Cytokine Expression Patterns and Single Nucleotide Polymorphisms (SNPs) in Patients with Chronic Borreliosis.

(1) Background: Genetically based hyperinflammation may play a role in pathogen defense. We here questioned whether alterations in circulating monocytes/macrophages, inflammatory biomarkers and a functional SNP (single nucleotide polymorphisms) of the Interleukin-6 (IL-6) promotor might play a role in patients with persistent, and treatment resistant borreliosis. (2) Methods: Leukocyte subpopulations were studied by flow cytometry; plasma cytokines were determined by a chemiluminescence based ELISA (Immulite®), and genotypes of the IL-6 promotor SNP rs1800795 were determined by pyrosequencing. (3) Results: In a cohort of n = 107 Lyme borreliosis patients, who concomitantly manifested either malignant diseases (group 1), autoimmune disorders (group 2), neurological diseases (group 3), or morbidities caused by multiple other infectious complications (group 4), we found decreased numbers of anti-inflammatory CD163-positive macrophages, elevated concentrations of inflammatory cytokines, and an imbalance of IL-6 promotor SNP rs1800795 genotypes. The most prominently upregulated cytokines were IL-1ß, and IL-8. (4) Conclusions: Increased pro-inflammatory phenotypes identified by monocyte/macrophage subtypes and concomitantly increased cytokines appear to be valid to monitor disease activity in patients with persistent Lyme borreliosis. Patterns may vary by additional co-morbidities. In patients with autoimmune diseases, increased frequencies of a heterozygous IL-6 promotor SNP rs1800795 were identified. This functional SNP may guide chronic inflammation, impacting other cytokines to trigger trigger chronicity and therapeutic resistance in Lyme borreliosis.

Health-related quality of life in cancer patients treated with PD-(L)1 inhibitors: a systematic review.

INTRODUCTION: A systematic review was performed to explore the health-related quality of life (HRQoL) outcomes among cancer patients receiving PD-(L)1 inhibitors compared to those receiving traditional cytotoxic therapy. Areas covered: Citations from PubMed and the American Society of Clinical Oncology meeting library were examined. Cross-references from original studies and review articles were also reviewed. Eligible trials included randomized controlled trials of cancer patients treated with one of the PD-(L)1 inhibitors and reporting HRQoL outcomes. A total of 11 studies were included in the current review. PD-(L)1 inhibitors were associated with a consistent prolongation of the time to symptomatic deterioration. This was shown with the three agents (nivolumab, pembrolizumab, and atezolizumab) as well as across a variety of solid tumors (lung cancer, melanoma, head and neck cancer and urothelial cancer). Moreover, PD-(L)1 inhibitor therapy was associated with better symptomatic control at different follow-up points. This was observed regardless of the agent used of the solid tumor treated. Expert commentary: Across a variety of solid tumor indications as well as a variety of PD-(L)1 inhibitors, the use of PD-(L)1 inhibitors is associated with an improvement in the quality of life. The utility of patient-reported outcomes in predicting clinical benefit from these agents needs to be explored further.

Impact of Time to Start Systemic Therapy on the Outcomes of Patients with Metastatic Colorectal Cancer Treated with First Line FOLFOX Chemotherapy; a Patient-Level Pooled Analysis of Two Clinical Trials.

BACKGROUND: Impact of time to start first-line systemic chemotherapy following diagnosis of metastatic colorectal cancer (mCRC) needs to be studied. METHODS: This is a pooled analysis of the raw data of the comparator arms of two randomized studies (NCT00272051; NCT00305188). Univariate and multivariate analyses of predictors of overall and progression-free survival were conducted through Cox regression analysis. Factors with statistically significant P value (P < 0.05) in the univariate part of the analysis were included in the multivariate analysis. RESULTS: In univariate analysis, time to start systemic therapy did not affect overall or progression-free survival (P=0.694; P= 0.891 respectively). In multivariate analysis for overall survival, the following factors were predictive of worse overall survival: younger age (P = 0.019), higher ECOG performance score (P = 0.001), more than one site of metastatic disease (P = 0.002), colon site of the primary tumor (P = 0.004), and no oncologic surgery to the primary tumor (P < 0.001). Likewise, in multivariate analysis for progression-free survival, the following factors were predictive of worse progression-free survival: no oncologic surgery to the primary (P < 0.001), more than one organ of metastatic disease (P < 0.001), and no concurrent bevacizumab administration (P = 0.015). CONCLUSION: Time to start systemic chemotherapy does not appear to impact overall or progression-free survival among mCRC patients.

