Exploiting frequent and specific expression of PRL3 in pediatric solid tumors for first-in-child use of PRL3-zumab humanized antibody.

Phosphatase of regenerating liver 3 (PRL3) is a specific tumor antigen overexpressed in a broad range of adult cancer types. However, its physiological expression in pediatric embryonal and mesenchymal tumors and its association with clinical outcomes in children is unknown. We sought to profile the expression of PRL3 in pediatric tumors in relation to survival outcomes, expression of angiogenesis markers, and G-protein-coupled receptor (GPCR)-mitogen-activated protein kinase (MAPK) signaling targets. PRL3-zumab, a first-in-class humanized antibody, was administered in a dose escalation schedule in a first-in-child clinical trial to study toxicity, pharmacokinetics, and clinical outcomes. Among 64 pediatric tumors, PRL3 was most frequently expressed in neuroblastoma (100%), rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcomas (71%), and renal sarcomas (60%) but absent in paired normal tissues. PRL3 was expressed in 75% of relapsed tumors and associated with shorter median event-free survival. Microarray profiling of PRL3-positive tumors showed elevation of angiogenin, TIMP1 and TIMP2, and GPCR-MAPK signaling proteins that commonly interacted with PRL3. The first use of PRL3-zumab in a pediatric patient saw no adverse events. A 28.6% reduction in maximum target lesion diameter was achieved when PRL3-zumab was administered concurrently with hypofractionated radiation. These findings support wider exploration of PRL3 expression in embryonal and mesenchymal tumors and further clinical application of PRL3-zumab in pediatric patients.

Airway interventions for tracheobronchial involvement in esophageal carcinoma: a retrospective cohort outcome study and algorithmic approach.

Background: In advanced esophageal carcinoma (EC), there is limited data on risk factors predicting tracheobronchoesophageal fistula (TEF) formation and survival among patients who required airway interventions. Methods: A retrospective analysis of consecutive patients with EC, who had airway involvement requiring intervention, was conducted from 1998 to 2018. Demographics, clinical progress, disease stage, treatment and survival outcomes were recorded. Patients were followed up till death or until completion of the study. Survival was estimated with the Kaplan-Meier method and curves compared by log-rank test. Multivariate analyses of risk factors were performed using Cox proportional hazard regression. Results: A total of 122 patients were included. The median (IQR) survival from time of airway intervention was 3.30 (1.57-6.88) months, while the median (IQR) survival from time of histological diagnosis was 8.90 (4.91-14.45) months. Tumour location within 20 mm of the carina, prior radiotherapy and/or esophageal stenting were significantly associated with formation of TEF. Mid EC [adjusted hazard ratio (HR) 1.9; 95% confidence interval (CI): 1.1-3.2] or presence of TEF (adjusted HR 1.8; 95% CI: 1.0-3.2) were associated with lower survival. Patients receiving chemotherapy (adjusted HR 0.46; 95% CI: 0.25-0.84), or esophageal stenting whether before or after airway intervention (adjusted HR 0.32; 95% CI: 0.15-0.68 and adjusted HR 0.51; 95% CI: 0.29-0.90) were associated with increased survival. Conclusions: Factors associated with TEF formation include airway location, radiotherapy and prior esophageal stenting, and the development of TEF was associated with poorer survival. An algorithmic approach towards tracheobronchial involvement in EC is proposed based on these findings and a review of the literature.

"3G" Trial: An RNA Editing Signature to Guide Gastric Cancer Chemotherapy.

