Significant Decrease In Survival Research Articles

Chronic toxicity of clothianidin, imidacloprid, chlorpyrifos, and dimethoate to Apis mellifera L. larvae reared in vitro.

The effects of chronic exposure to two neonicotinoids (clothianidin and imidacloprid) and two organophosphates (chlorpyrifos and dimethoate) on survival, developmental rate and larval weight of honey bee larvae reared in vitro were determined. Diets containing chemicals were fed to larvae with the range of concentrations for each compound based on published acute toxicity experiments and residues found in pollen and nectar, both components of the larval diet. Four concentrations of each compound and controls were tested: chlorpyrifos: 0.5, 0.8, 1.2, 8 mg/L; clothianidin: 0.1, 0.4, 2, 10 mg L-1 ; dimethoate: 0.02, 1, 6, 45 mg L-1 ; imidacloprid: 0.4, 2, 4, 10 mg L-1 ; positive control: dimethoate (45 mg L-1 ); solvent control: acetone or methanol; and negative control. A significant decrease in survival, relative to the solvent control, occurred in the 0.8, 1.2 and 8 mg L-1 chlorpyrifos, 0.4, 2 and 10 mg L-1 clothianidin, and 45 mg L-1 dimethoate diets, but not the imidacloprid diets. The treatment of larval diets with clothianidin, dimethoate and imidacloprid did not affect survival, developmental rate, or weight of immature honey bees; however, treatment with chlorpyrifos did. Overall, our results are valuable for evaluating the chronic toxicity of these pesticides to developing honey bees. © 2018 Society of Chemical Industry.

A distinct class of antioxidant response elements is consistently activated in tumors with NRF2 mutations

NRF2 is a redox-responsive transcription factor that regulates expression of cytoprotective genes via its interaction with DNA sequences known as antioxidant response elements (AREs). NRF2 activity is induced by oxidative stress, but oxidative stress is not the only context in which NRF2 can be activated. Mutations that disrupt the interaction between NRF2 and KEAP1, an inhibitor of NRF2, lead to NRF2 hyperactivation and promote oncogenesis. The mechanisms underlying NRF2's oncogenic properties remain unclear, but likely involve aberrant expression of select NRF2 target genes. We tested this possibility using an integrative genomics approach to get a precise view of the direct NRF2 target genes dysregulated in tumors with NRF2 hyperactivating mutations. This approach revealed a core set of 32 direct NRF2 targets that are consistently upregulated in NRF2 hyperactivated tumors. This set of NRF2 “cancer target genes” includes canonical redox-related NRF2 targets, as well as target genes that have not been previously linked to NRF2 activation. Importantly, NRF2-driven upregulation of this gene set is largely independent of the organ system where the tumor developed. One key distinguishing feature of these NRF2 cancer target genes is that they are regulated by high affinity AREs that fall within genomic regions possessing a ubiquitously permissive chromatin signature. This implies that these NRF2 cancer target genes are responsive to oncogenic NRF2 in most tissues because they lack the regulatory constraints that restrict expression of most other NRF2 target genes. This NRF2 cancer target gene set also serves as a reliable proxy for NRF2 activity, and high NRF2 activity is associated with significant decreases in survival in multiple cancer types. Overall, the pervasive upregulation of these NRF2 cancer targets across multiple cancers, and their association with negative outcomes, suggests that these will be central to dissecting the functional implications of NRF2 hyperactivation in several cancer contexts.

The prostanoid pathway contains potential prognostic markers for glioblastoma

Prostanoids derived from the activity of cyclooxygenases and their respective synthases contribute to both active inflammation and immune response in the tumor microenvironment. Their synthesis, deactivation and role in glioma biology have not yet been fully explored and require further study. Using quantitative real time PCR, gas chromatography/ electron impact mass spectrometry and liquid chromatography/ electrospray ionization tandem mass spectrometry, we have further characterized the prostanoid pathway in grade IV glioblastoma (GBM). We observed significant correlations between high mRNA expression levels and poor patient survival for microsomal PGE synthase 1 (mPGES1) and prostaglandin reductase 1 (PTGR1). Conversely, high mRNA expression levels for 15-hydroxyprostaglandin dehydrogenase (15-HPGD) were correlated with better patient survival. GBMs had a higher quantity of the prostanoid precursor, arachidonic acid, versus grade II/III tumors and in GBMs a significant positive correlation was found between arachidonic acid and PGE2 content. GBMs also had higher concentrations of TXB2, PGD2, PGE2 and PGF2α versus grade II/III tumors. A significant decrease in survival was detected for high versus low PGE2, PGE2 + PGE2 deactivation products (PGEMs) and PGF2α in GBM patients. Our data show the potential importance of prostanoid metabolism in the progression towards GBM and provide evidence that higher PGE2 and PGF2α concentrations in the tumor are correlated with poorer patient survival. Our findings highlight the potential importance of the enzymes 15-HPGD and PTGR1 as prognostic biomarkers which could be used to predict survival outcome of patients with GBM.