Impact of primary tumor side on the outcomes of patients with non-metastatic colon cancer; a patient-level pooled analysis of two clinical trials.

OBJECTIVE: To assess the impact of primary tumor side on the outcomes of non-metastatic colon cancer patients included in two clinical trials. METHODS: Overall and disease-free survivals were assessed according to the side of the tumor, through Kaplan-Meier analysis. Univariate and Multivariate analysis of predictors of disease-free survival was performed through Cox regression analysis. RESULTS: Kaplan-Meier analysis of disease-free survival according to the side of the primary tumor was conducted. In the overall cohort, the right-sided disease has longer disease-free survival compared to left-sided disease (p = 0.005). When the analysis was repeated among different treatment strata (observation, adjuvant 5FU/LCV, adjuvant edrecolomab), right-sided colon cancer has longer disease-free survival among observation-treated patients only (p = 0.020). Multivariate analysis was conducted among the three subsets of adjuvant treatment. The left side of the primary tumor was predictive of worse disease-free survival in patients treated with observation only (p = 0.005) but not in patients treated with adjuvant 5FU/LCV (p = 0.345) or patients treated with adjuvant edrecolomab (p = 0.661). CONCLUSION: Stage II right-sided colon cancer patients have better disease-free survival compared to stage II left-sided colon cancer patients when treated with surgery only. This survival difference disappears if patients were treated with adjuvant fluoropyrimidines.

Assessment of the external validity of the American Joint Committee on Cancer 8th staging system for anal carcinoma.

BACKGROUND: The current study evaluates the prognostic value of the 8th edition of the American Joint Committee on Cancer (AJCC) staging system for patients with anal carcinoma. PATIENTS AND METHODS: The Surveillance, Epidemiology and End Results (SEER) database (2004-2014) was explored and AJCC 6th and 8th stages were formulated. Through Kaplan-Meier analysis, overall survival analyses were performed. The Cox regression model (adjusted for age, gender, histology, ethnicity, subsite and grade) was calculated for cancer-specific survival and, subsequently, pairwise comparisons of hazard ratios were calculated. RESULTS: A total of 11,934 anal carcinoma patients were included in the analysis. Overall survival was compared according to both AJCC 6th and 8th systems. For both staging systems, the p value for the trend in overall survival was significant (p < .0001). Nevertheless, for the AJCC 6th system, stage IIIA and IIIB curves were overlapping; while for the AJCC 8th system, the median survival for stage IIB was lower than the mean survival for stage IIIA (74 months vs. 96 months). Moreover, stage IIIB and stage IIIC curves were overlapping. The cause-specific (cancer-specific) Cox regression hazard was calculated for both staging systems. Pairwise hazard ratio comparisons between different AJCC 6th stages were performed and all p values for comparisons were significant (p < .05). Pairwise hazard ratio comparisons between different AJCC 8th stages were performed and only the following comparisons were significant (p < .0001) (I vs. IIA; IIA vs. IIB; IIIC vs. IV). The C-statistic (using death from anal carcinoma as the dependent variable) for the AJCC 6th staging system was: 0.681 (SE: 0.009; 95% CI: 0.664-0.698); while the C-statistic for the AJCC 8th staging system was 0.687 (SE: 0.008; 95% CI: 0.670-0.703). CONCLUSIONS: There is no evidence of significant improvement in the AJCC 8th edition compared to AJCC 6th (or 7th) edition in terms of overall or cancer-specific survival prediction.

Comparison of three prognostic models for predicting cancer-specific survival among patients with gastrointestinal stromal tumors.

