Independent Prognostic Factor For Recurrence Research Articles

Abstract OT3-13-01: First in Human Study of AG01 a chimerized monoclonal antibody to Progranulin/Glycoprotein 88 (GP88)

Abstract Progranulin (PGRN/GP88) is an 88 kDa glycoprotein characterized by seven and a half double cysteine rich repeats in the granulin-epithelin family. PGRN/GP88 is an autocrine biological driver of tumorigenesis, survival & drug resistance in several cancers including breast, ovarian, multiple myeloma, prostate cancers, non-small cell lung carcinoma (NSCLCA) & digestive cancers. PGRN/GP88 tissue expression is an independent prognostic factor of recurrence while elevated serum PGRN/GP88 level in metastatic breast, lung & prostate cancer patients is associated with poor outcomes such as progression & shortened survival. An anti-human PGRN/GP88 monoclonal antibody inhibiting PGRN/GP88 action has been developed & expressed as recombinant antibody in CHO cells. Activities including pharmacology, manufacturing, formulation & GLP toxicology studies have been carried out. The IND application has been cleared by the Food and Drug Administration to proceed with the first-in-human AG01 clinical study in adult patients ((pts) with advanced solid tumors. We present an ongoing First in Human Phase 1A (dose escalation,1+(3+3) & IB (expansion cohorts) study of AG01 in pts advanced solid tumor malignancies (1A) with 4 expansion cohorts (1B) in pts with advanced Triple Negative Breast Cancer (TNBC), Hormone Resistant ER+/Her2- BC, advanced NSCLC & mesothelioma. Study Design: This is an open-label, dose escalation study of AG01 antibody administered intravenously (IV) over 90 minutes every 14 days +/- 1 day (1A), followed by 4 predefined expansion cohorts, which will be treated at the RP2D determined in the phase 1A of this study. In the 1A part, initially accelerated titration design will be utilized to guide dose progression & estimation of the maximum tolerated dose (MTD and/or maximum administered dose (MAD). In the 1A portion of the study pts with advanced relapsed/refractory solid tumor malignancies who failed 1 or more standard of care (SOC) therapies (tx) or for whom no SOC tx exists will be accrued. The primary objective of the 1A part is to determine the MTD and/or MAD of AG01. Secondary objectives are to determine the RP2D, assess the safety/tolerability, the pharmacokinetics (PKs) & immunogenicity of AG01 & the preliminary anti-tumor activity of AG01 via RECIST 1.1. The exploratory objectives are to determine PGRN/GP88 expression in tumor tissue and PGRN/GP88 blood levels using A&G’s ELISA test. In the 1B Cohort Expansion phase, 4 separate cohorts of pts with PGRN/GP88 tissue expression of 1+, 2+, 3+ by IHC will be enrolled. Cohort 1- TNBC: ER and/or PR < 1% by IHC, HER2 < 3+ by IHC and/or FISH negative, pts must have failed 1 or more SOC tx for metastatic BC. Cohort 2- Hormone-resistant BC: ER and/or PR >1%, HER2 < 3+ by IHC and/or FISH negative, failed 1 or more prior hormonal tx (HT) or HT/CD4/6 kinase inhibitor tx or other targeted tx. Cohort 3- NSCLCA: metastatic/recurrent NSCLCA failed 2 or more SOC tx. Cohort 4 -Mesothelioma- failed 1 or more SOC tx for metastatic/recurrent mesothelioma or not a candidate for SOC tx. The primary objective of 1B part is to evaluate the antitumor efficacy of AG01 by overall response rate (ORR) defined as completed response (CR), partial response (PR), stable disease >=24 weeks (SD) (CR+PR+ SD) based on RECIST v1.1 in the 4 cohorts with each cohort assessed separately for response. Secondary objectives are to evaluate progression free survival (PFS), duration of response (DOR) & overall survival (OS) of pts in cohorts 1-4, & to evaluate the ORR, DOR & PFS based on GP88 tissue expression, to further characterize the PKs & the safety/tolerability of AG01. Exploratory objectives in 1B part will assess AG01 effect on circulating PGRN/GP88 levels in plasma or other potential biomarkers in the 4 cohorts. The estimated study sample is approximately 77 pts; 17 pts for the 1A part & 60 pts for 1B part. The study is open to accrual at the UMGCCC. Supported by NCI grants R44CA224718 and R44CA162629 Citation Format: KATHERINE TKACZUK, Paula Rosenblatt, Ranee Mehra, Katherine Scilla, Nancy Tait, Binbin Yue, Ginette Serrero. First in Human Study of AG01 a chimerized monoclonal antibody to Progranulin/Glycoprotein 88 (GP88) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-13-01.

Prognostic value of tumor budding in patients with stage II and III colon cancer: A single-institution experience.

