Reduction In Disease-free Survival Research Articles

Long-term consequences of positive surgical margin after partial nephrectomy for renal cell carcinoma: multi-institutional analysis.

The aim of the study was to determine the impact of positive surgical margins (PSM) after PN on very long-term recurrence in a contemporary cohort. Patients who underwent PN for a localized renal tumour were included. Patients were stratified according to the presence of PSM. Data on patients' characteristics, the tumour, the peri- and postoperative events were collected. Disease-free survival (DFS) and overall survival (OS) were assessed by the Kaplan-Meier method and compared by the log-rank test. Sensitivity analyses using weighted propensity score analysis was performed to account for potential selection biases arising from the nonrandom allocation of patients to different groups. A total of 1115 patients were included in the study. The incidence of PSM was 5.4% (n = 61). The median follow-up time was 51months for the PSM group and 61months for the NSM group (p = 0.31). Recurrence rates were significantly higher in the PSM group (13%, n = 8) compared to the NSM group (7%, n = 73) (p = 0.05). This resulted in a significant reduction in DFS in the PSM group (p = 0.004), particularly pronounced in patients with clear cell renal cell carcinoma. Additionally, OS was significantly lower in the PSM group (p < 0.01). Propensity score analysis confirmed a decrease in DFS for the PSM group (p = 0.05), while there was no significant difference in OS between the two groups (p = 0.49). In this retrospective multicenter study, PSM impact on oncological outcomes, increasing recurrence, but no difference in OS was observed post-adjustment for biases.

A Critical Assessment of Diagnostic Criteria for the Tall Cell Subtype of Papillary Thyroid Carcinoma—How Much? How Tall? And When Is It Relevant?

Tall cell papillary thyroid carcinoma (TC-PTC) is considered adverse histology. However, previous studies are confounded by inconsistent criteria and strong associations with other adverse features. It is therefore still unclear if TC-PTC represents an independent prognostic factor in multivariate analysis and, if it does, what criteria should be employed for the diagnosis. We retrospectively reviewed 487 PTCs from our institution (where we have historically avoided the prospective diagnosis of TC-PTC) for both the height of tall cells (that is if the cells were two, or three, times as tall as wide) and the percentage of tall cells. On univariate analysis, there was significantly better disease free survival (DFS) in PTCs with no significant tall cell component (< 30%) compared to PTCs with cells two times tall as wide (p = 0.005). The proportion of tall cells (30–50% and > 50%) was significantly associated with DFS (p = 0.012). In a multivariate model including age, size, vascular space invasion, and lymph node metastasis, the current WHO tall cell criteria, met by 7.8% of PTCs, lacked statistical significance for DFS (p = 0.519). However, in the subset of tumours otherwise similar to the American Thyroid Association (ATA) guidelines low-risk category, WHO TC-PTC demonstrated a highly significant reduction in DFS (p = 0.004). In contrast, in intermediate to high-risk tumours, TC-PTC by WHO criteria lacked statistical significance (p = 0.384). We conclude that it may be simplistic to think of tall cell features as being present or absent, as both the height of the cells (two times versus three times) and the percentage of cells that are tall have different clinical significances in different contexts. Most importantly, the primary clinical significance of TC-PTC is restricted to PTCs that are otherwise low risk by ATA guidelines.

Comprehensive Genomic Profiling (CGP)-Informed Personalized Molecular Residual Disease (MRD) Detection: An Exploratory Analysis from the PREDATOR Study of Metastatic Colorectal Cancer (mCRC) Patients Undergoing Surgical Resection.

A majority of patients with metastatic colorectal cancer (mCRC) experience recurrence post curative-intent surgery. The addition of adjuvant chemotherapy has shown to provide limited survival benefits when applied to all patients. Therefore, a biomarker to assess molecular residual disease (MRD) accurately and guide treatment selection is highly desirable for high-risk patients. This feasibility study evaluated the prognostic value of a tissue comprehensive genomic profiling (CGP)-informed, personalized circulating tumor DNA (ctDNA) assay (FoundationOne®Tracker) (Foundation Medicine, Inc., Cambridge, MA, USA) by correlating MRD status with clinical outcomes. ctDNA analysis was performed retrospectively on plasma samples from 69 patients with resected mCRC obtained at the MRD and the follow-up time point. Tissue CGP identified potentially actionable alterations in 54% (37/69) of patients. MRD-positivity was significantly associated with lower disease-free survival (DFS) (HR: 4.97, 95% CI: 2.67–9.24, p < 0.0001) and overall survival (OS) (HR: 27.05, 95% CI: 3.60–203.46, p < 0.0001). Similarly, ctDNA positive status at the follow-up time point correlated with a marked reduction in DFS (HR: 8.78, 95% CI: 3.59–21.49, p < 0.0001) and OS (HR: 20.06, 95% CI: 2.51–160.25, p < 0.0001). The overall sensitivity and specificity at the follow-up time point were 69% and 100%, respectively. Our results indicate that MRD detection using the tissue CGP-informed ctDNA assay is prognostic of survival outcomes in patients with resected mCRC. The concurrent MRD detection and identification of actionable alterations has the potential to guide perioperative clinical decision-making.

KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis

BackgroundFrequent truncation mutations of the histone lysine N-methyltransferase KMT2C have been detected by whole exome sequencing studies in various cancers, including malignancies of the prostate. However, the biological consequences of these alterations in prostate cancer have not yet been elucidated.MethodsTo investigate the functional effects of these mutations, we deleted the C-terminal catalytic core motif of Kmt2c specifically in mouse prostate epithelium. We analysed the effect of Kmt2c SET domain deletion in a Pten-deficient PCa mouse model in vivo and of truncation mutations of KMT2C in a large number of prostate cancer patients.ResultsWe show here for the first time that impaired KMT2C methyltransferase activity drives proliferation and PIN formation and, when combined with loss of the tumour suppressor PTEN, triggers loss of senescence, metastatic dissemination and dramatically reduces life expectancy. In Kmt2c-mutated tumours we show enrichment of proliferative MYC gene signatures and loss of expression of the cell cycle repressor p16INK4A. In addition, we observe a striking reduction in disease-free survival of patients with KMT2C-mutated prostate cancer.ConclusionsWe identified truncating events of KMT2C as drivers of proliferation and PIN formation. Loss of PTEN and KMT2C in prostate cancer results in loss of senescence, metastatic dissemination and reduced life expectancy. Our data demonstrate the prognostic significance of KMT2C mutation status in prostate cancer patients. Inhibition of the MYC signalling axis may be a viable treatment option for patients with KMT2C truncations and therefore poor prognosis.

Deeper sections reveal residual tumor cells in rectal cancer specimens diagnosed with pathological complete response following neoadjuvant treatment.

Guidelines and requirements for diagnosing pathological complete response (pCR) in rectal adenocarcinoma following neoadjuvant treatment vary, and there is currently no consensus on the appropriate number of sections to examine per formalin-fixed, paraffin-embedded (FFPE) tissue block. The consequences of systematic use of deeper sections on the diagnostic accuracy and prognosis for patients classified as ypT0 rectal cancer were investigated. In this retrospective study, 23 out of 155 patients who underwent neoadjuvant therapy and surgical resection between 2015 and 2020 were diagnosed with ypT0 rectal cancer. Three additional deeper sections were cut from each FFPE block from the primary tumor site and reviewed for presence of residual tumor cells. Additional sections revealed residual viable tumor cells in seven patients (30.4%), reducing the rate of pCR in the cohort from 14.8 to 10.3%. Of the seven patients, three patients later had local recurrence or distant metastasis during the follow-up period, compared with one patient with no residual tumor cells in deeper sections (p = 0.07). A nonsignificant reduction in disease-free survival (p = 0.08) was observed in the patients with residual tumor. Systematic use of deeper sections in evaluation of tumor regression in rectal cancer reveals the presence of residual tumor cells in a subset of patients originally diagnosed with pCR based on a single section per FFPE block. Although the results are not statistically significant, it cannot be excluded that accurately distinguishing complete from near-complete response may be clinically relevant for prognostic prediction.

Donor Socioeconomic Status As a Predictor of Altered Immune Function and Treatment Response Following Hematopoietic Cell Transplantation for Hematologic Malignancy

