OS In Univariate Analysis Research Articles

Pathological Chemotherapy Response Score in Patients Affected by High Grade Serous Ovarian Carcinoma: The Prognostic Role of Omental and Ovarian Residual Disease.

Background: The chemotherapy response score (CRS) has emerged as a simple and reproducible histopathological grading system for assessing chemotherapy response in patients affected by ovarian high-grade serous carcinoma.Objective: To evaluate the prognostic impact of histological tumor response in ovarian and omental surgical specimens from patients with advanced stage ovarian high-grade serous carcinoma.Study Design: A cohort of 161 women were identified from the database of Department of Gynecology, “Fondazione Policlinico Universitario Agostino Gemelli IRCCS” of Rome, Italy between January 2014 and December 2017 with a follow-up of 65 months. All the omentum, the ovarian tissue and peritoneal samples, defined as “other sites,” were reviewed by gynecological pathologists to assign a CRS of 1–3 to the omentum and ovarian sites and a score of 0–1 to the peritoneal tissue. The Cox proportional hazards regression and the log-rank test were used to assess the survival pattern and the prognostic value of the CRS adjusting for age and stage. The Kaplan-Meier method was applied to estimate the progression free and overall survival.Results: The evaluation of adnexal disease showed significant differences in PFS, both in univariate and in multivariate analyses. On PFS univariate analysis, ovCRS1 vs. ovCRS3: HR, 2.27; 95% CI, 1.37–3.77; p = 0.001; ovCRS2 vs. ovCRS3: HR, 1.83; 95% CI, 1.03–3.23; p = 0.04, and on PFS multivariate model ovCRS1 vs. ovCRS3; HR, 2.53; 95% CI, 1.5–4.24; p = 0.001 and ovCRS2 vs. ovCRS3; HR, 1.90; 95% CI, 1.08–3.37; p = 0.03. Regarding the omental residual disease, as expected, CRS showed a significant prognostic value for OS and PFS; in detail the median PFS of patients with CRS1, 2 and 3 was 15, 15, and 22 months, respectively, the median OS was 41 and >50 months, respectively. Moreover, the univariate analysis for OS suggested that in our cohort the “other sites” score of 0 was significantly associated with an improvement in overall survival compared to score 1.Conclusions: We demonstrated for the first time the prognostic significance of adnexal CRS confirming also the prognostic role of omental CRS.

Is There a Novel Prognostic Parameter for Well-Differentiated Neuroendocrine Tumours? The Prognostic Value of Albumin and Hemoglobin in Patients Well-Differentiated Neuroendocrine Tumours

BACKGROUND: Neuroendocrine tumours (NETs) are a heterogeneous group of tumours. There are no well-established prognostic factors for accurately predicting survival of patients with well-differentiated NETs. Prognostic value of inflammatory markers was evaluated in some solid tumours previously. However, it was not well documented in orphan tumours like well-differentiated NETs. We aimed to find out a novel and easy-accessible prognostic parameter by using hemogram & biochemical parameters in patients with well-differentiated NETs. PATIENTS AND METHODS: 132 patients with well-differentiated NETs were analyzed, retrospectively. Patients were subgrouped into two groups with respect to the cut-off value that was determined by ROC analysis. Survival analysis was performed by using the Kaplan-Meier method with the Long-rank test. p<0.05 was considered statistically significant. RESULTS: The cut-off value was defined as 47.94 for AlbXHb. High-risk (AlbXHb < 47.94) group had significantly increased risk of death ( HR:5.16, 95%CI 1.45-18.38 p=0.011). AlbXHb was a significant prognostic factor for OS in univariate analyses (HR=0.925 95% CI 0.878-0.974, p=0.003). CONCLUSION: We demonstrated that AlbXHb might be a novel prognostic factor for well-differentiated NETs, but it needs further evaluation by randomized clinical trials. We believe that this novel parameter has feasible accuracy for predicting disease outcomes. Key words: albumin, hemoglobin, well-differentiated neuroendocrine tumour

PS1257 LYMPHOCYTE TO MONOCYTE RATIO (LMR) PREDICTS PROGRESSION‐FREE SURVIVAL INDEPENDENTLY FROM FLIPI AND IS USEFUL IN IDENTIFYING PATIENTS WITH EARLY DISEASE PROGRESSION

