Alveolar epithelial cells of lung fibrosis patients are susceptible to severe virus-induced injury.

Patients with pulmonary fibrosis (PF) often experience exacerbations of their disease, characterised by a rapid, severe deterioration in lung function that is associated with high mortality. Whilst the pathobiology of such exacerbations is poorly understood, virus infection is a trigger. The present study investigated virus-induced injury responses of alveolar and bronchial epithelial cells (AECs and BECs, respectively) from patients with PF and age-matched controls (Ctrls). Air-liquid interface (ALI) cultures of AECs, comprising type I and II pneumocytes or BECs were inoculated with influenza A virus (H1N1) at 0.1 multiplicity of infection (MOI). Levels of interleukin-6 (IL-6), IL-36γ and IL-1ß were elevated in cultures of AECs from PF patients (PF-AECs, n = 8-11), being markedly higher than Ctrl-AECs (n = 5-6), 48 h post inoculation (pi) (P<0.05); despite no difference in H1N1 RNA copy numbers 24 h pi. Furthermore, the virus-induced inflammatory responses of PF-AECs were greater than BECs (from either PF patients or controls), even though viral loads in the BECs were overall 2- to 3-fold higher than AECs. Baseline levels of the senescence and DNA damage markers, nuclear p21, p16 and H2AXγ were also significantly higher in PF-AECs than Ctrl-AECs and further elevated post-infection. Senescence induction using etoposide augmented virus-induced injuries in AECs (but not viral load), whereas selected senotherapeutics (rapamycin and mitoTEMPO) were protective. The present study provides evidence that senescence increases the susceptibility of AECs from PF patients to severe virus-induced injury and suggests targeting senescence may provide an alternative option to prevent or treat the exacerbations that worsen the underlying disease.

Conditionally reprogrammed asthmatic bronchial epithelial cells express lower FOXJ1 at terminal differentiation and lower IFNs following RV-A1 infection.

Primary bronchial epithelial cells (pBECs) obtained from donors have limited proliferation capacity. Recently, conditional reprogramming (CR) technique has overcome this and has provided the potential for extended passaging and subsequent differentiation of cells at air-liquid interface (ALI). However, there has been no donor-specific comparison of cell morphology, baseline gene expression, barrier function, and antiviral responses compared with their "parent" pBECs, especially cells obtained from donors with asthma. We, therefore, collected and differentiated pBECs at ALI from mild donors with asthma (n = 6) for the parent group. The same cells were conditionally reprogrammed and later differentiated at ALI. Barrier function was measured during the differentiation phase. Morphology and baseline gene expression were compared at terminal differentiation. Viral replication kinetics and antiviral responses were assessed following rhinovirus (RV) infection over 96 h. Barrier function during the differentiation phase and cell structural morphology at terminal differentiation appear similar in both parent and CR groups, however, there were elongated cell structures superficial to basal cells and significantly lower FOXJ1 expression in CR group. IFN gene expression was also significantly lower in CR group compared with parent asthma group following RV infection. The CR technique is a beneficial tool to proliferate pBECs over extended passages. Considering lower FOXJ1 expression, viral replication kinetics and antiviral responses, a cautious approach should be taken while choosing CR cells for experiments. In addition, as lab-to-lab cell culture techniques vary, the most appropriate technique must be utilized to best match individual cell functions and morphologies to address specific research questions and experimental reproducibility across the labs.

A cGAS-dependent response links DNA damage and senescence in alveolar epithelial cells: a potential drug target in IPF.