AIM: To evaluate the predictive value for cancer-specific survival of the models of the American Joint Committee on Cancer (AJCC) stage, NIH and Armed Forces Institute of Pathology (AFIP) among patients with gastrointestinal stromal tumors (GISTs). METHODS: Surveillance, Epidemiology and End Results database (2010-2014) was accessed. Overall survival analysis and adjusted cancer-specific Cox regression hazard was calculated. RESULTS: For gastric GISTs, concordance-index according to AJCC was 0.834; according to NIH was 0.833; according to AFIP was 0.836. Concordance-index for nongastric GISTs according to AJCC was 0.800, according to NIH was 0.801 and according to AFIP was 0.799. CONCLUSION: The performance of the three models is comparable with regards to cancer-specific survival prediction.

External validation of the 8th American Joint Committee on Cancer staging system for gall bladder carcinoma.

BACKGROUND: To validate the changes within the American Joint Committee on Cancer (AJCC) 8th staging system for gall bladder carcinoma compared to AJCC 7th staging system. METHODS: Surveillance, Epidemiology and End Results (SEER) database [2004-2014] was queried. Kaplan-Meier survival analyses and Log-rank testing were assessed according to both AJCC 7th and 8th staging systems. Likewise, Cox cancer-specific hazard ratio was evaluated according to both staging systems. RESULTS: Overall survival was assessed according to the two staging systems; and P values for overall trend (log/rank test) were significant (P<0.001) for both scenarios. Cox regression cancer-specific hazard adjusted for age, gender, histology, gender and surgery was evaluated according to the two staging systems. According to AJCC 7th staging system, the following pair wise hazard ratio comparisons were significant (II vs. IIIA; IIIB vs. IVA; IVA vs. IVB). According to AJCC 8th staging system, the following pair wise hazard ratio comparisons were significant (II vs. IIIA; IVA vs. IVB). C-statistic was assessed using death from gall bladder carcinoma as the dependent variable; and the findings for the two staging systems were as follows: AJCC 7th staging system: 0.684 (SE: 0.008; 95% CI: 0.667-0.701); AJCC 8th staging system: 0.682 (SE: 0.009; 95% CI: 0.665-0.698). CONCLUSIONS: There is a comparable discriminatory performance for AJCC 8th staging system compared to AJCC 7th staging system. Change form location-based to number-based N category assessment does not improve the overall prognostic performance of the staging system.

Exploring the differences between early-onset gastric cancer and traditional-onset gastric cancer.

BACKGROUND: The current study sought to explore the potential clinical, epidemiological and genetic differences between early-onset gastric cancer (E-gastric cancer: defined as 20-39 years) and traditional-onset gastric cancer (T-gastric cancer: defined as ≥40 years). METHODS: Datasets from the following sources were searched: Surveillance, Epidemiology and End Results database [2000-2014], Behavioral Risk Factor Surveillance Survey and the cancer genome atlas (TCGA). Clinicopathological characteristics, trends, and genetic findings were compared between E-gastric cancer and T-gastric cancer. Moreover, correlations with relevant risk factors were sought after. RESULTS: A total of 95,323 gastric cancer patients were identified in the period from 2000 to 2014. While T-gastric cancer was decreasing during the study period (-1.4; P<0.05), E-gastric cancer was stable during the study period. E-gastric cancer is less prevalent in males (51.1% vs. 61.0%; P<0.0001), and white patients (68.9% vs. 71.4%; P<0.0001). E-gastric cancer patients usually present with poorly differentiated histology (55.3% vs. 48.0%; P<0.0001) as well as more aggressive histological subtypes (e.g., diffuse histology or linitis plastica). No difference can be detected with regards to risk factor correlations between E-gastric cancer and T-gastric cancer. Only four patients with E-gastric cancer were available in the provisional TCGA dataset at the time of the study. CONCLUSIONS: E-gastric cancer is a potentially distinct disease entity with specific clinicopathological and trend patterns compared to conventional T-gastric cancer. Further studies are needed to explore the potential etiologic basis as well as to investigate the clinical consequences of this distinction. The impact of this distinction on minority populations requires further assessment as well.

Validation of the eighth clinical American Joint Committee on Cancer stage grouping for esophageal cancer.

