ΔNp63-restricted viral mimicry response impedes cancer cell viability and remodels tumor microenvironment in esophageal squamous cell carcinoma.

Tumor protein p63 isoform ΔNp63 plays roles in the squamous epithelium and squamous cell carcinomas (SCCs), including esophageal SCC (ESCC). By integrating data from cell lines and our latest patient-derived organoid cultures, derived xenograft models, and clinical sample transcriptomic analyses, we identified a novel and robust oncogenic role of ΔNp63 in ESCC. We showed that ΔNp63 maintains the repression of cancer cell endogenous retrotransposon expression and cellular double-stranded RNA sensing. These subsequently lead to a restricted cancer cell viral mimicry response and suppressed induction of tumor-suppressive type I interferon (IFN-I) signaling through the regulations of Signal transducer and activator of transcription 1, Interferon regulatory factor 1, and cGAS-STING pathway. The cancer cell ΔNp63/IFN-I signaling axis affects both the cancer cell and tumor-infiltrating immune cell (TIIC) compartments. In cancer cells, depletion of ΔNp63 resulted in reduced cell viability. ΔNp63 expression is negatively associated with the anticancer responses to viral mimicry booster treatments targeting cancer cells. In the tumor microenvironment, cancer cell TP63 expression negatively correlates with multiple TIIC signatures in ESCC clinical samples. ΔNp63 depletion leads to increased cancer cell antigen presentation molecule expression and enhanced recruitment and reprogramming of tumor-infiltrating myeloid cells. Similar IFN-I signaling and TIIC signature association with ΔNp63 were also observed in lung SCC. These results support the potential application of ΔNp63 as a therapeutic target and a biomarker to guide candidate anticancer treatments exploring viral mimicry responses.

Improving Outcome of Superior Mediastinal Lymph Node Dissection During Esophagectomy: A Novel Approach Combining Continuous and Intermittent Recurrent Laryngeal Nerve Monitoring.

OBJECTIVE: This study aimed at demonstrating the effects and learning curve of utilizing combined intermittent and continuous recurrent laryngeal nerve (RLN) monitoring for lymphadenectomy during esophagectomy. BACKGROUND: RLN lymphadenectomy is oncologically important but is technically demanding. Vocal cord (VC) palsy as a result from RLN injury, carries significant morbidities. METHODS: This is a retrospective study of consecutive esophageal squamous cell carcinoma (ESCC) patients who underwent transthoracic esophagectomy from 2010 to 2020. Combined nerve monitoring (CNM) included: CNM which involved a periodic stimulating left vagal electrode and intermittent nerve monitoring which utilized a stimulating probe to identify the RLNs. The integrity of the RLNs was assessed both intermittently and continuously. This technique was introduced in 2014. Patients were divided into "before CNM" and "CNM" groups. The primary outcome was the difference in number of RLN lymph nodes harvested and VC palsy rate. Learning curves were demonstrated by cumulative sum (CUSUM) analysis. RESULTS: Two hundred and fifty-five patients were included with 157 patients in "CNM" group. The mean number of RLN lymph nodes harvested was significantly higher (4.31 vs 0.45, P < 0.0001) for the "CNM" group. VC palsy rates were significantly lower (17.8% vs 32.7%, P = 0.007). There was an initial increase in VC palsy rate, peaked at around 46 cases. The increase in lymph nodes harvested above the mean plateaued at around 96 cases. CONCLUSIONS: CNM helped improve bilateral RLN lymphadenectomy. Lymph node harvesting was increased with reduction of VC palsy after a learning curve.

FA01.01: MINIMALLY INVASIVE APPROACH RESULTS IN BETTER OUTCOME COMPARED TO OPEN ESOPHAGECTOMY-A PROPENSITY SCORE MATCHED ANALYSIS.