Alveolar epithelial cell (AEC) senescence is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Mitochondrial dysfunction including release of mitochondrial DNA (mtDNA) is a feature of senescence, which led us to investigate the role of the DNA-sensing guanine monophosphate-adenine monophosphate (GMP-AMP) synthase (cGAS) in IPF, with a focus on AEC senescence. cGAS expression in fibrotic tissue from lungs of patients with IPF was detected within cells immunoreactive for epithelial cell adhesion molecule (EpCAM) and p21, epithelial and senescence markers, respectively. Submerged primary cultures of AECs isolated from lung tissue of patients with IPF (IPF-AECs, n = 5) exhibited higher baseline senescence than AECs from control donors (Ctrl-AECs, n = 5-7), as assessed by increased nuclear histone 2AXγ phosphorylation, p21 mRNA, and expression of senescence-associated secretory phenotype (SASP) cytokines. Pharmacological cGAS inhibition using RU.521 diminished IPF-AEC senescence in culture and attenuated induction of Ctrl-AEC senescence following etoposide-induced DNA damage. Short interfering RNA (siRNA) knockdown of cGAS also attenuated etoposide-induced senescence of the AEC line, A549. Higher levels of mtDNA were detected in the cytosol and culture supernatants of primary IPF- and etoposide-treated Ctrl-AECs when compared with Ctrl-AECs at baseline. Furthermore, ectopic mtDNA augmented cGAS-dependent senescence of Ctrl-AECs, whereas DNAse I treatment diminished IPF-AEC senescence. This study provides evidence that a self-DNA-driven, cGAS-dependent response augments AEC senescence, identifying cGAS as a potential therapeutic target for IPF.

Self DNA perpetuates IPF lung fibroblast senescence in a cGAS-dependent manner.

Senescence and mitochondrial stress are mutually reinforcing age-related processes that contribute to idiopathic pulmonary fibrosis (IPF); a lethal disease that manifests primarily in the elderly. Whilst evidence is accumulating that GMP-AMP synthase (cGAS) is crucial in perpetuating senescence by binding damaged DNA released into the cytosol, its role in IPF is not known. The present study examines the contributions of cGAS and self DNA to the senescence of lung fibroblasts from IPF patients (IPF-LFs) and age-matched controls (Ctrl-LFs). cGAS immunoreactivity was observed in regions of fibrosis associated with fibroblasts in lung tissue of IPF patients. Pharmacological inhibition of cGAS or its knockdown by silencing RNA (siRNA) diminished the escalation of IPF-LF senescence in culture over 7 days as measured by decreased p21 and p16 expression, histone 2AXγ phosphorylation and/or IL-6 production (P < 0.05, n = 5-8). The targeting of cGAS also attenuated etoposide-induced senescence in Ctrl-LFs (P < 0.05, n = 5-8). Levels of mitochondrial DNA (mDNA) detected by qPCR in the cytosol and medium of IPF-LFs or senescence-induced Ctrl-LFs were higher than Ctrl-LFs at baseline (P < 0.05, n = 5-7). The addition of DNAse I (100 U/ml) deaccelerated IPF-LF senescence (P < 0.05, n = 5), whereas ectopic mDNA or the induction of endogenous mDNA release augmented Ctrl-LF senescence in a cGAS-dependent manner (P < 0.05, n = 5). In conclusion, we provide evidence that cGAS reinforces lung fibroblast senescence involving damaged self DNA. The targeting of cGAS to supress senescent-like responses may have potential important therapeutic implications in the treatment of IPF.

Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts.

Increasing evidence highlights that senescence plays an important role in idiopathic pulmonary fibrosis (IPF). This study delineates the specific contribution of mitochondria and the superoxide they form to the senescent phenotype of lung fibroblasts from IPF patients (IPF-LFs). Primary cultures of IPF-LFs exhibited an intensified DNA damage response (DDR) and were more senescent than age-matched fibroblasts from control donors (Ctrl-LFs). Furthermore, IPF-LFs exhibited mitochondrial dysfunction, exemplified by increases in mitochondrial superoxide, DNA, stress and activation of mTORC1. The DNA damaging agent etoposide elicited a DDR and augmented senescence in Ctrl-LFs, which were accompanied by disturbances in mitochondrial homoeostasis including heightened superoxide production. However, etoposide had no effect on IPF-LFs. Mitochondrial perturbation by rotenone involving sharp increases in superoxide production also evoked a DDR and senescence in Ctrl-LFs, but not IPF-LFs. Inhibition of mTORC1, antioxidant treatment and a mitochondrial targeting antioxidant decelerated IPF-LF senescence and/or attenuated pharmacologically induced Ctrl-LF senescence. In conclusion, increased superoxide production by dysfunctional mitochondria reinforces lung fibroblast senescence via prolongation of the DDR. As part of an auto-amplifying loop, mTORC1 is activated, altering mitochondrial homoeostasis and increasing superoxide production. Deeper understanding the mechanisms by which mitochondria contribute to fibroblast senescence in IPF has potentially important therapeutic implications.

