5-year RFS Research Articles

Aldehyde Dehydrogenase 2 (ALDH2) Expression Predicts a Poor Prognosis in Acute Myeloid Leukemia

Introduction: The aldehyde dehydrogenase 2 (ALDH2) gene encodes for an enzyme of the aldehyde dehydrogenase family involved in oxidative alcohol metabolism and protection from hypoxic stress. Using a comparative proteomic approach based on in vivo biotinylation, we have recently identified a marked overexpression of ALDH2 in a rat model of acute myeloid leukemia (AML). In solid tumors, ALDH2 has been described to reduce sensitivity to anthracyclines, a mainstay in the treatment of AML. Here, we analyzed the prognostic impact of ALDH2 expression levels in AML.Methods: Using oligonucleotide microarrays, we analyzed ALDH2 gene expression in pretherapeutic bone marrow or blood samples from 492 AML patients who received intensive chemotherapy within the AMLCG-1999 trial (GSE37642). Results were validated in an additional cohort of 270 intensively treated younger AML patients from the HOVON group (GSE6891).Results: When dichotomized at the first quartile, higher transcript levels of ALDH2 predicted poorer overall (5-year OS 20.2% vs 41.7% for high vs low expression, respectively), event-free (5-year EFS 11.9% vs 30.0%) and relapse-free survival (5-year RFS 22.1% vs 45.0%) (log-rank test: P < 0.001 for all variables). Patients with higher ALDH2 levels had significantly lower rates of complete remission on induction chemotherapy (53% vs 63%; P < 0.05). In multivariate Cox regression analyses including age, gender, primary vs secondary AML, ECOG, WBC, LDH, cytogenetic risk and molecular risk, high ALDH2 expression, among others, remained an independent adverse prognostic factor for OS (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.11 to 2.04; P= 0.008), EFS (HR, 1.43; 95% CI, 1.08 to 1.90; P= 0.012) and RFS (HR, 1.82; 95% CI, 1.24 to 2.67; P= 0.002). Finally, the prognostic impact of ALDH2 was confirmed in a second cohort of 270 intensively treated younger AML patients from the HOVON group (GSE6891). Again, when dichotomized at the first quartile, high ALDH2 significantly predicted inferior OS (5-year OS 37.3% vs 59.4%; P= 0.003) and EFS (5-year EFS 28.8% vs 53.0%; P < 0.001).Conclusion: We identified high ALDH2 expression as an adverse prognostic factor in two large independent cohorts of intensively treated AML patients. DisclosuresLenz:Celgene, JJ, Hexal, Roche, BMS, Novartis, Bayer: Consultancy; AstraZeneca, Gilead, JJ, Celgene, Novartis, Bayer: Research Funding. Hiddemann:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Outcome after Midam Regimen and Impact of Post-Remission Strategy in Patients with Relapsing or Refractory Acute Myeloid Leukemia

Introduction. The immune-conjugate gemtuzumab ozogamicin (GO) represents the main available therapeutic possibility beyond combinations of anthracycilines and cytarabin for patients with refractory or relapsed acute myeloid leukemia (AML). Combining GO, intermediate dose Ara-c and mitoxantrone (MIDAM) has been shown as a valid option as salvage therapy based on a prospective phase II study including 62 patients (Chevallier JCO 2007). Whether this regimen is safe in patients undergoing allogeneic hematopoietic stem-cell transplantation (allo-HSCT) as post-remission therapy remained to be determined.Method. This retrospective study included the consecutive patients with relapsed or refractory AML treated by the MIDAM regimen in our center (Clermont-Ferrand University Hospital) between 2008 and 2013. MIDAM consisted of GO 9 mg/m2 on day 4, cytarabine 1g/m2 every 12 hours on days 1 through 5, and mitoxantrone 12 mg/m2/d on days 1 through 3. GO is available according to a compassionate use program in France.Results. A total of 86 consecutive patients with relapsed (n=62) or refractory (n=24) AML were included. Median age was 60 years (range, 17 to 75 years old). The MIDAM regimen was administered as salvage therapy after 1 (n=73) or more (n=13) therapeutic lines. Distribution according to ELN 2008 cytogenetic risk classification was as following: favorable (n=12), intermediate-1 (n=23), intermediate-2 (n=15) and high risk (n=22). Complete response (CR) rate was 63% including 23 patients (27%) CR with delayed platelets recovery (CRp). Treatment failure was observed in 23 (27%) patients. Nine (10%) deaths during induction occurred. Infusion-related reaction was observed in 24 (28%) patients and tumor lysis syndrome were seen in 4 (4.6%) patients. Eight (9.3%) patients had veno-occlusive disease (VOD).CR rate (CR+CRp) was significantly better in patients with low WBC (71% if <10 G/L vs 44% if WBC >10 G/L, P=0.028) and in those with good performance status (70% if ECOG 0 or 1 vs 27% if ECOG >1, P=0.003). No significant influence of percentage of CD33 positive cells was found.Among the 54 patients with CR or CRp, post-remission therapy consisted of chemo-based approaches in 13 patients (chemotherapy only, n=10; chemotherapy + auto-HSCT, n=3) because a lack of allogeneic donor and allo-HSCT in 29 patients (including 7 with consolidation chemotherapy prior to allo-HSCT). Twelve patients did not receive any consolidation therapy. Median follow up was 6 years. Among patients achieving CR or CRp, 2-year RFS was 25%. No influence of neither age, WBC count, percentage of CD33 positive cells nor ELN 2008 risk cytogenetic group was observed on RFS. Allo-HSCT as post-remission therapy confers significant better RFS compared to chemo-based approaches and absence of consolidation therapy (51%, 33% and 9%, respectively, P=0.001). Among the whole population, 2-year OS was 20%. High WBC count (>10 G/L), intermediate and high risk ELN cytogenetic, ECOG performance status more than one were significant adverse prognostic factors on OS. Allo-HSCT as post-remission therapy was associated with better 2-year OS (43%) compared to those without available donor and treated by chemo-based approaches (15%) (P=0.005). Importantly, among patients treated by allogenic stem cell transplantation, no veno-occlusive disease was found.Conclusion. The MIDAM regimen in relapsed or refractory AML is an option therapeutic as a salvage chemotherapy with a relatively acceptable toxicity profile. Allogeneic transplantation is the consolidation of choice and can be performed after this regimen with no increased risk of VOD. DisclosuresTournilhac:GILEAD: Honoraria, Other: Travel Funding, Research Funding; Janssen: Honoraria, Other: travel funding; Abbvie: Honoraria, Other: Travel funding; AMGEN: Other: Travel funding, Research Funding; ROCHE: Honoraria, Other: Travel funding, Research Funding. Guieze:GILEAD: Other: Educational Presentation; JANSSEN: Other: Educational Presentation; ABBVIE: Other: Educational Presentation.

