NCOG-08. BIOPSY-ONLY GLIOBLASTOMA (BO-GBM) AS A HETEROGENEOUS GROUP OF PATIENTS

BACKGROUND “Biopsy-only” glioblastoma is associated with a heterogeneous functional and survival outcome. It is an understudied group of patients which has been reported to represent 21% of histologically confirmed GBM in the US National Cancer Data Base. Pattern of care included radiotherapy-temozolomide (RT-TMZ) completed in 15% of patients, any other form of oncologic treatment in 60%, and supportive care alone in 25% of patients. Our objective was to explore treatment and prognosis of BO-GBM. MATERIAL AND METHODS Patients with BO-GBM included in a prospective regional glioma SIRIC cohort in 2014-2017 were retrospectively reviewed for patient characteristics, MRI finding, treatment allocation and delivery. PFS and OS were analyzed. RESULTS Of 535 patients included in the cohort, 449 patients were included at initial surgery, of which 158 patients (35%) underwent biopsy only. Of 158 patients, 18 were excluded for missing data leaving 139 patients for the present analysis. Fifty-four (39%) were referred to RT-TMZ, 68 (49%) considered unfitted for RT received chemotherapy upfront (CT-UF), 17 (12%) were referred to palliative care. Groups differed at baseline for age (mean 60 and 68 years, for RT-TMZ, CT-UF respectively); KPS (70, 60 for RT-TMZ, CT-UF); mean tumor surface (793, 1420 mm2 for RT-TMZ, CT-UF); and tumor extension (bilateral in 6.4% and 29.3% for RT-CT and CT-UF respectively). Median OS was 14 months (95% CI, 9.65-18.71) and 8 months (95% CI, 4.62-7.67) for RT-TMZ, CT-UF respectively. CONCLUSION Inoperable GBM constitute a large and heterogeneous population in which one third of patients are amenable to standard of care, with survival outcome close to the one of patients who underwent surgery. Patients considered unfit for RT-CT at diagnosis exhibit a poor survival outcome. Thus, reliable criteria are needed to help selecting patients for adequate treatment while new strategies are warranted for BO-GBM unfit for RT.

Prognostic Significance of KIF11 and KIF14 Expression in Pancreatic Adenocarcinoma

Available biomarkers for pancreatic adenocarcinoma (PAC) are inadequate to guide individual patient prognosis or therapy. Therefore, herein we aimed to verify the hypothesis that differences in the expression of KIF11 and KIF14, i.e., molecular motor proteins being primarily implicated in cell division events could account for the differences in the clinical outcome of PAC patients. In-house immunohistochemistry was used to evaluate the protein expressions of KIF11 and KIF14 in PAC, whereas RNA-seq datasets providing transcript expression data were obtained from public sources. IHC and mRNA results were correlated with clinicopathological features and overall survival (OS). Furthermore, the genes co-expressed with KIF11 or KIF14 were predicted and functionally annotated. In our series, malignant ducts displayed more intense but less abundant KIF11 staining than normal-appearing ducts. The former was also true for KIF14, whereas the prevalence of positive staining was similar in tumor and normal adjacent tissues. Based on categorical immunoreactive scores, we found KIF11 and KIF14 to be frequently downregulated or upregulated in PAC cases, respectively, and those with elevated levels of either protein, or both together, were associated with better prognosis. Specifically, we provide the first evidence that KIF11 or KIF14 proteins can robustly discriminate between patients with better and worse OS, independently of other relevant clinical risk factors. In turn, mRNA levels of KIF11 and KIF14 were markedly elevated in tumor tissues compared to normal tissues, and this coincided with adverse prognosis, even after adjusting for multiple confounders. Tumors with low predicted KIF11 or KIF14 expression were seen to have enrichment for circadian clock, whereas those with high levels were enriched for the genomic instability-related gene set. KIF11 and KIF14 were strongly correlated with one another, and CEP55, ASPM, and GAMT were identified as the main hub genes. Importantly, the combined expression of these five genes emerged as the most powerful independent prognostic indicator associated with poor survival outcome compared to classical clinicopathological factors and any marker alone. In conclusion, our study identifies novel prognostic biomarkers for PAC, which await validation.