247 Background: Tumor budding has recently been recognized as one important prognostic factor for recurrence in patients with localized colon cancer. Nevertheless, not all guidelines consider tumor budding in the decision-making process for selecting patients for adjuvant chemotherapy. We aim to assess the prognostic value of tumor budding in a cohort of patients with stage II and III colon cancer. Methods: We included patients with pathologically confirmed diagnosis of stage II and III colon cancer at Hospital Universitario La Paz and tumor budding assessment available, from October 2016 to August 2021. Tumor budding was reported following the recommendations from the 2016 International Tumour Budding Consensus Conference. Results: A total of 390 patients were included. Patients were predominantly men (55%) and had a median age of 75 (35-95). Fifty percent of the patients were stage II and 50% were localized in the right colon. Tumor budding was reported as low, intermediate, and high in 186 (48%), 110 (28%), and 94 (24%) patients, respectively. After a median follow up of 18 months, 63 recurrences and 73 deaths were observed. Time to recurrence was significantly worse for patients with high tumor budding. At 24 months, 91%, 79%, and 67% of patients with low, intermediate and high budding were recurrence-free. Median TTR was not reached in any of the three cohort (P <0.001). Comparing high vs low or intermediate budding, the hazard ratio (HR) for recurrence was 0.13 [confidence interval (CI)95%: 0.05 to 0.32; P < 0.001]. We performed a univariate analysis with the most relevant clinic-pathological features. T4, N2, R1, bowel obstruction or perforation, positive resection margins (R1), lymphovascular or perineural invasion, and mismatch repair protein status were found to be statistically associated with TTR and entered the multivariate analysis. T4, N2, R1 and high tumor budding (HR: 0.48 [CI95%: 0.28 to 0.84], P = 0.011) were independent prognostic factors for recurrence at the multivariate analysis. Conclusions: High tumor budding is an adverse independent prognostic factor for recurrence in patients with stage II and III colon cancer and should be acknowledge when considering adjuvant chemotherapy.

Combining γ-GT, PIVKA-II, and AFP to predict long-term prognosis in patients with hepatocellular carcinoma after hepatectomy.

Hepatocellular carcinoma (HCC) is one of the top five contributors to the cancer burden in China, with a poor prognosis and heavy disability-adjusted life year burden. The criteria used for HCC prognosis are complicated and therefore restricted in routine clinical practice. Multiple factors influence HCC malignancy and progression. In this study, we retrospectively evaluated 173 patients with HCC who underwent curative resection for 9 years to evaluate the correlation of a combination of γ-glutamyl transferase (γ-GT), protein induced by vitamin K absence or antagonist-II (PIVKA-II), and α-fetoprotein (AFP) with the long-term survival of patients with HCC. Multivariate analysis revealed that the γ-GT level was an independent prognostic factor for recurrence. The prediction rate of early recurrence with γ-GT, PIVKA-II, and AFP levels individually was 63.5%, 79.4%, and 39.7%, respectively, whereas the prediction rate of early recurrence was 95.2% with the combination of γ-GT, PIVKA-II, and AFP levels as a composite indicator. Our long-term retrospective study revealed that γ-GT, PIVKA-II, and AFP can aid in predicting long-term prognosis of HCC recurrence. The combination of γ-GT, PIVKA-II, and AFP can further aid in identifying patients with early recurrence. Together, γ-GT, PIVKA-II, and AFP may a be used to develop a new prediction method to improve the prognosis of patients with HCC, and our results indicate the requirement of more active HCC treatment strategies.

Prognostic significance for recurrence of fibroblast growth factor receptor 2 in intrahepatic cholangiocarcinoma patients undergoing curative hepatic resection.

The fibroblast growth factor receptor 2 (FGFR2) fusion gene is frequently found as a genetic abnormality in the FGFR pathway in patients with intrahepatic cholangiocarcinoma (ICC). The FGFR fusion protein, produced from the FGFR fusion gene, is thought to cause tumor cell growth. To date, there have been few reports on the relationship between pathologic FGFR2 expression and prognosis in patients who have undergone hepatectomy for ICC, and on the relationship between FGFR2 and tumor-infiltrating lymphocytes (TILs). We enrolled 92 patients who underwent hepatectomy for ICC and performed immunohistochemical staining for FGFR2 and cluster of differentiation 8, and hematoxylin and eosin staining for evaluating TILSs. The relationships between the FGFR2 and clinicopathological characteristics and outcomes were analyzed, and patients were classified into positive (n=18) and negative (n=74) FGFR2 groups. The FGFR2-positive group contained more men (p<0.0001) and had lower serum albumin (p=0.0355) and higher carcinoembryonic antigen (p=0.0099). Furthermore, multivariable analyses revealed that the FGFR2-positive group had worse disease-free survival (DFS) (p=0.0002). Multivariate analysis showed that the independent prognostic factors for DFS were maximum tumor size (≥5cm) (p=0.0011), tumor localization (perihilar type) (p=0.0180), and FGFR2 positivity (p=0.0029). There was no significant difference in TILs count between the two groups. We showed that FGFR2 high expression was an independent prognostic factor for recurrence of resected ICC.