Predictors and survival benefit of achieving pentafecta in a contemporary series of open radical cystectomy.

Pentafecta provides a comprehensive approach for standardized reporting of surgical and oncologic outcomes after radical cystectomy and urinary diversion. We aimed to report the rate, predictors of achieving pentafecta and its impact on long-term survival in a contemporary series of open radical cystectomy (ORC). A retrospective analysis of a computerized database of patients treated with ORC between 2004 till 2014 was performed. Pentafecta criteria included negative soft tissue surgical margin (STSM), retrieval of ≥16 lymph nodes, absence of clinical recurrence within 12 months after surgery, absence of high-grade complication (GIII-V) within 90 days after surgery, and absence of urinary diversion related complications at 12 months follow-up. Multivariate analysis was used to identify predictors of achieving pentafecta. Pentafecta was achieved in 545 (33.6%) patients out of 1624 included in the study. Absence of ≥16 LN yield was the first cause of missing pentafecta (49.5%). Multivariate analysis identified: ASA Score grades ≥III (OR=0.7, 95%CI 0.6-0.9, P=0.04), BMI≥35 (OR=0.5, 95%CI 0.3-0.8, P=0.007), perioperative blood transfusion (≥4 units) (OR=0.5, 95%CI 0.3-0.7, P=0.001), and ileal conduit (OR=0.7, 95%CI 0.5-0.9, P= 0.01) as independent predictors of missing pentafecta. Patients who achieved pentafecta had higher estimated 5-year RFS than their counterparts (81.7% vs. 62.5%; P<0.0001). Pentafecta was achieved in nearly one third of patients after ORC. Achievement of pentafecta was associated with better long-term recurrence-free survival. Obesity (class II, III), perioperative blood transfusion (>4 units), associated comorbidities, and ileal conduit were independent predictors of missing pentafecta.

Adjuvant nivolumab for hepatocellular carcinoma (HCC) after surgical resection (SR) or radiofrequency ablation (RFA) (NIVOLVE): A phase 2 prospective multicenter single-arm trial and exploratory biomarker analysis.

4070 Background: The NIVOLVE trial was designed to assess the efficacy and safety of nivolumab as an adjuvant therapy for HCC, and to identify biomarkers predictive of recurrence in patients after SR or RFA (Registration # UMIN 000026648). Methods: The trial involved 11 sites and was conducted in patients with HCC who showed a complete response after SR (n = 33) or RFA (n = 22) (ITT). Overall, 53 of 55 patients with Child-Pugh A received nivolumab (240 mg/body every 2 weeks (8 cycles)), followed by nivolumab (480 mg/body every 4 weeks (8 cycles)) within 6 weeks after SR or RFA. The primary endpoint was the 1 year recurrence-free survival rate (RFSR). The key secondary endpoint was RFS. Exploratory biomarker analysis included mutations, copy number alterations, and tumor mutation burden in tumor tissues. Techniques included next generation sequencing, immunohistochemical staining (IHC) of formalin-fixed paraffin-embedded tissues (n = 31, 13 with recurrence and 18 without) for CD8, PD-1, PD-L1, Foxp3, and β-catenin, and ctDNA analysis using pre-nivolumab whole blood by deep sequencing (CAPP-seq; Avenio). Results: The 1-year RFSR and median RFS were 76.7% and 26.0 months (95% confidence interval (CI), 23.9–28.1), respectively, with no difference between SR and RFA. Copy number gains (CNGs) in WNT/β-catenin related genes ( APC, CTNNB1, TCF7L1, TCF7L2) (n = 8) correlated with shorter RFS (positive: 11.8 months vs. negative: not reached [NR]; p = 0.0003). IHC revealed that negative staining for PD-1 (p &lt; 0.0001), a low combined positive score for PD-L1 (p = 0.0113), a low number of CD8+ tumor infiltrating lymphocytes (TILs) (p = 0.0130), and positivity for Foxp3+ cells (p = 0.0076) correlated with recurrence. Treatment-related adverse events (AEs) (n = 53) were as follows: all grades, 68%; grades 3–4 (18.9%); and immune related AEs, 25%. HCC cases with low numbers of CD8+ TILs or cases positive for Foxp3+ cells (n = 16) showed a significantly shorter RFS (16.8 months [95% CI, 8.7–25.1]) than those with high numbers of CD8+ TILs and those positive for PD-1/PD-L1 expression (n = 15) (NR [95% CI,26.2months–NR]) (p &lt; 0.0001). HCC cases with activation of the WNT/β-catenin pathway assessed by IHC (n = 9) showed shorter RFS (17.0 months [95% CI,1.1–26.2]) than those without activation (n = 22) (NR [95% CI,24.7 months–NR]) (p = 0.0191). Patients positive for ctDNA (n = 10) before nivolumab tended to have shorter RFS than those without ctDNA (n = 30) (26.2 vs. NR). There was no correlation between TMB and RFS. Conclusions: The 1 year RFSR and RFS in the NIVOLVE trial were 76.6% and 26.0 months, respectively. No new safety signal was observed. CNG in WNT/β-catenin-related genes, activation of the WNT/β-catenin pathway, the presence of Foxp3+ cells, and low numbers of CD8+ TILs may predict recurrence after SR or RFA with adjuvant nivolumab. Clinical trial information: 000026648.