BACKGROUND: Esophagectomy remains the mainstay treatment for esophageal cancer. Minimally invasive techniques have gained popularity in recent years. Whether minimally invasive methods result in equivalent or superior outcome to open esophagectomy or not is still controversial. The aim of the current study is to compare outcomes of minimally invasive and open esophagectomy from a single institution, using propensity score matching to lessen biases. METHODS: From 1994-2016, 724 patients with squamous cell cancer of the esophagus who underwent esophagectomy were studied. Data were retrieved from a prospectively collected database. Patients were divided into two groups: 453 had open esophagectomy (open group), and 271 had VATS esophagectomy with gastric mobilization either via laparotomy or laparoscopically (MIE group). A propensity score was generated for each patient based on age, gender, tumor level, use of neoadjuvant therapy, American Society of Anaesthesiologists (ASA) score, pathologic stage of disease, site of anastomosis, and residual tumour (R) categories and the two matched groups were compared in clinico-pathological features, morbidity and mortality rates, and long-term survival. All statistical calculations were performed with SPSS version 24 (SPSS, Chicago, IL). RESULTS: A total of 158 patients in MIE and 187 in open group are matched for comparison (1:3 matching). MIE resulted in less blood loss (220 vs 400ml, P < 0.001) but longer operative time (461 vs 305 mins, P < 0.001). Wound infection (3.7% vs 10.7%, P = 0.01) and respiratory complications (29% vs 55.1%, P < 0.001) were also less in MIE group. Except for a higher rate of conduit ischemia (6.3% vs 1.6%, P = 0.02), MIE had comparable surgical outcomes with open technique in rates of anastomotic leakage (5.7% vs 5.3%, P = 0.89), recurrent laryngeal nerve palsy (20.1% vs 18.7%, P = 0.10), reoperation (10.8% vs 8.6%, P = 0.49), and length of postoperative hospital stay (13 vs 14 days, P = 0.50). Lymph node harvest was significantly higher with MIE (35 vs 21, P < 0.001), a longer median survival was also evident compared to the open group (42.3 vs 24.7 months, P = 0.03). CONCLUSION: Although requiring longer operative time, MIE led to less wound and respiratory complications without jeopardizing surgical and oncological outcome. The more comprehensive lymphadenectomy could potentially improve prognosis. DISCLOSURE: All authors have declared no conflicts of interest.

Continuous intraoperative vagus nerve stimulation for monitoring of recurrent laryngeal nerve during minimally invasive esophagectomy.

For squamous cell carcinoma of the esophagus, extended mediastinal lymphadenectomy especially around the bilateral recurrent laryngeal nerves (RLN) is associated with high risk of nerve injury. This does not only result in hoarseness of voice, increase the chance of pulmonary complications, but would also affect the quality of life of patients in the long term. Methods to improve safety of lymphadenectomy are desirable. Continuous intraoperative nerve monitoring (CIONM) based on a system using vagus nerve stimulation was tested. In thyroidectomy, this system has been shown to be useful. Our patient cohort was unselected, with the intent to perform bilateral RLN dissection undergoing video-assisted thoracoscopic (VATS) esophagectomy. Intermittent nerve stimulation for mapping and CIONM were employed to monitor left RLN nodal dissection, while only intermittent stimulation was used for the right RLN. CIONM has the potential to aid RLN dissection. The learning curves for the placement technique of CIONM, the threshold level and the interpretation of myographic amplitude and latency have been overcome. With the availability of nerve mapping and CIONM, more aggressive and thorough nodal dissection may be possible with less fear of RLN injury.

Does preoperative 25-hydroxyvitamin D status significantly affect the calcium kinetics after total thyroidectomy?