Recurrence and survival in endometrioid endometrial cancer - a population-based cohort study

ObjectiveThe aim of this study was to investigate recurrences and survival in endometrioid endometrial cancer (EC) in a complete population-based cohort. MethodsA regional population-based study including women with endometrioid EC, identified by the Swedish Quality Registry for Gynecological Cancer (SQRGC), where primary surgery was performed between 2010 and 2017. Patient characteristics and outcomes, including recurrences, were retrieved from the SQRGC and completed by records reviews. Overall (OS), net (NS) and disease-free survival (DFS) were calculated using the Kaplan-Meier method. The Fine and Gray proportional subdistribution hazards' regression model was used for risk factors for recurrence. ResultsThere were 1630 women included in the study, whereof 136 (8.3%) had a recurrence with a median time to recurrence of 22.5 months (range 3.2–59.3). One site of recurrence was diagnosed in 69.1%, while 27.2% being only vaginal. The total 5-year OS was 88.0%(95% CI:86.4–89.7) and the 5-year NS 98.6%(95% CI:96.5–100.7). If no recurrence occurred, the OS was 91.9%(95% CI:90.4–93.3) and NS 102.8%(95% CI:100.9–104.8). For only vaginal recurrence, 5-year OS was 77.0%(95% CI:64.0–92.6) compared to 36.1%(95% CI:27.5–47.3) for all other recurrences. The total 5-year DFS was 83.9%(95% CI:82.0–85.7). In the multivariable analysis, age, FIGO stage and primary treatment were found independent factors for recurrence with a HR of 1.29(95% CI:1.11–1.51;p = 0.001) for age, 2.78(95% CI:1.80–4.29;p < 0.001) for FIGO stage III and 1.84(95% CI:1.22–2.78;p 0.004) for adjuvant treatment. ConclusionThere is an overall low recurrence rate for endometrioid ECs with a minor portion being only vaginal, associated with a favorable survival in contrast to other recurrences with a poor prognosis. Age, FIGO stage III and adjuvant treatment were found independent prognostic factors for recurrence.

GAB1 as a Marker of Recurrence in Anterior Skull Base Meningioma.

About one-third of anterior skull base meningiomas show Hedgehog pathway activation. We have recently identified GAB1 as a surrogate marker for Hedgehog pathway-activated meningiomas. To determine the reproducibility and prognostic value of GAB1 marker in anterior skull base meningiomas. A retrospective bicentric cohort of anterior skull base meningiomas, operated from 2005 to 2015, was constituted. GAB1 immunohistochemistry was performed in 2 centers, and the GAB1 score was assessed. Clinical and pathological data were reviewed to determine the prognostic value of the GAB1 score, along with classical factors of recurrence. One hundred forty-eight patients were included (median follow-up of 72 ± 46 months). 78% of patients had gross total resection. Eighty-four percentage of patients harbored grade 1 meningiomas. GAB1 immunohistochemistry was positive (ie, GAB1 staining score was >250) in 53 cases (35%). GAB1-positive cases were mainly at olfactory groove, of meningothelial grade 1 subtype, and showed greater recurrence (36% vs 14%, P = .002), greater requirement for multiple surgeries (17% vs 4.2%, P = .014), and more likely evolution toward diffuse skull base infiltration (15% vs 3%, P = .0017). By multivariable Cox regression analysis, incomplete surgical resection (hazard ratios [HR] = 8.3, 95% IC [3.7-18.2], P < .001), male sex (HR = 5.4, 95% IC [2.2-13.5], P < .001), GAB1 positivity (HR = 3.2, 95% CI [1.5-6.9], P = .004), and Ki67 index >4 (HR = 2.2, 95% IC [1.2-4.6], P = .035) were independent prognostic factors for recurrence. GAB1 marker is an independent prognostic factor for anterior skull base meningioma and could be useful for both prognostic evaluation and identification of Hedgehog-activated meningiomas.

CD155 immunohistochemical expression in upper tract urothelial carcinoma predicts poor prognosis.

A novel immune checkpoint, CD155/T-cell immunoreceptor with Ig and ITIM domains, has been recognized as a new therapeutic target in addition to conventional immune checkpoints, such as anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-L1), for urothelial carcinoma (UC). Fibroblast growth factor receptor (FGFR) is considered another new therapeutic target for UC. As FGFR3-mutant UC may be associated with decreased T-cell infiltration, FGFR3 inhibition may facilitate lymphocyte invasion into the tumor microenvironment. Although a combined effect of immune checkpoint inhibitors and FGFR inhibition is expected, the combined expression profiles of CD155, PD-L1 and FGFR3 have not been evaluated in upper tract UC (UTUC). The present study aimed to investigate the association between CD155 expression and clinicopathological factors in 208 patients with UTUC undergoing radical nephroureterectomy. Furthermore, the expression profiles of CD155, PD-L1 and FGFR3 were compared. Immunohistochemical analysis was performed using tissue microarray specimens and survival analyses were performed using the Kaplan-Meier method and the Cox proportional hazards model. High immunohistochemical expression of CD155 was observed in 177 patients (85.1%) and it was associated with advanced pathological stage and lymphovascular invasion. The survival rate was lower among patients with tumors exhibiting high CD155 expression than among those with tumors with low CD155 expression. In addition, multivariate survival analysis revealed that high CD155 expression was an independent prognostic factor for recurrence (hazard ratio=7.32, 95% CI=1.01-53.35, P=0.049). FGFR3 and immune checkpoint signaling molecules, such as CD155 and PD-L1, had a weak negative correlation. The present results indicated that the expression of CD155 is a useful marker for predicting the recurrence of UTUC. In addition, the immunohistochemical expression profiles of CD155, PD-L1 and FGFR3 may further the understanding of the role of FGFR-targeted therapies in immunotherapy for UTUC.