The Prevalence of CD30 Expression and Relationship to Survival in Patients with Peripheral T-Cell Lymphoma (PTCL)

Objective: To define the prevalence of CD30 expression and the relationship to survival in patients with peripheral T-cell lymphoma (PTCL). Materials and Methods: A 12-year retrospective study of 135 PTCL patients was completed. Their tissue specimens were stained for CD30 antibody and the results were correlated with clinical data and survival. Results: One hundred thirty-five patients were enrolled. The subtypes of PTCL were classified as PTCL-NOS (36.3%), nasal NKTCL (17.8%), AITL (15.6%), CTCL (13.3%), SPTCL (11.1%), ALCL (4.4%), C-ALCL (0.7%), and EATL (0.7%). The expression of CD30 in the PTCLs was 34.8%, which significantly associated with histological subtypes (p<0.001). There was a higher prevalence in ALCL or C-ALCL (100.0%), nasal NKTCL (79.2%), and PTCL- NOS (30.6%). The median survival was 25 months with a projected 5-year survival of 37.0%. CD30 positivity was significantly associated with poor survival outcome (CD30⁻ 30 months versus CD30⁺ 14 months, p=0.013). From Cox regression analysis, PTCL subtypes were independent prognostic predictor for survival in the present study. Conclusion: The expression of CD30 in PTCLs was demonstrated in one-third of patients and was associated with histological subtypes and inferior survival outcome. Keywords: CD30, Survival, Peripheral T-cell lymphoma

NUT Carcinoma Arising from the Parotid Gland: A Case Report and Review of the Literature

NUT carcinoma is an aggressive carcinoma with an overall poor survival outcome. The mediastinum and head and neck area, especially the sinonasal region, are among the common sites of disease. Histopathological diagnosis of NUT carcinoma is often very challenging due to its overlapping features with other poorly differentiated carcinomas. We report a case of NUT carcinoma arising from the parotid gland of a young female patient. Primary NUT carcinoma of salivary gland is very rare, with only 15 such cases reported in the literature to date. Our case highlights the diagnostic challenges associated with such lesions.

SOX1 and PAX1 Are Hypermethylated in Cervical Adenocarcinoma and Associated with Better Prognosis

Background. The increased risk and poor survival outcome of cervical adenocarcinoma (CAC) demand for effective early diagnostic biomarkers that can predict the disease progression and outcome. The purpose of this study was to investigate the value of methylation status of SOX1 and PAX1 in the detection and prognosis of CAC. Methods. We performed a quantitative methylation-specific polymerase chain reaction in 205 cervical paraffin-embedded specimens (175 CACs, 30 noncancer cervical tissues). Overall and progression-free survival (OS and PFS, respectively) rates were calculated and compared using the Kaplan-Meier method. The prognostic value of SOX1m and PAX1m on CAC patients was assessed by the Cox regression model. A mathematical formula combining SOX1m, PAX1m, and age was constructed for survival prediction. Results. The methylation status of SOX1 and PAX1 was higher in CAC tissues than in noncancer cervical tissues. In addition, SOX1m-positive CAC patients showed a higher 5-year OS rate than SOX1m-negative patients. In CAC patients with smaller tumor size (<4 cm), the PAX1m-positive group showed a higher 5-year PFS rate than the PAX1m-negative group. In the algorithm combining SOX1m, PAX1m, and age, the low-risk group showed a better 5-year OS and PFS rate than the high-risk group. Conclusion. SOX1 and PAX1 methylation levels are higher in CAC than in normal cervical tissues and are potential biomarkers for monitoring CAC prognosis.