BACKGROUND: Although previous studies have suggested that low preoperative 25-hydroxyvitamin D (25-OHD) is a risk factor for hypocalcemia after total thyroidectomy, the impact of preoperative 25-OHD on calcium (Ca)/parathyroid hormone (PTH) kinetics in the immediate postoperative period remains unclear. The study compared the postoperative Ca/PTH kinetics between different preoperative 25-OHD levels. PATIENTS: A total of 281 patients who underwent a total thyroidectomy were analyzed. Serum Ca was measured preoperatively within 1 h after surgery (Ca-D0) and on the following morning (Ca-D1). Preoperative 25-OHD was also measured after overnight fasting while postoperative PTH was checked at skin closure on day 0 (PTH-D0) and on the following morning on day 1 (PTH-D1). The Ca/PTH kinetics were compared between three groups (group I: preoperative 25-OHD < 10 ng/mL; group II: 25-OHD = 10-20 ng/mL; group III: 25-OHD > 20 ng/mL). RESULTS: Group I had significantly lower preoperative Ca (p = 0.016) and Ca-D0 (p = 0.036) but higher PTH-D1 (p = 0.015) than groups II and III. PTH-D0, Ca-D1, and the rate of clinically significant hypocalcemia were similar in the three groups. Group I had a significantly smaller Ca drop (-0.02 vs. 0.01 and 0.02 mmol/L, p = 0.011) and a tendency for a significantly smaller PTH drop (0.4 vs. 0.5 and 1.0 pmol/L, p = 0.073) than groups II and III. PTH-D1 (OR = 1.550) and 25-OHD (OR = 0.958) were independent factors for Ca drop from day 0 to day 1. CONCLUSIONS: Although group I began with lower serum Ca, those patients tended to have a greater PTH response to Ca drop and so preoperative 25-OHD did not significantly affect the overall Ca kinetics from preoperative to day 1.

Efficacy, safety and immunogenicity of a human rotavirus vaccine (RIX4414) in Hong Kong children up to three years of age: a randomized, controlled trial.

BACKGROUND: A phase III, double-blind, randomized, controlled trial was conducted in Hong Kong to evaluate the efficacy, safety and immunogenicity of a human rotavirus vaccine, RIX4414 (Rotarix) against severe rotavirus gastroenteritis in children up to three years of age. METHODS: Healthy infants aged 6-12 weeks were enrolled between 08-December-2003 and 31-August-2005 and received two oral doses of either RIX4414 vaccine (N=1513) or placebo (N=1512) given 2 months apart. Vaccine efficacy was assessed from two weeks post-Dose 2 until the children were two and three years of age. Anti-rotavirus IgA seroconversion rate was calculated pre-vaccination and 1-2 months post-Dose 2 using ELISA (cut-off=20 U/mL) for 100 infants. Safety was assessed until the children were two years of age; serious adverse events (SAEs) were recorded throughout the study period. RESULTS: In children aged two and three years of life, vaccine efficacy against severe rotavirus gastroenteritis was 95.6% (95% CI: 73.1%-99.9%) and 96.1% (95% CI: 76.5%-99.9%), respectively. The seroconversion rate 1-2 months after the second dose of RIX4414 was 97.5% (95% CI: 86.8%-99.9%). At least one SAE was recorded in 439 and 477 infants who were administered RIX4414 and placebo, respectively (p-value=0.130). Six intussusception cases were reported (RIX4414=4; placebo=2) and none was assessed to be vaccine-related. CONCLUSION: RIX4414 was efficacious, immunogenic and safe in the prevention of rotavirus gastroenteritis for at least two years post-vaccination in Hong Kong children.

Do low preoperative vitamin D levels reduce the accuracy of quick parathyroid hormone in predicting postthyroidectomy hypocalcemia?