Background:Despite the overall good prognosis of follicular lymphoma (FL), approximately 20 to 30% of the cases experience early progression after first line therapy and suffer adverse survival (Casulo et al., 2015; Shi et al., 2017). Several efforts have been made to identify pre‐treatment factors useful to assess prognosis, however currently available parameters do not allow to accurately stratify patients before treatment. Lymphocyte to monocyte ratio (LMR) has been previously identified as an useful prognostic markers in diffuse large B‐cell lymphoma treated with Rituximab‐based chemotherapy (Rambaldi et al., 2013).Aims:In this study we aimed to evaluate the potential role of LMR in identifying patients with FL experiencing early progression after first line therapy.Methods:831 patients with a diagnosis of grade 1–3a FL were identified in the Bergamo Lymphoid Cancer Registry (NCT03131531) between 1983 to 2017. Cases managed with watchful observation after diagnosis (N = 145) or receiving local therapy (N = 121) or without adequate clinical information or follow‐up data (N = 117) were excluded from the analysis. The remaining patients (N = 448) with stage II‐IV disease and receiving first line chemotherapy at diagnosis were included in the study. The majority of the patients were treated with Rituximab‐based therapy (72%). Chemotherapy regimens included CHOP (N = 298), CVP (N = 76), Bendamustine (N = 22), Chlorambucil (N = 34) or others (N = 18). Rituximab maintenance was administered to 61 patients.Patients with early progression were defined as those with a PFS event before 30 months from first‐line treatment start (PFS30). Receiver operating characteristic (ROC) analysis was performed to assess the optimal cut‐off of LMR to predict PFS30. Kaplan‐Meyer curves, log‐rank tests and Cox models were used for survival analyses.Results:In the study population, 26% of the patients experienced early progression and were characterized by a shorter median OS compared to the other group (6.3 vs 17 years, P &lt; 0.0001, Figure 1A). The optimal cut‐off of LMR to predict PFS30 was identified, with patients with LMR ≤2 or &gt;5.2 (N = 176) being at higher risk for a PFS event compared to those with LMR &gt;2 and ≤5.2 (N = 272) (Figure 1B). In multivariate analysis for PFS, LMR retained its significance independently from FLIPI (P = 0.0001). The simple addition of LMR to standard FLIPI permitted to refine patient prognosis in terms of PFS (Figure 1C) and OS (Figure 1D), with three groups identified i.e. low risk (FLIPI low and favorable LMR), intermediate risk (FLIPI low and unfavorable LMR; FLIPI int or high and favorable LMR) and high risk (FLIPI int or high and unfavorable LMR). Specifically, 57 (36%) patients with intermediate FLIPI were upgraded in the high risk category and 80 (54%) high risk FLIPI were downgraded into the intermediate one. Patients in the new high risk category were characterized by a 42% probability to have a PFS event before 30 months, compared to the 22% and 10% of the intermediate and low risk group, respectively. LMR was significantly associated with OS in univariate analysis (P = 0.047), but not in multivariate analysis with FLIPI (P = 0.11). The combined LMR and FLIPI index predicted survival with a 30‐months OS of 96%, 94% and 85% in the low, intermediate and high risk category, respectively (P = 0.0032).Summary/Conclusion:LMR is a significant prognostic factor for PFS in FL, independent from FLIPI and closely related to the use of Rituximab. The combination of LMR with currently available prognostic markers can be useful in identifying high patient before the start of first line treatment.image

Elevated serum activin A and PD-L1 and survival in the CCTG MA.31 phase III trial (trastuzumab vs. lapatinib) in first-line HER2+ metastatic breast cancer.

1031 Background: In MA.31 the trastuzumab-taxane combination led to longer PFS than lapatinib-taxane in HER2+ metastatic breast cancer (MBC). In MA.31 we previously reported the prognostic/predictive utility of pretreatment serum PD-L1 (SABCS 2018, PD3-10) and serum activin A (SABCS 2016, P6-07-06) separately; here we evaluate them combined. Methods: MA.31 accrued 652 centrally and/or locally-identified HER2-positive patients, and pretreatment serum was available for 382 patients (184 in trastuzumab arm, 198 in lapatinib arm). The ELLA immunoassay platform (ProteinSimple, San Jose, CA) was used to quantitate serum PD-L1, and ELISA for activin A (R&amp;D Systems, Minneapolis, MN). Results: In correlation analysis, pretreatment serum PD-L1 was moderately correlated with serum activin A (r = 0.21, p = 0.004). In univariate analysis for OS, the combination of higher serum PD-L1 and higher serum activin A (median cutpoints) (vs. both low) was significant for shorter OS in the trastuzumab arm (HR 6.62, p=0.0005) and in the lapatinib arm (HR 3.25, p=0.0003)(table). In multivariate analysis for OS (17 covariates included), elevated serum activin A/PD-L1 combination remained the most significant independent covariate in the trastuzumab arm (HR 12.40, p=0.001), and in the lapatinib arm (HR 5.2, p=0.0001). Conclusions: In the CCTG MA.31 trial, elevated pretreatment serum activin A (TGF-B superfamily) and PD-L1 was associated with a shorter OS to HER2-targeted treatment. Multiple mechanisms, including immune evasion, may decrease the effectiveness of HER2-targeted therapy. Elevated serum activin A and PD-L1 may identify HER2-positive MBC patients who would benefit from inhibitors of the HER2, PD-1, and activin A pathways. [Table: see text]

Sorafenib: Experience and Better Manage­ment of Side Effects Improve Overall Survival in Hepatocellular Carcinoma Patients: A Real-Life Retrospective Analysis

Background: Sorafenib is the first-line treatment for advanced hepatocellular carcinoma (HCC). The management of its side effects is improving. This study aimed to assess, in real life, if this translates into a better prognosis. Methods: This was a retrospective study of advanced HCC patients treated with sorafenib between 2007 and 2017. Results: 188 advanced HCC patients received > 4 weeks of sorafenib. Median treatment duration was 5.4 months and median overall survival (mOS) 10 months (95% confidence interval 15–27). Sorafenib was initiated in 65 patients in 2007–2012 and 123 in 2013–2017. Both groups were comparable except for Barcelona Clinic liver cancer class. Tumor progression, disease control (DC) rate, and incidence of toxicity were similar in the 2 periods, but the duration of treatment (4.3 vs. 5.9 months; p < 0.01) and mOS (8 vs. 12 months; p < 0.002) differed. Among progressive disease patients, mOS was similar (7 months) but for those who had DC at 8 weeks, mOS was longer in the recent period (13 vs. 27 months; p < 0.0001). In the univariate analysis of OS, the period of treatment had a prognostic value. Conclusion: When comparing 2 periods of treatment in advanced HCC patients under sorafenib, duration of treatment and mOS were higher in the recent period. While mOS did not differ for patients who progressed, it was 2-fold higher in the recent period for those who had tumor control. Improvements in the use of sorafenib seem to be associated with better outcomes limited to patients with DC.