Induction chemotherapy in patients with resectable laryngeal cancer: A meta-analysis.

Head and neck squamous cell carcinoma (SCC) ranks 6th among the most frequently diagnosed carcinomas globally. Laryngeal carcinoma is quite common, and 95% of the cases are SCCs. Since the introduction of larynx-preserving surgery, induction chemotherapy (IC) has played a substantial role. The aim of IC is to shrink or downstage primary laryngeal carcinomas, increasing the chances of complete surgical removal, particularly in cases with advanced but potentially resectable lesions. The aim of the present study was to investigate the value of IC in patients with resectable laryngeal cancer. A meta-analysis was performed of randomized controlled trials (1985–2017) investigating the effect of IC on survival, disease control, larynx-preserving surgery and disease-free survival. Engauge-Digitizer software was used to construct Kaplan-Meier curves and RevMan software was used for the analysis of the data. A total of 12 trials (4,320 patients) were included. There was no significant difference in local recurrence or locoregional control between patients receiving and those not receiving IC (P>0.05). However, the experimental group (IC) exhibited a lower propensity for distant metastasis by 11.7% (95% confidence interval: 10.3–13.3%, P=0.02) compared with the control group (no IC). Among patients with laryngeal cancer, larynx preservation was possible in those who responded well to IC, without a significant decrease in survival compared with radical surgery (P<0.05). Taking into consideration these findings, IC confers an advantage in terms of lowering the risk of distant metastasis in patients with resectable laryngeal carcinoma, and enables laryngeal preservation in responders. Moreover, IC increases the overall survival rate in patients with locally advanced but resectable LC.

Survival after PICU admission: The impact of multiple admissions and complex chronic conditions

ObjectiveFactors predicting survival over time after pediatric intensive care unit (PICU) admissions are not fully understood. The primary aim of the current study was to investigate whether multiple admissions (MADM) compared to single PICU admissions (SADM) were associated with poor survival over time after being admitted to PICU facilities. Our secondary aim was to investigate if the presence of a complex chronic condition (CCC) would further impair prognosis.DesignA closed cohort of all children up to 16 years of age admitted to the three PICUs in Sweden between 2008 and 2010 was prospectively collected and followed until 2012, providing survival data for at least one but up to four years of follow-up.SettingThree Swedish tertiary referral centers for pediatric intensive care and extracorporeal membrane oxygenation (ECMO) care were used.PatientsIn total, 3,688 Swedish children with 5,019 PICU admissions were included.InterventionsNo interventions were conducted.MeasurementsAn extensive data set was recorded, including up to four-year survival information following first PICU admission. The patients were assigned to seven admission diagnostic groups, which were then divided into SADM or MADM groups. The difference in survival over time and mortality rates (MR) and mortality rate ratios (MRR) were calculated. SADM and MADM groups with and without an existing CCC were formed. The difference in survival over time between groups was calculated.Main resultsA highly significant difference in survival over time was noted between SADM and MADM patients (p<0.0001), which was intensified by the presence of a CCC. MADM patients with a CCC had the worst outcome, while SADM patients without a CCC had the best outcome. MADM patients with no CCC demonstrated decreased survival over time compared to SADM patients with a CCC. Survival over time was statistically worsened for patients with MADM compared to SADM for the following admission diagnostic groups: Cardiovascular, Gastrointestinal/Renal, Respiratory, Neurological, and Miscellaneous. The mortality rate (deaths/patient year of follow-up) during the time of follow-up was 0.023 for SADM and 0.062 for MADM patients. The mortality rate ratio (MRR) between these groups was 2.69.ConclusionCompared to single admissions, multiple admissions to PICU were associated with a significant decrease in survival over time in some but not all diagnostic groups. Regarding our secondary aim, we found that when the presence of a CCC is factored into the survival analysis, survival over time is further impaired.