REGOSTA: A randomized, placebo-controlled, double-blinded, multicenter study evaluating the efficacy and safety of regorafenib (REGO) as maintenance therapy after first-line treatment in patients (pts) with osteosarcoma (OS) and non-osteosarcomas (non-OS) of bone (non-Ewing, non-chondrosarcomas and non-chordomas).

TPS11576 Background: Pts with OS and non-OS of bone are treated with a multimodal sequence therapy of neoadjuvant chemotherapy (CT), surgery and adjuvant CT, followed by a close surveillance until recurrence. At recurrence, the prognosis remains poor with objective response rates of 3-29%, and a median Progression-Free Survival (PFS) of less than 4 months in OS. There is a clinical need to reduce the risk of recurrence after the initial treatment sequence. The REGOBONE study reported a significant clinical benefit of regorafenib compared to placebo in patients with relapsed OS (median PFS: 16.4 versus 4.1 weeks). Methods: This multicenter trial is ongoing to study the efficacy and safety of maintenance REGO in pts &gt; = 16 years, with complete remission after initial treatment sequence of their bone sarcoma. 168 pts will be randomly allocated in a 1:1 ratio to receive either oral REGO or its matching placebo (control arm) at a daily dose of 120mg, continuously and for a maximum of 12 months. Randomization will be stratified according to the following risk factors: metastases (mets) at diagnosis and/or poor response to neoadjuvant CT versus no mets at diagnosis and good response to neoadjuvant CT. The primary objective is to compare the efficacy (Relapse-Free Survival) between the 2 arms. The expected 3-year RFS rates are 55% in the control arm and 74.6% in the REGO arm (HR = 0.5). 66 events will provide 80% power to show significant improvement in RFS, using a 2-sided log-rank test at a 5% level. Secondary endpoints include Time to Treatment Failure, Overall Survival, Quality of Life, safety profile, and compliance to treatment. Radiological endpoints will be evaluated using the RECIST 1.1. Translational objectives will be to identify predictive biomarkers for efficacy of REGO as maintenance therapy using liquid biopsies. As of Feb 1st, 2021, 3 patients have been randomized. 15 sites of the French Sarcoma Group will participate. Clinical trial information: NCT04055220.

Neoadjuvant and adjuvant nivolumab (nivo) with anti-LAG3 antibody relatlimab (rela) for patients (pts) with resectable clinical stage III melanoma.

9502 Background: Neoadjuvant therapy (NT) for pts with clinical stage III melanoma remains an active area of research interest. Recent NT trial data demonstrates that achieving a pathologic complete response (pCR) correlates with improved relapse-free (RFS) and overall survival (OS). Checkpoint inhibitor (CPI) NT with either high or low dose ipilimumab and nivolumab regimens produces a high pCR rate of 30-45% but with grade 3-4 toxicity rate of 20-90%. In metastatic melanoma (MM), the combination of nivo with rela (anti Lymphocyte Activation Gene-3 antibody) has demonstrated a favorable toxicity profile and responses in both CPI-naïve and refractory MM. We hypothesized that NT with nivo + rela will safely achieve high pCR rates and provide insights into mechanisms of response and resistance to this regimen. Methods: We conducted a multi-institutional, investigator-initiated single arm study (NCT02519322) enrolling pts with clinical stage III or oligometastatic stage IV melanoma with RECIST 1.1 measurable, surgically-resectable disease. Pts were enrolled at 2 sites and received nivo 480mg IV with rela 160mg IV on wks 1 and 5. Radiographic response (RECIST 1.1) was assessed after completion of NT; surgery was conducted at wk 9 and specimens were assessed for pathologic response per established criteria. Pts received up to 10 additional doses of nivo and rela after surgery, with scans every 3 mo to assess for recurrence. The primary study objective was determination of pCR rate. Secondary objectives included safety, radiographic response by RECIST 1.1, event-free survival (EFS), RFS, and OS analyses. Blood and tissue were collected at baseline, at day 15, day 28, and at surgery for correlative analyses. Results: A total of 30 pts (19 males, median age 60) were enrolled with clinical stage IIIB/IIIC/IIID/IV (M1a) in 18/8/2/2 pts, respectively. 29 pts underwent surgery; 1 pt developed distant metastatic disease while on NT. pCR rate was 59% and near pCR ( &lt; 10% viable tumor) was 7% for a major pathologic response (MPR, pCR + near pCR) of 66%. 7% of pts achieved a pPR (10-50% viable tumor) and 27% pNR (≥50% viable tumor). RECIST ORR was 57%. With a median follow up of 16.2 mos, the 1 -year EFS was 90%, RFS was 93%, and OS was 95%. 1-year RFS for MPR was 100% compared to 80% for non-MPR pts (p = 0.016). There were no treatment related gr 3/4 AEs that arose during NT; 26% of pts had a gr 3/4 AE that began during adjuvant treatment. Conclusions: Neoadjuvant and adjuvant treatment with nivo and rela achieved high pCR and MPR rates with a favorable toxicity profile in the neoadjuvant and adjuvant settings. Pts with MPR had improved outcomes compared to non-MPR pts. Translational studies to discern mechanisms of response and resistance to this combination are underway. Clinical trial information: NCT02519322.

Intra-corporeal robot-assisted versus open radical cystectomy: a propensity score-matched analysis comparing perioperative and long-term survival outcomes and recurrence patterns.