AIM: To validate the American Joint Committee on Cancer (AJCC) clinical staging system for esophageal cancer using Surveillance, Epidemiology and End Results database. METHODS: Cancer-specific survival analyses for clinically-staged patients with esophageal cancer according to both seventh and eighth editions were conducted through Kaplan-Meier analysis. RESULTS: For cancer-specific survival according to both seventh and eighth clinical systems, p-values for pairwise comparisons were nonsignificant in many comparisons. C-index for adenocarcinoma was: 0.671 according to the seventh AJCC and 0.671 according to the clinical eighth AJCC. C-index for squamous cell carcinoma according to the seventh AJCC was: 0.634 and 0.643 according to clinical eighth AJCC. CONCLUSION: Minimal improvement was achieved by the eighth clinical AJCC staging system for esophageal cancer.

Immune-related musculoskeletal toxicities among cancer patients treated with immune checkpoint inhibitors: a systematic review.

AIM: Immune-related musculoskeletal toxicities are uncommon but potentially serious adverse events; and they may accompany the use of immune checkpoint inhibitors (ICIs). The objective of this systematic review is to assess the patterns of these musculoskeletal toxicities. METHODS & RESULTS: PubMed database has been searched till May 2017. Clinical studies and case reports reporting the occurrence of immune-related musculoskeletal toxicities (other than arthralgia and myalgia) in cancer patients treated with ICIs were included. Eight trials with 2263 participants were included. Likewise, nine case reports reporting the outcomes of 12 patients were included. CONCLUSION: Immune-related arthritis and myositis occur uncommonly in cancer patients treated with ICIs. Further studies are required to better describe the pathogenesis as well as the time course of these events.

Cigarette smoking as a risk factor for the development of and mortality from hepatocellular carcinoma: An updated systematic review of 81 epidemiological studies.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and its incidence has increased during the past decade. While hepatitis B and C virus infections and alcohol were established risk factors, the impact of smoking on the incidence and mortality of HCC was needed to be confirmed. METHODS: We reviewed cohort and case-control studies evaluating the association between cigarette smoking and incidence and mortality of HCC from MEDLINE and Google Scholar. We also checked reference lists of original studies and review articles manually for cross-references up to February 2016. We extracted the relevant information on participant characteristics and study outcomes, as well as information on the methodology of the studies. We also assessed the quality of the included trials using critical appraisal skills program checklists. Meta-analysis was performed by using RevMan 5.3 software. RESULTS: A total of 81 studies were included in the systematic review. Pooled OR for HCC development with current smokers was 1.55 (95% CI: 1.46 to 1.65; P < 0.00001). Pooled OR for HCC development with former smokers was 1.39 (95% CI: 1.26 to 1.52; P < 0.00001) and pooled OR for HCC development with heavy smokers was 1.90 (95% CI: 1.68 to 2.14; P < 0.00001). Pooled OR for the mortality of current smokers with HCC was 1.29 (95% CI: 1.23 to 1.34; P < 0.00001); and for former smokers with HCC, it was 1.20 (95% CI: 1.00 to 1.42; P = 0.04). CONCLUSIONS: Cigarette smoking increases the incidence and mortality of HCC. Further studies are needed to evaluate possible impact of quitting smoking on decreasing this risk.

Impact of liver transplantation on the risk of second malignant tumors among hepatocellular carcinoma patients.

BACKGROUND: Population-based data on the development of second malignant neoplasms (SMNs) following the diagnosis of hepatocellular carcinoma (HCC) are uncommon. We evaluated this clinical vignette in HCC patients within the Surveillance, Epidemiology and End Results (SEER) database. METHODS: The SEER database (1973-2012) was queried using the SEER*Stat program to determine the clinico-pathological features of HCC patients with more than one year survival who developed SMNs. Standardized incidence ratios (SIRs) were calculated to determine the risk of each type of subsequent cancers. Relative risk was assessed to determine the impact of liver transplantation on the development of second malignant neoplasms. RESULTS: On SIR analysis, the following sites have an enhanced risk of developing an SMN following the diagnosis of HCC: tongue, anal canal, liver, lung, kidney, thyroid, non-Hodgkin lymphoma (both nodal and extra-nodal disease) and acute monocytic leukemia (P < 0.05 for all sites). A significantly higher RR was found for the development of lung cancer (RR = 2.096), thyroid cancer (RR = 3.045) and non-Hodgkin lymphoma (RR = 3.822) among patients who underwent liver transplantation compared to those who did not (P < 0.05). CONCLUSION: There is an excess risk for developing a number of SMNs among patients diagnosed with HCC.

