External Validation of a Nomogram to Predict Survival and Benefit of Concurrent Chemoradiation for Stage II Nasopharyngeal Carcinoma.

A nomogram was recently published by Sun et al. to predict overall survival (OS) and the additional benefit of concurrent chemoradiation (CCRT) vs. radiotherapy (RT) alone, in stage II NPC treated with conventional RT. We aimed to assess the predictors of OS and to externally validate the nomogram in the IMRT era. We analyzed stage II NPC patients treated with definitive RT alone or CCRT between 2001 and 2011 under the territory-wide Hong Kong NPC Study Group 1301 study. Clinical parameters were studied using the Cox proportional hazards model to estimate OS. The nomogram by Sun et al. was applied with 1000 times bootstrap resampling to calculate the concordance index, and we compared the nomogram predicted and observed 5-year OS. There were 482 patients included. The 5-year OS was 89.0%. In the multivariable analysis, an age > 45 years was the only significant predictor of OS (HR, 1.98; 95%CI, 1.15-3.44). Other clinical parameters were insignificant, including the use of CCRT (HR, 0.99; 95%CI, 0.62-1.58). The nomogram yielded a concordance index of 0.55 (95% CI, 0.49-0.62) which lacked clinically meaningful discriminative power. The nomogram proposed by Sun et al. should be interpreted with caution when applied to stage II NPC patients in the IMRT era. The benefit of CCRT remained controversial.

BRCA mutation testing for ovarian cancer in the context of available targeted therapy: Survey and consensus of Hong Kong specialists.

AIMS: BRCA mutation (BRCAmut) testing is an important tool for the risk assessment, prevention and early diagnosis of breast cancer (BC) and ovarian cancer (OC), and more recently, for determining patient susceptibility to targeted therapy. This study assessed the current BRCAmut testing patterns and explored physicians' perspectives on the utilities and optimal sequencing of the testing, in order to facilitate and standardize testing practices. METHODS: Medical specialists in BC and OC in Hong Kong were invited to complete a questionnaire on BRCAmut testing practices. A panel of specialists with extensive BRCAmut testing experience was also convened to develop consensus statements on testing, using the Delphi method and an anonymous electronic voting system. RESULTS: The survey respondents (n = 71) recognized family history (FH) of BC and/or OC and an early age of onset as key factors for referring BRCAmut testing. The proportion of respondents who would test all OCs regardless of FH or age, as per the recent international guideline, was low (28.2%). The largest hurdles to testing were the cost, as well as the availability of next-generation sequencing-accredited testing and genetic counseling facilities. The panelists suggested that the sequence of somatic testing followed by germline testing may help address both the imminent need of treatment planning and longer term hereditary implications. The potential emotional and financial burdens of BRCAmut testing should be weighed against the potential therapeutic benefits, and the type and timing of testing personalized. CONCLUSIONS: Accessibility of BRCAmut testing to all at-risk individuals will be achievable through improvements in testing affordability, as well as widened availability of accredited testing and genetic counseling facilities.

Regulating the Membrane Transport Activity and Death of Cells via Electroosmotic Manipulation.

Although the volume of living cells has been known to heavily influence their behavior and fate, a method allowing us to control the cell size in a programmable manner is still lacking. Here, we develop a technique in which precise changes in the cellular volume can be conveniently introduced by varying the voltage applied across a Nafion membrane that separates the culture medium from a reservoir. It is found that, unlike sudden osmotic shocks, active ion transport across the membrane of leukemia K562 cells will not be triggered by a gradual change in the extracellular osmolarity. Furthermore, when subjected to the same applied voltage, different lung and nasopharyngeal epithelial cancer cells will undergo larger volumetric changes and have a 5-10% higher death rate compared to their normal counterparts. We show that such distinct response is largely caused by the overexpression of aquaporin-4 in tumor cells, with knockout of this water channel protein resulting in a markedly reduced change in the cellular volume. Finally, by taking into account the exchange of water/ion molecules across the Nafion film and the cell membrane, a theoretical model is also proposed to describe the voltage-induced size changes of cells, which explain our experimental observations very well.

Role of MIF/CXCL8/CXCR2 signaling in the growth of nasopharyngeal carcinoma tumor spheres.