To compare perioperative and long-term oncological outcomes and recurrence patterns between robot-assisted radical cystectomy with intra-corporeal urinary diversion (iRARC) and open radical cystectomy (ORC). We retrospectively analyzed 177 bladder cancer patients who received iRARC or ORC at Fujita Health University between 2008 and 2020. Our primary endpoint was long-term oncological outcomes. As a secondary endpoint, we examined perioperative outcomes, complications, and recurrence patterns. These outcome measures were compared between the propensity score (PS)-matched cohorts. PS-matched analysis resulted in 60 matched pairs from iRARC and ORC groups. The iRARC cohort was associated with significantly longer operative time (p = 0.02), lower estimated blood loss (p < 0.001), lower blood transfusion rate (p < 0.001), shorter length of hospital stay (p < 0.001), fewer overall complications (p = 0.03), and lower rate of postoperative ileus (p = 0.02). There was no statistically significant difference between iRARC and ORC in 5-year RFS (p = 0.46), CSS (p = 0.63), and OS (p = 0.71). RFS and CSS were also comparable, even in locally advanced (≥ cT3) disease. Multivariate analysis identified lymphovascular invasion as a robust predictor of RFS, CSS, and OS. The number of recurrence was similar between the groups, while extra-pelvic lymph nodes were more frequent in iRARC than that in ORC (22.7% vs. 7.7%). iRARC has favorable perioperative outcomes, fewer complications, and comparable long-term survival outcomes, including locally advanced (≥ cT3) disease, compared to that in ORC. Our results need to be validated in prospective randomized clinical trials.

Prognostic value of Balkan endemic nephropathy and gender on upper tract urothelial carcinoma outcomes after radical nephroureterectomy: A cohort study

BackgroundTo identify the prognostic impact of residence in a BEN-endemic area and gender on upper tract urothelial carcinoma (UTUC) outcomes in Serbian patients treated with radical nephroureterectomy (RNU). MethodsThe study included 334 consecutive patients with UTUC. Patients with permanent residence in Balkan endemic nephropathy (BEN) or non-endemic areas from their birth to the end of follow-up were included in the analysis. Cox regression analyses were used to address recurrence-free (RFS) and cancer-specific survival (CSS) estimates. ResultsFemale patients were more likely to have preoperative pyuria (P = 0.01), tumor multifocality was significantly associated with the female gender (P = 0.003). Gender was not associated with pathologic stage and grade, lymph node metastasis, lymphovascular invasion, adjuvant chemotherapy, bladder cancer history, tumor size, distribution of tumor location, preoperative anemia and demographic characteristics. A total of 107 cases recurred, with a median time to bladder recurrence of 24.5 months. History of bladder tumor (HR, 1.98; P = 0.005), tumor multifocality (HR, 3.80; P < 0.001) and residence in a BEN-endemic area (HR, 1.81; P = 0.01) were independently associated with bladder cancer recurrence. The 5-year bladder cancer RFS for the patients from areas of BEN was 77.8 % and for the patients from non-BEN areas was 64.7 %. The 5-year CSS for the men was 66.2% when compared to 66.6% for the women (P = 0.55). ConclusionsResidence in a BEN-endemic area represents an independent predictor of bladder cancer recurrence in patients who underwent RNU. Gender cannot be used to predict outcomes in a single-centre series of consecutive patients who were treated with RNU for UTUC.

Development of Prognostic Evaluation Model to Predict the Overall Survival and Early Recurrence of Hepatocellular Carcinoma.

BackgroundThe aberrant expressions of lncRNAs have been frequently demonstrated to be closely associated with the prognosis of patients in many cancer types including hepatocellular carcinoma (HCC). Integration of these lncRNAs might provide accurate evaluation of HCC. Therefore, this study aims to develop a novel prognostic evaluation model based on the expression of lncRNAs to predict the survival of HCC patients, postoperatively.Patients and MethodsRNA sequencing (RNA-seq) analysis was performed for 61 HCC patients (training cohort) to screen prognosis-associated lncRNAs with univariate Cox regression and Log rank test analyses. Multivariate Cox regression analysis was then applied to establish the final model, which was further verified in a validation cohort (n=191). Moreover, performance of the mode was assessed with time-dependent receiver operating characteristic curve (tdROC), Harrell’s c-index, and Gönen & Heller’s K.ResultsAfter a serial statistical computation, a novel risk scoring model consisting of four lncRNAs and TNM staging was established, which could successfully divide the HCC patients into low-risk and high-risk groups with significantly different OS and RFS in both training and validation cohorts. tdROC analysis showed that this model achieved a high performance in predicting OS and 2-year RFS in both cohorts. Gene Set Enrichment Analysis revealed that HCC tumor tissues with high-risk score have stronger capacities in immune escape and resistance to treatment.ConclusionWe successfully established a novel prognostic evaluation model, which exhibited reliable capacity in predicting the OS and early recurrence of HCC patients with relatively higher accuracy.

Retrospective study of malignant phyllodes tumors of the breast: Younger age, prior fibroadenoma surgery, malignant heterologous elements and surgical margins may predict recurrence

PurposeThe potential recurrence rate of malignant phyllodes tumors (MPTs) of the breast is high, and the prognostic factors are still unclear. We therefore aim to study the factors affecting the outcome of MPTs. MethodsA retrospective review of MPT patients treated from 2006 to 2020 at our institution was conducted. Univariate and multivariate Cox proportional hazard models were used to examine the influence of different variables on RFS. Moreover, significant prognostic factors were combined to construct the nomogram to predict the probability of relapse occurring in MPT patients. The 5-year and 10-year RFS rates were estimated using the Kaplan–Meier method. ResultsDuring the study period, 188 MPT patients were identified. The presence of malignant heterologous elements was observed in 23 (12.2%) patients with MPT, and the patients with malignant heterologous elements who received chemotherapy had longer RFS, which could reduce the risk of recurrence (p = 0.022). Recurrence occurred in 56/188 (29.8%) patients, of whom 47 experienced local recurrence and 11 experienced distant metastases. The 5-year and 10-year cumulative RFS rates were 77.5% and 70.1%, respectively. Age (p = 0.041), fibroadenoma surgery history (p = 0.004), surgical margins (p = 0.001) and malignant heterologous elements (p < 0.001) were independent risk factors for postoperative RFS. Subsequently, a nomogram was built, with a C-index of 0.64 (95% CI: 0.629–0.661), to predict the risk of recurrence. ConclusionThe results of this study showed that younger age, fibroadenoma surgery history, malignant heterologous elements and surgical margins <1 cm predict a higher incidence of recurrence in MPT patients. Patients with malignant heterologous elements treated with chemotherapy could have a reduced risk of recurrence.