Southern Ocean deep-water carbon export enhanced by natural iron fertilization.

The addition of iron to high-nutrient, low-chlorophyll regions induces phytoplankton blooms that take up carbon. Carbon export from the surface layer and, in particular, the ability of the ocean and sediments to sequester carbon for many years remains, however, poorly quantified. Here we report data from the CROZEX experiment in the Southern Ocean, which was conducted to test the hypothesis that the observed north-south gradient in phytoplankton concentrations in the vicinity of the Crozet Islands is induced by natural iron fertilization that results in enhanced organic carbon flux to the deep ocean. We report annual particulate carbon fluxes out of the surface layer, at three kilometres below the ocean surface and to the ocean floor. We find that carbon fluxes from a highly productive, naturally iron-fertilized region of the sub-Antarctic Southern Ocean are two to three times larger than the carbon fluxes from an adjacent high-nutrient, low-chlorophyll area not fertilized by iron. Our findings support the hypothesis that increased iron supply to the glacial sub-Antarctic may have directly enhanced carbon export to the deep ocean. The CROZEX sequestration efficiency (the amount of carbon sequestered below the depth of winter mixing for a given iron supply) of 8,600 mol mol(-1) was 18 times greater than that of a phytoplankton bloom induced artificially by adding iron, but 77 times smaller than that of another bloom initiated, like CROZEX, by a natural supply of iron. Large losses of purposefully added iron can explain the lower efficiency of the induced bloom(6). The discrepancy between the blooms naturally supplied with iron may result in part from an underestimate of horizontal iron supply.

The relationship between nutritional status, inflammatory markers and survival in patients with advanced cancer: a prospective cohort study.

BACKGROUND: Malnutrition and elevated inflammatory markers have a negative impact on clinical outcomes in cancer patients. Few studies have investigated the associations between inflammatory makers, nutritional status and survival. This study investigates the association between nutritional status, inflammatory markers and overall survival (OS) in patients with advanced cancer. METHODS: This prospective cohort study recruited 114 adult patients from January 2007 to January 2010. It included patients diagnosed with advanced cancer, good Eastern Cooperative Oncology Group (ECOG) performance status 0-2, a prognosis of more than 3 months and had not received chemotherapy for advanced cancer prior to enrollment. Baseline data were collected prior to commencement of chemotherapy. Patients were followed up from the date of baseline nutritional assessment until the date of death or the date that data were last updated, whichever came first. RESULTS: Malnourished cancer patients had statistically significant higher concentrations of serum C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR) or modified Glasgow Prognostic Score (mGPS) prior to starting chemotherapy. In univariate analyses to predict survival, mGPS 1 or 2 had a hazard ratio (HR) of 1.81 (95 % confidence interval (CI) 1.13-2.89) and NLR ≥ 5 had a HR of 1.13 (95 % CI 1.08-4.60) and malnutrition (HR of 1.66 for Patient-Generated Subjective Global Assessment (PG-SGA) B (95 % CI 1.02-2.71), and HR for severely malnourished patients (PG-SGA C) was 2.73 (95 % CI 1.50-4.96). CONCLUSIONS: Inflammatory markers were statistically associated with malnutrition. Malnutrition and mGPS were significant independent predictors of overall survival in patients with advanced cancer.

A persistent neutrophil-associated immune signature characterizes post-COVID-19 pulmonary sequelae.