Prognostic Significance of Survivin Expression and Combined Analysis with Cancer Stem Cell and Epithelial-Mesenchymal Transition-related Markers in Patients with Rectal Cancer Undergoing Preoperative Chemoradiotherapy.

To identify the candidate marker predicting treatment response and survival outcome in rectal cancer patients who received preoperative chemoradiotherapy (CRT). Between 2000 and 2015, 159 patients with histologically-confirmed rectal adenocarcinoma underwent preoperative CRT followed by surgery. Among them, 70 patients were enrolled and the expression of survivin, cancer stem cell markers (CD44 and CD133) and epithelial-mesenchymal transition markers (E-cadherin and TWIST1) in pretreatment biopsy specimens were evaluated by immunohistochemistry. Associations between the expression of markers and clinical outcomes were evaluated. The median follow-up period of all patients was 71 (range=15-203) months. Five-year overall (OS), disease-free (DFS), locoregional recurrence-free (LRRFS) and distant metastasis-free (DMFS) survival were 80.5%, 60.2% 90.1% and 76.5%, respectively. A significant association between survivin overexpression and worse treatment outcome was shown on univariate analyses for OS, DFS and DMFS (p=0.022, 0.002, and 0.005, respectively). On multivariate analysis, survivin overexpression was an adverse prognosticator for DFS and DMFS (p=0.007 and 0.015, respectively), with a borderline significant trend towards a shorter OS (p=0.069). Four other single biomarkers were not associated with survival outcomes. However, overexpression of both survivin and CD44 was significantly associated with worse OS on multivariate analysis (p=0.003). Survivin combined with CD44 might be a candidate biomarker for the prediction of recurrence and survival in patients who received preoperative CRT for rectal cancer. Further research with a larger population is needed to validate these results.

Possibility of Conversion Surgery and Histological Evaluation in Definite cT4 Patients of Esophageal Cancer Treated with Preoperative Chemoradiation Followed by Surgery

Patients of cT4NxM0 have been regarded as appropriate candidates for definitive chemoradiation (CRT) but as controversial for surgery following preoperative CRT. There is wide variation of mixed rate of cT3 in cT4 among institutions despite of best diagnostic technology. Objectives of this study are (1) to select definite cT4 (d-cT4) patients with consistent histological evidence and to compare d-cT4 with marginal cT3 from view of prognosis, (2) to discuss the possibility of conversion surgery in d-cT4. Marginally resectable 126 patients with cT3-4NxM0 were enrolled to preoperative CRT regimen. The regimen included cisplatin (70 mg/m2 on day 1 and 28), 5-FU (700 mg/m2 on days 1-5 and 28-32) and radiotherapy (RT, total 50.4 Gy/28F). Within 6 weeks after the accumulated RT dose reached 50.4 Gy, the feasibility of esophagectomy was evaluated in all patients. Histological evidence of disappeared tumors by CRT are coagulation necrosis with/without replacement by fibrosis, xantho-granulomatous region with/without foreign body giant cells, and deposition of keratinized tissue without viable tumor cells. Three stages of surgical curability were defined as Cur A; Stage 0∼lll, D>N and R0, as Cur B; neither Cur A nor C, and as Cur C; residual tumor and R2. Out of categorized 4 Grades (Gr 0 to 3) of histological effectiveness of CRT, no viable cancer cells were defined Gr 3. Conclusions were drawn from a retrospective analysis of phase II study for including marginal cT3 and cT4. The reasons which esophagectomy was not feasible were CR evaluation after CRT in 9 patients, PD after CRT in 6, and toxicities of CRT in 3. After all, 108 patients (average 64 years old, 43-80) were treated with CRT followed by surgery. By final examination of the differences between pretreatment T stages and pathological findings of surgical specimens, d-cT4 were 40 (37%) patients (between 11 of cT4a and 29 of cT4b, there was no statistical difference of survivals). As other 68 operated patients were not verified as d-cT4, they were defined as “cT3/<4” in this study. R0 surgeries were done in 93 (86%) patients. In d-cT4, 22 (55%) were evaluated in Cur A, and 9 (22.5%) in Cur C, on the other hand in cT3/<4, 60 (88%) in Cur A and 1 (1.5%) in Cur C, respectively. Gr 3 histological effectiveness was presented in 11 (28%) patients of d-cT4, and 30 (44%) in cT3/<4. In univariate analyses for OS, age younger than 75, R0 and Gr 3 were not significant (p=0.92, p=0.24, p=0.16, respectively), and Cur A and cT3/<4 were significant (p=0.002, p<0.001, respectively). In a multivariate analysis for OS, only cT3/<4 alone was significant (Exp.β 3.0, 95%CI 1.22-7.30, p=0.17). In 40 patients of d-cT4, 2 and 4-year survival rates were 56% and 42%, respectively. Although we presented possibility of conversion surgery for definite cT4 and a fair evaluation of preoperative CRT, more effective multimodality therapy is expected because of the significant prognostic impact of depth of tumor invasion.

Safety and efficacy of nivolumab in metastatic renal cell carcinoma (mRCC): Results from the NIVOREN GETUG-AFU 26 study.

