Metronomic oral cyclosphosphamide as third-line systemic treatment or beyond in patients with inoperable locoregionally advanced recurrent or metastatic nasopharyngeal carcinoma

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Prognostication of serial post-intensity-modulated radiation therapy undetectable plasma EBV DNA for nasopharyngeal carcinoma

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Lymphopenia Association with Planning Target Volume and Lung V5 and its effect on survival of esophageal cancer receiving neoadjuvant chemo-radiation with Dutch CROSS regime

Poster presentation: no. P-064Background: Radiation has a strong lympholytic effect. This effect has been overlooked for decades until recently. As immunotherapy is becoming one of the main systemic treatment of various cancer, it is important to adopt best radiation technique to preserve lymphocyte numbers. Radiation-induced lymphopenia has been reported to be adversely associated with overall survival and recurrence free survival in various cancers including lung, pancreatic and head and neck cancer. Data of lymphopenia effect on esophageal cancer is lacking. We therefore sought to study the association of lymphopenia and overall survival in esophageal cancer patients who have undergone neoadjuvant chemo-radiation according to Dutch CROSS trial regime. One of the possible mechanism of severe lymphopenia in radiotherapy is the large volume of low dose bath killing large number of circulating lymphocytes in both systemic and pulmonary circulation. As there is report of relationship of low dose lung dosimetry parameters with lymphopenia in NSCLC, we also aim to study this relationship in esophageal cancer. Methods: All esophageal cancer patients from June 2012 to April 2015 in our tertiary university hospital who have received neoadjuvant chemo-radiation according to Dutch CROSS trial regime has been retrospectively reviewed. Total subjects eligible for review is 51. One subject has died before the start of chemo-radiation and thus was excluded from analysis. Lymphocyte nadir was defined as the minimum lymphocyte value measured between the start of neoadjuvant chemo-radiation and the operation date. Relationships between lymphocyte nadirs with overall survival (OS) and recurrence free survival (RFS) were evaluated with Cox-regression analysis. Association between Planning Target volume (PTV) and lung dose- volume histogram (DVH) parameters were analysed with Pearson correlation coefficients. Results: 48 out of 50 subjects have normal baseline lymphocyte counts. Low lymphocyte nadir is found to have negative effect on patient's overall survival (OS). On multi-variable Cox regression with backward elimination analysis, patients with higher lymphocyte nadirs exhibited significantly improved OS (hazard ratio [HR] Z=0.656 per 0.1 x 10^9 lymphocytes/L, p=0.009). Of note, No significant relationships with OS were seen in baseline total white cell count, lymphocyte count and neutrophil count. Analyses of lung DVH parameters revealed significant correlations at lower doses (lung V1-V15: P.05). For instance, the correlation coefficient of V1, V5 and V10 were -0.566, -0.495 and -0.419 respectively. Larger PTV was also associated with lower lymphocyte nadir ( r= -0.367 P= 0.008). Conclusion(s): Lower lymphocyte nadir is associated with poorer overall survivial in this group of patients. Higher low dose lung DVH and larger PTV are associated with lower lymphocyte nadir. These findings shall be confirmed with prospective data in future studies. This also suggests immune preserving radiation strategy in radiation by suppressing low dose lung DVH may improve OS in this group of patients.postprin

Transcriptional regulation of the promoter of the rat frizzled related protein gene by CREB

Frizzled related proteins (Frps) are secreted proteins structurally similar to frizzled receptors; they bind Wnt via the cysteine-rich domain and antagonize the Wnt signaling pathway. In this study, we have investigated the mechanisms regulating the transcriptional regulation of rat Frp (rFrp) promoter. From previous findings, we know that the transcriptional activation domain of rFrp resides in the region -202 to -144 relative to the transcription start site, and that it is essential for efficient promoter activity. The study presented here was designed to identify trans-acting factors that bind to this critical domain of the rFrp promoter and to elucidate the pathway involved in the regulation of rFrp expression. Electrophoretic mobility shift assay (EMSA) demonstrated that specific DNA-protein binding activities fall into two adjacent core sequences with (CTTTGGGGG) at -197 to -189 and (AGATGATGTAA) at -151 to -141 of the rFrp promoter. Reporter assay showed that these core sequences are both required for the activation of rFrp promoter. Mutation within either one or both core sequence drastically reduced the promoter activity. Southwestern blotting showed that the estimated molecular mass of the distinct binding protein to the (AGATGATGTAA) domain is about 43 kDa. Further EMSA suggested CREB as the trans-acting factor in the DNA-protein complex, which was out competed by CREB consensus oligonucleotides and supershifted by anti-CREB antibody. Overexpression of PKA and CREB also transactivated rFrp promoter, and dominant-negative CREB inhibited the promoter activity in transient reporter assays. More importantly, CREB, phosphorylated CREB and the adaptor protein CBP were found binding to the endogenous rFrp promoter using chromatin immunoprecipitation assay. Collectively, our results demonstrate the induction of rFrp promoter activity by PKA and CREB in vitro, and the binding of CREB and CBP to the rFrp promoter core motif in vivo.link_to_subscribed_fulltex