Interstitial lung disease and associated fibrosis occur in a proportion of individuals who have recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through unknown mechanisms. We studied individuals with severe coronavirus disease 2019 (COVID-19) after recovery from acute illness. Individuals with evidence of interstitial lung changes at 3 to 6 months after recovery had an up-regulated neutrophil-associated immune signature including increased chemokines, proteases, and markers of neutrophil extracellular traps that were detectable in the blood. Similar pathways were enriched in the upper airway with a concomitant increase in antiviral type I interferon signaling. Interaction analysis of the peripheral phosphoproteome identified enriched kinases critical for neutrophil inflammatory pathways. Evaluation of these individuals at 12 months after recovery indicated that a subset of the individuals had not yet achieved full normalization of radiological and functional changes. These data provide insight into mechanisms driving development of pulmonary sequelae during and after COVID-19 and provide a rational basis for development of targeted approaches to prevent long-term complications.

Ageing mechanisms that contribute to tissue remodeling in lung disease.

Age is a major risk factor for chronic respiratory diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and certain phenotypes of asthma. The recent COVID-19 pandemic also highlights the increased susceptibility of the elderly to acute respiratory distress syndrome (ARDS), a diffuse inflammatory lung injury with often long-term effects (ie parenchymal fibrosis). Collectively, these lung conditions are characterized by a pathogenic reparative process that, rather than restoring organ function, contributes to structural and functional tissue decline. In the ageing lung, the homeostatic control of wound healing following challenge or injury has an increased likelihood of being perturbed, increasing susceptibility to disease. This loss of fidelity is a consequence of a diverse range of underlying ageing mechanisms including senescence, mitochondrial dysfunction, proteostatic stress and diminished autophagy that occur within the lung, as well as in other tissues, organs and systems of the body. These ageing pathways are highly interconnected, involving localized and systemic increases in inflammatory mediators and damage associated molecular patterns (DAMPs); along with corresponding changes in immune cell function, metabolism and composition of the pulmonary and gut microbiomes. Here we comprehensively review the roles of ageing mechanisms in the tissue remodeling of lung disease.

Senescence of IPF Lung Fibroblasts Disrupt Alveolar Epithelial Cell Proliferation and Promote Migration in Wound Healing.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease marked by excessive accumulation of lung fibroblasts (LFs) and collagen in the lung parenchyma. The mechanisms that underlie IPF pathophysiology are thought to reflect repeated alveolar epithelial injury leading to an aberrant wound repair response. Recent work has shown that IPF-LFs display increased characteristics of senescence including growth arrest and a senescence-associated secretory phenotype (SASP) suggesting that senescent LFs contribute to dysfunctional wound repair process. Here, we investigated the influence of senescent LFs on alveolar epithelial cell repair responses in a co-culture system. Alveolar epithelial cell proliferation was attenuated when in co-culture with cells or conditioned media from, senescence-induced control LFs or IPF-LFs. Cell-cycle analyses showed that a larger number of epithelial cells were arrested in G2/M phase when co-cultured with IPF-LFs, than in monoculture. Paradoxically, the presence of LFs resulted in increased A549 migration after mechanical injury. Our data suggest that senescent LFs may contribute to aberrant re-epithelialization by inhibiting proliferation in IPF.

The spatial pattern of nitrogen cycling in the Adirondack Park, New York.

Maps of canopy nitrogen obtained through analysis of high-resolution, hyperspectral, remotely sensed images now offer a powerful means to make landscape-scale to regional-scale estimates of forest N cycling and net primary production (NPP). Moreover, recent research has suggested that the spatial variability within maps of canopy N may be driven by environmental gradients in such features as historic forest disturbance, temperature, species composition, moisture, geology, and atmospheric N deposition. Using the wide variation in these six features found within the diverse forest ecosystems of the 2.5 million ha Adirondack Park, New York, USA, we examined linkages among environmental gradients and three measures of N cycling collected during the 2003 growing season: (1) field survey of canopy N, (2) field survey of soil C:N, and (3) canopy N measured through analysis of two 185 x 7.5 km Hyperion hyperspectral images. These three measures of N cycling strongly related to forest type but related poorly to all other environmental gradients. Further analysis revealed that the spatial pattern in N cycling appears to have distinct inter- and intraspecific components of variability. The interspecific component, or the proportional contribution of species functional traits to canopy biomass, explained 93% of spatial variability within the field canopy N survey and 37% of variability within the soil C:N survey. Residual analysis revealed that N deposition accounted for an additional 2% of variability in soil C:N, and N deposition and historical forest disturbance accounted for an additional 2.8% of variability in canopy N. Given our finding that 95.8% of the variability in the field canopy N survey could be attributed to variation in the physical environment, our research suggests that remotely sensed maps of canopy N may be useful not only to assess the spatial variability in N cycling and NPP, but also to unravel the relative importance of their multiple controlling factors.