577 Background: Nivolumab (N) has been approved for the treatment of mRCC after failure of 1 or 2 tyrosine kinase inhibitors (TKI) based on the results of Checkmate 025 study. Right after approval, we initiated the NIVOREN GETUG-AFU 26 study (NCT03013335), a French multicenter prospective study to evaluate safety and efficacy of N in a “real world setting”. Methods: Patients (pts) with clear cell mRCC could be enrolled if they had received at least one TKI. Compared with the pivotal trial, inclusion criteria allowed patients with more than 2 previous lines of treatment, including previous mTOR inhibitors, ECOG PS 2, asymptomatic brain metastases (BM) or impaired renal function. The primary objective of the study was the safety of N, efficacy being the main secondary objective. Between February 2016 and June 2017, 729 pts have been enrolled. We report the results from the first 528 pts. Results: All pts had clear cell mRCC, median age was 64, 77.2% were male. ECOG PS was &gt; 1 in 73 pts (14.7%), 27.5% pts had received prior everolimus, 29.7% pts had received more than 2 previous lines, IMDC risk groups were 19%/54.9%/26.1% for good/intermediate and poor risk respectively; 69 (14%) pts had BM at screening. With a median follow up of 13.1 months, median duration of treatment was 4.1 months [0-15.6], with 31.4% of pts still on therapy. Treatment discontinuation due to adverse event (AE) occurred in (48) 13.3% pts . 64 serious related AE have been reported in 52 pts (9.9%) including 7 renal failures and 6 pneumonitis. Median PFS was 4.4 months 95%CI[3;4.6] . At the time of this analysis, 170 pts have died and 12 months OS rate was 66.4% 95%CI[ 61.7; 70.7]. In subgroups analysis, ECOG-PS &gt; 1 (Hazard Ratio (HR) = 2.450 [1.704;3.523]), more than 2 previous lines (HR = 1.442 [1.059;1.963]) and prior use of everolimus (HR = 1.704 [1.250;2.322]) were associated with reduced OS in univariate analysis. Conclusions: We report the first analysis of the largest prospective real world setting study of N in mRCC. NIVOREN study demonstrates that N safety and efficacy in a “real world” prospective study are comparable to the pivotal study. Clinical trial information: NCT03013335.

Polymorphisms in beta-defensin pathways and clinical outcomes in metastatic colorectal cancer patients treated with FOLFIRI-bevacizumab in two randomized phase III trials.

662 Background: Beta defensin 1 (DEFB1) and 2 (DEFB4A) are antimicrobial peptides secreted from colonic epithelial cells in response to inflammation. DEFB1 has been shown to serve as a tumor suppressor, whereas high concentrations of DEFB4A are linked with angiogenesis. This study examines the impact of single nucleotide polymorphisms (SNPs) in beta-defensin pathways in two independent phase III trials: FIRE-3 and TRIBE. Methods: The OncoArray database containing 530K SNP markers provided by Illumina was used to find associations between clinical outcomes and 10 functional SNPs from DEFB1, DEFB4A, PPARG, NFKB1, MUC2, and TLR4 genes. Patients treated with first-line FOLFIRI/bevacizumab (bev) in the randomized phase III FIRE-3 trial (n = 107) and TRIBE trial (n = 215) served as discovery and validation cohorts respectively. The FIRE-3 FOLFIRI and cetuximab (cet) arm served as a negative control (n = 129). Results: A total of 451 patients were included. The NFKB1 rs3821958 SNP showed significant association with OS and PFS in overall pts and those with left-sided CRC. Compared to pts carrying the mutant A allele, those with the wild-type G/G genotype had a shorter median OS (19 vs 40 mts) and PFS (9.2 vs 11.7 mts) in both univariate ((OS: HR = 2.32, 95%CI 1.21-4.42, p = 0.006) (PFS: HR = 1.93, 95%CI: 1.11-3.37, p = 0.014)) and multivariable analysis ((OS: HR = 2.90, 95%CI 1.47-5.70, p = 0.002) (PFS: HR = 2.08, 95%CI:1.18-3.67, p = 0.012)). This finding was validated in TRIBE, where carriers of G allele had shorter PFS in univariate analysis (HR = 1.44, p = 0.019). Opposite results were observed in pts receiving cet, where G/G carriers had improved OS in univariate analysis (HR = 0.46, p = 0.048). Pts with left-sided CRC who carried the wild-type allele had poorer OS and PFS in both trials. Conclusions: NFKB1 rs3821958 SNP is known to activate DEFB1 and is downstream of EGFR. Harboring a mutant allele in this SNP confers a mortality benefit in left-sided and overall pts treated with bev, and worsens OS in pts receiving cet. Hence, NFKB1 could serve as an important predictive biomarker. Future studies are warranted to further elucidate its role in colorectal cancer.

Management and outcome of children and adolescents with non-medulloblastoma CNS embryonal tumors in Spain: room for improvement in standards of care.

Non-medulloblastoma CNS embryonal tumors (former PNET/Pineoblastomas) are aggressive malignancies with poor outcome that have been historically treated with medulloblastoma protocols. The purpose of this study is to present a tumor-specific, real-world data cohort of patients with CNS-PNET/PB to analyze quality indicators that can be implemented to improve the outcome of these patients. Patients 0-21years with CNS-PNET treated in eight large institutions were included. Baseline characteristics, treatment and outcome [progression-free and overall survival (PFS and OS respectively)] were analyzed. From 2005 to 2014, 43 patients fulfilled entry criteria. Median age at diagnosis was 3.6years (range 0.0-14.7). Histology was pineoblastoma (9%), ependymoblastoma (5%), ETANTR (7%) and PNET (77%). Median duration of the main symptom was 2weeks (range 0-12). At diagnosis, 28% presented with metastatic disease. Seventeen different protocols were used on frontline treatment; 44% had gross total resection, 42% craniospinal radiotherapy, 86% chemotherapy, and 33% autologous hematopoietic stem cell transplantation (aHSCT). Median follow-up for survivors was 3.5years (range 1.7-9.3). 3-year PFS was 31.9% (95% CI 17-47%) and OS 35.1% (95% CI 20-50%). Age, extent of resection and radiotherapy were prognostic of PFS and OS in univariate analysis (p < 0.05). Our series shows a dismal outcome for CNS-PNET, especially when compared to patients included in clinical trials. Establishing a common national strategy, implementing referral circuits and collaboration networks, and incorporating new molecular knowledge into routine clinical practice are accessible measures that can improve the outcome of these patients.