Nomograms Combining Clinical and Imaging Parameters to Predict Recurrence and Disease-free Survival After Concurrent Chemoradiotherapy in Patients With Locally Advanced Cervical Cancer

To investigate the value of nomograms based on clinical prognostic factors (CPF), intravoxel incoherent motion diffusion weighted imaging (IVIM-DWI) and MRI-derived radiomics in predicting recurrence and disease-free survival (DFS) after concurrent chemoradiotherapy (CCRT) for locally advanced cervical cancer (LACC). Retrospective analysis of data from 115 patients with ⅠB-ⅣA cervical cancer who underwent CCRT and had been followed up consistently. All patients were randomized 2:1 into training and validation groups. Pre-treatment IVIM-DWI parameters (ADC-value, D-value, D*-value and f-value) and pre- and post-treatment three-dimensional radiomics parameters (from axial T2WI) of primary lesions were measured. The LASSO algorithm and Logistic regression analysis were used to filter texture features and calculate radiomics score (Rad-score). Multivariate Logistic and Cox regression analysis was used to construct nomograms to predict recurrence and DFS for patients with LACC after CCRT respectively, with internal and external validation. External beam radiotherapy dose, f-value, pre-treatment and post-treatment Rad-score were independent prognostic factors for recurrence and DFS in patients with cervical cancer, forming Model1 and Model2, with OR values of 0.480, 1.318, 3.071, 3.200 and HR values of 0.322, 3.372, 5.138, 7.204. The area under the curve (AUC) of Model1 for predicting recurrence of cervical cancer was 0.977, with internal and external validation C-indexes of 0.977 and 0.962. The AUC for Model2 predicting disease-free survival (DFS) at 1, 3, and 5 years was 0.895, 0.888 and 0.916 respectively, with internal and external C-indexes of 0.860 and 0.892. The decision curves analysis and clinical impact curves further indicate the high predictive efficiency and stability of nomograms. The nomograms based on clinical, IVIM-DWI and radiomics parameters have high clinical value in predicting recurrence and DFS of patients with LACC after CCRT and can provide a reference for prognostic assessment and individualized treatment of cervical cancer patients.

Radiological Features of Microvascular Invasion of Hepatocellular Carcinoma in Patients with Non-Alcoholic Fatty Liver Disease

Background: The aim of the present study was to evaluate the presence and the prognostic value of the radiological signs of microvascular invasion (MVI) of hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD). Methods: Between January 2015 and December 2017, all patients (91 patients) with de novo HCC or HCC recurrence occurring at least 2 years after the last treatment in NAFLD (36 patients) or with hepatitis C virus (HCV) liver disease (55 patients) were included. Each HCC was treated with liver resection and transplantation to obtain the anatomopathological confirmation of MVI. All patients had at least one available computed tomography (CT) scan or magnetic resonance imaging (MRI) performed no more than one month prior to the treatment. The clinical data of each patient, tumor burden (diameter, margins, two-trait predictor of venous invasion (TTPVI), and peritumoral enhancement), the recurrence rate (RR) after a 1-year follow-up, and the time to recurrence (TTR) were collected. Results: The NAFLD–HCC nodules were larger as compared to HCV–HCC (51 mm vs. 36 mm, p = 0.004) and showed a higher prevalence of TTPVI (38.9 vs. 20.0%, p = 0.058). At multivariate analysis, nodule diameter &gt;50 mm was found to be the only independent prognostic factor of TTPVI (hazard ratio: 21.3, 95% confidence interval: 4.2–107.7, p &lt; 0.001), and the presence of TTPVI was confirmed to be the only independent prognostic factors of recurrence (hazard ratio: 2.349, 95% confidence interval: 1.369–4.032, p = 0.002). No correlations were found between TTR and irregular tumor margins or peritumoral enhancement. Conclusion: The NAFLD–HCC patients had larger tumors at diagnosis and showed a more frequent presence of radiological signs of MVI as compared to the HCV–HCC patients. The MVI was related to a more rapid recurrence after curative treatments, demonstrating the prognostic value of this radiological diagnosis.