Piscine orthoreovirus infection in Atlantic salmon (Salmo salar) protects against subsequent challenge with infectious hematopoietic necrosis virus (IHNV)

Infectious hematopoietic necrosis virus (IHNV) is endemic in farmed rainbow trout in continental Europe and in various salmonid fish species at the Pacific coast of North America. IHN has never occurred in European Atlantic salmon (Salmo salar) farms, but is considered as a major threat for the European salmon industry. Another virus, Piscine orthoreovirus (PRV), is widespread in the sea phase of Atlantic salmon, and is identified as the causative agent of heart and skeletal muscle inflammation. The aim of this study was to investigate the interactions between a primary PRV infection and a secondary IHNV infection under experimental conditions. A PRV cohabitation challenge was performed with Atlantic salmon. At peak of PRV viremia the fish were challenged by immersion with an IHNV genogroup E isolate. Clinical signs and morbidity were monitored. Target organs were sampled at selected time points to assess viral loads of both pathogens. Antiviral immune response and presence of histopathological findings were also investigated. Whereas the PRV-negative/IHNV positive group suffered significant decrease in survival caused by IHNV, the PRV infected groups did not suffer any morbidity and showed negligible levels of IHNV infection. Antiviral response genes were induced, as measured in spleen samples, from PRV infected fish prior to IHNV challenge. In conclusion, PRV-infection protects Atlantic salmon against IHNV infection and morbidity, most likely by inducing a protective innate antiviral response.

Clinical features, treatment, prognosis, and outcome of 47 patients with pure squamous cell carcinoma of the prostate.

7 Background: Pure squamous cell carcinoma of the prostate is a rare entity. Data regarding clinical features, management, and treatment outcomes are limited. As such, management of this cancer has been variable throughout the reported literature, and with limited success. Methods: A systematic review of the literature and secondary data analysis was performed to characterize clinical features, management, and survival outcomes. Results: In total, 47 cases of histologically-confirmed pure squamous cell carcinoma of the prostate were included in analysis. Pure squamous cell carcinoma of the prostate is a disease of older males with mean age at diagnosis of 68.5 years (range 42-85). Urinary obstruction was reported as a presenting symptom in 60% of cases. PSA was usually normal with a mean value of 1.6 (n = 11). The disease was metastatic at diagnosis in 32% of patients among cases that stage was reported (n = 31). The most common sites ( &gt; 30%) of distant metastases are bone and lymph nodes. Metastasis to lung, liver, and brain were 20%, 7%, and 7%, respectively. In terms of management, chemotherapy was given in 28% of cases, radiation in 30%, and prostatectomy in 25.5%. Hormone therapy was rarely attempted (4%). Metastatic disease was associated with a significant decrease in survival when compared to localized disease, p = 0.006. Surgical management was associated with significantly increased survival, p = 0.041. Overall 1-year survival was 32%, while 3-year survival was 9%. Conclusions: Squamous cell carcinoma of the prostate has an aggressive clinical course and is associated with poor prognosis. There is urgent need for early detection and the development of novel treatment options.[Table: see text]

Immune response of Exopalaemon carinicauda infected with an AHPND-causing strain of Vibrio parahaemolyticus

To investigate the immune response of Exopalaemon carinicauda infected with an AHPND-causing strain of Vibrio parahaemolyticus (VPAHPND), three-generation breeding of shrimp selected for their survival to VPAHPND infection was applied to explore the relationship between immune parameters and AHPND-resistant capacity of E. carinicauda. In this study, the LD50 dose of 48 h and survival rates at 144 h of shrimp to VPAHPND increased from 106.0 to 106.6 cfu ml−1 and from 26.67% to 36.67% by three successive generations selection, respectively, while there was no significant difference between the first and second generation (p > .05). Then the immune parameters including vibrio density, total hemocyte counts (THCs), hemocyanin (HEM) concentration, antibacterial activity, activities of four immune enzymes, and expressions of eight immune-related genes were determined in the shrimp of the first (G1) and the third selective generation (G3). The results showed that the shrimp in G1 and G3 generation cleared most of VPAHPND infecting hepatopancreas during 24 h and 6 h post injection, respectively. The levels of THCs, HEM concentration, antibacterial activity, immune enzymes including lysozyme (LZM) activity, alkaline phosphatase (AKP) activity in cell-free hemolymph, and the expression levels of Tollip, ALF, cathepsin B in hemocytes and hepatopancreas, crustin, LZM, SR in hepatopancreas and LGBP in hemocytes were higher in G3 generation than in G1 generation after infection with VPAHPND, suggesting that these parameters may serve as potential disease-resistant indicators for evaluating the physiological status and disease-resistant capability of shrimp when infected with VPAHPND. To further test the role of above genes in the shrimp immune response, RNAi was used to suppress their expressions and a significant decrease in survival was observed in knockdown shrimp infected with VPAHPND as compared to controls.