P1.05-038 Patterns of Recurrence in Curatively Resected Stage I Lung Cancer

The patterns of recurrence after curative resection for pathologically stage I non-small cell lung cancer (NSCLC) were investigated according to the cell type. The medical records of stage I NSCLC patients who undergone curative resection at Asan Medical Center between 2000 and 2009 were reviewed. Total 940 patients with pathologically proven stage I NSCLC were included. Patients with lepidic-type adenocarcinoma (LTA) were 74, other adenocarcinoma (ADC) 580, and squamous cell carcinoma (SCC) 246. Median length of follow-up was 62 months (3∼189), median survival was 146 months, and median disease-free survival (DFS) was 109 months. During follow-up, recurrence occurred in 221 patients (23.5%). Number of recurrence is grouped by every 6 months. Incidence of recurrence was peaked within 2 years after resection, then gradually decreased thereafter. Recurrence LTA (AIS/MIA) group was significantly rare (13.5%) throughout the all follow-up period (median DFI of 60months), and its distribution shows relatively even distribution. Comparing ADC and SCC, ADC seemed to show better 5-year OS in univariate analysis (p=0.003), but not in multivariate analysis. Furthermore, there were no significant difference in 5-year DFS (p=0.331). ADC shows higher proportion of distant metastasis, even though ADC group has lower T-stage. SCC shows higher incidence of local recurrence. Recurrence of ADC occurred within 2 years after resection, and shows higher proportion of distant metastasis (74.0% Vs. 57.2) even though ADC group has lower T-stage. Most of recurrence of both ADC and SCC groups were peaked within 2 years after resection. LTA group shows significantly delayed pattern of recurrence.

Clonal Hematopoiesis Associated with Adverse Outcomes Following Autologous Stem Cell Transplantation for Non-Hodgkin Lymphoma

▪BackgroundClonal hematopoiesis of indeterminate potential (CHIP) is an age-related phenomenon characterized by the presence of somatic mutations in peripheral blood (PMIDs: 25426837, 25426838). Although CHIP was originally defined in healthy older adults without cytopenias, it can be found in other contexts as well. For example, one recent report described four patients with therapy-related myeloid neoplasm (TMN) arising after treatment for other cancers, all of which were driven by TP53 mutations that could be found at very low levels in samples drawn years before the development of TMN (PMID: 25487151). However, there has not yet been a more systematic study of CHIP in this type of context.In this study, we sought to understand how CHIP behaves and influences outcomes in the context of autologous stem cell transplantation (ASCT), arguably the most extreme selective pressure that can be studied in the context of native hematopoiesis. We hypothesized that in patients with Non-Hodgkin Lymphoma (NHL) undergoing ASCT, the presence of CHIP at the time of transplantation would be associated with an increased risk of TMN and other adverse outcomes.MethodsWe analyzed exome sequencing data from 10 patients with TMN after ASCT (City of Hope Cancer Center, Duarte, CA), and performed targeted sequencing of 116 genes on banked, mobilized peripheral blood from an additional 401 patients with NHL who underwent ASCT (Dana Farber Cancer Institute, Boston, MA), to determine whether there is a clonal connection between CHIP at the time of ASCT and subsequent TMN, and to determine whether the presence of CHIP at the time of ASCT influences subsequent outcomes.ResultsIn 7 of 10 TMN patients for whom we analyzed exome sequencing data, mutations present at the time of TMN were also detectable in the pre-ASCT sample. PPM1D, a key mediator of the DNA damage pathway, was mutated in 2 patients, as was TP53 (2 patients), TET2 (2 patients) and PRPF8 (1 patient). In our larger cohort of 401 unselected ASCT patients, CHIP was common (121 patients, 30.2%) and was associated with older age but not with other demographic or treatment-related factors. PPM1D was the most commonly mutated gene (54 mutations in 48 patients).In the ASCT cohort of 401 patients, 18 patients developed TMN. The presence of CHIP at the time of ASCT significantly increased this risk: the 10-year cumulative incidence of TMN, with death and allogeneic transplant as competing risks, was 12.4% for patients with CHIP, compared to 3.5% for patients without CHIP (P=0.002, Figure 1A). Moreover, the presence of CHIP at the time of ASCT conferred significant risks beyond TMN alone, as patients with CHIP had significantly inferior overall survival compared to patients without CHIP (10-year OS 30.6% versus 60.9%, P=0.0003, Figure 1B). This difference was driven primarily by late mortality and not by an increased risk of relapse or by the difference in rate of TMN. Although other variables were associated with OS in univariate analysis, multivariate analysis in a Cox proportional hazards model showed that only older age (60 or above), aggressive lymphoma, and presence of CHIP were significantly associated with survival.ConclusionWe show that CHIP at the time of ASCT for NHL is common and is associated with an increased risk of TMN and decreased overall survival independent of the TMN risk. These results have substantial clinical and translational implications. They suggest the need to specifically study the connection between CHIP and lymphoma more deeply, which could be accomplished by assessing CHIP in patients with newly diagnosed lymphoma prior to the administration of any chemotherapy or mobilizing agents. They also suggest the need to consider alternative therapeutic approaches for patients with lymphoma and a high risk of TMN who are being considered for ASCT. Finally, they underscore the need to study clonal hematopoiesis in the context of treatment for other cancers to determine whether these results may be relevant to an even larger number of patients. [Display omitted] DisclosuresLindsley:MedImmune: Research Funding; Takeda Pharmaceuticals: Consultancy. Mar:H3 Biomedicine: Other: Spouse's employment. LaCasce:Forty Seven: Consultancy; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy. Koreth:LLS: Research Funding; amgen inc: Consultancy; takeda pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; kadmon corp: Membership on an entity's Board of Directors or advisory committees; prometheus labs inc: Research Funding; millennium pharmaceuticals: Research Funding. Ritz:Kiadis: Membership on an entity's Board of Directors or advisory committees. Soiffer:Kiadis: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