Gastric cancer cases are often diagnosed at an advanced stage with poor prognosis. Platinum-based chemotherapy has been internationally accepted as first-line therapy for inoperable or metastatic gastric cancer. To achieve greater benefits, selection of patients eligible for this treatment is critical. Although gene expression profiling has been widely used as a genomic classifier to identify molecular subtypes of gastric cancer and to stratify patients for different chemotherapy regimens, its prediction accuracy can be improved. Adenosine-to-inosine (A-to-I) RNA editing has emerged as a new player contributing to gastric cancer development and progression, offering potential clinical utility for diagnosis and treatment. Using a systematic computational approach followed by both in vitro validations and in silico validations in The Cancer Genome Atlas (TCGA), we conducted a transcriptome-wide RNA editing analysis of a cohort of 104 patients with advanced gastric cancer and identified an RNA editing (GCRE) signature to guide gastric cancer chemotherapy. RNA editing events stood as a prognostic and predictive biomarker in advanced gastric cancer. A GCRE score based on the GCRE signature consisted of 50 editing sites associated with 29 genes, predicting response to chemotherapy with a high accuracy (84%). Of note, patients demonstrating higher editing levels of this panel of sites presented a better overall response. Consistently, gastric cancer cell lines with higher editing levels showed higher chemosensitivity. Applying the GCRE score on TCGA dataset confirmed that responders had significantly higher levels of editing in advanced gastric cancer. Overall, this newly defined GCRE signature reliably stratifies patients with advanced gastric cancer and predicts response from chemotherapy. SIGNIFICANCE: This study describes a novel A-to-I RNA editing signature as a prognostic and predictive biomarker in advanced gastric cancer, providing a new tool to improve patient stratification and response to therapy.

What is the value of third-line chemotherapy in advanced gastroesophageal cancer? A 5-year retrospective analysis at a single center.

AIM: The survival benefit of using a non-cross resistant second-line chemotherapy in the third-line setting in metastatic gastroesophageal cancer is unproven. We evaluated the utility of third-line chemotherapy in patients treated at a single institution. METHODS: Between 2010 and 2014, efficacy and toxicity data of patients who received three or more lines of systemic therapies for metastatic gastroesophageal adenocarcinoma at the National Cancer Centre Singapore was retrospectively analyzed. RESULTS: Thirty-two (6%) patients received three or more lines of chemotherapy. The median age and ECOG performance status were 59 years (36-82) and 1 (0-2), respectively. Majority of patients (88%) had tumor located in the stomach and 13 patients (41%) had diffuse histology or poorly cohesive or signet ring cells. Four (12%) patients had HER2-positive disease. Prior therapy was platinum (100%), fluoropyrimidine (97%), taxane (63%), irinotecan (28%), anthracycline (13%) and ramucirumab (3%). Third-line therapy consisted of 24 (75%) monotherapy, 6 (19%) doublet, 1 (3%) triplet chemotherapy and 1 (3%) clinical trial. Monotherapy irinotecan (44%) was most common, followed by docetaxel (19%) and paclitaxel (9%). Of 22 patients evaluable for response, there was 1 (5%) partial response, 9 (41%) stable disease. Median overall survival was 18.3 weeks (4.3-65.1). Of 30 patients evaluable for toxicities, 17 (57%) experienced at least one grade 3 or 4 toxicities. CONCLUSION: The benefit of using non-cross resistant second-line regimens as third-line chemotherapy was small with moderate toxicity. Newer agents such as nivolumab or TAS-102 or clinical trial may be preferred.

PRL3-zumab as an immunotherapy to inhibit tumors expressing PRL3 oncoprotein.

Tumor-specific antibody drugs can serve as cancer therapy with minimal side effects. A humanized antibody, PRL3-zumab, specifically binds to an intracellular oncogenic phosphatase PRL3, which is frequently expressed in several cancers. Here we show that PRL3-zumab specifically inhibits PRL3+ cancer cells in vivo, but not in vitro. PRL3 antigens are detected on the cell surface and outer exosomal membranes, implying an 'inside-out' externalization of PRL3. PRL3-zumab binds to surface PRL3 in a manner consistent with that in classical antibody-dependent cell-mediated cytotoxicity or antibody-dependent cellular phagocytosis tumor elimination pathways, as PRL3-zumab requires an intact Fc region and host FcγII/III receptor engagement to recruit B cells, NK cells and macrophages to PRL3+ tumor microenvironments. PRL3 is overexpressed in 80.6% of 151 fresh-frozen tumor samples across 11 common cancers examined, but not in patient-matched normal tissues, thereby implicating PRL3 as a tumor-associated antigen. Targeting externalized PRL3 antigens with PRL3-zumab may represent a feasible approach for anti-tumor immunotherapy.