Introduction: Hematopoietic cell transplantation (HCT) carries significant risks for mortality, which are not proportionally shared across individuals. Among HCT recipients, we have previously shown that low socioeconomic status (SES) is predictive of increased mortality following HCT, and the underlying mechanism for this outcome is not fully explained by race, insurance status or access to care. Furthermore, following HCT, the donor immune system replaces that of the recipient, leading to long-term engraftment with donor-derived immune cells. Previous work has not addressed the influence of donor socioeconomic factors on HCT recipient outcomes. Therefore, we hypothesized that SES would impact donor hematopoietic cells and this effect would be transferrable and associated with adverse recipient outcomes.Methods: Recipients of matched unrelated donor allogeneic peripheral blood stem cell HCT between 2000-2013 for hematologic malignancy, resided in the United States (US) with a documented ZIP code, and had a HCT donor with documented US ZIP code were identified from the Center for International Blood and Marrow Transplantation Research (CIBMTR). Using donor ZIP code, SES measures of household income, poverty, education, housing and employment were derived from the U.S. Census American Community Survey. A standardized donor SES composite score was computed as an equally weighted average of the 5 standardized SES variables (mean composite score = 0, standard deviation (SD) = 1). Multivariable models, adjusted for donor and recipient characteristics, were used to evaluate associations between donor SES composite score with HCT recipient disease free survival (DFS), overall survival (OS), treatment related mortality (TRM), relapse, and acute and chronic graft versus host disease (GVHD). Results were considered significant if P < 0.01.Results: Among 2,005 HCT recipients, median age at diagnosis was 51 years (range 1-77), 44% were female, and 55% had acute myeloid leukemia. Median post-HCT follow up was 120 months (range 4-219). Donors were 44% female and median age at hematopoietic cell donation was 34.7 years (range 18-62). The standardized donor composite scores ranged from -2.6 to 3.9, with a higher composite score indicative of greater socioeconomic disadvantage. Multivariable analyses identified significant associations between the standardized donor SES composite score and DFS (HR 1.07 per SD SES, 95% CI 1.02-1.13; p=0.0088), OS (HR 1.09 per SD SES, 95% CI 1.04-1.15; p=0.0007), and TRM (HR 1.10 per SD SES, 95% CI 1.03-1.17; p=0.0049). Significant associations were not identified between donor SES and relapse or GVHD. Quantitatively, recipients transplanted with cells from a donor of greater socioeconomic disadvantage (i.e. SES composite score 2 SD above the mean) experienced a 10% reduction in DFS and OS, and a 5% increase in TRM at 3 years compared with those transplanted with cells from a high-SES donor (SES composite score 2 SD below the mean) (Figure).Conclusions: For the first time, we have demonstrated that socioeconomic disadvantage among HCT donors results in adverse transplant outcomes in the HCT recipient. This novel finding suggests that SES has biologic impacts down to the stem cell level that persist even when transplanted into a new host during HCT. The implications of these findings are broad and suggest the need for public health interventions targeting socioeconomic support as a means for preventing social disparities in cancer treatment outcomes. [Display omitted] DisclosuresVerneris: Novartis: Other: advisory board; jazz: Other: advisory board; Fate Therapeutics: Consultancy.

Optimum adjuvant trastuzumab duration for human epidermal growth factor receptor-2 positive breast cancer: a network meta-analysis of randomized trials.

BackgroundAdjuvant trastuzumab treatment for 12 months is the standard-of-care for early HER2-positive breast cancer; however, the optimal duration is unclear. We performed a network meta-analysis (NMA) to determine the optimal treatment duration.MethodsWe identified 16 randomized controlled trials involving 29,837 patients that assessed trastuzumab treatment in HER2-positive early breast cancer. Our NMA compared six trastuzumab durations: observation, T-9 weeks, T-12 weeks, T-6 months, T-12 months, and T-24 months. We assessed overall survival (OS), disease-free survival (DFS), acceptability, and cardiotoxicities and grade 3–4 nonhematologic toxicities, and ranked the durations in terms of efficacy and safety by surface under the cumulative ranking (SUCRA).ResultsPairwise meta-analysis showed that while T-6 months was associated with a significant reduction in DFS compared to T-12 months. In our NMA, increasing or decreasing durations showed a significant benefit in DFS compared to observation; however, decreasing durations was not associated with a significant reduction in DFS compared with T-12 months, regardless of the lymph node and hormone receptor statuses. SUCRA ordered the optimum durations of trastuzumab treatment based on PFS as T-12 months (95.6%), T-24 months (69.6%), T-6 months (53.2%), T-9 weeks (41.2%), T-12 weeks (34.3%) and observation (6.1%).ConclusionsEscalating trastuzumab treatment beyond T-12 months confers no additional survival benefit but increased risk of cardiotoxicities. Furthermore, de-escalating treatment confers no improvement on OS compared to T-12 months. These data suggest that T-12 months is the most appropriate treatment schedule for HER2-positive early breast cancer.

Metabolic syndrome is a predictor of all site and liver-specific recurrence following primary resection of colorectal cancer: Prospective cohort study of 1006 patients

IntroductionLarge epidemiological studies have demonstrated the link between metabolic syndrome and cancer development, including colorectal cancer. However, the influence of metabolic syndrome on disease progression is less well studied, particularly in the post-surgical setting. This study investigates the effect of metabolic syndrome on colorectal cancer recurrence (all-site and liver-specific) after curative surgery for Stage I-III disease. Materials and methodsConsecutive patients who underwent curative resection for Stage I-III colorectal cancer in a single UK centre were prospectively recruited. Disease-free and overall survival with metabolic syndrome as a factor, were determined using the Kaplan-Meier technique. Hazard ratios for all-site and liver-specific recurrence were determined using univariable and multivariable Cox-regression models. Results1006 patients were recruited and followed up for a median of 50 months (IQR 30–67). 177 patients (17.6%) met the criteria for metabolic syndrome. 245 patients (25.4%) developed recurrence, 161 (16.0%) of these had liver recurrence. The presence of metabolic syndrome was associated with a reduction in disease-free survival from 69 to 58 months (p < 0.001) and overall survival from 74 to 61 months (p < 0.001). Metabolic syndrome was an independent predictor of all-site (HR 1.76; p < 0.001) and liver-specific (HR 1.74; p = 0.01) recurrence. ConclusionMetabolic syndrome is a predictor of all-site and liver-specific recurrence after primary resection of stage I-III colorectal cancer.