Macrophage migration inhibitory factor (MIF) and CXCL8 (also named IL-8) are strongly expressed in the tissues of nasopharyngeal carcinoma (NPC). However, their role in the growth of NPC has not been fully examined. This study aims to evaluate the functions of MIF and CXCL8 on the growth of NPC tumor spheres. The elevated expression of CXCL8 in tumor over normal tissues was confirmed in 37 pairs of biopsies from NPC patients. In the in vitro study, all the poorly differentiated NPC cell lines, including the EBV-positive C666-1, and the EBV-negative CNE-1, CNE-2, SUNE-1, HNE-1 and HONE-1 cells, were found to express CXCL8 and MIF. Therefore, the EBV-positive C666-1 cell was selected to examine for the role of MIF and CXCL8 in the growth of the NPC tumor spheres. Functional study showed that the growth of C666-1 tumor spheres, under the nutrient poor or growth factor supplemented culture conditions, could be inhibited by the CXCL8 specific peptide inhibitor. The growth of the tumor spheres could also be reduced by the CXCR2 specific inhibitor SB225002 or the PI3K/AKT inhibitor LY294002, indicating that the endogenously produced CXCL8 plays an autocrine role in the growth of the tumor spheres. Further mechanistic studies revealed that the gene expression of CXCL8 could be reduced by the MIF specific small interfering RNA (siRNA) or NF-κB inhibitor parthenolide, and the growth of tumor spheres was also reduced after MIF siRNA transfection. Taken together, the present study highlights the role of MIF/CXCL8/CXCR2 axis in the growth of NPC tumor spheres. Chemotherapeutic interference of this signaling pathway may help to control the growth of the NPC tumor.

Cervical nodal metastases from occult primary: undifferentiated carcinoma versus squamous cell carcinoma.

PURPOSE/OBJECTIVE: Controversy exists regarding the management of cervical lymph node metastases from occult primary. Oncologists face a major challenge in adopting an optimal approach. This study attempted to compare the clinical course of two different histologic findings of this disease entity. MATERIALS AND METHODS: A retrospective analysis was performed for all patients referred to our institution between 1988 and 1998 with cervical lymph node metastases from an unknown primary. Case records of consecutive unselected patients with histologically confirmed carcinoma in cervical lymph nodes were reviewed. Those with histologic findings other than squamous cell carcinoma (SCC) or undifferentiated carcinoma (UDC) and lymphadenopathies at the supraclavicular fossa alone or below the clavicles at the time of diagnosis were excluded. There were 45 patients identified with a mean follow-up of 36 months (range, 4-110 months). Thirty-seven were men and eight were women. The mean age was 57 (range, 29-91). There were 32 patients with SCC and 13 patients with UDC. Treatment modality included surgery (S) alone in 1 patient (2%), radiotherapy (RT) alone in 24 patients (53%), and combined modality in 20 patients (45%). (Twelve patients (27%) had combined S and RT, 8 patients (18%) had combined chemotherapy and RT.) Twenty-eight patients (62%) were treated with radical intent. For those patients treated by radical RT, the RT field covered both sides of the neck and the potential mucosal primary (PMP) sites, including the entire pharyngeal axis. The median radiation doses to the lymph nodes and the PMP were 65 Gy (range, 60-70 Gy) and 60 Gy (range, 40-70 Gy), respectively. RESULTS: At the time of analysis, ultimate control of disease above the clavicles according to N stage, treatment intent, and histologic type was as follows: N1s, 7 of 7 (100%); N2s, 15 of 26 (58%); N3s, 1 of 12 (8%); radical intent, 19 of 28 (68%); palliative intent, 3 of 17 (18%); UDC, 11 of 13 (85%); SCC,11 of 32 (34%). Eleven patients remained alive and disease free, with a median follow-up of 79 months (range, 27-110 months). The 5-year disease-specific survival (DSS) for the radical treatment group and the palliative treatment group were 67% and 18%, respectively (p =.0011). Significant difference in 5-year DSS was observed among the different N groups: 100% for N1s, 55% for N2s, and 0% for N3s, respectively (p =.0001). There was also a significant difference in the 5-year DSS between UDC and SCC: 81% for UDC vs 34% for SCC (p =.01). No significant difference in the 5-year DSS was observed on the basis of treatment modality in the radically treated group: 63% for RT alone vs 75% for S + RT (p =.711). CONCLUSIONS: UDC histologic findings in our series are associated with better locoregional control and DSS than SCC. Our results in local control, emergence of primary tumor, and DSS are comparable with other published data. However, disease control of advanced nodal stage remains poor; more aggressive treatment approaches, like the use of concurrent chemoradiation or altered fractionation scheme, should be explored.