Transcriptional regulation of the promoter of the rat frizzled related protein gene by CREB

Frizzled related proteins (Frps) are secreted proteins structurally similar to frizzled receptors; they bind Wnt via the cysteine-rich domain and antagonize the Wnt signaling pathway. In this study, we have investigated the mechanisms regulating the transcriptional regulation of rat Frp (rFrp) promoter. From previous findings, we know that the transcriptional activation domain of rFrp resides in the region -202 to -144 relative to the transcription start site, and that it is essential for efficient promoter activity. The study presented here was designed to identify trans-acting factors that bind to this critical domain of the rFrp promoter and to elucidate the pathway involved in the regulation of rFrp expression. Electrophoretic mobility shift assay (EMSA) demonstrated that specific DNA protein binding activities fall into two adjacent core sequences with (CTTTGGGGG) at -197 to -189 and (AGATGATGTAA) at -151 to -141 of the rFrp promoter. Reporter assay showed that these core sequences are both required for the activation of rFrp promoter. Mutation within either one or both core sequence drastically reduced the promoter activity. Southwestern blotting showed that the estimated molecular mass of the distinct binding protein to the (AGATGATGTAA) domain is about 43 kDa. Further EMSA suggested CREB as the trans-acting factor in the DNA-protein complex, which was out competed by CREB consensus oligonucleotides and supershifted by anti-CREB antibody. Overexpression of PKA and CREB also transactivated rFrp promoter, and dominant-negative CREB inhibited the promoter activity in transient reporter assays. More importantly, CREB, phosphorylated CREB and the adaptor protein CBP were found binding to the endogenous rFrp promoter using chromatin immunoprecipitation assay. Collectively, our results demonstrate the induction of rFrp promoter activity by PKA and CREB in vitro, and the binding of CREB and CBP to the rFrp promoter core motif in vivo

Suppression of the tumorigenicity of mutant p53-transformed rat embryo fibroblasts through expression of a newly cloned rat nonmuscle myosin heavy chain-B

In our previous study, a rat homolog of human nonmuscle myosin heavy chain-B (nmMHC-B) was identified by mRNA differential display comparing of transformed against nontransformed Rat 6 cells overexpressing mutant p53(val135) gene. The nmMHC-B was found to be expressed in normal Rat 6 embryo fibroblast cell line, but markedly suppressed in the mutant p53(val135) transformed Rat 6 cells. To examine the possible involvement of nmMHC-B in cell transformation, we first cloned and sequenced the full length cDNA of rat nmMHC-B, which was then cloned into an ecdysone-expression vector. The resulting construct was introduced into the T2 cell line, a mutant p53(val135)-transformed Rat 6 cells lacking the expression of the endogenous nmMHC-B, The clonal transfectants, expressing muristerone A-induced nmMHC-B, displayed a slightly flatter morphology and reached to a lower saturation density compared to the parental transformed cells. Reconstitution of actin filamental bundles was also clearly seen in cells overexpressing the nmMHC-B, In soft agar assays, nmMHC-B transfectants formed fewer and substantially smaller colonies than the parental cells in response to muristerone A induction. Moreover, it was strikingly effective in suppressing the tumorigenicity of the T2 cells when tested in nude mice. Thus, the nmMHC-B, known as a component of the cytoskeletal network, may act as a tumor suppressor gene. Our current finding may reveal a novel role of nmMHC-B in regulating cell growth and cell signaling in nonmuscle cells

Should Surgery be Performed in Patient with Marginal Resectable Anaplastic Thyroid Cancer?

ePoster presentationBackground: Anaplastic thyroid cancer (ATC) is rare but nearly lethal thyroid carcinoma. There is a dilemma on whether surgery or patient directed palliative care on patient with marginal resectable tumors. We aim to study the prognostic factor and treatment outcome in patients with extra-thyroidal extensions and lymph node metastasis. Methods: Over 40 years, patients with complete records diagnosed with ATC with extrathyroidal extension or presence of lymph node metastasis were recruited. Medical records were respectively reviewed. Impact on surgery and other treatment modality and other clinicopathological factor on survival were evaluated. Results: Forty three patients (72.1% female) with median age of 72 were included in the study. 34 (79.1%) patients had extra-thyroidal extension, while 21 (48.8%) had lymph node metastasis. Median overall survival was 14.6 weeks. Younger than 70 (p=0.003), patient treated with surgery (p=0.018) or radiotherapy (p<0.001) were the independent predictive factor of longer overall survival. 28 (63.1%) patients underwent operation, while 20 (46.5%) achieved macroscopic clearance (R0/R1) and 8 (18.6%) had gross residual disease during operation (R2). Patient undergoing operation have a longer survival (19.1 vs 5.4 weeks, p=0.001). While debulking surgery (R2) provided a survival benefit for patients with stage IVb disease. (14.7 vs 5.4 weeks, p= 0.035) Conclusions: Debulking surgery followed by radiotherapy could be considered for young patients with marginal resectable ATC. It prolongs survival and palliative patients symptoms

Prescription compliance of prn symptom control medications for terminal cancer patients in an oncology centre in Hong Kong

Conference Theme: Transforming Palliative Car