Whee Sze Ong

Janus Kinase 3–Activating Mutations Identified in Natural Killer/T-cell Lymphoma

UNLABELLED 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.

Late toxicities after conventional radiation therapy alone for nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE We sought to evaluate the nature and frequency of late toxicities in a cohort of nasopharyngeal cancer (NPC) patients treated with conventional radiotherapy alone. METHODS AND MATERIALS Seven-hundred and ninety-six consecutive NPC patients treated using conventional radiotherapy at a single center from 1992 to 1995 were retrospectively analyzed. Patients with histology proven, completely staged, Stage I-IVB World Health Organization Type I-III NPC and completed radical radiotherapy were included. Patients with incomplete staging investigations, distant metastases at diagnosis, previous treatment, and incomplete radiotherapy were excluded. Radiotherapy-related complications were categorized using the RTOG Late Radiation Morbidity Scoring Criteria. RESULTS Median follow-up was 7.2 years. The 5-year overall survival and disease free survival were 69% and 56%, respectively, and the corresponding 10-year rates were 52% and 44%. Among 771 patients with at least 3 months of follow-up post treatment, 565 (73%) developed RT-related complications. Diagnosed neurological complications were cranial nerve palsies (n=70; 9%), temporal lobe necrosis (n=37; 5%), Lhermittes syndrome (n=7; 1%), and brachial plexopathy (n=2; 0.3%). Non-neurological complications included xerostomia (n=353; 46%), neck fibrosis (n=169; 22%), hypo-pituitarism (n=48; 6%), hearing loss (n=120; 16%), dysphagia (n=116; 15%), otorrhea (n=101; 13%), tinnitus (n=94; 12%), permanent tube feeding (n=61; 8%), trismus (n=45; 6%), second malignancies within treatment field (n=17; 2%), and osteo-radionecrosis (n=13; 2%). CONCLUSIONS While radiotherapy is curative in NPC, many patients suffer significant late treatment morbidities with conventional radiotherapy techniques.

The influence of primary site on outcomes in leiomyosarcoma: a review of clinicopathologic differences between uterine and extrauterine disease.

Background: Leiomyosarcomas (LMS) comprise 25% of soft tissue sarcomas. Recent reports suggest differences in treatment outcomes between uterine (uLMS) and extrauterine (eLMS) disease that may reflect distinct disease biologies. We sought to identify prognostic factors in LMS and clinicopathologic differences between uLMS and eLMS. Methods: This is a single-center retrospective study evaluating 97 eligible patients treated for LMS between 2002 and 2010. Results: Median follow-up was 21.2 months. uLMS affected 53% of patients, and was less common beyond age 60 years compared with eLMS (10% vs. 37%, P=0.002). Seventy-two percent of patients presented with nonmetastatic disease. Of these, 94% underwent curative surgery, among whom more uLMS patients achieved negative surgical margins (90% vs. 45%, P=0.003). There were no significant differences in adjuvant therapy use and relapse patterns between uLMS and eLMS. Half of metastatic patients received palliative chemotherapy, among whom 76% received anthracycline-based chemotherapy in first line to which response rate was 31%. Median overall survival was 45.2 months, 49.8 months in uLMS, and 40.5 months in eLMS (P=0.294). Among patients without metastases, median survival was 60.8 months (77.3 vs. 48.1 mo in uLMS and eLMS, respectively, P=0.194). In metastatic disease, median survival was 20.7 months (22.0 vs. 17.5 mo in uLMS and eLMS, respectively, P=0.936). Advanced disease stage, bone metastases and lack of metastasectomy prognosticated for inferior survival. Conclusions: While demonstrating interesting clinicopathologic differences, the evidence for uLMS and eLMS being biologically distinct remains inconclusive. Disease stage is prognostically most important in LMS.

Does early post-operative intraperitoneal chemotherapy (EPIC) for patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) make a difference?