Epigenetic mismatch repair deficiency in endometrioid endometrial cancer correlates with poor outcome (385)

Epigenetic mismatch repair deficiency in endometrioid endometrial cancer correlates with poor outcome (385)

Comparison of clinical results between high grade patterns in stage I lung adenocarcinoma.

BackgroundThe histological subtype has been introduced in invasive lung adenocarcinoma. The predominant micropapillary and solid subtypes are categorized as high‐grade patterns and provide a worse prognosis. However, the prognostic analysis of high‐grade patterns has not previously been fully investigated. Thus, this study aimed to investigate the prognostic role of high‐grade patterns in pathological stage I lung adenocarcinoma.MethodsPatients with stage I lung adenocarcinoma and micropapillary or solid components were reviewed. Clinicopathological features and clinical course were compared in these subtypes, and prognostic factors were analyzed in high‐grade patterns.ResultsThe patients were classified into five groups based on the presence of micropapillary or solid subtypes, namely, micropapillary predominant, solid predominant, both nonpredominant subtypes, only minor micropapillary subtype, and only minor solid subtype present. Disease‐free interval was significantly different, and the micropapillary predominant group showed worse disease‐free interval (p = 0.001). Contrastingly, the solid predominant group showed significantly worse overall survival among high‐grade patterns (p = 0.035). The multivariate analysis revealed an association between smoking, micropapillary predominant, blood vessel invasion, and visceral pleural invasion with recurrence and more association between solid predominant and visceral pleural invasion with overall survival.ConclusionsClinical results were different in stage I high‐grade adenocarcinoma. The predominant micropapillary subtype is the independent prognostic factor for recurrence. However, the solid subtype is the significant factor for overall survival. Furthermore, the predominant subtype is the most valuable and independent prognostic factor for predicting recurrence or survival.

MEDB-58. Risk factors and risk prediction models for medulloblastoma recurrence

BACKGROUND: There is a clear need for systematic appraisal of models/factors predicting medulloblastoma recurrence because clinical decisions about adjuvant treatment are taken on the basis of such variables. METHODS： A total of 273 patients diagnosed with medulloblastoma were retrospectively analyzed. The pre-rediotherapy neutrophile-lymphocyte ratio (NLR) was calculated, and other clinical characteristics were collected such as genetic type , whether with dissemination, degree with excision. The Kaplan-Meier method was used for survival analysis. Cox regression models was used to identify independent prognostic factors. R software was used to develop a nomogram with all the independent prognostic factors included. The prognostic predictive ability of the nomogram was evaluated by Concordance-index (C-index), area under the curve (AUC), and calibration curve. RESULTS: The median median progression-free survival time was 63.8 months in overall cohort. Univariate and multivariate cox hazards regression analysis identified independent prognostic factors associated with the PFS of patients with medulloblastoma to include age, residual tumor volume ＞1.5cm3 after excision, NLR ＞4.5, whether with dissemination before RT, and whether the genetic type is group 3,which were integrated to establish a nomogram. The C-indexes of nomogram were 0.696 and 0.676 in the training and validation cohort, respectively. The AUC of predicting 3-years PFS showed satisfactory accuracy as well (Training cohort: AUC=0.696; Validation cohort: AUC=0.676). The calibration curve showed agreement between the ideal and predicted values. Kaplan-Meier curves based on the PFS showed significant differences between nomogram predictive low-, and high groups (P < 0.001). CONCLUSIONS: We found that pre-treatment NLR was an independent prognostic factor for recurrence or metastasis of medulloblastoma after treatment. In combination with NRL and clinical factors, nomogram has a good prediction of PFS in patients with medulloblastoma after radiotherapy. It has the potential to facilitate more precise risk stratification to guide personalized treatment of medulloblastoma.

Lack of Prognostic Value of Pretreatment Neutrophil-to-Lymphocyte Ratio in Early Breast Cancer

Background: Breast cancer is a highly heterogeneous disease with large differences in the risk of recurrence. An elevated neutrophil-to-lymphocyte ratio (NLR) is correlated with a poor prognosis in a variety of tumors, and although it is still controversial in breast cancer, there are multiple studies, including meta-analysis, suggesting this. The purpose of this study was to analyze the prognostic value of preoperative NLR in an Argentine population of patients with nonmetastatic breast cancer, not exposed to neoadjuvant treatment. Methods: Retrospective multicenter cohort study that includes patients over 18 years of age from three centers in the city and province of Buenos Aires who have had surgery for early breast cancer between January 1, 1999, and December 31, 2014. Based on the previous literature, a cutoff value of 2.0 was defined. Results: A total of 791 patients were eligible for the analysis. Median age was 55 years (IQR 45–65). Median NLR was 1.92 (IQR 1.50–2.56). The distribution of groups according to the 8th edition of the AJCC was 54.1% for stage I, 35.6% stage II, and 10.4% stage III. Among the different tumor phenotypes, 79.0% were HR+/HER2−, 11.4% were HR+ or−/HER2+, and 9.2% were HR−/HER2−. With a median follow-up of 5.3 years, 112 patients (14.2%) had disease recurrence. Stage III patients had a higher NLR than stage I and stage II patients (p = 0.002). The rest of the clinical and pathological characteristics did not show differences in the groups according to NLR. There were no differences in relapse-free survival according to the NLR (p = 0.37), and itdid not change after adjusting for other prognostic variables. Conclusion: We consider it is important to determine the efficacy of prognostic markers that are easily accessible and of simple, systematic application. However, NLR does not appear to be an independent prognostic factor for recurrence in our population. In this sense, we consider it is important to publish negative results in order to avoid publication bias.