Association of Circulating Tumor DNA With Disease-Free Survival in Breast Cancer

Fragmented DNA is continuously released into the circulation following apoptosis and necrosis of both cancerous and noncancerous cells; when it is released by cancer cells, it is specifically known as circulating tumor DNA (ctDNA). Previous studies have suggested that ctDNA can reflect tumor burden and guide potential therapeutic targets. To determine the association of ctDNA with breast cancer disease-free survival (DFS) and progression-free survival in early, locally advanced, and metastatic breast cancer. An electronic search was conducted using the Cochrane Library, ScienceDirect, PubMed, and Embase from July 30, 2019, to October 31, 2019; all languages were included. The following search terms were used: ctDNA OR circulating tumor DNA OR liquid biopsy AND breast cancer OR breast carcinoma OR breast tumor AND prognosis OR survival. All titles were screened, and the appropriate abstracts were reviewed. If any data were missing, the authors contacted the study authors for permission to access data and extrapolate hazard ratios (HRs). To be included in the analysis, the studies had to meet the following prespecified inclusion criteria: (1) a ctDNA blood sample was measured; (2) DFS, progression-free survival, or relapse-free survival was reported as an HR; and (3) the patient population only had breast cancer. Retrospective and prospective observational cohort studies were included. Two authors (C.C. and C.F.) independently reviewed the literature. All data were recorded independently by both authors and were compared at the end of the reviewing process to limit selection bias. Duplicates were removed and any disparities were clarified. Data were pooled using a fixed-effects or random-effects model according to the study heterogeneity. This study adhered to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE). The primary outcome was the association of ctDNA with DFS or relapse-free survival in breast cancer. Secondary outcomes focused on subgroup analysis in the setting of early breast cancer and metastatic breast cancer. From a total of 263 publications found using the predefined search terms, data from 8 studies (3.0%) reporting on 739 patients in total were suitable for inclusion. Circulating tumor DNA gene variation detection (both before and after treatment) was statistically significantly associated with shorter DFS (HR, 4.44; 95% CI, 2.29-8.61; P < .001). Detection of ctDNA was statistically significantly associated with a reduction in DFS in both the early breast cancer subgroup (HR, 8.32; 95% CI, 3.01-22.99; P < .001) and the metastatic or locally advanced subgroup (HR, 1.91; 95% CI, 1.35-2.71; P < .001). Pretreatment and posttreatment plasma sample collection was analyzed in both early and metastatic groups. The posttreatment group encompassed both surgical and oncologic therapy. Pretreatment plasma detection of ctDNA was statistically significantly associated with reduced DFS (HR, 3.30; 95% CI, 1.98-5.52; P < .001). Posttreatment sampling of ctDNA failed to achieve statistical significance (HR, 8.17; 95% CI, 1.01-65.89; P = .05). In this systematic review and meta-analysis, elevated plasma ctDNA was associated with a high risk of relapse. This finding suggests that plasma ctDNA may provide an excellent method to stratify risk and personalize patient follow-up.

AMBLor: A prognostic and stratifying biomarker for adjuvant immunotherapy of AJCC stage II melanomas.

e22094 Background: The success of adjuvant therapy for patients with AJCC stage III melanomas coupled with the increased risk of mortality for patients with AJCC stage IIB compared to IIIA tumours has paved the way to adjuvant immunotherapy trials for patients with sentinel lymph node (SLNB) –ve AJCC stage II disease. However, the lack of biomarkers able to appropriately stratify high-risk tumour subsets limits patient recruitment. We have recently identified the combined immunohistochemical (IHC) expression of AMBRA1 and Loricrin (AMBLor) in the epidermis overlying non-ulcerated AJCC stage I melanomas as a robust prognostic biomarker and valuable pre SLNB test. Methods: Retrospective analysis of AMBLor was performed in three geographically distinct cohorts of AJCC stage II melanomas using a clinically validated automated IHC assay and semi quantitative binary scoring analysis to define high vs low risk subgroups. Results: Data revealed loss of AMBLor overlying non-ulcerated high risk AJCC stage IIA or B tumours correlated with a significant reduction in disease free survival (DFS) at 12 years to 55% compared to 89% for patients with AMBLor low risk tumours (P = 0.015; HR 4.83, 95% CI: 2.29-10.14). Sub-cohort multivariate analysis of 80 non ulcerated stage IIB tumours also revealed reduced DFS at 12 years to 68% in AMBLor high-risk compared to 83% in AMBLor low-risk tumour subsets, with an assay sensitivity of 97% and a negative predictive value of 90%. Furthermore, sub-cohort analysis of SLNB –ve AJCC stage IIA or B tumours additionally identified 5 genuinely low risk cases in which DFS at 10 years was 100% compared to only 36% in 37 patients in which AMBLor was lost. Conclusions: Collectively these data indicate AMBLor as a novel prognostic biomarker for patients with non-ulcerated AJCC stage II melanomas as well as companion/stratifying biomarker for adjuvant immunotherapy, the use of which will increase clinician confidence for patient recruitment as well as reduce patient morbidity.