THE PROGNOSTIC SIGNIFICANCE OF MYXOID MATRIX IN RETROPERITONEAL WELL-DIFFERENTIATED LIPOSARCOMA

Objective: to assess the influence of the myxoid matrix in retroperitoneal well-differentiated liposarcoma(WDLPS ) on the long-term results of surgical treatment of patients.Material and Methods. The study included 111 patients with primary retroperitoneal WDLPS who underwent radical surgical treatment in Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation. Histological slides of all surgical specimens were reviewed by experienced pathologist and reclassified according to criteria of WHO (2013) for histological subtypes of the WDLPS . Patients were divided into groups depending on presence or absence of the myxoid matrix in WDLPS and enrolled in intergroup analysis of overall (OS ) and recurrence-free (RFS) survival.Results. OS was significantly worse in the group of patients with the myxoid matrix in the tumor (p=0.002; log-rank test). The median OS was 142 (95 % CI , 108, 176) months in the group without the myxoid matrix, and 84 (95 % CI , 29, 139) months in the group with the myxoid matrix. The 5-year survival rates were 79 % and 44 % in the groups without myxoid matrix and with myxoid matrix, respectively. RFS was also significantly worse in the group of patients with the myxoid matrix than in the group of patients without the myxoid matrix (p=0.006; log-rank test). The median RFS was 55 (95 % CI , 38, 72) months in the WDLPS group without the myxoid matrix, and 31 (95 % CI , 15, 47) months in the WDLPS group with the myxoid matrix. The 2-year RFS rates were 75 % and 44 % in the groups without the myxoid matrix and with the myxoid matrix, respectively.Conclusion. The results of the study demonstrated that the presence of the myxoid matrix in WDLPS was associated with poor prognosis. We believe that the presence of the myxoid matrix in WDLPS can serve as an effective morphological marker of a less favorable prognosis for retroperitoneal WLPS .

Phase II trial of prophylactic hyperthermic intraperitoneal chemotherapy in patients with locally advanced gastric cancer after curative surgery

BackgroundHIPEC is an emerging procedure to treat peritoneal metastasis of gastric cancer. Data about HIPEC in locally advanced gastric cancer is scarce. The purpose of this trial is to evaluate the safety and toxicity of prophylactic HIPEC with cisplatin for patients with locally advanced gastric cancer.MethodsFrom March 2015 to November 2016, a prospective, randomized phase II trial was conducted. After radical gastrectomy, patients in the experimental group underwent HIPEC with cisplatin followed by adjuvant chemotherapy with SOX regime. Patients in the other group were treated with SOX regime alone. Postoperative complications and patient survival were compared.ResultsIn total, 50 patients were eligible for analyses. No significant difference was found in the incidence of postoperative complications including anastomotic/intestinal leakage, liver dysfunction, bone marrow suppression, wound infection and ileus (P > 0.05). Mean duration of hospitalization after radical gastrectomy was 11.7 days. 12.2 days in experimental group and 10.8 days in control group respectively (P = 0.255). The percentage of patients with elevated tumor markers was 12.1% in experimental group, which was significantly lower than 41.2% in control group (P = 0.02). 3-year RFS of patients who treated with or without prophylactic HIPEC were 84.8 and 88.2% respectively (P = 0.986). In the multivariate analysis, pathological T stage was the only independent risk factor for the RFS of patients (P = 0.012, HR =15.071).ConclusionAdditional intraoperative HIPEC with cisplatin did not increase postoperative complications for locally advanced gastric cancer after curative surgery. Prophylactic HIPEC with cisplatin was safe and tolerable, while it did not reduce the risk of peritoneal recurrence in this trial, supporting further studies to validate the efficacy of it.Trial registrationChinese Clinical Trial Registry, ChiCTR2000038331. Registered 18 September 2020 - Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=59692.