Metastatic gastric cancer: Does the site of metastasis make a difference?

BACKGROUND: Metastatic gastric cancer has a poor prognosis. We aim to study how clinical features and prognosis differs between different metastatic sites, and to identify prognostic factors for overall survival. METHODS: We retrospectively reviewed patients with metastatic gastric adenocarcinoma managed at a tertiary referral cancer center over a 5-year period. We divided our cohort into three groups based on the site(s) of metastasis at presentation-peritoneal metastasis only (P), distant metastasis only (D), and peritoneal and distant metastases (PD). RESULTS: We studied 470 patients with 175 (37.2%), 193 (41.1%) and 102 (21.7%) patients in the P, D and PD groups, respectively. Patients with peritoneal disease (both P and PD) had higher proportions of patients experiencing chemotherapy disruption due to unplanned hospitalizations, which were also of a longer average duration. The P group had the longest overall median survival of 8.9 months compared to the PD and D groups with 7.4 and 5.5 months, respectively (P < 0.001). On multivariate Cox regression analysis, the presence of ≥1 metastatic site (hazard ratio [HR] 1.67; 95% confidence interval [CI], 1.23-2.28; P  =  0.001) was significantly associated with increased overall mortality, whereas palliative systemic chemotherapy (HR 0.29; 95% CI, 0.22-0.37; P < 0.001) and palliative gastrectomy (HR 0.24; 95% CI, 0.15-0.39; P < 0.001) were significantly associated with decreased overall mortality. CONCLUSION: Metastatic gastric cancer represents a heterogeneous disease, with specific disease complications and treatment outcomes unique to different metastatic sites. We can consider novel multimodality therapies for patient subgroups with isolated metastatic disease and good prognostic factors in a bid to improve long-term survival.

Gastric peritoneal carcinomatosis - a retrospective review.

AIM: To characterize patients with gastric peritoneal carcinomatosis (PC) and their typical clinical and treatment course with palliative systemic chemotherapy as the current standard of care. METHODS: We performed a retrospective electronic chart review of all patients with gastric adenocarcinoma with PC diagnosed at initial metastatic presentation between January 2010 and December 2014 in a single tertiary referral centre. RESULTS: We studied a total of 271 patients with a median age of 63.8 years and median follow-up duration of 5.1 mo. The majority (n = 217, 80.1%) had the peritoneum as the only site of metastasis at initial presentation. Palliative systemic chemotherapy was eventually planned for 175 (64.6%) of our patients at initial presentation, of which 171 were initiated on it. Choice of first-line regime was in accordance with the National Comprehensive Cancer Network Guidelines for Gastric Cancer Treatment. These patients underwent a median of one line of chemotherapy, completing a median of six cycles in total. Chemotherapy disruption due to unplanned hospitalizations occurred in 114 (66.7%), while cessation of chemotherapy occurred in 157 (91.8%), with 42 cessations primarily attributable to PC-related complications. Patients who had initiation of systemic chemotherapy had a significantly better median overall survival than those who did not (10.9 mo vs 1.6 mo, P < 0.001). Of patients who had initiation of systemic chemotherapy, those who experienced any disruptions to chemotherapy due to unplanned hospitalizations had a significantly worse median overall survival compared to those who did not (8.7 mo vs 14.6 mo, P < 0.001). CONCLUSION: Gastric PC carries a grim prognosis with a clinical course fraught with disease-related complications which may attenuate any survival benefit which palliative systemic chemotherapy may have to offer. As such, investigational use of regional therapies is warranted and required validation in patients with isolated PC to maximize their survival outcomes in the long run.