Angiotensin receptor autoantibodies as exposures that modify disease progression: Cross sectional, longitudinal and in vitro studies of prostate cancer

Circulating angiotensin type I receptor (AT1R) agonistic autoantibodies (AT1RaAbs) that bind and chronically activate the receptor have been associated with a number of diseases suggesting that while the autoantibodies are not necessarily causative they may promote disease progression. The prostate has a local renin angiotensin system. The current study examines associations between AT1RaAbs and prostate cancer (PCA), disease-free survival (DFS), overall survival (OS) and AT1RaAb effects on PCA cell phenotype.In a cross-sectional set of serum obtained from 151 men diagnosed with PCA, nonmalignant prostate disease or no disease, higher serum AT1RaAb levels were associated with PCA and non-organ confined PCA. The odds ratio for PCA was 6.3 (95% confidence interval 2.2 to 18) for a positive 1:1600 titer and 18 (95% confidence interval 6.9 to 45) at AT1RaAb levels > 1.04 μg/ml, (p < 0.0001). In a longitudinal set of pre-diagnosis samples from 109 men, DFS hazard ratios of 2.2 (95% confidence interval 1.4 to 3.5) and 1.6 (95% confidence interval 1.0 to 2.5) for most proximal to diagnosis and most distal to diagnosis samples, respectively, were found for high versus low AT1RaAb groups. Hazard ratios for OS in most proximal and distal samples were 2.4 (95% confidence interval 1.6 to 3.6) and 1.8 (95% confidence interval 1.1 to 2.8), respectively. Accelerated failure modeling of survival indicated that a 1 μg/ml increase in AT1RaAb levels was associated with a reduction of DFS and OS by 20% at the most proximal time point and by 15% at the most distal time points. Adjusting for age, did not affect the association with DFS in proximal samples but changed distal time point DFS and OS to a 10% decrease for every 1 μg/ml increase in AT1RaAb. Additional adjustments for body mass index, systolic blood pressure and prostate-specific antigen did not appreciably alter these associations. AT1RaAb treatment of PC3, DU145, and LNCaP cells significantly increased the maximal growth rate approximately 2-fold and invasiveness approximately 3-fold. ConclusionsThese observations provide evidence supporting AT1RaAbs as exposures that may modify prostate cancer progression and indicate they may be predictive markers for risk stratification.

Downregulation of IQGAP2 Correlates with Prostate Cancer Recurrence and Metastasis

IQGAP2 was recently reported as a tumor suppressor of prostate cancer (PC). Nonetheless, its clinical implications remain unknown. To address this issue, we extracted data related to IQGAP2 mRNA expression and genomic alterations from multiple large datasets within the Oncomine and cBioPortal databases and performed in silico analyses to determine a potential association of IQGAP2 mRNA expression and its genomic alterations with PC progression. In 4 cohorts consisting of 118 normal prostate tissues and 277 PCs, IQGAP2 mRNA expression was significantly elevated particularly in low-grade (primary Gleason score ≤3) PCs; these changes separate PC from normal tissues with area under curve values of 0.7-0.8. Significant reductions in IQGAP2 mRNA levels and gene copy number occurred in more than 70 metastases compared to at least 230 local PCs. This duo-alteration in IQGAP2 expression supports IQGAP2 elevation suppressing and its downregulation facilitating PC progression. Deletion and missense mutations were detected in 23 of 492 primary PCs; these alterations significantly associate with PC recurrence (HR=2.71; 95% CI: 1.35-5.44; P=.005) after adjusting for known risk factors and correlate with reductions in disease-free survival (DFS, P=.002). IQGAP2 (5q13.3) genomic alterations were observed in SPOP-marked PCs and co-occurred with deletion in the RN7SK (16p12.2), SNORA50A (16q21), and SNORA50C (17q23.3) genes; the co-occurrence associated with reductions in DFS (P=4.14e-4). In two independent PC populations, MSKCC (n=130) and TCGA provisional (n=490), reductions in IQGAP2 mRNA expression were significantly associated with DFS. Collectively, this investigation reveals an association of IQGAP2 with PC progression.

