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PDF file - 83K, JAK1 and JAK3 mutation status in NKTCL cases

PDF file - 110K, Non-synonymous somatic mutations identified in the Discovery set of four NKTCL cases

PDF file - 75K, Sequence analysis summary of tumor and blood samples from four NKTCL cases

PDF file - 74K, Primer sets used for Sanger sequencing and HRM analysis

PDF file - 185K, Representative HRM curves of a NKTCL case confirmed as heterozygous JAK3A573V mutation

The molecular pathogenesis of natural killer/T-cell lymphoma (NKTCL) is not well understood. We conducted whole-exome sequencing and identified Janus kinase 3 (JAK3) somatic–activating mutations (A572V and A573V) in 2 of 4 patients with NKTCLs. Further validation of the prevalence of JAK3 mutations was determined by Sanger sequencing and high-resolution melt (HRM) analysis in an additional 61 cases. In total, 23 of 65 (35.4%) cases harbored JAK3 mutations. Functional characterization of the JAK3 mutations support its involvement in cytokine-independent JAK/STAT constitutive activation leading to increased cell growth. Moreover, treatment of both JAK3-mutant and wild-type NKTCL cell lines with a novel pan-JAK inhibitor, CP-690550, resulted in dose-dependent reduction of phosphorylated STAT5, reduced cell viability, and increased apoptosis. Hence, targeting the deregulated JAK/STAT pathway could be a promising therapy for patients with NKTCLs. Significance: Gene mutations causing NKTCL have not been fully identified. Through exome sequencing, we identified activating mutations of JAK3 that may play a significant role in the pathogenesis of NKTCLs. Our findings have important implications for the management of patients with NKTCLs. Cancer Discov; 2(7); 591–7. ©2012 AACR. This article is highlighted in the In This Issue feature, p. 569.

In recent years remarkable progress has been made towards the understanding of proposed hallmarks of cancer development and treatment. However with its increasing incidence, the clinical management of cancer continues to be a challenge for the 21st century. Treatment modalities comprise of radiation therapy, surgery, chemotherapy, immunotherapy and hormonal therapy. Radiation therapy remains an important component of cancer treatment with approximately 50% of all cancer patients receiving radiation therapy during their course of illness; it contributes towards 40% of curative treatment for cancer. The main goal of radiation therapy is to deprive cancer cells of their multiplication (cell division) potential. Celebrating a century of advances since Marie Curie won her second Nobel Prize for her research into radium, 2011 has been designated the Year of Radiation therapy in the UK. Over the last 100 years, ongoing advances in the techniques of radiation treatment and progress made in understanding the biology of cancer cell responses to radiation will endeavor to increase the survival and reduce treatment side effects for cancer patients. In this review, principles, application and advances in radiation therapy with their biological end points are discussed.

Nasopharyngeal cancer (NPC) is a common malignancy affecting Asian countries, especially the Chinese population. Treatment regimes and results have improved over the years with better overall survival outcome data. Radiotherapy with or without chemotherapy is successful in many patients. Local recurrences are treated with nasopharyngectomy or another course of radiotherapy. The upper cervical spine and skull base can also be involved in NPC patients. Possible aetiologies are osteoradionecrosis, chronic infection and tumour invasion. This article reviews the NPC involvement of C1-2 due to the various pathologies as well as the diagnostic and surgical treatment strategies. Three clinical cases that were surgically treated are discussed along with a review of the current literature.

Introduction: Our study investigates whether an approximation of breast cancer molecular subtypes using the hormone receptors and HER-2 status prognosticates for disease control after breast conservation therapy (BCT) in node-negative Asian breast cancer patients. Methods and Materials: We retrospectively reviewed 541 women with node-negative breast cancers treated with BCT between 1989 and 2007. Hormone receptors and HER-2 status were obtained from patients’ histological report. All patients received radiotherapy. Thirty-six percent and 68% of women received chemotherapy and hormonal treatment respectively. Results: Median follow-up of patients is 72 months. Five-year local recurrence free survival (LRFS) is 97.2% for the cohort but differs between subtypes: luminal A, 0.8%; luminal B, 1.4%; HER-2, 3.6% and basal-like, 12.7% (P = 0.047). The 5-year distant disease free survival (DDFS) is 96.4% for the cohort but differs between subtypes: luminal A, 98.2%; luminal B, 92.6%; HER-2, 89.5% and basal-like, 91.5% (P = 0.019). The 5-year disease free survival (DFS) is 94.4% for the cohort but differs between subtypes: luminal A, 97.4%; luminal B, 92.7%; HER-2, 86.3% and basal-like, 85.0% (P = 0.007). Univariate analysis with luminal A as baseline revealed an association of the other 3 subtypes with decreased DFS (P = 0.007), Hazard Ratio (HR) of 2.2, 4.4 and 3.3 to Luminal B, HER-2 and basal subtypes, respectively. On multivariate analysis, HER-2 subtype (AHR = 3.3, 95% CI, 1.1 to 9.8, P = 0.036) and basal-like subtype (HR = 3.5, 95% CI, 1.2 to 9.9, P = 0.019) prognosticate adversely for DFS. Conclusion: The combination of hormone receptors and HER-2 status can be used as surrogates for molecular subtypes in Asian breast cancer patients with node-negative disease to prognosticate LRFS, DFS and DDFS. Keywords: Histological subtypes, Lumpectomy, Outcomes, Prognostic factors