Abstract Introduction: Peritoneal carcinomatosis (PC) is increasingly being treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), with or without early post-operative intraperitoneal chemotherapy (EPIC). We compared the morbidities, overall survival (OS) and disease free survival (DFS) between two groups of patients who underwent CRS and HIPEC alone and with EPIC at our institution. Methods: A retrospective review of 111 patients with PC who were treated with CRS + HIPEC or CRS + HIPEC + EPIC in a single institution between January 2008 and April 2014 was performed. EPIC with 5-fluorouracil or paclitaxel was utilised, depending on the primary tumour. Results: Patients who received EPIC had a higher proportion of grade III and above post- operative complications (58% versus 25%; p = 0.048) and a longer duration of hospitalisation (16 days versus 13 days; p = 0.019) than patients without EPIC. There were no significant OS and DFS differences between the EPIC and no EPIC groups (log-rank p = 0.231 and p = 0.144, respectively). Conclusion: The use of EPIC after CRS + HIPEC for PC potentially results in increased morbidity and longer hospitalisation, and is unlikely to affect survival outcomes. Based on our experience, EPIC is not recommended after CRS and HIPEC.

Effect of concomitant statin, metformin, or aspirin on rituximab treatment for diffuse large B-cell lymphoma

Several pre-clinical studies report that statins interfere with the surface binding of rituximab to CD20. This study investigated the effects of statins in patients with diffuse large B-cell lymphoma (DLBCL) receiving rituximab-based chemoimmunotherapy, and the impact of commonly used drugs, metformin and aspirin, on the clinical outcomes of patients receiving chemoimmunotherapy. We included 213 patients with DLBCL who received rituximab-based chemoimmunotherapy. Details of statin, metformin, and aspirin use and initiation of chemoimmunotherapy were abstracted from medical records. All patients received rituximab, and 47 (22.1%) were taking statins. The median age of patients receiving statins was significantly higher compared to those who did not (p <0.001). Response rates between patients receiving and not receiving statins were not significantly different (85.1% vs. 87.3%; p = 0.688). Event-free survival (EFS) was not significantly different (p = 0.352). Overall survival was lower in patients receiving statins compared to those who did not (p = 0.036). However, it was no longer significant after adjustment for age (p = 0.140). Metformin had no impact on the response rate (p = 0.268), EFS (p = 0.574), and overall survival (p = 0.141). Aspirin had no impact on the response rate (p = 0.784), EFS (p = 0.836), and overall survival (p = 0.779). Statins do not interfere with rituximab, and need not be withheld during rituximab administration. Larger studies are needed to confirm the impact of metformin and aspirin on patients with DLBCL receiving chemoimmunotherapy.

Prognostic Relevance of the Peritoneal Surface Disease Severity Score Compared to the Peritoneal Cancer Index for Colorectal Peritoneal Carcinomatosis.

Background. Peritoneal Carcinomatosis Index (PCI) is a widely established scoring system that describes disease burden in isolated colorectal peritoneal carcinomatosis (CPC). Its significance may be diminished with complete cytoreduction. We explore the utility of the recently described Peritoneal Surface Disease Severity Score (PSDSS) and compare its prognostic value against PCI. Methods. The endpoints were overall survival (OS), progression-free survival (PFS), and survival less than 18 months (18 MS). Results. Fifty patients underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for CPC from 2003 to 2014, with 98% achieving complete cytoreduction. Median OS was 28.8 months (95% CI, 18.0–39.1); median PFS was 9.4 months (95% CI, 7.7–13.9). Univariate analysis showed that higher PCI was significantly associated with poorer OS (HR 1.11; 95% CI, 1.03–1.20) and PFS (HR 1.09; 95% CI, 1.03–1.14). Conversely, PSDSS was not associated with either endpoint. Multivariate analysis showed that PCI, but not PSDSS, was predictive of OS and PFS. PCI was also able to discriminate survival outcomes better than PSDSS for both OS and PFS. There was no association between 18 MS and either score. Conclusion. PCI is superior to PSDSS in predicting OS and PFS and remains the prognostic score of choice in CPC patients undergoing CRS/HIPEC.

Dose-escalated intensity-modulated radiotherapy and irradiation of subventricular zones in relation to tumor control outcomes of patients with glioblastoma multiforme