Biphasic Alteration of Butyrylcholinesterase (BChE) During Prostate Cancer Development

Butyrylcholinesterase (BChE) is a plasma enzyme that hydrolyzes ghrelin and bioactive esters, suggesting a role in modulating metabolism. Serum BChE is reduced in cancer patients. In prostate cancer (PC), the down-regulation is associated with disease recurrence. Nonetheless, how BChE is expressed in PC and its impact on PC remain unclear. We report here the biphasic changes of BChE expression in PC. In vitro, BChE expression was decreased in more tumorigenic PC stem-like cells (PCSLCs), DU145, and PC3 cells compared to less tumorigenic non-stem PCs and LNCaP cells. On the other hand, BChE was expressed at a higher level in LNCaP cells than immortalized but non-tumorigenic prostate epithelial BPH-1 cells. In vivo, BChE expression was up-regulated in DU145 xenografts compared to LNCaP xenografts; DU145 cell-derived lung metastases displayed comparable levels of BChE as subcutaneous tumors. Furthermore, LNCaP xenografts produced in castrated mice exhibited a significant increase of BChE expression compared to xenografts generated in intact mice. In patients, BChE expression was down-regulated in PCs (n = 340) compared to prostate tissues (n = 86). In two independent PC populations MSKCC (n = 130) and TCGA Provisional (n = 490), BChE mRNA levels were reduced from World Health Organization grade group 1 (WHOGG 1) PCs to WHOGG 3 PCs, followed by a significant increase in WHOGG 5 PCs. The up-regulation was associated with a reduction in disease-free survival (P = .008). Collectively, we demonstrated for the first time a biphasic alteration of BChE, its down-regulation at early stage of PC and its up-regulation at advanced PC.

TRKB tyrosine kinase receptor is a potential therapeutic target for poorly differentiated oral squamous cell carcinoma.

It has been reported that one of the neurotrophin receptors, tropomyosin receptor kinase B (TRKB), is frequently overexpressed in various tumor tissues including oral squamous cell carcinoma (OSCC), and that its upregulation promotes tumor progression in human cancers. However, the correlation between TRKB overexpression and clinicopathological characteristics is not fully elucidated. Here, we present the correlation between the expression levels of TRKB and/or its secreted ligand, brain-derived neurotrophic factor (BDNF), and clinicopathological characteristics, especially regarding tumor differentiation, tissue invasion, and disease-free survival in patients with OSCC. The results obtained through immunohistochemical analysis of human OSCC tumor specimens showed that the expression levels of TRKB and/or BDNF, were significantly higher in moderately and poorly differentiated OSCC (MD/PD-OSCC) tumor cells than in well differentiated cells (WD-OSCC). Moreover, the OSCC tumors highly expressing TRKB and/or BDNF exhibited promotion in tissue invasion and reduction in disease-free survival in the patients. In an orthotopic transplantation mouse model of human OSCC cell lines, administration of a TRKB-specific inhibitor significantly suppressed the tumor growth and invasion in PD-OSCC-derived tumor cells, but not in WD-OSCC-derived tumor cells. Moreover, the TRKB inhibitor selectively blocked BDNF-induced tumor cell proliferation and migration accompanied with the suppression of TRKB phosphorylation in PD-OSCC but not in WD-OSCC in vitro. Taken together, these data suggest that the BDNF/TRKB signaling pathway may regulate tumor progression in poorly differentiated OSCC. Expression levels of signal molecules may be an accurate prognosis marker for tumor aggressiveness, and the molecules may be an attractive target for new OSCC therapies.

Clinical significance of sarcopenia in the treatment of patients with primary hepatic malignancies, a systematic review and meta-analysis.

