Nicotinamide adenine dinucleotide metabolism in the immune response, autoimmunity and inflammageing.

Metabolism is dynamically regulated to accompany immune cell function, and altered immunometabolism can result in impaired immune responses. Concomitantly, the pharmacological manipulation of metabolic processes offers an opportunity for therapeutic intervention in inflammatory disorders. The nicotinamide adenine dinucleotide (NAD+ ) is a critical metabolic intermediate that serves as enzyme cofactor in redox reactions, and is also used as a co-substrate by many enzymes such as sirtuins, adenosine diphosphate ribose transferases and synthases. Through these activities, NAD+ metabolism regulates a broad spectrum of cellular functions such as energy metabolism, DNA repair, regulation of the epigenetic landscape and inflammation. Thus, the manipulation of NAD+ availability using pharmacological compounds such as NAD+ precursors can have immune-modulatory properties in inflammation. Here, we discuss how the NAD+ metabolism contributes to the immune response and inflammatory conditions, with a special focus on multiple sclerosis, inflammatory bowel diseases and inflammageing. LINKED ARTICLES: This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc.

Glycolysis - a key player in the inflammatory response.

The inflammatory response involves the activation of several cell types to fight insults caused by a plethora of agents, and to maintain the tissue homoeostasis. On the one hand, cells involved in the pro-inflammatory response, such as inflammatory M1 macrophages, Th1 and Th17 lymphocytes or activated microglia, must rapidly provide energy to fuel inflammation, which is essentially accomplished by glycolysis and high lactate production. On the other hand, regulatory T cells or M2 macrophages, which are involved in immune regulation and resolution of inflammation, preferentially use fatty acid oxidation through the TCA cycle as a main source for energy production. Here, we discuss the impact of glycolytic metabolism at the different steps of the inflammatory response. Finally, we review a wide variety of molecular mechanisms which could explain the relationship between glycolytic metabolites and the pro-inflammatory phenotype, including signalling events, epigenetic remodelling, post-transcriptional regulation and post-translational modifications. Inflammatory processes are a common feature of many age-associated diseases, such as cardiovascular and neurodegenerative disorders. The finding that immunometabolism could be a master regulator of inflammation broadens the avenue for treating inflammation-related pathologies through the manipulation of the vascular and immune cell metabolism.

Clinical and technological transition in breast cancer.

This article is a summary of the conference "Clinical and technological transition in breast cancer" that took place in the Congress of the Spanish Society of Radiation Oncology, placed in Vigo (Spain) on June 21, 2013. Hugo Marsiglia and Philip Poortmanns were the speakers, the first discussed about "Clinical and technological transition" and the second about "EORTC clinical trials and protocols".

Multicenter phase II clinical trial of preoperative capecitabine with concurrent radiotherapy in patients with locally advanced rectal cancer.

INTRODUCTION: To assess pathologic complete response, sphincter preservation rates and toxicity profile of preoperative chemoradiation with capecitabine in resectable locally advanced rectal cancer. MATERIALS AND METHODS: Fifty-eight patients from six Spanish centers were included (March 2004 to June 2005) with histological/cytological diagnosis of locally advanced rectal cancer, age between 18 and 80 years, ECOG 0-2, adequate bone marrow, renal and hepatic functions. Prior chemotherapy/radiotherapy was not allowed. Preoperative treatment was capecitabine 825 mg/m(2) bid concomitant to radiotherapy (45 + 5.4 Gy boost over 5.5 weeks). Surgery was performed 4-8 weeks after completion of chemoradiotherapy. RESULTS: Fifty-eight patients were enrolled in this study: 60.3 % males, median age of 64.5 (30.9-78.7) years, 28.6 % with ECOG 0 and 71.4 % with ECOG 1. Median distance of tumor from the anal verge was 7 (1-12) cm. Fifty-two (89.6. %) patients completed preoperative chemoradiotherapy. Primary tumor and node downstaging occurred in 61.1 and 69.6 % of patients, respectively. Surgery was performed in 55 patients (94.8 %): 80 % had negative lymph nodes and 72.7 % underwent sphincter-preserving procedures. A pathologic complete response was observed in 10.5 % (95 % CI 2.5-18.5) of the patients. Main grade I-II toxicities were leucopenia (43.1 %), neutropenia (24.1 %), anemia (36.2 %), diarrhea (32.8 %) and skin disorders (5.1 %), from which diarrhea (6.9 %), leucopenia (1.7 %) and skin disorders (1.7 %) reached grade III. There were no grade IV toxicities. CONCLUSIONS: Preoperative capecitabine-based chemoradiation is a well-tolerated and effective neoadjuvant treatment for locally advanced rectal cancer that achieves encouraging rates of tumor downstaging.

Long-term changes in pulmonary function after incidental lung irradiation for breast cancer: a prospective study with 7-year follow-up.

