Predictive factors for long-term survival after surgery for pancreatic ductal adenocarcinoma: Making a case for standardized reporting of the resection margin using certified cancer center data.

Factors for overall survival after pancreatic ductal adenocarcinoma (PDAC) seem to be nodal status, chemotherapy administration, UICC staging, and resection margin. However, there is no consensus on the definition for tumor free resection margin. Therefore, univariate OS as well as multivariate long-term survival using cancer center data was analyzed with regards to two different resection margin definitions. Ninety-five patients met inclusion criteria (pancreatic head PDAC, R0/R1, no 30 days mortality). OS was analyzed in univariate analysis with respect to R-status, CRM (circumferential resection margin; positive: ≤1mm; negative: >1mm), nodal status, and chemotherapy administration. Long-term survival >36 months was modelled using multivariate logistic regression instead of Cox regression because the distribution function of the dependent data violated the requirements for the application of this test. Significant differences in OS were found regarding the R status (Median OS and 95%CI for R0: 29.8 months, 22.3-37.4; R1: 15.9 months, 9.2-22.7; p = 0.005), nodal status (pN0 = 34.7, 10.4-59.0; pN1 = 17.1, 11.5-22.8; p = 0.003), and chemotherapy (with CTx: 26.7, 20.4-33.0; without CTx: 9.7, 5.2-14.1; p < .001). OS according to CRM status differed on a clinically relevant level by about 12 months (CRM positive: 17.2 months, 11.5-23.0; CRM negative: 29.8 months, 18.6-41.1; p = 0.126). A multivariate model containing chemotherapy, nodal status, and CRM explained long-term survival (p = 0.008; correct prediction >70%). Chemotherapy, nodal status and resection margin according to UICC R status are univariate factors for OS after PDAC. In contrast, long-term survival seems to depend on wider resection margins than those used in UICC R classification. Therefore, standardized histopathological reporting (including resection margin size) should be agreed upon.

NOTCH1, HIF1A and other cancer-related proteins in lung tissue from uranium miners--variation by occupational exposure and subtype of lung cancer.

BACKGROUND: Radon and arsenic are established pulmonary carcinogens. We investigated the association of cumulative exposure to these carcinogens with NOTCH1, HIF1A and other cancer-specific proteins in lung tissue from uranium miners. METHODOLOGY/PRINCIPAL FINDINGS: Paraffin-embedded tissue of 147 miners was randomly selected from an autopsy repository by type of lung tissue, comprising adenocarcinoma (AdCa), squamous cell carcinoma (SqCC), small cell lung cancer (SCLC), and cancer-free tissue. Within each stratum, we additionally stratified by low or high level of exposure to radon or arsenic. Lifetime exposure to radon and arsenic was estimated using a quantitative job-exposure matrix developed for uranium mining. For 22 cancer-related proteins, immunohistochemical scores were calculated from the intensity and percentage of stained cells. We explored the associations of these scores with cumulative exposure to radon and arsenic with Spearman rank correlation coefficients (r(s)). Occupational exposure was associated with an up-regulation of NOTCH1 (radon r(s) = 0.18, 95% CI 0.02-0.33; arsenic: r(s) = 0.23, 95% CI 0.07-0.38). Moreover, we investigated whether these cancer-related proteins can classify lung cancer using supervised and unsupervised classification. MUC1 classified lung cancer from cancer-free tissue with a failure rate of 2.1%. A two-protein signature discriminated SCLC (HIF1A low), AdCa (NKX2-1 high), and SqCC (NKX2-1 low) with a failure rate of 8.4%. CONCLUSIONS/SIGNIFICANCE: These results suggest that the radiation-sensitive protein NOTCH1 can be up-regulated in lung tissue from uranium miners by level of exposure to pulmonary carcinogens. We evaluated a three-protein signature consisting of a physiological protein (MUC1), a cancer-specific protein (HIF1A), and a lineage-specific protein (NKX2-1) that could discriminate lung cancer and its major subtypes with a low failure rate.

Innate defense regulator peptide 1018 in wound healing and wound infection.

Innate defense regulators (IDRs) are synthetic immunomodulatory versions of natural host defense peptides (HDP). IDRs mediate protection against bacterial challenge in the absence of direct antimicrobial activity, representing a novel approach to anti-infective and anti-inflammatory therapy. Previously, we reported that IDR-1018 selectively induced chemokine responses and suppressed pro-inflammatory responses. As there has been an increasing appreciation for the ability of HDPs to modulate complex immune processes, including wound healing, we characterized the wound healing activities of IDR-1018 in vitro. Further, we investigated the efficacy of IDR-1018 in diabetic and non-diabetic wound healing models. In all experiments, IDR-1018 was compared to the human HDP LL-37 and HDP-derived wound healing peptide HB-107. IDR-1018 was significantly less cytotoxic in vitro as compared to either LL-37 or HB-107. Furthermore, administration of IDR-1018 resulted in a dose-dependent increase in fibroblast cellular respiration. In vivo, IDR-1018 demonstrated significantly accelerated wound healing in S. aureus infected porcine and non-diabetic but not in diabetic murine wounds. However, no significant differences in bacterial colonization were observed. Our investigation demonstrates that in addition to previously reported immunomodulatory activities IDR-1018 promotes wound healing independent of direct antibacterial activity. Interestingly, these effects were not observed in diabetic wounds. It is anticipated that the wound healing activities of IDR-1018 can be attributed to modulation of host immune pathways that are suppressed in diabetic wounds and provide further evidence of the multiple immunomodulatory activities of IDR-1018.