BackgroundThe impact of sarcopenia on outcomes following treatment for primary liver tumors remains contentious. Therefore, we performed a systematic literature review and meta-analysis to evaluate the clinical significance of sarcopenia in the treatment of patients with primary liver tumors.Data sourcesA systematic literature search was performed in English through February 1, 2017 in databases.ResultsThere were significant differences between patients with and without sarcopenia in overall 1- and 3-year survival (1 year: OR: 0.43; 95% CI: 0.27-0.68; P=0.0004; 3 year: OR: 0.67; 95% CI: 0.47-0.96; P=0.03). However, overall 5-year survival showed no significant difference between the groups (OR: 0.61; 95% CI: 0.35-1.07; P=0.08). Patients with sarcopenia showed a significant 53% reduction in disease-free survival within 5 years (OR: 0.47; 95% CI: 0.28-0.79; P=0.005). Also, sarcopenia had a significantly negative impact on recurrence in patients with primary liver tumors (RR: 2.71; 95% CI: 1.46-5.05; P=0.002). Regarding complications rate, we concluded that there was a statistically significant difference between two groups in overall complications rate (RR: 2.52; 95% CI: 1.50-4.22; P=0.0005). However, the major complications rate showed no significant difference between the groups (RR: 1.19; 95% CI: 0.65-2.20; P=0.57).ConclusionsSarcopenia seemed to have a negative effect on overall survival in patients with primary liver tumors in the early phase post-treatment, but further research is needed to investigate the prognostic impact on overall survival over the longer term. Moreover, sarcopenia could significantly increase the incidence rates of post-treatment recurrence and overall complications in patients with primary liver tumors.

Transarterial chemoembolization prior to liver transplantation for patients with hepatocellular carcinoma: A meta-analysis.

A debate exists over whether using preoperative transarterial chemoembolization for patients with hepatocellular carcinoma before liver transplantation. Numerous studies have been investigating on this, but there is still no unanimous conclusion about the effect of preoperative transarterial chemoembolization. We conducted the meta-analysis of all available studies to systematically evaluate the influence of preoperative transarterial chemoembolization on liver transplant. A systematic search was performed by two authors (Si TF. and Guan RY.) through PubMed, Embase, Cochrane, and Science Citation Index Expanded, combined with Manual Retrieval and Cited Reference Search. The searching cut-off date was 2016/07/31, and all the data obtained were statistically analyzed using Review Manager version 5.1 software (Copenhagen, The Nordic Cochrane Center, The Cochrane Collaboration, 2011) recommended by Cochrane Collaboration. The study showed that there was no difference between the experimental group and the control group on perioperative mortality (RR=1.10, 95% confidence interval (CI)=[0.49-2.48], P=0.82) or biliary complications (RR=0.96, 95%CI=[0.66-1.39], P=0.83). Preoperative transarterial chemoembolization had no obvious effect on improving overall survival (HR=1.05, 95%CI=[0.65-1.72], P=0. 83) but would result in a higher rate of vascular complications (RR=2.01, 95%CI=[1.23-3.27], P=0.005) and a reduction of disease free survival (HR=1.66, 95%CI=[1.02-2.70], P=0.04). Subgroup analysis also revealed that patients from transarterial chemoembolization group in Asia had a much lower overall survival rate (HR=2.65, 95%CI=[1.49-4.71], P=0.0009) compared with the control group. Considering the possible adverse impacts on liver transplantation and the variation in sensitivity to transarterial chemoembolization, clinicians should be more cautious when considering transarterial chemoembolization as the bridging therapy for patients in the waiting list.

EA5142 adjuvant nivolumab in resected lung cancers (ANVIL): The newest study in the ALCHEMIST platform.

TPS8575 Background: There have been no advances in the systemic treatment of resected lung cancers in the last decade. This is in contrast to advanced disease where molecularly targeted therapies for patients with oncogene-driven tumors have replaced and/or delayed chemotherapy and where immunotherapy drugs that target the programmed death receptor pathway (PD-1 or PD-L1) are now utilized in first and second line. The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) is a National Cancer Institute (NCI) sponsored National Clinical Trials Network (NCTN) initiative to address the role of genomic testing and personalized therapies in the adjuvant treatment of non-small cell lung cancers. EA5142 is the newest of the ALCHEMIST studies, investigating adjuvant nivolumab in patients not eligible for the EGFR or ALK directed trials. Methods: ALCHEMIST is a clinical trial platform that consists of integrated protocols: ALCHEMIST Screening (A151216; NCT02194738), ALCHEMIST-EGFR (A081105; NCT02193282), ALCHEMIST-ALK (E4512; NCT02201992), and ALCHEMIST-nivo (EA5142; NCT02595944). In ALCHEMIST-Screening, up to 8,000 patients with pathologically confirmed stage IB (≥ 4 cm)-IIIA NSCLC will be enrolled either before or after surgical resection. Tumors that are non-squamous histology will be centrally genotyped for EGFR mutations and ALK rearrangements. Patients with EGFR or ALK-positive tumors are offered enrollment in trials evaluating adjuvant erlotinib or crizotinib, respectively. In the ~80% of patients enrolled with tumors that have wildtype EGFR and ALK or those with squamous histology central testing will be performed for PD-L1 utilizing immunohistochemistry (DAKO 28-8). Adjuvant therapy is allowed but not required. Patients are randomized to nivolumab 240 mg IV over 3 minutes every 2 weeks for up to 1 year versus standard of care observation, stratified by stage, histology, prior adjuvant treatment, and PD-L1 status ( &gt; / = 1% or &lt; 1%). ANVIL has enrolled 52 of 714 planned patients to detect co-primary endpoints of a 30% improvement in overall survival and/or a 33% reduction in disease free survival favoring nivolumab. EA5142 is currently open at over 400 centers nationwide. Clinical trial information: NCT02595944.