PURPOSE: To evaluate late pulmonary function changes after incidental pulmonary irradiation for breast cancer. METHODS AND MATERIALS: Forty-three consecutive female patients diagnosed with breast carcinoma and treated with postoperative radiation therapy (RT) at the same dose (50 Gy) and fractionation (2 Gy/fraction, 5 days/week) were enrolled. Pulmonary function tests (PFT) and ventilation/perfusion scans were performed before RT and 6, 12, 24, and 84 months afterward. RESULTS: Forty-one patients, mean age 55 years, were eligible for the analysis. No differences were found in the baseline PFT values for age, smoking status and previous chemotherapy; women undergoing mastectomy showed baseline spirometric PFT values lower than did women treated with conservative surgery. The mean pulmonary dose was 10.9 Gy, being higher in women who also received lymph node RT (15.8 vs 8.6, P<.01). Only 1 patient experienced symptomatic pneumonitis. All PFT values showed a reduction at 6 months. From then on, the forced vital capacity and forced expiratory volume in 1 second began their recovery until reaching, and even exceeding, their baseline values at 7 years. Diffusing capacity of the lungs for carbon monoxide and ventilation/perfusion scans continued to reduce for 24 months and then partially recovered their baseline values (-3.5%, -3.8%, and -5.5%, respectively). Only the percentage difference at 7 years in the ventilation scan correlated with the dosimetric parameters studied. Other variables, such as age, smoking status, previous chemotherapy, and concomitant tamoxifen showed no significant relation with changes in PFT (ΔPFT) values at 7 years. CONCLUSIONS: The study of reproducible subclinical parameters, such as PFT values, shows how their figures decrease in the first 2 years but practically recover their baseline values in the long term. The extent of the reduction in PFT values was small, and there was no clear association with several dosimetric and clinical parameters.

Risk-adapted adjuvant chemotherapy after concomitant fluoropyrimidine-radiotherapy neoadjuvant treatment for patients with resectable cT3-4 or N+ rectal cancer.

Adjuvant chemotherapy in rectal cancer is not well defined.After neoadjuvant chemoradiation and surgery, at least a short period of treatment with 5-fluorouracil is recommended, and some investigators claim a more aggressive approach, in particular, for those patients with a high risk of systemic relapse. Nevertheless, there are few studies about adjuvant combination therapy tolerance and efficacy, and no randomized trials have been conducted comparing fluoropyrimidines versus combination therapy such as folinic acid plus 5-fluorouracil plus oxaliplatin(FOLFOX), considered the standard of care in stage IIIcolon cancer. We present an institutional series of risk adapted adjuvant therapy. Sixty evaluable patients who had received treatment with neoadjuvant fluoropyrimidine radiotherapy and surgery now received adjuvant fluoropyrimidines in the case of pT0-2N0 or oxaliplatin based combination in the case of pT3-4 or N+ . Overall, 33 patients experienced downstaging to pT2-0N0 (55%) and27 patients were restaged as pT3-4 or N+ (45%) after surgery. Local recurrence rate was 5% (three patients), one local and one local plus systemic in the adjuvant single agent group and one local plus systemic in the adjuvant FOLFOX group. Systemic relapse occurred in 14 patients(23.3%), five (15%) in the single-agent group and nine(33.3%) in the FOLFOX group. Disease-free survival at 3 years for patients in the good prognostic group(pT0-2N0) and poor prognostic group (pT3-4 or N+ ) were 78.7 and 62.2%, respectively. Severe diarrhoea was more frequent with fluoropyrimidines and neutropenia, mucositis and peripheral neuropathy were more common with FOLFOX. There were no toxic deaths. A risk-adapted adjuvant therapeutic decision is feasible with an acceptable safety profile even with the use of oxaliplatin based combinations. Three-year disease-free survival compares favourably with historical controls, especially in those patients with high risk factors for relapse.Phase III controlled trials are needed.

Radiation oncology: future needs and equipment. Current situation in Spain.

Spain's radiation oncology infrastructure has evolved in terms of both quantity and structure since the last analysis was carried out in 1999. The purpose of this paper is to describe the current facilities, basically consisting of external radiotherapeutic units, and to present a calculation model for estimating the number of irradiation units required to guarantee equitable cover for radiotherapeutic treatment. An electronic questionnaire was designed to be accessed via a link on the Spanish Association of Radiotherapy and Oncology Web page. The questionnaire provides details of the current state of Spain's radiotherapeutic facilities, and a descriptive study has been performed with analytical data. The scope of the study included all the centres providing oncology-radiotherapy in Spain. The units analysed encompassed the centres and irradiation units actively providing care in 2004. Ninety-seven centres were detected, in which 177 external radiotherapy units were registered. Forty-five of these were cobalt units and 132 were accelerators. The rate of radiotherapy use in Spain based on the best scientific evidence available and on its rate of use with cancer has been estimated at 61%. The number of external irradiation units available in 2004 (177) is clearly lower than the number desirable (266-316).

Guillain-Barre syndrome in a patient with diffuse large B-cell lymphoma, and rituximab maintenance therapy. An association beyond anecdotal evidence?

Paraneoplastic neurological syndromes constitute an unusual manifestation of cancer. The objective of this case report is to debate the association between rituximab therapy and Guillain-Barre syndrome. We present the case of a 57 years old patient, with diffuse large-B cell lymphoma in complete remission, who consulted our hospital because of symmetric lower extremity weakness, developed while being treated with a rituximab maintenance schedule. Our main conclusion is that plasma cell dysregulation due to rituximab should be clarified in future studies.