Background Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with high relapse rate. In this study, we aimed to determine if dose-escalated (DE) radiotherapy improved tumor control and survival in GBM patients. Methods We conducted a retrospective analysis of 49 and 23 newly-diagnosed histology-proven GBM patients, treated with DE radiotherapy delivered in 70 Gy (2.33 Gy per fraction) and conventional doses (60 Gy), respectively, between 2007 and 2013. Clinical target volumes for 70 and 60 Gy were defined by 0.5 and 2.0 cm expansion of magnetic resonance imaging T1-gadolinium-enhanced tumor/surgical cavity, respectively. Bilateral subventricular zones (SVZ) were contoured on a co-registered pre-treatment magnetic resonance imaging and planning computed tomography dataset as a 5 mm wide structure along the lateral margins of the lateral ventricles. Survival outcomes of both cohorts were compared using log-rank test. Radiation dose to SVZ in the DE cohort was evaluated. Results Median follow-up was 13.6 and 15.1 months for the DE- and conventionally-treated cohorts, respectively. Median overall survival (OS) of patients who received DE radiotherapy was 15.2 months (95% confidence interval [CI] =11.0–18.6), while median OS of the latter cohort was 18.4 months (95% CI =12.5–31.4, P=0.253). Univariate analyses of clinical and dosimetric parameters among the DE cohort demonstrated a trend of longer progression-free survival, but not OS, with incremental radiation doses to the ipsilateral SVZ (hazard ratio [HR] =0.95, 95% CI =0.90–1.00, P=0.052) and proportion of ipsilateral SVZ receiving 50 Gy (HR =0.98, 95% CI =0.97–1.00, P=0.017). Conclusion DE radiotherapy did not improve survival in patients with GBM. Incorporation of ipsilateral SVZ as a radiotherapy target volume for patients with GBM requires prospective validation.

Cutaneous versus Non-Cutaneous Angiosarcoma: Clinicopathologic Features and Treatment Outcomes in 60 Patients at a Single Asian Cancer Centre

Background: Angiosarcoma (AS) is an uncommon soft tissue sarcoma with dismal prognosis that presents either cutaneously (C-AS) or non-cutaneously (NC-AS). We compared the clinical features and treatment outcomes between these 2 groups. Methods: A single-centre study evaluating 60 AS patients between 2002 and 2012 was performed. Results: The median age was 70 years. C-AS of the scalp or face comprised 66% of patients. C-AS patients were older than NC-AS (median age 74 vs. 56 years; p < 0.001). Proportionately more C-AS patients presented with non-metastatic disease (86 vs. 50%; p = 0.007). Amongst resected C-AS and NC-AS patients, rates of positive surgical margins (53 vs. 50%; p = 1.00) and adjuvant therapy (25 vs. 43%; p = 0.626) were not significantly different, though proportionately fewer C-AS patients relapsed (36 vs. 78%; p = 0.038). Paclitaxel was the most common agent in first line palliative systemic therapy, achieving an objective response rate of 56%. Median overall survival was 11.2 months, with no significant difference between C-AS and NC-AS (11.3 vs. 9.8 months; p = 0.895). Conclusion: Distinct from AS in the West, our series demonstrates a clear preponderance of scalp AS. Disparities in clinical characteristics between C-AS and NC-AS did not translate into survival differences.

Serglycin expression: An independent marker of distant metastases in nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) has a high propensity for metastasis. The purpose of this study was for us to determine whether serglycin expression can be used to predict distant metastases.

Do elderly patients benefit from enrollment into Phase I Trials

BACKGROUND Despite the significant burden of cancer in the older population, their outcomes in the context of phase I studies have been poorly studied. While the Royal Marsden Hospital (RMH) prognostic score (albumin, lactate dehydrogenase [LDH], number of metastatic sites) is validated in this setting, its utility among the elderly is uncertain. METHODS A total of 296 consecutive patients who were treated in 20 phase I trials from 2005 to 2012 in our unit were analysed. Clinical characteristics and outcomes between young (<65, n=202) and older patients (≥65, n=94) were compared. RESULTS The median age of the older patients was 69 years (65-84) and 71% were males. Although elderly patients had more co-morbidities and lower albumin levels at baseline, there was no significant difference in survival (8.8 months versus 9.9 months, p=0.68) and clinical benefit rate (69% versus 56%, p=0.07) compared to younger patients after median follow-up of 7.1 months (0.36-50.6 months). Age (p=0.23) did not have any bearing on occurrence of grade 3/4 toxicities. Twenty-six percent of elderly patients experienced grade 3/4 toxicities. The prognostic factors for overall survival (OS) identified in multivariate analysis were prior lines of chemotherapy (0-2 versus ≥3), baseline sodium levels (≥135 versus <135 mmol/L) and platelet levels (≤400 versus >400×10(9)). We developed a risk nomogram based on the factors prognostic of survival with concordance index of 0.65. The RMH model yielded a concordance index of 0.635. CONCLUSION Elderly patients enrolled into phase I clinical trials had similar survival outcomes and toxicity profiles compared to younger patients. Risk scoring models to aid patient selection need further clarification.