The Effects of Primary Tumor Location on Survival after Liver Resection for Colorectal Liver Metastasis in the Mediterranean Population.

(1) Background: There is an abundance of literature available on predictors of survival for patients with colorectal liver metastases (CRLM) but minimal information available on the relationship between the primary tumor location and CRLM survival. The studies that focus on the primary tumor location and CRLM survival exhibit a great deal of controversy and inconsistency with regard to their results (some studies show statistically significant connections between the primary tumor location and prognosis versus other studies that find no significant relationship between these two factors). Furthermore, the majority of these studies have been conducted in the West and have studied more diverse and heterogenous populations, which may be a contributing factor to the conflicting results. (2) Methods: We included patients who underwent liver resection for CRLM between December 2004 and January 2019 at two university-affiliated medical centers in Israel: Carmel Medical Center (Haifa) and Rabin Medical Center (Petach Tikvah). Primary tumors located from the cecum up to and including the splenic flexure were labeled as right-sided primary tumors, whereas tumors located from the splenic flexure down to the anal verge were labeled as left-sided primary tumors. (3) Results: We identified a total of 501 patients. Of these patients, 225 had right-sided primary tumors and 276 had left-sided primary tumors. Patients with right-sided tumors were significantly older at the time of liver surgery compared to those with left-sided tumors (66.1 + 12.7 vs. 62 + 13.1, p = 0.002). Patients with left-sided tumors had slightly better overall survival rates than those with right-sided tumors. However, the differences were not statistically significant (57 vs. 50 months, p = 0.37 after liver surgery). (4) Conclusions: The primary tumor location does not significantly affect patient survival after liver resection for colorectal liver metastasis in the Mediterranean population.

Short- and Long-Term Outcomes in Elderly Patients Following Hand-Assisted Laparoscopic Surgery for Colorectal Liver Metastasis.

(1) Background: Hand-assisted laparoscopic surgery (HALS) has engendered growing attention as a safe procedure for the resection of metastatic liver disease. However, there is little data available regarding the outcomes of HALS for colorectal liver metastasis (CRLM) in patients over the age of 75. (2) Methods: We compare the short- and long-term outcomes of patients >75-years-old (defined in our study as "elderly patients" and referred to as group 1, G1), with patients <75-years-old (defined in our study as "younger patients" and referred to as group 2, G2). (3) Results: Of 145 patients, 28 were in G1 and 117 were in G2. The most common site of the primary tumor was the right colon in G1, and the left colon in G2 (p = 0.05). More patients in G1 underwent laparoscopic anterior segment resection compared with G2 (43% vs. 39% respectively) (p = 0.003). 53% of patients in G1 and 74% of patients in G2 completed neoadjuvant therapy (p = 0.04). The median size of the largest metastasis was 32 (IQR 19-52) mm in G1 and 20 (IQR 13-35) mm in G2 (p = 0.001). The rate of complications (Dindo-Clavien grade ≥ III) was slightly higher in G1 (p = 0.06). The overall 5-year survival was 30% in G1 and 52% in G2 (p = 0.12). (4) Conclusions: Hand-assisted laparoscopic surgery for colorectal liver metastasis is safe and effective in an elderly patient population.

The Association between Preoperative Vitamin D Levels and Postoperative Complications in Patients Undergoing Colorectal Liver Metastasis Surgery.

(1) Background: Over the past several years, there has been a renewed interest with regard to the effect of pre-operative vitamin D levels on post-surgical outcomes. Pre-operative vitamin D deficiency has been associated with many negative post-operative outcomes. However, the role of vitamin D in postoperative outcomes in colorectal liver metastasis (CRLM) resection is relatively uninvestigated. Our study investigated the correlation between preoperative vitamin D levels and postoperative complications in patients undergoing resection for CRLM. (2) Methods: We retrospectively examined the post-operative course of 109 patients, who were evaluated based upon preoperative vitamin D levels: the first group had vitamin D levels less than 25 nmol/L (VIT D < 25 nmol/L) (n = 12) vs. the second group who had vitamin D levels equal to or greater than 25 nmol/L (VIT D ≥ 25 nmol/L) (n = 97). (3) Results: Patients with lower pre-operative vitamin D levels (VIT D < 25 nmol/L) had significantly higher rates of blood transfusions (33.3% vs. 10.3%, p = 0.01), post-operative surgical complications (50% vs. 17.5%, p = 0.009), and infectious complications (25% vs. 7.2%, p = 0.04). However, there was no difference in overall survival seen between the two groups. (4) Conclusions: The results of our study indicate that patients with preoperative vitamin D deficiency (defined as preoperative vitamin D levels less than 25 nmol/L) may have an increased risk of postoperative complications in patients undergoing liver surgery for metastatic colorectal cancer.

Immunomodulatory germline variation associated with the development of multiple primary melanoma (MPM).