239P Primary squamous cell carcinoma of the stomach (PSCCS) - A systematic review and meta-analysis

Background PSCCS is a rare entity with less than 150 cases reported in the literature. This study was undertaken to identify the demographic profile, patterns of care and survival data in this subset of stomach cancer. Methods Full length papers of all cases of PSCCS reported and published in English from 1950 to 2016 were independently searched and retrieved by the authors from PUBMED, Google Search and Cochrane Library. Results:32studieswithN=91werefoundtobeeligibleformeta-analysis.Eligibility criteria included full length papers, case series and reports, published in English language between 1950 and 2016. Only cases in which no other synchronous malignancyexceptforPSCCSwereincluded.Medianageofthecohortwas65years (Range 17 - 83). 72 (79.1%) were male and 19 (20.9%) were female. 63 (69.2%) patients wereofAsianoriginand28(30.8%)wereofnon-Asianorigin.Themaximumbulkof the tumour was noted in the fundus/cardia of the stomach (n = 28, 35.4%), followed by body, pylorus/antrum and post gastrectomy stump. 20% of the patients were found to bemetastaticupfront.9(9.9%)patientshadidentifiableriskfactorsfordevelopmentof squamous cell carcinoma like radiation or corrosive injury, gastrectomy or cyclophosphamide intake. Surgery was the soletreatment in n = 27 (33%), adjuvantor neoadjuvantchemotherapywasdeliveredinn=24(29.6%)andpalliativetreatmentin n=15(18.5%).Adjuvantorneoadjuvanttherapysignificantlyimprovedprogression freesurvival(PFS)butnotoverallsurvival(OS).Thechemotherapyregimen administered was heterogeneous and the most effective regimen could not be identified. OS ranged from 0 to 72 months with median of 12 months. 3 year OS was 43%. Only T stage was found to be a significant factor for OS in univariate analysis (p = 0.029). Conclusions PSCCS is a rare entity with limited data available on causation or management strategies. Adjuvant or neoadjuvant chemotherapy in addition to surgery improves PFS. Legal entity responsible for the study AIIMS Funding AIIMS Disclosure All authors have declared no conflicts of interest.

The role of EUS-FNA in the diagnosis and grading of pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors (PNETs) exhibit various tumor behaviors and symptoms that are difficult for physicians to stage and predict prognosis. We assess prognostic factors combined with staging classifications to optimal the models and try to improve follow-up strategy to monitor liver metastases after surgery.Patients with PNETs treated at Sun Yat-sen Memorial Hospital between 2000 and 2015 were recruited. Patients were regrouped on the basis of functional status and mitotic rates. Nomograms to predict the prognostic values of classifications (AJCC, ENETS, and WHO) were constructed; the accuracy of the nomograms were quantified by the C-index and calibration plots.We identified 78 PNETs patients with pathological reports. Correlations with OS in univariate analysis included nonfunctional status (P = 0.002), CgA>200 ng/ml (P < 0.001), Ki-67 (3–20%, P = 0.014; >20%, P < 0.001), and mitotic rate (3–20/10HPF, P = 0.011; >20/10HPF, P < 0.001). By multivariate analysis, nonfunctional status and mitotic rate maintained significance (P = 0.039; 3–20/10HPF, P = 0.015; >20/10HPF, P = 0.007). Evaluating the new proposed system, the difference in OS between low- and high-groups was statistically significant (P = 0.001). The C-index of the regrouped nomograms were higher than that of premise ones (AJCC cohort, 0.605 v 0.576, P < 0.01; ENETS cohort, 0.73 v 0.691, P < 0.01; WHO cohort, 0.678 v 0.603, P < 0.01).An prognostic model based on mitotic rates and functional status correlates strongly with survival. PNETs should return visits every 2 months for the first half years, and every 3 months as followed until 2 years after surgery.

Differential expression of the epigenetic methylation-related protein DNMT1 by breast cancer molecular subtype and stromal histology.