ES23.05 GGN Issues

As low-dose computed tomography (LDCT) is increasingly popular, the possibility of detecting ground-glass nodules (GGN) has also increased significantly, which was uncommon in the era of chest radiography as a regular health examination. Although the term GGN can be focal interstitial fibrosis, inflammation, hemorrhage and malignancies, we mainly focus on GGN that is pathologically malignant. A substantial proportion of GGNs detected at screening CT are transient [1]. It is important to avoid overtreatment of transient GGNs. The possibility of spontaneous regression of newly diagnosed GGN should always be considered before invasive treatment is decided. Several sets of guidelines are already available for the management of GGNs found on CT scans or via CT screening [2,3]. Obviously, there are differences in the recommendations of each guideline for some specific scenarios. One of the important reasons is that the correlation between radiographic appearance and histologic diagnosis is far from reliable [4]. Some people simply thought GGN referred to the site without blocking of alveolar cavity pathologically, and ground-glass opacity (GGO) components therefore represented the lepidic growth pattern of adenocarcinoma. However, both lepidic and non-lepidic growth patterns can present as GGNs on CT images [5]. So, GGO is a rather unspecific radiologic feature involving various pathologic conditions. The radiologic feature of GGO has a significant impact on clinical results. Several studies have revealed that the presence of a GGO component was a significantly favorable prognostic factor in early-stage NSCLC [6,7]. In Fu’s study, the 5-year RFS rates were 100% in the pure-GGN group no matter what histological type [8]. Such excellent prognosis naturally makes people think that it is not only the result of surgery, but also that these lesions might be indolent tumors even in the absence of any kind of treatment. Concerns have been raised about the possibility that premature surgical resection may represent‘overtreatment’. This is a good understanding of why Dr. Sepesi takes timing and indications for resection as an important issue for the treatment of GGN [9]. Although the precise surgical indications have not been determined, for obvious reasons a higher ratio of solid component need resected more urgently. The presence of a solid component is associated with a much higher risk for invasive adenocarcinoma [10]. However, there were different measurement results using different attenuation thresholds in regard to defining the solid or ground-glass components. Visual assessment of nodule morphologic structure on chest CT images Is still commonly used in clinical practice. However, interobserver and intraobserver discrepancies in nodule categorization cannot be ignored, especially disagreement on the size and presence of a solid component may lead to different management in the majority of cases with such discrepancies [11]. In order to evaluate the growth rate of GGNs in an accurate, reproducible, and sensitive manner, some measures on three-dimensional volumetry, such as volume doubling time (VDT) and mass doubling time (MDT), are getting more and more applications. High-grade invasive tumors show significantly shorter VDTs and MDTs than do low-grade invasive ones [12]. If the measurements of VDT and MDT can be popularized, they have the potential to become important references for evaluating GGN surgical indications. Furthermore, since the framework combining radiomics with deep learning (RDL) has the potential to predict high-grade lung adenocarcinoma, RDL might be a supplemental tool to screen high-risk subgroup in GGN patients for pathologists in the future [13]. Given the low aggressiveness of GGNs, it has been proposed that some GGNs meeting certain conditions could be cured by a limited surgical resection instead of a major lung resection. The trial of JCOG 0201 made a lot of exploratory work [14,15]. Long-term survival of patients in the trial of JCOG 0201 revealed that radiologic criteria of a consolidation/tumor ratio (CTR) ≤0.25 and a size≤ 2.0 cm or CRT ≤0.50 and a size ≤ 3.0 cm were both able to define a homogeneous subgroup with an excellent prognosis. Whether these radiologic criteria can be validated, we need to wait for the results of some prospective clinical trials, such as JCOG1211 [16] and GALGB140503 (NCT00499330). In term of surgical extent, the extent of lymphadenectomy is also an important issue. In Zhang’s study, there was no lymph node metastasis in GGN patients with CTR≤0.50, regardless of the tumor size [17]. This raises the question as to whether lymph nodes dissection is necessary in patients whose CT features manifest as GGO prominently. In summary, the decision to treat GGNs must consider both the aggressiveness of nodules and competing risks. Although more and more evidence come from retrospective studies on sublobar resection, high-quality evidence is needed to support a paradigm shift in clinical practice. There will be an ever-increasing tumor localization technology development to facilitate care for surgical management of GGNs. GGN, Surgery, Management

Phase II trial of escalating doses of neoadjuvant atezolizumab for patients with non-metastatic urothelial carcinoma ineligible for cisplatin-based neoadjuvant chemotherapy.

442 Background: For patients (pts) with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy (cisplatin), the standard of care option is radical cystectomy (RC) alone. This prospective clinical trial investigated the safety and efficacy of escalating doses of atezolizumab (ATZ) as neoadjuvant therapy prior to RC in pts with non-metastatic urothelial cancer. Methods: This single-arm, single institution, phase II trial investigated the administration of one (n = 6), two (n = 5) or three (n = 9) cycles of ATZ (1200 mg IV given every 3 weeks) in pts with MIBC who are either ineligible for or refused cisplatin prior to RC. Key inclusion criteria were urothelial carcinoma of the bladder (T2-T4a,N0-1,M0) and inability to receive cisplatin-based treatment (eGFR &lt; 60 mL/min, G≥2 neuropathy/hearing loss, pt decision). Pts with high-risk disease ( &gt; pT2 or LN+) at the time of RC were eligible to receive adjuvant ATZ for up to 16 total cycles. Primary efficacy endpoint was pathologic complete response (pCR; pT0N0). Important secondary endpoints were safety of treatment, rates of pathologic downstaging and biomarker assessments in serial tissue samples. Pts were followed for up to 2 years following RC. Results: Among 20 pts with MIBC, median age was 69 (range 61-81) and 75% were male. Most commonly pts were cisplatin-ineligible due to low GFR (35%), hearing loss (25%) or neuropathy (10%); remainder refused cisplatin (30%). At trial enrollment, pT2, pT3, and pT4 was present in 80%, 15%, and 5% of pts and 10% had enlarged pelvic lymph nodes ( &gt; 10 mm) on scans. All pts completed intended treatment cycles and all had RC within the defined timeframe ( &gt; 3 weeks from last and &lt; 12 weeks from first treatment). pCR at RC was 10% (2/20 pts), and was observed in pts receiving 1 and 2 cycles of ATZ. Pathologic downstaging (≤pT1N0) was achieved in 25% (5/20 pts) and observed across all three dose levels. Adjuvant ATZ was given to 8 pts. TRAEs of any grade during perioperative period occurred in 75% and G3 TRAEs in 10% (diarrhea, fecal incontinence). There were no G4 or G5 events. Median follow-up from the time of RC was 21.4 months at the time of data cutoff in 10/2020. Among evaluable pts, 1-year RFS and OS were 71% and 94% while 2-year RFS and OS were 64% and 75%. Conclusions: This prospective trial supports the safety and efficacy of ATZ as neoadjuvant therapy in MIBC. Although pCR and rates of downstaging were lower than what was previously reported in comparable neoadjuvant trials of checkpoint inhibitors in MIBC, pCRs in this trial were seen even in pts receiving only 1-2 doses of ATZ. Many pts had a durable recurrence-free period and all 4 evaluable pts who had pathologic downstaging were alive and disease free at 2 years post RC. Translational and biomarker work from this study is also being pursued. Clinical trial information: NCT02451423.