Prospective evaluation of quality of life and nutrition before and after treatment for nasopharyngeal carcinoma.

OBJECTIVE: To prospectively assess quality of life in patients undergoing chemoradiation therapy for nasopharyngeal cancer. Concurrent chemoradiotherapy is standard for advanced nasopharyngeal cancer; however, the toxic effects of this treatment are substantial. DESIGN: Prospective evaluation of quality of life and nutritional status before and after treatment for nasopharyngeal carcinoma. PATIENTS AND INTERVENTION: A cohort of 14 patients, treated with concurrent chemoradiotherapy for 7 weeks, completed the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire and Head and Neck Module before and 3, 6, 12, and 24 months after treatment. Changes in score were analyzed and correlated with the toxic effect grade. RESULTS: Quality of life issues during the 24 months of follow-up included poorer global health (P = .01), fatigue (P = .01), appetite loss (P<.001), swallowing difficulties (P = .002), sense problems (P = .03), difficulty with social eating (P = .005), dental problems (P = .045), trismus (P = .001), xerostomia (P<.001), sticky saliva (P = .001), cough (P = .02), and feeling ill (P = .03). Pain (P = .004) and emotional functioning (P<.001) significantly improved from the pretreatment rating. The median weight loss was 7 kg, with most weight loss occurring during treatment, despite nutritional support with gastrostomy feeding tubes. One patient still required percutaneous endoscopic gastrostomy feeding at 2 years after treatment. Physician-scored toxic effects correlated poorly with quality-of-life scores. CONCLUSIONS: Quality of life and functional assessment should be important end points in the follow-up of patients with nasopharyngeal cancer who receive chemoradiotherapy. This study supports the need for ongoing support and rehabilitation in a multidisciplinary setting.

Line Transect Surveys Underdetect Terrestrial Mammals: Implications for the Sustainability of Subsistence Hunting.

Conservation of Neotropical game species must take into account the livelihood and food security needs of local human populations. Hunting management decisions should therefore rely on abundance and distribution data that are as representative as possible of true population sizes and dynamics. We simultaneously applied a commonly used encounter-based method and an infrequently used sign-based method to estimate hunted vertebrate abundance in a 48,000-km2 indigenous landscape in southern Guyana. Diurnal direct encounter data collected during three years along 216, four-kilometer -long transects consistently under-detected many diurnal and nocturnal mammal species readily detected through sign. Of 32 species analyzed, 31 were detected by both methods; however, encounters did not detect one and under-detected another 12 of the most heavily hunted species relative to sign, while sign under-detected 12 never or rarely collected species relative to encounters. The six most important game animals in the region, all ungulates, were not encountered at 11-40% of village and control sites or on 29-72% of transects where they were detected by sign. Using the sign methodology, we find that tapirs, one of the terrestrial vertebrates considered most sensitive to overexploitation, are present at many sites where they were never visually detected during distance sampling. We find that this is true for many other species as well. These high rates of under-detection suggest that behavioral changes in hunted populations may affect apparent occurrence and abundance of these populations. Accumulation curves (detection of species on transects) were much steeper for sign for 12 of 16 hunted species than for encounters, but that pattern was reversed for 12 of 16 species unhunted in our area. We conclude that collection of sign data is an efficient and effective method of monitoring hunted vertebrate populations that complements encounter and camera-trapping methods in areas impacted by hunting. Sign surveys may be the most viable method for large-scale, management-oriented studies in remote areas, particularly those focused on community-based wildlife management.