Effects of dietary inclusion of Spirulina meal on growth and hematological parameters of cultured Asian sea bass, Lates calcarifer

This study was conducted to investigate the effects of dietary inclusion of Spirulina platensis on growth performance and hematological parameters of juvenile Asian sea bass (Lates calcarifer) reared in a freshwater culture system. Five experimental diets were prepared by replacing fish meal protein with the microalga at replacement levels of 5% (SP5), 10% (SP10), 20% (SP20) and 30% (SP30), and the substitution effect was compared with a control diet (Con) in which fish meal was the sole protein. Fish were stocked in net cages placed in a 150-ton tank with a stocking density of 20 fish per cage. After 8 weeks of feeding trial, the fish did not show any significant differences in growth performance but numerically higher weight gain and specific growth rate were achieved in the fish stock fed diet SP10 compared to other treatments. Feed conversion ratio and survival rate of fish were significantly affected by the inclusion of Spirulina in the diets. Except for crude ash content, whole-body proximate composition of the experimental fish was also significantly influenced by the diets. Regarding the effects of diets on blood parameters, only hematocrit, hemaglobin, HDL-c and AST were significantly affected by the inclusion of Spirulina in the diets. This study demonstrated that Spirulina could replace up to 10% of FM protein in practical diets of juvenile Asian sea bass without negative effects on growth performance. However, replacement of fish meal with Spirulina meal at 5% might be considered for commercial use considering a significant decrease in survival above this value.

112 - Tyrosine Nitration is Necessary for the Survival of Schwannoma Cells

Production of peroxynitrite and formation of nitrotyrosine, implicated in cell death in neurodegeneration and inflammatory conditions, is also found in multiple tumors. Paradoxically, whether tyrosine nitration plays a role in tumor cell survival is unknown. Neurofibromatosis Type 2 (NF2) is caused by mutations in the merlin tumor suppressor gene, leading to merlin loss-of-function and schwannoma formation. Here we report that tyrosine nitration regulates energy metabolism and supports NF2-associated schwannoma cell survival. Schwannomas from NF2 patients and human and mouse merlin-deficient Schwann cells (MD-SC) showed increased levels of nitrotyrosine compared with wild type (WT)-SC, together with decreased expression of manganese superoxide dismutase and increased expression of neuronal nitric oxide synthase. There was a significant decrease in survival of MD-SC but not WT-SC upon: 1) inhibition of nitric oxide production, 2) superoxide and peroxynitrite scavenging, and 3) prevention of tyrosine nitration by urate, suggesting that one or more nitrated proteins are necessary for MD-SC survival. In addition, the levels and activity of mitochondrial complex I to IV were decreased in MD-SC compared with WT-SC, associated with decreased mitochondrial oxygen consumption and membrane potential, without changes in mitochondrial content. Tyrosine nitration prevention in MD-SC increased the levels and activity of the mitochondrial electron transport chain complexes, as well as the mitochondrial function to WT-SC levels. Moreover, nitrated Hsp90, an oxidized protein we showed down-regulates mitochondrial activity, was associated with mitochondria in MD-SC and schwannomas from NF2 patients. This is one of many nitrated proteins present in these cells. The identification of additional nitrated proteins supporting schwannoma cell survival could provide novel targets for the treatment of solid tumors where these nitrated proteins are present.

139 - A Distinct Class of Antioxidant Response Elements is Consistently Activated in Tumors with Oncogenic NRF2 Mutations

