Aim: The fragile histidine triad (FHIT) gene was discovered and proposed as a tumor suppressor gene for most human cancers. It encodes the most active common human chromosomal fragile region, FRA3B. We studied the prevalence of loss of FHIT expression in various tumors and correlated its loss with various clinicopathologic features. Methods: To determine whether the absence of FHIT expression correlates with clinical variables such as grade, stage, and survival time, we assessed FHIT expression using immunohistochemistry. More than 1,800 tumors from more than 75 tumor categories were analyzed by immunohistochemistry in a tissue microarray format.

Mutation-induced activation of Wnt-β Catenin signaling pathway is frequent in CRC. The E3 ubiquitin ligase, RNF43, has been reported to negatively regulate the Wnt signaling pathway and RNF43 mutations are frequently seen in CRC. However, its role in Middle Eastern CRC remains unclear. Therefore, we employed Exome and Sanger sequencing technology to assess the frequency of RNF43 mutations and its association with other clinico-pathological features in Middle Eastern CRC. RNF43 mutations were found in 5.9% (13/220) of CRC cases and was inversely correlated to APC and TP53 mutations. A strong association of RNF43 mutations with right sided and sporadic microsatellite instable (MSI) CRC was observed. No association was identified between RNF43 mutation and other clinico-pathological features including BRAF mutation, age, tumor histological subtype, tumor grade or patients’ prognosis. Multivariate logistic regression analysis revealed that MSI status and wild type APC were independent predictor of RNF43 mutation. We conclude that RNF43 mutations occur in Middle Eastern CRC at comparable frequencies with BRAF mutations and represent a distinct molecular subtype which further enhances our understanding of how different mutational subsets of Wnt tumor suppressor genes link to distinct tumor characteristics, which might be considered for treatment strategies for CRC patients.

Objective: Recently, lymph node ratio (LNR) has emerged as an alternative to American Joint Committee on Cancer (AJCC) N stage, with superior prognostic value. The utility of LNR in Middle Eastern Papillary thyroid carcinoma (PTC) remains unknown. Therefore, we retrospectively analyzed a large cohort of 1407 PTC patients for clinico-pathological associations of LNR. Methods: Receiver operating characteristics (ROC) curve was used to determine the cut-off for LNR. We also performed multivariate logistic regression analysis to determine whether LNR or AJCC N stage was superior in predicting recurrence in PTC. Results: Based on ROC curve analysis, a cut-off of 0.15 was chosen for LNR. High LNR was significantly associated with adverse clinico-pathological characteristics such as male sex, extrathyroidal extension, lymphovascular invasion, multifocality, bilateral tumors, T4 tumors, lateral lymph node (N1b) involvement, distant metastasis, advanced tumor stage, ATA high risk category and tumor recurrence. On multivariate analysis, we found that LNR was a better predictor of tumor recurrence than AJCC N stage (Odds ratio: 1.96 vs. 1.30; p value: 0.0184 vs. 0.3831). We also found that LNR combined with TNM stage and ATA risk category improved the prediction of recurrence-free survival, compared to TNM stage or ATA risk category alone. Conclusions: The present study suggests LNR is an independent predictor of recurrence in Middle Eastern PTC. Integration of LNR with 8th edition AJCC TNM staging system and ATA risk stratification will improve the accuracy to predict recurrence in Middle Eastern PTC and help in tailoring treatment and surveillance strategies in these patients. Citation Format: Sandeep K. Parvathareddy, Abdul K. Siraj, Zeeshan Qadri, Saeeda O. Ahmed, Nabil Siraj, Felisa DeVera, Padmanaban Annaiyappanaidu, Maria A. Sabido, Wael Haqawi, Hassan Aldossari, Khawla S. Al-Kuraya. Lymph node ratio is superior to AJCC N stage for predicting recurrence in papillary thyroid carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5177.

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Predicting the pattern of recurrence is necessary to establish optimal surveillance and treatment strategies. We identified patient population that remain at risk for an event and clarify changes in the hazard rate (HR) for tumor recurrence overtime in Middle Eastern patients with Papillary Thyroid Cancer (PTC). Data for 1201 PTC patients from single institute with median follow-up of 9.5 years were analyzed. Estimated HR were plotted overtime for the entire cohort, as well as for radioactive iodine (RAI) ablation in patients separately. The changes in risk were further analyzed according to clinical variable and factors predictive of early (≤ 5years) and late (>5 years) recurrence were explored using Cox regression analysis. Tumor recurrence was noted in 18.4% (221/1201) patients. The annualized hazard of PTC recurrence was highest during the first 5 years (2.8%), peaking between 1 - 2 years (3.7%), with a second smaller peak between 13 - 14 years (3.2%). Patients receiving RAI therapy had a lower hazard of recurrence compared to those who did not receive RAI therapy (1.5% vs 2.7%, p = 0.0001). Importantly, this difference was significant even in the intermediate-risk PTC patients (0.7% vs 2.3%; p = 0.0001). Interestingly, PTC patients who were male, aged ≥ 55 years, with lymph node involvement and advanced stage disease were still at high risk for late recurrence. In conclusion, we confirmed the validity of double-peaked time-varying pattern for risk of recurrence in Middle-Eastern PTC patients. Furthermore, according to the time distribution of recurrence hazard, we could formulate individualized treatment and surveillance plans in PTC patients. Citation Format: Abdul K. Siraj, Sandeep K. Parvathareddy, Zeeshan Qadri, Saud Azam, Felisa De Vera, Maha Al-Rasheed, Wael Haqawi, Hassan AlDossari, Khawla S. Al-Kuraya. Annual hazard rate of recurrence in Middle-Eastern papillary thyroid cancer over a long-term follow-up [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 730.