Does presence of a mid-ocean ridge enhance biomass and biodiversity?

In contrast to generally sparse biological communities in open-ocean settings, seamounts and ridges are perceived as areas of elevated productivity and biodiversity capable of supporting commercial fisheries. We investigated the origin of this apparent biological enhancement over a segment of the North Mid-Atlantic Ridge (MAR) using sonar, corers, trawls, traps, and a remotely operated vehicle to survey habitat, biomass, and biodiversity. Satellite remote sensing provided information on flow patterns, thermal fronts, and primary production, while sediment traps measured export flux during 2007-2010. The MAR, 3,704,404 km(2) in area, accounts for 44.7% lower bathyal habitat (800-3500 m depth) in the North Atlantic and is dominated by fine soft sediment substrate (95% of area) on a series of flat terraces with intervening slopes either side of the ridge axis contributing to habitat heterogeneity. The MAR fauna comprises mainly species known from continental margins with no evidence of greater biodiversity. Primary production and export flux over the MAR were not enhanced compared with a nearby reference station over the Porcupine Abyssal Plain. Biomasses of benthic macrofauna and megafauna were similar to global averages at the same depths totalling an estimated 258.9 kt C over the entire lower bathyal north MAR. A hypothetical flat plain at 3500 m depth in place of the MAR would contain 85.6 kt C, implying an increase of 173.3 kt C attributable to the presence of the Ridge. This is approximately equal to 167 kt C of estimated pelagic biomass displaced by the volume of the MAR. There is no enhancement of biological productivity over the MAR; oceanic bathypelagic species are replaced by benthic fauna otherwise unable to survive in the mid ocean. We propose that globally sea floor elevation has no effect on deep sea biomass; pelagic plus benthic biomass is constant within a given surface productivity regime.

Integration of prospective quality of life and nutritional assessment as routine components of multidisciplinary care of patients with head and neck cancer.

BACKGROUND: Quality of life (QOL) and nutritional assessment of patients with head and neck cancer can provide additional information about the effects of treatment beyond the standard measures of disease control and survival. Integrating a prospective evaluation program into a multidisciplinary service may ensure that a more holistic model of care is developed. METHODS: Prospective evaluation of QOL and nutrition before and after treatment for head and neck cancer was implemented in 2001. All patients enrolled in the program were treated with curative intent. Patients completed the European Organisation for Research and Treatment of Cancer Core QOL Questionnaire and Head and Neck Specific Module before treatment and at 3, 6 and 12 months after completion of therapy. In conjunction, patients underwent nutritional assessment by body mass index, biochemical parameters and the patient-generated subjective global assessment tool. RESULTS: Among 288 patients who consented to participate in this study, 134 patients completed the QOL assessment criteria and were eligible for evaluation. Examples of QOL and nutritional data for patients with cancers of the oral cavity, oropharynx, nasopharynx, larynx, hypopharynx, parotid gland and paranasal sinus, and also unknown primary cancers are given. Implementation of this prospective assessment program required appropriate resources and was hampered by time constraints, logistics with blood tests and patient compliance. CONCLUSIONS: Despite difficulties with implementation, the information concerning QOL and nutritional status obtained in this study provided an appreciation of the long-term functional effects of treatment for head and neck cancer. Prospective QOL assessment and nutritional evaluation should become integral components of the care of patients with cancers of the head and neck.

Foliar nitrogen responses to elevated atmospheric nitrogen deposition in nine temperate forest canopy species.