BackgroundWe assessed the expression of methylation-related proteins 5-meC, DNMT1, and ISL-1 in breast cancer and evaluated their relationship to clinicopathological factors.MethodsImmunohistochemical staining for ER, PR, HER-2, Ki-67, 5-meC, DNMT1, and ISL-1 were performed on 348 breast cancer samples in tissue microarray. Samples were subgrouped into luminal A, luminal B, HER-2, or triple-negative breast cancer (TNBC) according to immunohistochemical staining for ER, PR, HER-2, and Ki-67. The tumor stroma was histologically subtyped into desmoplastic, sclerotic, normal-like, or inflammatory type.ResultsTumor expression of DNMT1 differed by molecular subtype: it was higher in TNBC and lower in luminal A (p < 0.001) samples. DNMT1 expression was also related to higher histologic grade, ER negativity, PR negativity, and higher Ki-67 LI (p < 0.001). In western blot, protein expressions of DNMT1 and ISL-1 were higher in TNBC and relatively lower in the remaining subtypes. High tumor expression of DNMT1 was associated with shorter OS in univariate analysis (p = 0.041). DNMT1 and 5-meC were differentially expressed by stromal phenotype: 5-meC was higher in normal-like type and lower in sclerotic type (p = 0.049); DNMT1 was higher in inflammatory and lower in sclerotic type (p < 0.001).ConclusionsTumor expression of DNMT1 in breast cancer differed by molecular subtype and stromal histological type. DNMT1 was highly expressed in TNBC and in breast cancer with inflammatory stromal type.

A retrospective cohort study of pancreatic neuroendocrine tumors at single institution over 15 years: New proposal for low- and high-grade groups, validation of a nomogram for prognosis, and novel follow-up strategy for liver metastases

PurposePancreatic neuroendocrine tumors (PNETs) exhibit various tumor behaviors and symptoms that are difficult for physicians to stage and predict prognosis. We assess prognostic factors combined with staging classifications to optimal the models and try to improve follow-up strategy to monitor liver metastases after surgery. MethodsPatients with PNETs treated at Sun Yat-sen Memorial Hospital between 2000 and 2015 were recruited. Patients were regrouped on the basis of functional status and mitotic rates. Nomograms to predict the prognostic values of classifications (AJCC, ENETS, and WHO) were constructed; the accuracy of the nomograms were quantified by the C-index and calibration plots. ResultsWe identified 78 PNETs patients with pathological reports. Correlations with OS in univariate analysis included nonfunctional status (P = 0.002), CgA>200 ng/ml (P < 0.001), Ki-67 (3–20%, P = 0.014; >20%, P < 0.001), and mitotic rate (3–20/10HPF, P = 0.011; >20/10HPF, P < 0.001). By multivariate analysis, nonfunctional status and mitotic rate maintained significance (P = 0.039; 3–20/10HPF, P = 0.015; >20/10HPF, P = 0.007). Evaluating the new proposed system, the difference in OS between low- and high-groups was statistically significant (P = 0.001). The C-index of the regrouped nomograms were higher than that of premise ones (AJCC cohort, 0.605 v 0.576, P < 0.01; ENETS cohort, 0.73 v 0.691, P < 0.01; WHO cohort, 0.678 v 0.603, P < 0.01). ConclusionAn prognostic model based on mitotic rates and functional status correlates strongly with survival. PNETs should return visits every 2 months for the first half years, and every 3 months as followed until 2 years after surgery.

Micro-RNAs in stage II colorectal cancer: Is there any role?

566 Background: Patients with stage II CRC have a varying survival outcome. Therefore, it is critical to identify new prognostic biomarkers that can help to identify more aggressive forms of the disease. The aim of this study was to identify the potential prognostic value of miRNAs in patients with stage II CRC. Methods: The study included 124 patients with stage II CRC who attended the NCI - Medical Oncology clinics, received treatment and followed-up during the period from January 2004 to December 2014. The expression levels of the five studied miRNAs were examined by qRT-PCR analysis. Additionally, blood samples were drawn from 41 patients recruited in the study in the last 3 years of recruitment to assess the level of miRNAs in blood. Results: In tumor tissues of 124 patients, miR-137, miR-145 and miR-320 were significantly under-expressed in 39.5%, 38.4% and 52.4% of cases, respectively while miR-21 and miR-498 were significantly over-expressed in 48.4% and 40.3%, respectively. On the other hand, assessment of these miRNAs in the blood of 41 cases revealed that miR-137, miR-145 and miR-320 were significantly under-expressed in 46.3%, 46.3% and 51.2% of cases, respectively while miR-21 and miR-498 were significantly over-expressed in 46.3% and 43.9%, respectively. The concordance between tissue and blood was weak with miR-320 and miR-145 (kappa 40-65%), intermediate with miR-498 and miR-137 (kappa 65-75%) while strong concordance has been achieved with miR-21 (kappa 75-85%). Performance status, over-expression of miR-21 and miR-498 and under-expression of miR-137, miR-145, and miR-320 were associated with significantly inferior DFS and OS in univariate analysis. In a multivariate analysis, deregulated miR-498 and miR-320 were independent prognostic factors for worse DFS, while over-expressed miR-498 and miR-21 were found to be independent prognostic factors for inferior OS. Conclusions: MiRNAs play an important role as prognostic markers in stage II CRC patients. Large-scale collaborative efforts are still absolutely essential to aid in determining the clinical potential of miRNAs as diagnostic, prognostic, and predictive biomarkers in CRC in order to achieve better survival outcomes.

Long term results of postoperative Intensity-Modulated Radiation Therapy (IMRT) in the treatment of Squamous Cell Carcinoma (SCC) located in the oropharynx or oral cavity.