Multiple primary melanoma (MPM) has been associated with a higher 10-year mortality risk compared to patients with single primary melanoma (SPM). Given that 3-8% of patients with SPM develop additional primary melanomas, new markers predictive of MPM risk are needed. Based on the evidence that the immune system may regulate melanoma progression, we explored whether germline genetic variants controlling the expression of 41 immunomodulatory genes modulate the risk of MPM compared to patients with SPM or healthy controls. By genotyping these 41 variants in 977 melanoma patients, we found that rs2071304, linked to the expression of SPI1, was strongly associated with MPM risk reduction (OR = 0.60; 95% CI = 0.45-0.81; p = 0.0007) when compared to patients with SPM. Furthermore, we showed that rs6695772, a variant affecting expression of BATF3, is also associated with MPM-specific survival (HR = 3.42; 95% CI = 1.57-7.42; p = 0.0019). These findings provide evidence that the genetic variation in immunomodulatory pathways may contribute to the development of secondary primary melanomas and also associates with MPM survival. The study suggests that inherited host immunity may play an important role in MPM development.

Autoimmune genetic risk variants as germline biomarkers of response to melanoma immune-checkpoint inhibition.

Immune-checkpoint inhibition (ICI) treatments improve outcomes for metastatic melanoma; however, > 60% of treated patients do not respond to ICI. Current biomarkers do not reliably explain ICI resistance. Given the link between ICI and autoimmunity, we investigated if genetic susceptibility to autoimmunity modulates ICI efficacy. In 436 patients with metastatic melanoma receiving single line ICI or combination treatment, we tested 25 SNPs, associated with > 2 autoimmune diseases in recent genome-wide association studies, for modulation of ICI efficacy. We found that rs17388568-a risk variant for allergy, colitis and type 1 diabetes-was associated with increased anti-PD-1 response, with significance surpassing multiple testing adjustments (OR 0.26; 95% CI 0.12-0.53; p = 0.0002). This variant maps to a locus of established immune-related genes: IL2 and IL21. Our study provides first evidence that autoimmune genetic susceptibility may modulate ICI efficacy, suggesting that systematic testing of autoimmune risk loci could reveal personalized biomarkers of ICI response.

Genetic markers of pigmentation are novel risk loci for uveal melanoma.

While the role of genetic risk factors in the etiology of uveal melanoma (UM) has been strongly suggested, the genetic susceptibility to UM is currently vastly unexplored. Due to shared epidemiological risk factors between cutaneous melanoma (CM) and UM, in this study we have selected 28 SNPs identified as risk variants in previous genome-wide association studies on CM or CM-related host phenotypes (such as pigmentation and eye color) and tested them for association with UM risk. By logistic regression analysis of 272 UM cases and 1782 controls using an additive model, we identified five variants significantly associated with UM risk, all passing adjustment for multiple testing. The three most significantly associated variants rs12913832 (OR = 0.529, 95% CI 0.415-0.673; p = 8.47E-08), rs1129038 (OR = 0.533, 95% CI 0.419-0.678; p = 1.19E-07) and rs916977 (OR = 0.465, 95% CI 0.339-0.637; p = 3.04E-07) are correlated (r(2) > 0.5) and map at 15q12 in the region of HERC2/OCA2, which determines eye-color in the human population. Our data provides first evidence that the genetic factors associated with pigmentation traits are risk loci of UM susceptibility.

The Expression Quantitative Trait Loci in Immune Pathways and their Effect on Cutaneous Melanoma Prognosis.

PURPOSE: The identification of personalized germline markers with biologic relevance for the prediction of cutaneous melanoma prognosis is highly demanded but to date, it has been largely unsuccessful. As melanoma progression is controlled by host immunity, here we present a novel approach interrogating immunoregulatory pathways using the genome-wide maps of expression quantitative trait loci (eQTL) to reveal biologically relevant germline variants modulating cutaneous melanoma outcomes. EXPERIMENTAL DESIGN: Using whole genome eQTL data from a healthy population, we identified 385 variants significantly impacting the expression of 268 immune-relevant genes. The 40 most significant eQTLs were tested in a prospective cohort of 1,221 patients with cutaneous melanoma for their association with overall (OS) and recurrence-free survival using Cox regression models. RESULTS: We identified highly significant associations with better melanoma OS for rs6673928, impacting IL19 expression (HR, 0.56; 95% CI, 0.41-0.77; P = 0.0002) and rs6695772, controlling the expression of BATF3 (HR, 1.64; 95% CI, 1.19-2.24; P = 0.0019). Both associations map in the previously suspected melanoma prognostic locus at 1q32. Furthermore, we show that their combined effect on melanoma OS is substantially enhanced reaching the level of clinical applicability (HR, 1.92; 95% CI, 1.43-2.60; P = 2.38e-5). CONCLUSIONS: Our unique approach of interrogating lymphocyte-specific eQTLs reveals novel and biologically relevant immunomodulatory eQTL predictors of cutaneous melanoma prognosis that are independent of current histopathologic markers. The significantly enhanced combined effect of identified eQTLs suggests the personalized utilization of both SNPs in a clinical setting, strongly indicating the promise of the proposed design for the discovery of prognostic or risk germline markers in other cancers. Clin Cancer Res; 22(13); 3268-80. ©2016 AACR.