Prognostic value of follistatin-like 3 in human invasive breast cancer.

Follistatin-like 3 (FSTL3) binds and inactivates activin, a growth factor involved with cell growth and differentiation. We have previously shown FSTL3 overexpression in invasive breast cancers, but its clinical relevance remained unexplored. Here we evaluate FSTL3 as a prognostic tool and its relation with clinical and pathological features of breast cancer. A cohort of 154 women diagnosed with invasive breast cancer between 2008 and 2012 was followed up for 5 years. Tumor samples were processed by immunohistochemistry to detect FSTL3 expression in tumor epithelium. FSTL3 expression was classified semiquantitatively and tested for possible correlation with age, menopause status, stage, tumor histological type and grade, estrogen receptor, progesterone receptor, and HER2 expression. Survival plots with Kaplan-Mayer statistics were used to assess whether FSTL3 expression predicted disease-free survival. Our findings show that FSTL3 staining was unrelated to menopausal status, histological type, disease stage, or receptor profile. However, the intensity of FSTL3 immunostaining correlated inversely with tumor size (r = -0.366, p<0.001) and with nuclear grade (p<0.01). The intensity of FSTL3 expression in the tumoral epithelium was not predictive of the disease-free survival (p = 0.991, log-rank test), even though the follow-up length and the study size were sufficient to detect a significant reduction in disease-free survival among women with stage III-IV compared to stage I-II disease (p<0.001). FSTL3 expression in invasive breast cancer is inversely associated with tumor size and nuclear grade but it does not predict disease relapse in the short term.

Angiogenin contributes to bladder cancer tumorigenesis by DNMT3b-mediated MMP2 activation.

Epigenetic-mediated gene activation/silencing plays a crucial role in human tumorigenesis. Eliciting the underlying mechanism behind certain epigenetic changes is essential for understanding tumor biology. Previous studies in human cancers revealed an unrecognized interplay between Angiogenin (ANG) and matrix metalloproteinase-2 (MMP2) leading to pronounced tumorigenesis. Here we provide multiple lines of evidence further indicating ANG oncogenic potential. ANG expression resulted in the hypomethylated state of the MMP2 gene, which led to increased gene expression of MMP2. More than that, our global DNA methylation microarray analysis showed that gene manipulation of ANG affected a variety of pathways, such as cell migration, angiogenesis and specifically, tumor suppressor genes. Mechanistically, ANG negatively regulated DNA methyltransferase 3b (DNMT3b) enzymatic activity by down-regulating its expression and inhibiting its recruitment to the MMP2 promoter. Consistent with this, ANG-MMP2 overexpression and DNMT3b underexpression correlated with reduction in disease free survival of human bladder cancer patients. Together, the results continue to establish ANG as an oncoprotein and further reveal that ANG contributes to oncogenesis by the activation of MMP2 through modulation of DNMT3b functions.

Neutrophil Extracellular Traps Promote the Development and Progression of Liver Metastases after Surgical Stress.

Risks of tumor recurrence after surgical resection have been known for decades, but the mechanisms underlying treatment failures remain poorly understood. Neutrophils, first-line responders after surgical stress, may play an important role in linking inflammation to cancer progression. In response to stress, neutrophils can expel their protein-studded chromatin to form local snares known as neutrophil extracellular traps (NET). In this study, we asked whether, as a result of its ability to ensnare moving cells, NET formation might promote metastasis after surgical stress. Consistent with this hypothesis, in a cohort of patients undergoing attempted curative liver resection for metastatic colorectal cancer, we observed that increased postoperative NET formation was associated with a >4-fold reduction in disease-free survival. In like manner, in a murine model of surgical stress employing liver ischemia-reperfusion, we observed an increase in NET formation that correlated with an accelerated development and progression of metastatic disease. These effects were abrogated by inhibiting NET formation in mice through either local treatment with DNAse or inhibition of the enzyme peptidylarginine deaminase, which is essential for NET formation. In growing metastatic tumors, we found that intratumoral hypoxia accentuated NET formation. Mechanistic investigations in vitro indicated that mouse neutrophil-derived NET triggered HMGB1 release and activated TLR9-dependent pathways in cancer cells to promote their adhesion, proliferation, migration, and invasion. Taken together, our findings implicate NET in the development of liver metastases after surgical stress, suggesting that their elimination may reduce risks of tumor relapse.