The transcription factor NRF2 (encoded by the gene Nuclear Factor, Erythroid 2 Like 2 [NFE2L2]) is a master regulator of the transcriptional response to oxidative stress. In the presence of excess reactive oxygen species, NRF2 induces expression of antioxidant genes via its interaction with regulatory DNA sequences known as antioxidant response elements (AREs). However, oxidative stress is not the only context in which NRF2 can be activated. Somatic mutations that disrupt the interaction between NRF2 and KEAP1, an important inhibitor of NRF2, lead to NRF2 hyperactivation and promote tumorigenesis. The exact mechanisms underlying NRF2’s oncogenic properties remain unclear, but likely involve aberrant expression of select NRF2 target genes. We tested this possibility using an integrative genomics approach, combining our own NRF2-centric functional genomics data with thousands of tumor genome and transciptome profiles from The Cancer Genome Atlas (TCGA), to get a precise view of the direct NRF2 target genes dysregulated in tumors with NRF2 hyperactivating mutations. This approach revealed a core set of 32 direct NRF2 targets that are consistently upregulated in NRF2 hyperactivated tumors. This set of NRF2 “cancer target genes” includes canonical redox-related NRF2 targets (NQO1, TRX, GCLC, etc.), as well as several target genes that have not been previously linked to NRF2 activation; NRF2-driven upregulation of this gene set is largely independent of the organ system where the tumor developed. This critical subset of NRF2 targets is significantly enriched for genes functionally linked to oncogenesis, and several features differentiate these genes from other NRF2 targets. One of the key distinguishing features is that the NRF2 cancer target genes are regulated by high affinity, switch-like AREs that fall within genomic regions that possess a distinct, ubiquitously permissive chromatin signature. This finding implies that the NRF2 cancer target genes are highly responsive to oncogenic NRF2 in most tissues because the AREs at these loci lack the epigenetic constraints that restrict expression of most other NRF2 targets genes. Notably, the NRF2 cancer target gene set also serves as a reliable proxy for NRF2 activity. Identification of tumors with hyperactive NRF2 is difficult because there are many routes to its activation – mutations in NRF2, KEAP1, or CUL3; epigenetic silencing of KEAP1; etc. – so we used this 32 gene set to infer NRF2 activity based on RNA-seq data from thousands of tumors profiled by the TCGA project. This approach revealed that high NRF2 activity is associated with significant decreases in survival in at least 10 different cancers, including liver hepatocellular carcinoma, papillary kidney carcinoma, urothelial bladder cancer, and head and neck squamous cell carcinoma. Overall, the pervasive upregulation of these NRF2 cancer targets across multiple cancers, and their association with negative prognostic outcomes, suggest that these genes will be central to dissecting the functional implications of NRF2 hyperactivation in several cancer contexts.

A Murine Combined Injury Model of Total Body Irradiation and Skin Wound

In the radiation terrorism scenario there will be combined injuries; we have developed a mouse model of combined injury (total body irradiation (TBI) plus defined skin wound). We measured the effect of TBI doses from 7.0 to 9.25 Gy irradiation on survival and healing of the skin wound. C57BL/6NTac female mice (8 weeks of age) were irradiated to doses of 0 Gy, 7.0 Gy, 8.0 Gy, 8.5 Gy, 9.0 Gy and 9.25 Gy TBI. Twenty-four hours before irradiation, the lower backs were shaved followed by depilation with NAIR. One hour after TBI, mice were anesthetized and a 25 mm length, 5 mm deep scalpel incision/wound was made in the skin. The wound was closed using staples. Control mice received no irradiation and no skin wound. Numbers of surviving mice were recorded daily. At 14, or 20 days after irradiation, groups of control and 0 Gy + wounded mice were sacrificed and wound healing was determined by measuring the tensile strength of each of ten 2 mm strips of skin per mouse across the wound using a 45N capacity tensile tester. On day 28 following irradiation, all remaining mice were tested. The LD50/30 for C57BL/6NTac mice was 9.25 Gy. In the combined injury model the LD50/30 was 8.5 Gy with significantly increased lethality with wounding at 8.5 Gy and 9.0 Gy. Mice irradiated to 9.0 Gy + wound and 8.5 Gy + wound had a statistically significant decrease in survival compared to those receiving 9.0 Gy or 8.5 Gy alone (p = 0.0073 and 0.0115, respectively). The number of deaths in the 8.5 Gy, 9.0 Gy and 9.25 Gy + wound groups was high. We tested the tensile strength in wounds from mice receiving 0 Gy + wound, 7.0 Gy + wound and 8.0 Gy + wound. Compared to the control (non-irradiated, non-wounded) mice tensile strength, the wounds in the combined injury mice were less completely healed at all times. At days 14 and 20, the healing in the 0 Gy + wound was so minimal that we did not measure the other groups until day 28. At 28 days, the mice in the 8.0 Gy + wound group still showed a significantly decreased tensile strength (1.1 ± 0.1 newtons) compared to 1.4 ± 0.1 newtons for the 0 Gy + wound (p = 0.0013). This murine combined injury model of TBI irradiation + wound revealed a clear decreased survival compared to mice receiving TBI only. While longer observation times are needed to monitor the rates of wound healing, mice receiving 8.0 Gy + wound had decreased wound healing compared to 0 Gy + wound.