Baseline GP2 immune response as an independent prognostic factor in a phase IIb study evaluating HER2/neu peptide GP2 (GLSI-100) versus. GM-CSF alone after adjuvant trastuzumab in HER2-positive women with breast cancer.

e12519 Background: Delayed type hypersensitivity (DTH) skin tests to GP2 were conducted in the randomized, active-controlled, single-blinded, multicenter Phase IIb trial investigating GLSI-100 (GP2+GM-CSF) administered in the adjuvant setting to node-positive and high-risk node-negative breast cancer patients with tumors expressing HER2. Previously it has been reported that subjects with baseline response to GP2 by DTH were more likely to experience a recurrence sooner than those without a positive baseline response. It was of interest to determine if this response was independent of other known prognostic factors. Methods: Patients were randomized and received GLSI-100 (500 mcg GP2: 125 mcg GM-CSF) or control (GM-CSF only) via 6 intradermal injections every 3-4 weeks as part of the Primary Immunization Series (PIS) for 6 months and 4 booster injections every 6 months thereafter. GP2 DTH skin tests were placed at baseline and after the 6th dose. After 48-72 hours, the largest perpendicular diameters of induration were measured and the orthogonal mean was calculated. Induration of over 5mm was considered a positive response. The relationship between prognostic factors such as demographic and disease characteristics and the baseline DTH response were investigated by logistic regression. Results: The study enrolled 180 patients who were HER2 3+ positive and low HER2 expressors (1-2+). After 5 years of follow-up, the Kaplan-Meier estimated 5-year DFS rate in the 46 HER2 3+ patients treated with GLSI-100, if completing the PIS, was 100% versus 89.4% (95% CI:76.2, 95.5%) in the 50 patients treated with GM-CSF (p = 0.0338). Just under 23% of subjects experienced an immune response to GP2 by DTH at baseline. The incidence was similar in patients who were HER2/neu positive and those considered low expressors and was equally distributed across GLSI-100 and placebo-treated subjects. Known prognostic factors such as hormone receptor status, stage at presentation, node status, etc. were evenly distributed across subjects that experienced a baseline DTH response to GP2 and those who did not. Each prognostic factor was investigated in a logistic model to determine if it predicted baseline DTH immune status. The prognostic factors did not predict baseline DTH immune response in the logistic models. There appears to be no correlation between baseline immune response to GP2 and known prognostic factors. Conclusions: Baseline GP2 immune response as measured by the delayed-type hypersensitivity test may be an independent prognostic factor for recurrence. Knowledge of this GP2 immune response may identify a patient with increased risk of rapid recurrence. Clinical trial information: 00524277.

Are Survival Outcomes Different for Young and Old Patients with Oral and Oropharyngeal Squamous Cell Carcinoma? A Systematic Review and Meta-Analysis.

Simple SummaryOral cancer was considered a disease of old age. However, there has been a recent surge in the incidence of oral cancer in young individuals. Age dependence on survival outcomes such as overall survival, disease-free survival, recurrence, distant metastasis and second primary in surgically treated oral cancer has been investigated several times and the results differ. This systematic review and meta-analysis has been conducted to address this concern. The results of the present research may facilitate age-dependent prognosis stratification, which would assist in treatment planning in oral cancer patients.This systematic review and meta-analysis aims to address whether age can be a determinant of overall survival (OS), disease-free survival (DFS), recurrence, distant metastasis (DM) and second primary (SP) in surgically treated oral and oropharyngeal squamous cell carcinoma (OOPSCC). A total of 4981 cases and 44254 controls from 25 comparative observational studies were included in the analysis. A significantly better OS (matched subgroup analysis: OR 1.64; 95% CI 1.31–2.04, overall analysis: OR 1.48; 95% CI 1.09–2.01) was observed in young patients compared to older adults, with heterogeneity ranging from moderate to severe. Worse DFS (unmatched subgroup analysis OR 0.43; 95% CI 0.27–0.68) was observed in young patients compared to older adults with minimal to moderate heterogeneity. The frequency of recurrence (OR 1.49; 95% CI 1.10–2.02) and DM (OR 1.83; 95% CI 1.10–3.03) was significantly higher in the young patients, as found in unmatched and matched subgroup analysis, with the least heterogeneities. Young age can be considered as an independent prognostic factor for recurrence and distant metastases in OOP-SCC. Larger and methodologically robust observational studies with longer follow-up are needed to establish the definitive role of age as an independent prognostic factor on OS and DFS in OOPSCC.