Despite its ecological importance, broad-scale use of foliar nitrogen as an indicator of ecosystem response to atmospheric N deposition has heretofore been obscured by its poorly understood intrinsic variability through time, space, and across species. We used a regional survey of foliar N conducted within a single growing season to observe that eight of nine major canopy tree species had increased foliar N in response to a gradient of N deposition in the Adirondack Park, New York. These results (1) add important foliar N evidence to support N saturation theory, (2) strongly reinforce the conclusion that N deposition is affecting the N status of forest ecosystems in the northeastern U.S., and (3) extend N saturation theory by identifying that temperate forest canopy species differ in their foliar N response to N deposition. Interestingly, species-specific differences were strongly related to two functional traits that arise from within-leaf allocations of N resources--leaf mass per area (LMA) and shade tolerance. Thus, combining species-specific knowledge of these functional traits with existing foliar N-centered remote sensing and ecosystem modeling approaches may provide a much-needed avenue to make broad-scale assessments of how persistently elevated rates of N deposition will continue to affect temperate forest ecosystems.

Nutrition intervention using an eicosapentaenoic acid (EPA)-containing supplement in patients with advanced colorectal cancer. Effects on nutritional and inflammatory status: a phase II trial.

GOALS: The aim of the study was to assess the impact of an eicosapentanoic acid-containing protein and energy dense oral nutritional supplement (EPA-ONS) on nutritional and inflammatory status, quality of life (QOL), plasma phospholipids (PPL) and cytokine profile, tolerance of irinotecan-containing chemotherapy and EPA-ONS in patients with advanced colorectal cancer (CRC) receiving chemotherapy. MATERIALS AND METHODS: Patients with advanced CRC having one prior chemotherapy regimen received 480 ml of EPA-ONS daily for 3 weeks before commencing chemotherapy with folinic acid, 5-fluorouracil, irinotecan (FOLFIRI), and continued for 3 cycles of treatment (9 weeks). All assessments including weight, body composition, C-reactive protein (CRP), QOL, dietary intake, PPL and cytokine analyses were performed at baseline, 3 and 9 weeks. RESULTS: Twenty-three patients were enrolled, 20 completed 3 weeks, and 15 completed 9 weeks. The mean EPA-ONS intake was 1.7 tetrapaks (408 ml) daily. There was a significant increase in mean weight (2.5 kg) at 3 weeks (p=0.03). Lean body mass (LBM) was maintained. Protein and energy intake significantly decreased after the commencement of chemotherapy (protein p=0.003, energy p=0.02). There was a significant increase in energy levels (p=0.03), whilst all other QOL measures were maintained. PPL EPA levels increased significantly over the first 3 weeks. Mean CRP increased by 14.9 mg/L over the first 3 weeks (p=0.004), but decreased to baseline levels by the end of the trial. There was a significant correlation between plasma IL-6 and IL-10 concentrations and survival, and between IL-12 and toxicity. CONCLUSION: Dietary counseling and the provision of EPA-ONS may result in maintenance of nutritional status and QOL, however randomized trials are required to evaluate the impact of EPA on toxicity from chemotherapy.

Evaluation of nutritional and inflammatory status of advanced colorectal cancer patients and its correlation with survival.

The purpose of this study was to evaluate novel inflammatory and nutritional prognostic factors in patients with advanced colorectal cancer (ACRC). All ACRC patients attending the clinic for palliative treatment were eligible for study. Demographics, including performance status (PS), C-reactive protein (CRP), albumin (Alb), Glasgow prognostic score (GPS), weight, weight history, body mass index (BMI), and nutritional status using the patient-generated subjective global assessment (PGSGA), were collected and correlated with survival. At a median follow-up of 29.8 mo, with a minimum follow-up of 15.7 mo, the median survival was 9.9 mo (0.8-21.8 mo). Fifteen (29%) patients were newly diagnosed (stage IV colorectal cancer), and 36 (71%) had received prior chemotherapy. Although the median BMI was 27 kg/m2 (range = 17-41 kg/m2), 28 of 50 (56%) were nutritionally at risk. In fact, 19 patients (38%) were critically in need of nutrition intervention (PGSGA score of > or =9). Thirty-three of 48 patients (69%) had an elevated CRP (>10 mg/l with a median of 21.1 mg/L), and 7 patients (15%) had both a CRP of >10 mg/l and hypoalbuminemia (< 35 g/l). A significant positive correlation was found between PGSGA score and CRP (P = 0.003; r = 0.430). Using univariate analysis, significantly worse survival was found for patients with poorer PS (P = 0.001), high GPS (P = 0.04), low Alb (P = 0.017), elevated serum alkaline phosphatase (SAP; P = 0.018), PGSGA score of > 9 (P = 0.001), and PGSGA group B/C (P = 0.02). Using the Cox proportional hazard model for multivariate survival analysis, type of treatment (hazard ratio, HR = 1.48; 95% confidence interval, CI = 1.11-1.79; P = 0.005), PS (HR = 2.37; 95% CI = 1.11-5.09; P = 0.026), GPS (HR = 2.27; 95% CI = 1.09-4.73; P = 0.028), and SAP (HR = 0.44; 95% CI = 0.18-1.07; P =0.069) remained significant predictors of survival. These preliminary data suggest that the type of treatment, PS, GPS, and SAP are important predictors of survival in ACRC.