Developmental toxicity of hydroxylated chrysene metabolites in zebrafish embryos

One of the primary sources of polycyclic aromatic hydrocarbons (PAHs) in marine environments is oil. Photochemical oxidation and microbial transformation of PAH-containing oils can result in the formation of oxygenated products. Among the PAHs in crude oil, chrysene is one of the most persistent within the water column and may be transformed to 2- and 6-hydroxychrysene (OHCHR). Both of these compounds have been shown to activate (2-OHCHR) and antagonize (6-OHCHR) the estrogen receptor (ER). Previous studies in our lab have shown that estrogen can significantly alter zebrafish development. However, little is known about the developmental toxicity of hydroxylated PAHs. Zebrafish embryos were exposed to 0.5–10μM of 2- or 6-OHCHR from 2h post-fertilization (hpf) until 76hpf. A significant decrease in survival was observed following exposure to 6-OHCHR – but not 2-OHCHR. Both OHCHRs significantly increased the percentage of overall deformities after treatment. In addition to cardiac malformations, ocular and circulatory defects were also observed in embryos exposed to both compounds, while 2-OHCHR generally resulted in a higher prevalence of effect. Moreover, treatment with 2-OHCHR resulted in a significant decrease in hemoglobin levels. ER nor G-Protein coupled estrogen receptor (GPER) antagonists and agonists did not rescue the observed defects. We also analyzed the expression of cardiac-, eye- and circulation-related genes previously shown to be affected by oil. Rhodopsin mRNA expresssion was significantly decreased by both compounds equally. However, exposure to 2-OHCHR significantly increased the expression of the hematopoietic regulator, runx1 (runt related transcription factor 1). These results indicate the toxicity of oxygenated photoproducts of PAHs and suggest that other targets and signaling pathways may contribute to developmental toxicity of weathered oil. Our findings also demonstrate the regio-selective toxicity of hydroxy-PAHs in the effects on eye and circulatory development and raise the need to identify mechanisms and ecological risks of oxy-PAHs to fish populations.

Survival associated with cachexia among SEER-Medicare beneficiaries with lung cancer.

e18117 Background: Lung cancer is the leading cause of cancer death in the United States. It is estimated that 60% of lung cancer patients are afflicted with cancer-associated cachexia syndrome (CACS) and approximately 10% of these patients will die due to CACS. We examined the impact of CACS on survival among lung cancer elderly patients. Methods: We conducted a retrospective study using SEER-Medicare data. Patients were included if diagnosed with first primary lung cancer between January 1, 2005 and December 31, 2010, at least 66 years of age, and continuously enrolled in Medicare Parts A and B in the 12 months prior to diagnosis. We identified cachexia in lung cancer patients using ICD-9 codes. Descriptive statistics were used to identify population characteristics. Propensity score (1:1 nearest neighbor) matching was performed between cachectic and non-cachectic lung cancer patients to compare survival. Results: We identified 84,518 lung cancer patients. Of these, 2,536 (3%) developed CACS after lung cancer diagnosis. The most common comorbid conditions among cachectic and non-cachectic groups were chronic obstructive pulmonary disease (50% versus 45.62%), congestive heart failure (8.56% versus 13.38%), diabetes (7.41% versus 14.75%), peripheral vascular disease (3.82% versus 6.85%), and renal disease (3.63% versus 6.14%). Propensity score 1:1 matching for confounding bias and adjustment for immortal time bias resulted in a cohort of 3734 matched patients. Eighty-eight percent of patients in the cachectic group died during the follow-up period compared to 78% in the non-cachectic group. Median survival time among non-cachectic lung cancer patients was significantly longer than cachectic lung cancer patients (log-rank p &lt; 0.0001). Specifically, median survival in non-cachectic patients was 201 days compared to 92 days among cachectic patients. Conclusions: The occurrence of CACS is independently associated with a significant decrease in survival among lung cancer elderly patients. The results of this study may be useful for identifying healthcare burden and planning treatment modalities for this population.

Association of MLL2 mutation positive non-small cell lung cancer with prognosis.