Recurrence of initially localized appendiceal mucinous neoplasms after radical resection: survey analysis and literature review.

Appendiceal mucinous neoplasm (AMN) is a rare tumor that may be successfully treated by appendectomy. However, some patients develop recurrence as pseudomyxoma peritonei. The present study investigated the recurrence rate after radial resection for AMN. A survey on AMN was sent to 171 institutions, and 286 cases were analyzed. The risk of recurrence was assessed according to clinical parameters. Recurrence rates were compared with data from the literature. There were 250 cases in the low-grade group and 36 in the high-grade group, with perforation being detected in 50 cases. After a median follow-up period of 30months, recurrence was detected in 17 cases, including 12 with high-grade histology and 10 with perforation. Two patients with low-grade histology and no perforation developed recurrence. Independent prognostic factors for recurrence were high-grade histology (p = 0.0001, RR = 8.56) and perforation (p = 0.0168, RR = 3.45). Four groups were classified by histology and perforation: group A: high-grade, perforation ( +), group B: high-grade, perforation (-), group C: low-grade, perforation ( +), group D: low-grade, perforation (-). Five-year recurrence rates in groups A, B, C, and D were 46.7, 25.9, 13.3, and 1.5%, respectively. All cases of recurrence were detected within 3years, except for two in group B. Recurrence in cases with low-grade histology and no perforation was rare; however, a postoperative survey for at least 3years is required. In contrast, cases with high-grade histology or perforation need to be monitored using a similar approach to colon cancer. Prophylactic CRS + HIPEC may be considered.

Male Gender Is Associated with Lymph Node Metastasis but Not with Recurrence in Papillary Thyroid Carcinoma.

Background The incidence of papillary thyroid carcinoma (PTC) is higher in females than in males, but it remains unclear whether gender is associated with the aggressiveness of this disease. We aimed to clarify the influence of gender on the risk of developing lymph node metastasis (LNM) and on the prognosis of PTC patients. Study Design. Retrospective cohort study. Setting. Academic tertiary care center. Methods Clinical data of PTC patients who were admitted to the Department of Endocrine and Breast Surgery, the First Affiliated Hospital of Chongqing Medical University, between January 2013 and December 2018 were retrospectively reviewed. The differences in clinical features and outcomes between female and male patients were compared. Univariate and multivariate logistic regression analyses were conducted to assess the impact of gender on LNM. Kaplan–Meier curves were used to estimate recurrence-free survival (RFS). Results A total of consecutive 2536 patients were enrolled in this study. Males accounted for 25.2% (639 cases) of all patients. Central lymph node metastasis (CLNM) and lateral lymph node metastasis (LLNM) rates were 52.5% (1346/2536) and 22.0% (558/2536), respectively. Male presented with higher LNM rates than female patients (65.7% vs. 51.2%; P < 0.001). Male gender was independently associated with LNM (OR = 1.93, 95% CI: 1.59–2.35; P < 0.001). After full adjustment, male gender still remained significantly associated with CLNM in all subgroups; however, subgroup analyses indicated no significant relationship between gender and LLNM. In addition, after a median follow-up period of 30 months, no significant difference was found in RFS between female and male patients (P=0.15). Conclusions This observational cohort study revealed that male gender was significantly associated with CLNM; whereas, LLNM was not different between female and male PTC patients in southwestern China. Moreover, currently, there is insufficient evidence to justify that male gender is an independent prognostic factor for recurrence.

Surgical skill and oncological outcome of laparoscopic radical hysterectomy: JGOG1081s-A1, an ancillary analysis of the Japanese Gynecologic Oncology Group Study JGOG1081

ObjectivesWe investigated whether surgical skill and procedure were related to oncological outcomes in cervical cancer patients who underwent Laparoscopic Radical Hysterectomy (LRH). MethodsWe previously assessed data of LRH from 251 patients with FIGO stage (2009) IA2, IB1and IIA1 cervical cancer collected for JGOG 1081s study. 1) The JGOG 1081s cohort study was re-examined to refine the surgical details and extend the follow-up period as chart review. 2) Unedited videos for recurrent cases and matched non-recurrent control cases were newly compared by experts for various surgical skills and surgical procedures using the modified Objective Structured Assessment of Technical Skills (OSATS) tool, without awareness of the recurrence status as video review. ResultsAfter a median follow-up of 46 months, tumors had recurred in 31 of the 251 patients. The five-year Recurrence-Free Survival rate was 86.9% (81.8–90.6) and five-year Overall Survival rate was 93.7% (87.5–96.8). Multivariate analysis from chart reviews found that an experience with LRH of less than 20 cases per institution was an independent prognostic factor for recurrence (Hazard Ratio (HR) 2.49, 95%CI 1.12–5.53, p = 0.025). For the surgical video review, we compared 23 videos of recurrent cases with 23 background-matched non-recurrent controls. Lower modified OSATS scores from the video review were consistently trended to have a higher risk of recurrence. ConclusionsOur new study has found that LRH surgical experience and skill trended to have better oncological outcomes.