NSD2 Regulates Pro-Metastatic Gene PTP4A3 through Chromatin Remodeling in Multiple Myeloma

Nuclear receptor-binding SET domain 2 (NSD2) is the primary oncogenic driver and represent a good druggable target due to its universal overexpression in t(4;14) MM. However, given the challenges in the development of small molecule inhibitors against NSD2, we took on a discovery approach to characterize NSD2 interactome as an alternative strategy to target NSD2. We employed SILAC-based mass-spectrometry coupled with gene ontology analysis to uncover the spectrum of NSD2-interacting proteins which are relevant in t(4;14) MM. Validation using in silico protein-protein interaction analysis and immunoprecipitation confirmed that SMARCA2, a bromodomain-containing chromatin remodeler, interacts with NSD2 independent of the SWI/SNF complex. SMARCA2 is primarily expressed in t(4;14) cell lines, and functional assays indicated that dual inhibition of SMARCA2 and NSD2 impairs growth of t(4;14)+ cells. Next, we performed RNA sequencing which led to the identification of PTP4A3 as a downstream target of NSD2 that is co-regulated by SMARCA2. Mechanistically, SMARCA2 is required for the recruitment of NSD2 to PTP4A3 promoter, leading to a transcriptionally permissive state for expression. Importantly, upregulation of PTP4A3 is sufficient for the activation of MYC, which is crucial for t(4;14) myelomagenesis. PFI-3, which belongs to the class of bromodomain and extra-terminal motif protein inhibitors (BETi), displaced SMARCA2 and NSD2 occupancy from PTP4A3 promoter, and selectively inhibited t(4;14) myeloma cell viability. Interestingly, PFI-3 treatment did not perturb the levels of NSD2 nor SMARCA2, rather, the targeting effect is achieved through their occupancy on oncogenes. Finally, high expression of NSD2 and SMARCA2 were predictive of poor survival outcome in a large cohort of myeloma patients. Collectively, we demonstrated a proof-of-concept of how histone modifying enzyme and chromatin remodeling complex cooperatively caused an altered epigenetic state in myelomagenesis through the regulation of an important myeloma gene. Our study proposed that the pharmacological inhibition of SMARCA2 may represent a novel strategy to target t(4;14) myeloma cells using BETi and also explore as combinational therapy with anti-myeloma agents that are currently in the clinics. Disclosures No relevant conflicts of interest to declare.

Biomarker exploration of microRNA-203 as a promising substrate for predicting poor survival outcome in colorectal cancer

Background Increasing studies indicated that microRNA-203 (miR-203) may play an important part in the prognosis of CRC. Nevertheless, the prognostic and influential mechanism of miR-203 expression in CRC remains to be inconclusive. Accordingly, we conducted the current study to investigate the biomarker performance of miR-203 in CRC. Methods In the present study, we conducted an evidence synthesis of the published literatures to identify the prognostic roles of miR-203 in patients with CRC. Moreover, several bioinformatics methods were applied for exploring the biomarker roles of miR-203. Results It was demonstrated that elevated miR-203 expression was clearly related to worse overall survival (HR: 1.55, 95% CI: 1.07–2.24, P = 0.021) for CRC. The gene Ontology (GO) analysis indicated that miR-203 targets were primarily involved in a series of GO items closely associated with the molecular pathogenesis of CRC. The pathway analysis exhibited the potential signal pathways of miR-203 involved in CRC including pathways in cancer, wnt pathway, prolactin signaling pathway, proteoglycans in cancer, FoxO pathway, focal adhesion and Ras pathway. By constructing a protein-protein interaction (PPI) network of the targets of miR-203, ten crucial proteins and a significant network module were retrieved and found to serve important roles in the molecular pathogenesis of CRC. Conclusions Our results indicated that miR-203 may function as a promising biomarker to monitor CRC survival outcomes and progression. Notably, large-scale prospective cohort studies and biological experiments are required to confirm our conclusions.