11598 Background: Myeloid/lymphoid or mixed-lineage leukemia protein 2 (MLL2) is an epigenetic regulator expressed in many tissues. Although MLL2 mutations are associated with poor prognosis in different types of cancer, the clinical impact of this gene in lung cancer remains unclear. Here, we evaluated the clinical and genomic characteristics of MLL2 alteration in non-small cell lung cancer (NSCLC) and compared it to small cell lung cancer (SCLC) Methods: Between 2014 and 2016 tumor samples of 194 Stage III and IV NSCLC patients and 50 SCLC patients underwent targeted-exome sequencing. The association of MLL2 mutation with survival outcomes was measured using Kaplan–Meier methods (PFS, OS). Cox’s proportional hazards regression model was performed for multivariate survival analyses with known clinical prognostic features. All tests were two-sided and p-values = 0.05 were considered statistically significant. Results: The MLL2 mutation rate was 17.5% (N=34) in NSCLC. Patients with mutant MLL2 had significantly lower overall survival (OS) (9.97 vs. 30.2 months, p &lt; 0.0001) and progression-free survival (PFS) (8.46 vs. 24.1 month, p = 0.0007) compared to those with wild type MLL2. The median overall survival in the entire NSCLC cohort was 23.3 months (95% CI: 16.5 – 34.4). Interestingly, MLL2 mutation was significantly more common in females (p = 0.017). There was no significant association of MLL2 mutation status with age, smoking history, race or histology . Using a multivariate Cox regression model with adjustments based on tumor stage, smoking histology and chemotherapy, MLL2 mutation remained the most remarkable prognostic factor in NSCLC: OS Hazard Ratio 2.79, p = 0.0001 and PFS Hazard Ratio 1.99, p &lt; 0.001. By comparison, the MLL2 mutation rate in SCLC was 24% (N=12) and showed no gender bias (p=0.874). There was no significant decrease in survival associated with MLL2 mutation in SCLC (OS p = 0.966, PFS p = 0.641). Conclusions: This study demonstrates that MLL2 mutation specifically impacts survival outcome only in NSCLC but not SCLC.

Combining two antifungal agents does not enhance survival of Galleria mellonella larvae infected with Madurella mycetomatis.

To determine whether combination therapy would improve therapeutic outcome in eumycetoma caused by Madurella mycetomatis. Survival, colony-forming units (CFU), melanisation and histopathology in M. mycetomatis-infected Galleria mellonella larvae treated with amphotericin B, itraconazole, terbinafine or combinations thereof were determined. Compared to larvae treated with 5% glucose, enhanced survival was obtained when M. mycetomatis-infected larvae were treated with amphotericin B, but not when they were treated with itraconazole or terbinafine. Combination therapy did not increase survival compared to 5% glucose-treated larvae, itraconazole-treated larvae or terbinafine-treated larvae. Compared to amphotericin B monotreatment, a significant decrease in survival was noted when this therapy was combined with either itraconazole or terbinafine. CFU, melanisation and histopathology did not differ between monotherapy, combination therapy or 5% glucose-treated larvae. Combining different classes of antifungal agents did not enhance the survival of M. mycetomatis-infected G. mellonella larvae. Instead of improving the therapeutic outcome, combining either itraconazole or terbinafine with amphotericin B resulted in significantly lower survival rates of infected larvae than amphotericin B monotherapy. This experimental study does not provide support for the use of combined amphotericin B and itraconazole, combined itraconazole and terbinafine or combined terbinafine and amphotericin B and should be confirmed in other animal models.

Relationship between response to induction chemotherapy and disease control in patients with advanced laryngeal carcinoma included in an organ preservation protocol.

The aim of the study is to analyze the relationship between the degree of response to induction chemotherapy and the disease control in patients with locally advanced laryngeal carcinomas candidates to total laryngectomy. This retrospective study includes 389 patients with T3-T4 laryngeal tumors candidates to total laryngectomy, diagnosed between 1985 and 2013, treated with induction chemotherapy in an organ preservation protocol. Five-year local recurrence-free survival for patients receiving conservative treatment with radiotherapy after a complete response to induction chemotherapy was 75.4%; for patients with partial response greater than 50%, it was 62.0%; and for patients with the absence of response, it was 32.7%. There were significant differences in local recurrence-free survival and laryngeal dysfunction-free survival according to the response to induction chemotherapy (P = 0.0001) at the expense of patients with absence of response to induction chemotherapy. Patients with partial response greater than 50% treated with radiotherapy had a tendency to have worse local recurrence-free survival and laryngeal dysfunction-free survival than patients with complete response, but the differences did not reach statistical significance. Patients with the absence of response after induction chemotherapy had significant differences in disease-specific survival according to the second treatment: for patients treated with surgery it was 70.2%, whereas for patients treated with radiotherapy, it was 28.2% (P = 0.0001). In patients with the absence of response to induction chemotherapy, conservative treatment with radiotherapy implies a significant decrease in survival.