A nomogram for decision-making assistance on surgical treatment of chronic osteomyelitis in long bones: Establishment and validation based on a retrospective multicenter cohort

BackgroundChronic osteomyelitis remains a major challenge for orthopedic surgeons due to its high recurrence rate. Surgeons currently have few tools to estimate the likelihood of individual recurrence. We here aimed to develop a nomogram to better estimate individual recurrence rate after surgical treatment of chronic osteomyelitis in long bones. MethodsWe first retrospectively identified patients as training cohort who had received surgical treatment of chronic osteomyelitis in long bones between January 2010 and January 2016 from four hospitals. Patient demographic, microbiological, clinical, and therapeutic variables were collected and analyzed. Univariate and multivariate analyses were performed successively to identify independently predictive factors for recurrence. To reduce overfitting, the Bayesian information criterion was used to reduce variables in the original model. Nomograms were created with the reduced model after model selection. The nomogram was then internally validated with bootstrap resampling. We then further validated the performance of the established nomogram in validation cohort (data from two distinct institutions). ResultsRecurrence was found in 136 of 655 (20.8%) and 52 of 201 patients (25.9%) in training and validation cohorts respectively. We included six independent prognostic factors for recurrence in our prediction model: number of previous recurrences, epiphysial involvement, preoperative serum albumin level, axial length of the infectious lesion, lesion-removal method, and application of a muscular flap. After incorporating these six factors, the nomogram achieved good discrimination, with concordance indexes of 0.82 (95% CI, 0.79–0.85) and 0.80 (95% CI, 0.78–0.83) in predicting recurrence in the training and validation cohorts, respectively. Calibration curves were well fitted for both training and validation cohorts. ConclusionsOur nomogram achieved good preoperative prediction of recurrence in chronic osteomyelitis of long bones. Using this nomogram, the recurrence risk can be confidently predicted for each patient and treatment plan. After considering and discussing the functional prognosis with patients, physicians can establish a rational therapeutic plan. Level of evidencePrognostic, Level III.

Abstract P5-17-10: Anti-progranulin (GP88) antibody AG01 inhibitory effect on the growth of triple negative breast cancer cells

Abstract Background: Triple negative breast cancer (TNBC) is characterized by invasiveness and short survival. Identifying novel TNBC targeted therapies to potentiate standard of care (SOC) therapy, is an unmet need. Progranulin (PGRN/GP88) is a biological driver of tumorigenesis, survival, and drug resistance in several cancers including breast cancer (BC). PGRN/GP88 tissue expression is an independent prognostic factor of recurrence while elevated serum PGRN/GP88 level is associated with poor outcomes such as progression of disease and shortened survival. Since PGRN/GP88 expression is elevated in 30% TNBC, we investigated the effect of inhibiting PGRN/GP88 effect on the proliferation and tumor growth of triple negative breast cancer cells. Methods: For this purpose, we have developed a neutralizing anti-human PGRN/GP88 monoclonal antibody AG01 and examined its effect on the proliferation, migration, signaling pathway activation and biomarker expression of two TNBC cell lines MDA-MB-231 and HS578-T expressing PGRN/GP88, both in vitro and in vivo. Results: The inhibition of PGRN/GP88 action by AG01 treatment reduced proliferation and migration in a dose-and time-dependent fashion in MDA-MB-231 and HS578-T cells. Western blot analysis showed decreased expression of phosphorylated protein kinases p-Src, p-AKT and p-ERK involved in proliferation and survival upon AG01 treatment for both cell lines. Transwell assay showed that AG01 treatment inhibited migration and invasion in a dose-dependent fashion. Microarray analysis of several oncoproteins in cells treated with AG01 or control antibody demonstrated the inhibition of the expression of several markers of migration and angiogenesis. In vivo xenograft studies with MDA-MB-231 cells injected in athymic nude mice showed that AG01 treatment inhibited tumor growth as well as Ki67 expression, mitotic index and microvessel counts when compared to antibody control treated mice. In vivo dose response of AG01 in MDA-MB-231 tumor bearing mice will be provided. Conclusion: TNBC is a disease with poor prognosis in need of novel targeted therapeutic solutions. PGRN/GP88 represents a therapeutic target for TNBC with two companion diagnostics (tissue test and ELISA to measure GP88 circulating levels). Blocking PGRN/GP88 with AG01 antibody treatment will provide novel targeted therapeutic option for TNBC which could address the issue of toxicity, and unresponsiveness associated with SOC. This work is supported by a grant CA 224718 from the National Cancer Institute to GS. Citation Format: Ginette Serrero, Rupa Guha, Jianping Dong, Binbin Yue. Anti-progranulin (GP88) antibody AG01 inhibitory effect on the growth of triple negative breast cancer cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-17-10.