompanied by a strong increase of the radio flux from its nucleus. These results imply that charged particles are accelerated to very high energies in the immediate vicinity of the black hole.

Differential protein expression induced by a lipid extract of Perna canaliculus in splenocytes of rats with adjuvant-induced arthritis.

The lipid extract of Perna canaliculus (Lyprinol) has known anti-inflammatory effects. However, the only information on mechanisms is regulation of cytokine secretion. Therefore, we conducted a proteomic study exploring the effects of Lyprinol on protein expression in splenocytes collected from AIA rats. Splenocytes from AIA rats fed with Lyprinol had increased protein expression of malate dehydrogenase (MDH). Lyprinol also decreased the expressions of 5 other proteins: protein-o-mannosyl- transferase 2 (PMT-2), Tdrd 7, telethonin, dynactin 2 and protein disulfide isomerase (PDI or glucose-regulated protein (GRP)). Besides MDH, PMT- 2, titin-cap protein and protein disulfide isomerase (PDI) are known to be related to metabolism. However, it is currently unknown if Lyprinol administration decreases metabolic glucose in the body and alleviates symptoms of inflammation and arthritis. Further experiments are required to correlate levels of citric acid intermediates and glucose to the severity of inflammation and pain in AIA rats fed Lyprinol.

A lipid extract of Perna canaliculus affects the expression of pro-inflammatory cytokines in a rat adjuvant-induced arthritis model.

As published initially in this same journal in 2000, the lipid extract of Perna canaliculus (New Zealand green-lipped mussel; Lyprinol) is known for its anti-inflammatory effects in animal models and in human controlled studies (arthritis; asthma). As a follow-up of its effects on pain in a rat model of adjuvant-induced arthritis (ALA), we studied its effects on the production of cytokines known to be associated with inflammation (IL-6, IL-1alpha TNF-alpha, IFN-gamma). Feeding with Lyprinol was associated with significantly decreased expression levels of TNF-alpha and IFN-gamma when compared to Naproxen (positive control) and, even more when compared with sham and extra-virgin olive oil (negative control). When compared to Naproxen, sham and extra-virgin olive oil, the levels of IL-6 and IL-1alpha were also marginally decreased in rats fed with Lyprinol. This study demonstrates that AIA rats fed with Lyprinol had decreased production ofcytokines associated with inflammation.

Hydrogen peroxide induces a rapid production of nitric oxide in mung bean (Phaseolus aureus).

Nitric oxide (NO) has recently been identified as an important signaling molecule in plant immune response. The present study aims to investigate the signaling pathway that leads to NO production. Using the NO specific fluorescent dye DAF-2DA, we observed rapid production of NO in mung bean leaves after the addition of 10 mM hydrogen peroxide (H(2)O(2)). NO was probably produced by a NOS-like enzyme in plants, as the NO production was inhibited by l-NAME, a NOS inhibitor. The NOS-like activity in the total leaf protein preparation of mung bean (Phaseolus aureus) was elevated 8.3-fold after 10 mM H(2)O(2) treatment, as demonstrated using the chemiluminescence NOS assay. The NOS-like activity was BH(4) dependent: omitting BH(4) in the reaction mixture of NOS assay reduced the NOS activity by 76%. We also found that the H(2)O(2) induced NO production was mediated via calcium ion flux, as it was blocked in the presence of a calcium ion channel blocker, verapamil. Results from the present study identified H(2)O(2) as an upstream signal that leads to NO production in plants. H(2)O(2) and NO, besides acting as two independent signaling molecules in plant immune response, may interrelate to form an oxidative cell death (OCD) cycle.