Nutritional assessment in cancer: comparing the Mini-Nutritional Assessment (MNA) with the scored Patient-Generated Subjective Global Assessment (PGSGA).

The evaluation of nutritional status in cancer patients is often neglected in spite of the fact that poor nutritional status may adversely affect prognosis and treatment tolerance. In day-to-day oncology practice, a sensitive but simply applied nutritional assessment tool is needed to identify at-risk patients. Several tools exist; however, none has been universally accepted. The aim of this study was to compare two potential tools, the Mini-Nutritional Assessment (MNA) and the scored Patient Generated Subjective Global Assessment (PGSGA). The MNA is more simply applied and does not require a trained dietitian. The PGSGA has been previously validated in cancer patients. One hundred fifty-seven newly diagnosed cancer patients were assessed using both tools. Of these, 126 were reassessed at 4-6 wk, and 104 were reassessed at Weeks 8-12 after initial assessment. A significant negative correlation was found between the tools at all three time periods (at baseline r = -0.76; P < 0.001). Taking the PGSGA as the most accepted nutritional assessment tool, at baseline the MNA demonstrated a sensitivity of 97% and specificity of 54%. At 4-6 wk MNA sensitivity was 79% and specificity was 69%. At 8-12 wk MNA sensitivity was 93% and specificity was 82%. When comparing the tools in elderly patients alone (>65 yr), similar results were obtained. Both tools were able to correctly classify patients as malnourished, although the MNA lacks specificity. Therefore, the PGSGA should be the tool of choice for nutritional assessment in cancer patients.

Baseline nutritional assessment in advanced cancer patients receiving palliative chemotherapy.

Depletion of nutritional reserves and significant weight loss can lead to an increased risk of morbidity, reduced chemotherapy response, and shorter survival in patients with cancer. Weight loss and malnutrition are recognized to result from multifactorial processes, which if assessed and managed appropriately may lead to improved treatment outcome. Numerous methodologies are used for the assessment of nutritional status. However, it remains unclear which of these tools is the most appropriate in the setting of cancer chemotherapy. The aim of this study was to investigate the use of various fundamental assessment tools that could be applied to the routine clinical evaluation of nutritional status in patients with advanced solid malignancies before treatment with palliative chemotherapy. We investigated the interrelationships between biochemical indices, anthropometric measures, and a nutritional screening tool, the Mini-Nutritional Assessment, in 73 patients. Many of these measures were highly interrelated, but the baseline history of weight loss in these patients was strongly correlated to the Mini-Nutritional Assessment (MNA) score (P < 0.0005). In turn, baseline weight loss and the MNA score were strongly correlated to serum C-reactive protein (a marker of acute-phase response). In some patients, malnutrition was linked to disease- or treatment-related upper digestive tract morbidity. Testing for the serum concentration of C-reactive protein at baseline may identify a subset of patients for whom a decline in nutritional status is linked to the presence of an active inflammatory response, a recognized precursor of cachexia