BIOACCUMULATION AND EFFECTS OF ALUMINIUM CONTENT IN ALLEATO 80 WG FUNGICIDE ON SOME LUMBRICIDAE SPECIES

The present study shows the results of the chronic test in evaluating the response of lumbricidae under the action of different concentrations of Alleato 80WG. The earthworm samples were taken from a plot of land cultivated with maize. Survival, biomass and aluminum content bioaccumulated in earthworms have been analyzed. Five replicates were carried out for each experiment. The survival rate showed maximum values (100%) for V5 (control sample), and (200 mg kg-1) (p=1) for V4. The other three concentrations (V2=500 mg kg-1; V3=400 mg kg-1; V4=300 mg kg-1) resulted in a significant decrease in survival compared to the control sample (V5). The trend line showed a significant decrease in survival with increasing concentration of toxic (R2=0.798; p<0.0001). All samples subjected to toxic indicated lower values of individual biomass (g). The aluminium amount was low in the underlayer/soil where earthworms were collected. The amount of aluminum bioaccumulated by earthworms increased with increasing the concentration of toxic (R2=0.839; p=0.029).

Prognostic Factors and Significance of Gastrointestinal Leak After Cytoreductive Surgery (CRS) with Heated Intraperitoneal Chemotherapy (HIPEC).

Gastrointestinal leak (GIL) after cytoreductive surgery with heated intraperitoneal chemotherapy (CRS/HIPEC) is associated with significant morbidity and mortality. This study aimed to identify GIL prognostic factors and its impact on overall survival. A retrospective analysis of a prospectively maintained database comprising 1270 CRS/HIPEC procedures was performed. Type of GIL, functional and resection status, morbidity, mortality, and survival were reviewed. Gastrointestinal leaks were identified in 8.7% (110/1270) of CRS/HIPEC procedures, including 53 anastomotic leaks (4.2%), 53 hollow viscus perforations (4.2%), and four leaks at unknown sites. The multivariate predictors of leak were Eastern Cooperative Oncology Group (ECOG) functional status (ECOG 1 vs. 0: odds ratio [OR] 2.12, p=0.009; ECOG 2 vs. 0: OR 2.90, p=0.004), and number of anastomoses (OR 5.34; p<0.0001). The in-hospital mortality rate for the GIL cohort was 21.8% (24/110), with a 72% (80/110) reoperation rate. The leak cohort had a higher major morbidityrate (88.3 vs. 23.3%; p<0.0001), a longer hospital stay (39.0 vs. 9.9days; p<0.0001), and a longer intensive care unit (ICU) stay (7.7 vs. 1.7days; p=0.0003). After surgical mortality was excluded, the overall survival periods for the leak and no-leak patients with complete cytoreduction were respectively 1.5 and 4.98years (p=0.0001). Clinically significant decreases in survival were observed for all primary malignancies. Gastrointestinal leak after CRS/HIPEC is a source of significant mortality, with a decrease in overall survival even after complete CRS. Preoperative functional status and number of anastomoses are predictors of leak for CRS/HIPEC patients.

The relationship between time to initiation of adjuvant chemotherapy and survival in breast cancer: a systematic review and meta-analysis.

It is known that adjuvant chemotherapy improves survival in women with breast cancer. It is not known whether the interval between surgery and the initiation of chemotherapy influences its effectiveness. To determine the relationship between time to initiation of adjuvant chemotherapy and survival in women with breast cancer, through a systematic review of the literature and meta-analysis. Systematic review of MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Database of Controlled Trials, Google Scholar, and abstracts presented at major international oncology conferences. The primary meta-analysis included only high-validity studies which directly measured the time from surgery to initiation of adjuvant chemotherapy and which controlled for major prognostic factors. Outcomes reported in the original studies were converted to a regression coefficient (β) and standard error corresponding to a 4-week delay in the initiation of chemotherapy. These relative risks were combined in both fixed- and random-effects models. Homogeneity was assessed by the Cochran χ 2 statistic and the I 2 statistic. Potential publication bias was investigated using standard error-based funnel plots. Meta-analysis of 8 high-validity studies demonstrated that a 4-week increase in TTAC was associated with a significant increase in the risk of death in both the fixed-effects model (RR 1.04; 95% CI, 1.01-1.08) and random-effects model (RR 1.08; 95% CI, 1.01-1.15). The association remained significant when the most highly weighted studies were sequentially removed from this analysis, and also when additional, lower validity studies were included in this analysis. Funnel plots showed no significant asymmetry to suggest publication bias. Increased waiting time from surgery to initiation of adjuvant chemotherapy is associated with a significant decrease in survival. Avoidance of unnecessary delays in the initiation of adjuvant chemotherapy has the potential to save the lives of many women with breast cancer.