Abstract PS6-52: Identification of Aurora kinase A as a biomarker for prognosis in obesity patients with early breast cancer

Abstract Background: Obesity is associated both with a higher risk of developing breast cancer, particularly in postmenopausal women, and with worse disease outcome for women of all ages. The molecular mechanisms that link obesity-breast cancer are complex and unclear. We hypothesized that overexpression of Aurora A was associated with poor survival in obesity breast cancer and related axis mechanism were involved.Methods: Fifty hundred and eighteen primary breast cancer specimens were collected from First Affiliated Hospital of China Medical University between January 2011 and November 2016. Our independent variable was BMI at baseline, categorized as overweight (BMI ≥ 25 kg/m2, as Obesity cohort), and normal (18.5 ≤ BMI &amp;lt; 25 kg/m2, as Non-obesity cohort). The Immunohistochemical (IHC) staining was performed with Aurora A, Survivin, MMP11, Cyclin B1 and Cathepsin L. Kaplan-Meier curve was used to analyze overall survival in our cohorts and TCGA-BRCA data (GSE3494). Log-rank test was used to calculate P value. PPI network analysis and MCODE model was used to analysis Aurora- altered signal pathway from GSE78958.Results: We validated Aurora A over expression using an independent cohort with a total of 517 breast carcinoma tissues (319 Non-Obesity patients and 198 Obesity Patients). The expression level of Aurora A-positive was significant higher in obesity breast carcinoma compared with non-obesity cancer carcinoma (χ2=9.79, P=0.002). In the immunohistochemistry assay, the results confirmed that the expression level of Aurora A-positive was significantly associated with hormone receptor status (68.4% vs 77.9%, P=0.015) and HER2 status (28.7% vs 17.9%, P=0.003). Aurora A-positive tumors had larger tumor size, though not statistically significant (78.1% vs. 71.1%, P=0.070). High Aurora A expression was remarkably and significantly associated with OS (8-year OS ratio: 69.5% vs 81.1%, OR=1.76, 95% CI:1.03~3.02, P=0.041) in Obesity Cohort. Interesting, higher expression of Aurora A was not associated with a shorter overall survival time among the Non-obesity breast cancer (8-year OS ratio:81.4% vs 85.8%, OR=1.40, 95% CI:0.79~2.45, P=0.229). As for RFS, the expression levels of Aurora A expression genes have no significance with RFS statistically in Non-Obesity patients. The in Aurora A low expression group was in high Aurora A expression in Non-Obesity Cohort ( 5-year RFS ratio:82.2% vs 83.2%, OR=1.29, 95% CI: 0.77~2.16, P=0.307). While 5-year RFS ratio in high Aurora A expression group of Aurora A were 71.3% was a little shorter than the 5-year RFS ratio in low Aurora A expression group (OR=1.58, 95% CI:0.96~2.57, P=0.072). Aurora A and Lymph node metastases were significantly poor prognostic factors for OS, and borderline significance was noted for high BMI. Kaplan-Meier survival analysis from TCGA database confirmed that the high Aurora A expression group had worse prognosis (HR=1.47, 95%CI:1.14-1.90, P=0.003). The KEGG pathway enrichment results were consistent with GO biological process term analysis, in which CCNB1 was enriched for upregulated Aurora A. In IHC correlation analyasis, Aurora A level on tumor cytoplasm had broad connections with Cyclin B1 (correlation coefficient = 0.227, P=0.001).Conclusions: Our finding demonstrate here for the first time that high expression of Aurora A was notably correlated with early recurrence and poor overall survival in obesity patients with early breast cancer. The Aurora A-Cyclin B1 axis could be a potential promising therapeutic target for cancer intervention and therapy. Keywords: Early breast cancer, obesity, Aurora A, Overall survival, Cyclin B1 Citation Format: Junnnan Xu, Tao Sun. Identification of Aurora kinase A as a biomarker for prognosis in obesity patients with early breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-52.

Systemic Immune-Inflammation Index Is a Prognostic Predictor in Patients with Intrahepatic Cholangiocarcinoma Undergoing Liver Transplantation.

Background It was reported that systemic immune inflammation index (SII) was related to poor prognosis in a variety of cancers. We aimed to investigate the ability of the prognostic predictors of SII in patients with intrahepatic cholangiocarcinoma (iCCA) undergoing liver transplantation (LT). Methods The 28 iCCA patients who underwent LT at our hospital between 2013 and 2018 were reviewed. Kaplan–Meier survival curves and Cox regression analyses were used to evaluate the prognostic significance of SII. Patients were divided into the high and low SII groups according to the cut-off value. Results The 1-, 3-, and 5-year OS rates were significantly lower in the high SII group (85.7%, 28.6%, and 21.4%, respectively) than in the low SII group (92.9%, 71.4%, and 57.2%, respectively; P = 0.009). The 1-, 3-, and 5-year RFS rates were, respectively, 57.1%, 32.7%, and 21.8% in the high SII group and 85.7%, 61.1%, and 61.1% in the low SII group (P = 0.021). SII ≥ 447.48 × 109/L (HR 0.273, 95% CI 0.082–0.908; P = 0.034) was an independent prognostic factor for OS. Conclusions Our results showed that SII can be used to predict the survival of patients with iCCA who undergo LT.

Evaluation of the significance of adjuvant chemotherapy in patients with stage ⅠA pancreatic ductal adenocarcinoma

BackgroundAlthough adjuvant chemotherapy is considered a standard treatment for resected pancreatic ductal adenocarcinoma (PDAC), its utility in stage ⅠA patients is unclear. We aimed to investigate the recurrence rate, surgical outcome, prognostic factors, effectiveness of adjuvant chemotherapy, and determination of groups in whom adjuvant chemotherapy is effective in patients with stage ⅠA PDAC. MethodsWe retrospectively analyzed 73 patients who underwent pancreatectomy and were pathologically diagnosed with stage ⅠA PDAC between 2000 and 2018. We evaluated the relation between clinicopathological factors, recurrence rates, and outcomes such as the recurrence-free and disease-specific survival rates (RFS and DSS, respectively). ResultsThe 5-year RFS and DSS rates were 52% and 58%, respectively. In multivariate analysis, a platelet-to-lymphocyte ratio (PLR) ≥ 170, prognostic nutrition index (PNI) < 47.5, and pathological grade 2 or 3 constituted risk factors for a shorter DSS (hazard ratios: 4.7, 4.6, and 4.1, respectively). Patients with 0–1 of these risk factors (low-risk group; n = 47) had significantly higher 5-year DSS rates than those with 2–3 risk factors (high-risk group; n = 26) (80% vs. 23%; P < 0.001). Patients in the low-risk group showed similar 5-year RFS rates regardless of whether they received or not adjuvant chemotherapy (75% vs 70%, respectively; P = 0.49). Contrarily, high-risk patients who underwent adjuvant chemotherapy had higher 5-year RFS rates than those who did not receive adjuvant chemotherapy (32% vs 0%; P = 0.045). ConclusionsIn stage IA PDAC, adjuvant chemotherapy seems to be effective only in a subgroup of high-risk patients.