[Influence of the surgeon as a factor in the surgical treatment of rectal cancer with preoperative radiochemotherapy. A comparative study]. / Influencia del factor cirujano en el tratamiento quirúrgico del cáncer de recto con radioquimioterapia preoperatoria. Estudio comparativo.

INTRODUCTION: In the last few years, changes have been introduced in rectal cancer surgery that have improved its results. These changes include autosuture devices, total mesorectal excision, and neoadjuvant treatment. The aim of the present study was to determine whether the surgeon influences the results of surgical treatment for rectal cancer. PATIENTS AND METHODS: A comparative, retrospective study was performed in 194 consecutive patients with rectal cancer who underwent preoperative radiotherapy. The patients were divided into two groups according to the type of surgeon performing the intervention: group I: 3 surgeons with 101 patients; group II: 16 surgeons with 93 patients. RESULTS: Sphincter-preserving surgery was performed in 77% of patients in group I and in 52% of those in group II (p < 0.001). In group I anterior resection was performed in 100%, 100% and 58% when the tumor was between 11-15 cm, 6-10 cm and 1-5 cm, respectively, compared with 100%, 69% and 23.5% in group II. Complications occurred in 41% of patients in group I and in 48% of those in group II (p = 0.037). Length of hospital stay was 9.9 days in group I and 13.9 days in group II (p < 0.001). Local recurrence occurred in 3.5% of patients in group I and in 11.3% of those in group II (p = 0.054). Survival was similar in both groups. CONCLUSIONS: The surgeon is a key factor in rectal cancer, despite the introduction of autosuture devices, neoadjuvant treatment, and total mesorectal excision. These patients should be operated on by experts in this type of surgery and not by surgeons who perform these interventions only occasionally.

Prognostic significance of vascular endothelial growth factor and cyclooxygenase-2 in patients with rectal cancer treated with preoperative radiotherapy.

PURPOSE: To analyze the prognostic value of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in patients with locally advanced rectal cancer treated with preoperative radiotherapy. METHODS: Eighty-one patients with locally advanced rectal cancer were studied. All patients received preoperative pelvic radiotherapy. Forty-seven patients received concomitant chemotherapy. Surgical resection was performed 4-8 weeks later in all patients. Immunohistochemical examination of COX-2 and VEGF was performed on the preirradiation diagnostic biopsies. An immunohistochemical score established from the extension and intensity of the markers was used for analysis. The log-rank test and proportional hazards regression analysis were used to calculate the probability that the biomarkers were associated with patient outcome. RESULTS: COX-2 expression was positive in 38 tumors (51%) while VEGF expression was positive in 43 (57%). The only clinicopathological parameter significantly associated with COX-2 or VEGF expression was performance status. None of the 2 markers were found to predict treatment response. There was no statistically significant correlation between COX-2 and VEGF. Univariate analysis identified pathological stage (pT, pN) as prognostic for disease-free survival. When VEGF expression was analyzed, disease-free survival was reduced among patients with VEGF-positive tumors (p = 0.047). This was specifically related to metastases-free survival (p = 0.016). These results were not observed for COX-2. After multivariate analysis, the pT and pN stage remained as independent prognostic factors. CONCLUSIONS: VEGF-positive expression is an indicator of poor disease-free survival, specifically linked to distant metastasis. More aggressive treatment strategies are warranted in pT3-4 and pN1-2 rectal cancer patients.

The expression of epidermal growth factor receptor results in a worse prognosis for patients with rectal cancer treated with preoperative radiotherapy: a multicenter, retrospective analysis.

BACKGROUND AND PURPOSE: Expression of epidermal growth factor receptor (EGFR) is observed in 50-70% of colorectal carcinoma and is associated with poor prognosis. The aim of this study was to determine the prognostic value of EGFR status before radiotherapy in a group of patients with locally advanced rectal cancer treated with preoperative radiotherapy. PATIENTS AND METHODS: Eighty-seven patients were studied retrospectively. Treatment consisted of pelvic radiotherapy, in 50 patients with concomitant chemotherapy and surgical resection. Immunohistochemistry for EGFR was determined at the preradiation biopsy and in the resected specimens. Immunohistochemical analysis for EGFR expression was evaluated according to extension and staining intensity. We defined positive staining (EGFR positive), when extension was 5% or more. RESULTS: A total of 52 of 87 tumors showed EGFR positive status at biopsy (60%) and EGFR expression was associated neither with clinical tumor stage nor with clinical nodal stage. EGFR positive expression was linked to a lack of pathologic complete response to preoperative radiotherapy (P=0.006). Disease-free survival was lower among patients with EGFR positive status before radiotherapy (P=0.003). In a multivariate analysis EGFR expression at biopsy was a statistically significant predictor of disease-free survival, RR=2.88(1.1-7.8), P=0.036. CONCLUSIONS: EGFR is expressed in a significant number of rectal tumors. EGFR-positive expression before radiotherapy is an indicator for poor response and low disease-free survival.