Immune-related neurological toxicities among solid tumor patients treated with immune checkpoint inhibitors: a systematic review.

INTRODUCTION: Immune-related neurologic toxicities are uncommon but serious adverse events that may be associated with the use of immune checkpoint inhibitors. The objective of this review is to assess the incidence and risk of neurologic toxicities which are potentially immune-related and occur with immune checkpoint treatment of solid tumors. Areas covered: PubMed database has been searched till January 2017. Clinical trials, case series and case reports reporting the occurrence of immune-related neurologic toxicities in solid tumor patients treated with immune checkpoint inhibitors were included. Eighteen trials with 4469 participants were included. The most common neurologic toxicities reported with these agents included sensory and motor peripheral neuropathies. Moreover, 17 case reports describing immune-related neurological events occurring with 22 patients were included. Expert commentary: Immune-related neurological toxicities occur uncommonly in cancer patients treated immune checkpoint inhibitors. Further studies are needed to better describe the course of these events (i.e. time to onset, time to resolution and responsiveness to different immunosuppressives).

Early stage hepatocellular carcinoma in the elderly: A SEER database analysis.

BACKGROUND: Scarce evidence exists regarding the management of elderly patients (≥70years) with hepatocellular carcinoma (HCC). This study assessed the presentation and outcomes of elderly patients with early stage HCC. METHODS: Patient with early stage HCC (T1/T2N0M0), ≥70years, diagnosed between 2004 and 2013 were identified from the SEER (Surveillance, Epidemiology, and End Results) database. Propensity score matching (for receipt of localized treatment) was performed considering baseline characteristics (age, gender, race, tumor (T) stage, tumor size, fibrosis score, alpha fetoprotein level and histological subtype). RESULTS: A total of 6693 patients were identified. The median age group was 75-80years, and 2457 patients received local treatment (either surgical or non-surgical treatment). Both before and after propensity score matching, cancer-specific and overall survival (P<0.0001 for all) were better in the local treatment group. When stratifying the overall survival according to age group (70-80years vs. >80years) in the post matching cohort, patients treated with local treatment have better overall survival than those not treated regardless of the age group (P<0.0001 for both groups). In multivariate analysis of the matched population: local treatment, normal AFP and age (70-80years) were associated with better overall survival (P<0.0001, P<0.0001, P=0.047; respectively). CONCLUSION: Within the known limitations of the current SEER analysis, it may be cautiously suggested that elderly patients with early HCC should be properly selected for potentially curative local therapies. Prospective confirmation of these results should be conducted.

Prognostic value of site-specific extra-hepatic disease in hepatocellular carcinoma: a SEER database analysis.

BACKGROUND: We the prognostic value of site-specific extra-hepatic disease in hepatocellular carcinoma (HCC) patients registered within the surveillance, epidemiology and end results (SEER) database. METHODS: SEER database (2010-2013) has been queried through SEER*Stat program to determine the prognosis of advanced HCC patients according to the site of extra-hepatic disease. Survival analysis has been conducted through Kaplan Meier analysis. RESULTS: A total of 4396 patients with stage IV HCC were identified in the period from 2010-2013 and they were included into this analysis. Patients with isolated regional lymph node involvement have better outcomes compared to patients with any other site of extra-hepatic disease (P < 0.0001 for both endpoints). Among patients with distant metastases, patients with bone metastases have better outcomes compared to patients with lung metastases (P < 0.0001 for both endpoints). Multivariate analysis revealed that younger age, normal alpha fetoprotein, single site of extra-hepatic disease, local treatment to the primary tumor and surgery to the metastatic disease were associated with better overall survival and liver cancer-specific survival. CONCLUSION: Within the limits of the current SEER analysis, HCC patients with isolated lung metastases seem to have worse outcomes compared to patients with isolated bone or regional nodal metastases.​.

Immune-related ocular toxicities in solid tumor patients treated with immune checkpoint inhibitors: a systematic review.