Clinically Applicable Deep Learning for Predicting Prognosis of Hepatocellular Carcinoma Directly From Histology Images

Background: Prognosis classifier is necessary for patients with hepatocellular carcinoma (HCC). Here, we developed a clinically applicable automatic system to predict prognosis directly from HCC histology image. Methods: In total, 1480 participants were enrolled (ZJU1: n=202, ZJU2: n=179, ZJU3: n=738, TCGA: n=361). We trained 7 convolutional neural network (CNN) nets to select the top one in learning HCC image. Firstly, lesion detector and lesion decomposer net (classifying lesion into five different classes) were developed in ZJU1 and validated in ZJU2. Second, a prognosis classifier using the classes derived from decomposer net was constructed by LASSO Cox in ZJU3. Lastly, the two nets and the prognosis classifier were validated in external TCGA. Findings: Of the 7 CNNs, VGG19 achieved the top performer for detecting lesion with an accuracy of 96.4%, and classifying lesion with test accuracy of 99% in ZJU2. In ZJU3, two classes derived from the decomposer net were significantly associated with RFS (p<0.001): the neuron status of lymphocytes (HR: 0.69, 95%CI: 0.57-0.84) and stroma (HR: 1.39, 95%CI: 1.14–1.70). Lastly, the detector and decomposer nets were used to automatically detect lesion and extract prognosticators in TCGA. The category-free, event and non-event NRI of the supplementing stage_AJCC with lymphocytes and stroma neuron status for predicting 2-year RFS were 31.2%, 12.8% and 18.4%, respectively. Moreover, the prognostic classifier was confirmed in TCGA cohorts. Interpretation: The two clinically applicable models can precisely detect lesion and extract the prognostic factors from histology images and holds great potential for prognosis prediction and decision-making. Funding: National Major Scientific and Technological Special Project (No.2017ZX10203205), and National Natural Science Foundation of China (81802889). Declaration of Interest: The authors declare no any ethical/legal conflicts involved in the article. Ethical Approval: The study was supported by National Major Scientific and Technological Special Project (No.2017ZX10203205), Science Foundation of Zhejaing province (LQ18H160006). The results in this study are in part based upon data from the TCGA.

Intermediate dose cytarabine improves survival and relapse-free rate compared with standard-dose cytarabine as post-remission treatment for acute myeloid leukemia: A retrospection study.

The exact dose of cytarabine still remain controversial for the management of patients with acute myeloid leukemia (AML) after complete remission (CR), but recent studies favor lower doses. This study aimed to investigate the toxic effects of single-intermediate dose (ID) cytarabine in patients with AML after achieving CR, compared with standard-dose cytarabine.In this retrospective study, AML patients who achieved CR after consolidation therapy before enrollment between 07/2008 and 05/2019 were included. All patients were divided into single-ID cytarabine and standard-dose cytarabine. The Kaplan-Meier method was used to compare overall survival (OS) and relapse-free time (RFS). Cox regression models were used to assess factors independently associated with OS and RFS. The toxic side effects of hematology and non-hematology were observed.52 patients were enrolled. There were 33 in ID group, 19 in Standard dose group. The 3-year RFS rate (40.4% vs 22.2%, P = .031) was better in the ID group than in the standard-dose group, while the 3-year OS rate was not different between the 2 groups (50.2% vs 27.8%, P = .074). Treatment stratage of ID cytarabine chemotherapy significantly improve the prognosis of AML regardless of patient age, risk grade, WBC count. There were no significant differences between the 2 groups in grade 3 to 4 bone marrow suppression, gastrointestinal symptoms, blood transfusion, infections.Patients with AML receiving ID cytarabine showed better survival and similar toxicity profiles compared with patients who received standard-dose cytarabine.

Living Donor Liver Transplantation for Hepatocellular Carcinoma: Appraisal of the United Network for Organ Sharing Modified TNM Staging.

Background: In deceased donor liver transplantation (DDLT), transplant eligibility for T3–T4 HCC requires successful downstaging (DS). Living donor liver transplantation (LDLT) can be considered selectively in these patients without DS, but its role is not defined. The objective of the current study was to assess outcomes of LDLT for HCC based on UNOS staging with no prior DS.Materials and Methods: Patients who underwent LDLT for HCC (n = 262) were staged based on modified UNOS TNM staging. High-risk factors were identified and 5-year recurrence free survival was compared in patients with T2–T4 HCC.Results: Median follow-up was 30.2 (16.4–46.3) months. Recurrence rate in T1, T2, T3, T4a, and T4b HCC was 0, 10.1, 16.1, 5.9, and 37.5% (P = 0.02), respectively. On multivariate analysis, AFP > 600 ng/mL [HR:11.7, P < 0.001] and T4b HCC (macrovascular invasion) [HR = 5.6, P = 0.03] were predictors of recurrence. After exclusion of AFP > 600 ng/mL, 5-year RFS for T2, T3, and T4a HCC was 94, 86, and 92% (P = 0.3). Rate of microvascular invasion between T2 and T3 HCC was 24.3 vs. 53.6% (P = 0.005), and between T2 and T4a HCC was 24.3 vs. 36.7% (P = 0.2). Overall, 26 (19.4%) patients were overstaged and 23 (17.1%) were understaged on preoperative imaging. The 5-year RFS in patients with identical preoperative and histopathological staging was 94, 87, and 94% (P = 0.6).Conclusion: LDLT without prior DS leads to comparable survival for UNOS T2, T3, and T4a HCC as long as AFP is < 600 ng/mL.