BackgroundTo report our long-term results with postoperative intensity-modulated radiation therapy (IMRT) in patients suffering from squamous-cell carcinoma (SCC) of the oral cavity or oropharynx.MethodsSeventy five patients were retrospectively analyzed. Median age was 58 years and 84 % were male. 76 % of the primaries were located in the oropharynx. Surgery resulted in negative margins (R0) in 64 % of the patients while 36 % suffered from positive margins (R1). Postoperative stages were as follows: stage1:4 %, stage2:9 %, stage3:17 %, stage4a:69 % with positive nodes in 84 %. Perineural invasion (Pn+) and extracapsular extension (ECE) were present in 7 % and 29 %, respectively. All patients received IMRT using the step-and-shoot approach with a simultaneously integrated boost (SIB) in 84 %. Concurrent systemic therapy was applied to 53 patients, mainly cisplatin weekly.ResultsMedian follow-up was 55 months (5–150). 13 patients showed locoregional failures (4 isolated local, 4 isolated neck, 5 combined) transferring into 5-year-LRC rates of 85 %. Number of positive lymph nodes (n > 2) and presence of ECE were significantly associated with decreased LRC in univariate analysis, but only the number of nodes remained significant in multivariate analysis. Overall treatment failures occurred in 20 patients (9 locoregional only, 7 distant only, 4 combined), transferring into 3-and 5-year-FFTF rates of 77 % and 75 %, respectively. The 3-and 5-year-OS rates were 80 % and 72 %, respectively. High clinical stage, high N stage, number of positive nodes (n > 2), ECE and Pn1 were significantly associated with worse FFTF and OS in univariate analysis, but only number of nodes remained significant for FFTF in multivariate analysis. Maximum acute toxicity was grade 3 in 64 % and grade 4 in 1 %, mainly hematological or mucositis/dysphagia. Maximum late toxicity was grade 3 in 23 % of the patients, mainly long-term tube feeding dependency.ConclusionPostoperative IMRT achieved excellent LRC and good OS with acceptable acute and low late toxicity rates. The number of positive nodes (n > 2) was a strong prognostic factor for all endpoints in univariate and the only significant factor for LRC and FFTF in multivariate analysis. Patients with feeding tubes due to postoperative complications had an increased risk for long-term feeding tube dependency.

EPID-27GLIOSTRY (GLIOBLASTOMA REGISTRY) OF THE AINO (ITALIAN ASSOCIATION OF NEURO-ONCOLOGY): ANALYSIS OF FACTORS INFLUENCING SURVIVAL IN GLIOBLASTOMA PATIENTS RECEIVING THE NITROSOUREA FOTEMUSTINE AT FIRST PROGRESSION FOLLOWING THE STUPP REGIMEN

BACKGROUND: Patients with glioblastoma at first progression after standard radiotherapy and temozolomide often receive nitrosoureas, but factors influencing survival following treatment with these drugs are not well known. We investigated a large cohort of glioblastoma patients who received the nitrosourea fotemustine (FTM) at first progression following the Stupp regimen. METHODS: Survival data and information on demographics, clinical, radiological, pathological, molecular and treatments factors were collected in 34 Italian Institutions. PFS and OS curves were drawn using the Kaplan-Meier method and both univariate and multivariate analysis were performed. RESULTS: Up to date 670 patients, who were enrolled between 2005 and 2012, are evaluable. Median PFS following FTM was 3.4 months. Factors correlated with PFS in univariate analysis were MGMT methylation and association of FTM with bevacizumab. Both MGMT status with an HR of 0.64 (0.52-0.79), p < 0,001, and association of FTM with bevacizumab with an HR of 0.71 (0.56-0.92), p < 0,008, remained significant after multivariate analysis. PFS was 4.3 months in methylated patients vs 3.0 months in unmethylated ones, and 4.9 months for FTM + bev vs 3.2 months for FTM alone. Median OS following FTM was 6.6 months. Factors correlated with OS in univariate analysis were age, Karnofsky Performance Score, extent of surgery, MGMT status and association of FTM with bev. MGMT status with HR of 0.60 (0.48-0.76), p < 0.001, and association of FTM with bev with HR of 0.73 (0.56-0.95), p = 0.022, remained significant after multivariate analysis. OS was 7.6 months in methylated patients vs 5.5 months in unmethylated ones, and 7.6 months for FTM + bev vs 6 months for FTM alone. CONCLUSIONS: MGMT is a factor of strong prognostic and predictive value in GBM patients treated at first progression with FTM. The association of bev with FTM could be superior over FTM alone.

The timing of autologous stem cell transplantation and the prognostic factors affecting the prognosis in children with relapsed Hodgkin lymphoma.

Although ASCT is used as a standard treatment following second remission for adults in oncology practice, data are lacking for relapsed childhood HL. Therefore, we evaluated the exact timing of the ASCT treatment, as well as factors affecting the prognosis in children with relapsed HL who underwent ASCT. Patients were divided into two groups (Group 1: ASCT after second remission [n = 6], Group 2: ASCT after >2 remissions [n = 3]). Overall, DFS rate was 64.8% at 24 months after ASCT. In Group 1, post-transplant DFS and OS were 83.3% and 75%, respectively, and the post-transplant response without event rate was 5/6 (83.3%). However, in Group 2 this was 1/3 (33.3%). Nonetheless, the timing of ASCT was not a significant prognostic factor for DFS and OS in univariate analyses (p = 0.21 and p = 0.73, respectively). Median follow-up time was 21 months after transplant, and DFS and OS were 62.5% and 75% in early relapse group (n = 6) at 24 months. DFS and OS were both 66.7% in late relapse (n = 3). In addition, response rates of ASCT without event were 66.7% for both early and late relapse groups. Relapse types (early: 3-12 months, late: >12 months) was not a significant prognostic factor for DFS and OS in univariate analyses (p = 0.96 and p = 0.92). While we found ASCT to be a useful treatment following second remission, it does not demonstrate better success in early relapse cases, when compared to late relapse cases. Therefore, after second remission for relapsed HL, ASCT is advisable regardless of the time of relapse.