INTRODUCTION: Immune-related ocular toxicities are uncommon but serious adverse events that may be associated with the use of immune checkpoint inhibitors. The objective of this review is to assess the incidence and risk of ocular toxicities which are potentially immune-related and occur with immune checkpoint treatment of solid tumors. Areas covered: PubMed database has been searched till June 2016. Prospective clinical trials reporting the occurrence of immune-related ocular toxicities in solid tumor patients treated with immune checkpoint inhibitors were included. Eleven trials with 4965 participants were included. These studies included one study for ipilimumab and tremelimumab, three studies for nivolumab, five studies for pembrolizumab and one study comparing pembrolizumab to ipilimumab. No atezolizumab studies were included. The most common ocular toxicities reported with these agents included uveitis and dry eyes. Pooled analysis for odds ratio of all-grade immune-related ocular toxicities is 3.40 [95% CI: 1.32-8.71; P = 0.01]. Expert commentary: Despite being uncommon, immune-related ocular toxicities (particularly uveitis and dry eyes) occur with a higher frequency in cancer patients treated immune checkpoint inhibitors compared to those treated with control regimens.

Prognostic value of site-specific metastases in pancreatic adenocarcinoma: A Surveillance Epidemiology and End Results database analysis.

AIM: To evaluate the prognostic value of site-specific metastases among patients with metastatic pancreatic carcinoma registered within the Surveillance, Epidemiology and End Results (SEER) database. METHODS: SEER database (2010-2013) has been queried through SEER*Stat program to determine the presentation, treatment outcomes and prognostic outcomes of metastatic pancreatic adenocarcinoma according to the site of metastasis. In this study, metastatic pancreatic adenocarcinoma patients were classified according to the site of metastases (liver, lung, bone, brain and distant lymph nodes). We utilized chi-square test to compare the clinicopathological characteristics among different sites of metastases. We used Kaplan-Meier analysis and log-rank testing for survival comparisons. We employed Cox proportional model to perform multivariate analyses of the patient population; and accordingly hazard ratios with corresponding 95%CI were generated. Statistical significance was considered if a two-tailed P value < 0.05 was achieved. RESULTS: A total of 13233 patients with stage IV pancreatic cancer and known sites of distant metastases were identified in the period from 2010-2013 and they were included into the current analysis. Patients with isolated distant nodal involvement or lung metastases have better overall and pancreatic cancer-specific survival compared to patients with isolated liver metastases (for overall survival: lung vs liver metastases: P < 0.0001; distant nodal vs liver metastases: P < 0.0001) (for pancreatic cancer-specific survival: lung vs liver metastases: P < 0.0001; distant nodal vs liver metastases: P < 0.0001). Multivariate analysis revealed that age < 65 years, white race, being married, female gender; surgery to the primary tumor and surgery to the metastatic disease were associated with better overall survival and pancreatic cancer-specific survival. CONCLUSION: Pancreatic adenocarcinoma patients with isolated liver metastases have worse outcomes compared to patients with isolated lung or distant nodal metastases. Further research is needed to identify the highly selected subset of patients who may benefit from local treatment of the primary tumor and/or metastatic disease.

Intraperitoneal chemotherapy and cytoreductive surgery for peritoneal metastases coupled with curative treatment of colorectal liver metastases: an updated systematic review.

INTRODUCTION: We aimed to assess the efficacy and safety of delivering intraperitoneal chemotherapy and cytoreductive surgery for peritoneal metastases coupled with curative treatment of colorectal liver metastases. Areas covered: A comprehensive literature search using PubMed was conducted to screen for eligible records. Studies evaluating colorectal surgery and intraperitoneal chemotherapy combined with curative treatment of liver metastases were included. We excluded duplicate publications. Sixty-seven full-text papers were assessed and six papers were finally included. The overall survival in the included studies ranged from 6-49 months. Five-year survival ranged from 18%-28%, three-year survival ranged from 22%-42% and two-year survival ranged from 34%-78%. Survival was lower in patients with liver metastases and peritoneal carcinomatosis (PC) than those with PC alone in the majority of studies. Expert commentary: This review poses questions rather than presenting answers. The heterogeneity of survival data suggests the possible benefit of this aggressive treatment approach in selected patients. Standardization of the technique used for intraperitoneal chemotherapy instillation, agent used as well as the systemic chemotherapy and targeted therapy type and duration through prospective controlled trials is required to provide an evidence of a higher strength to support or prohibit this treatment strategy.