BACKGROUND: Although some studies have suggested that low preoperative 25-hydroxyvitamin D (25-OHD) levels may increase the risk of hypocalcemia and decrease the accuracy of single quick parathyroid hormone in predicting hypocalcemia after total thyroidectomy, the literature remains scarce and inconsistent. Our study aimed to address these issues. METHODS: Of the 281 consecutive patients who underwent a total/completion total thyroidectomy, 244 (86.8%) did not require any oral calcium and/or calcitriol supplements (group 1), while 37 (13.2%) did (group 2) at hospital discharge. 25-OHD level was checked 1 day before surgery, and postoperative quick parathyroid hormone (PTH) was checked at skin closure (PTH-SC). Postoperative serum calcium was checked regularly. Hypocalcemia was defined by the presence of symptoms or adjusted calcium of <1.90 mmol/L. Significant factors for hypocalcemia were determined by univariate and multivariate analyses. The accuracy of PTH-SC in predicting hypocalcemia was measured by area under a receiver operating characteristic curve (AUC), and the AUC of PTH-SC was compared between patients with preoperative 25-OHD <15 and ≥15 ng/mL via bootstrapping. RESULTS: Preoperative 25-OHD level was not significantly different between groups 1 and 2 (13.1 vs. 12.5 ng/mL, p = 0.175). After adjusting for other significant factors, PTH-SC (odds ratio 2.49, 95% confidence interval 1.52-4.07, p < 0.001) and parathyroid autotransplantation (odds ratio 3.23, 95% confidence interval 1.22-8.60, p = 0.019) were the two independent factors for hypocalcemia. The AUC of PTH-SC was similar between those with 25-OHD <15 and ≥15 ng/mL (0.880 vs. 0.850, p = 0.61) CONCLUSIONS: Low 25-OHD was not a significant factor for hypocalcemia and did not lower the accuracy of quick PTH in predicting postthyroidectomy hypocalcemia.

A synopsis of current haemophilia care in Hong Kong.

OBJECTIVE: To provide a synopsis of current haemophilia care in Hong Kong. DESIGN: Retrospective survey. SETTING: All haematology units of the Hospital Authority in Hong Kong. PATIENTS: All patients with haemophilia A and haemophilia B. RESULTS: To date, there were 222 mild-to-severe haemophilia patients (192 type A, 30 type B) under regular public care in Hong Kong (43% were considered severe, 33% moderate, and 24% mild), which gave a crude prevalence of 6.8/100 000 male inhabitants. A total of 12.8 million units of Factor VIII and 3 million units of Factor IX were prescribed annually. This amounts to 1.83 units of FVIII per capita of the population, which is comparable to that of other developed countries. Leading causes of mortality were human immunodeficiency virus-related complications (10 cases) and cerebral bleeding (2 cases). The life expectancy of patients with severe haemophilia in Hong Kong is improving; currently the oldest patient is 60 years old. Such improved survival may be due to enhanced factor availability, prompt treatment of bleeding episodes at home, safer factor products, and better antiviral treatment. Primary prophylaxis is the accepted standard of care for severe and moderate cases, and "Factor First" has become hospital policy. However, 12 patients continue to present treatment challenges, due to the documented presence of factor inhibitors. In all, 28, 100, and 14 cases respectively were positive for human immunodeficiency virus, hepatitis C virus, and hepatitis B virus; the youngest patients with the corresponding infections being 28, 13, and 22 years old. Comprehensive care with dedicated physiotherapy, surgical support, and radionucleotide synovectomy may reduce morbidity further. CONCLUSION: A multidisciplinary approach can further improve the future care for haemophilia patients in Hong Kong.

High genetic diversity of HIV-1 viruses in Macao, China.

OBJECTIVE: To investigate the molecular epidemiology of recently diagnosed HIV-1 infection in Macao for better understanding the epidemiology in this Chinese city, in context of its relationship with other countries in Asia and the rest of the world. METHODS: Serum samples of HIV positive cases reported between 2005 and 2007 were collected from the Macao Public Health Laboratory. HIV genotype was determined by phylogenetic analysis of sequences from gag, RT, and env regions. RESULTS: A total of 30 HIV positive samples were genotyped. The HIV-1 viruses circulating in Macao were characterized by their relatively high genetic diversity. CRF01_AE was predominant (56%), followed by subtype B (13%), CRF12_BF (10%), G/CRF12_BF, A1/CRF10_AD and CRF07_BC, of which CRF12_BF and G/CRF12_BF were first reported in Southeast Asia. Phylogenetic analysis showed that there was no clear clustering of CRF01_AE strains but a distinct CRF12_BF cluster associated with injection drug use could be delineated. CONCLUSION: The results suggested that there were multiple introductions of HIV strains in Macao that have been circulating for an extended period of time, superimposed by an outbreak in injection drug users.

Using protection motivation theory to predict condom usage and assess HIV health communication efficacy in Singapore.

The number of individuals infected with HIV/AIDS continues to rise in Asia. Condom use is considered to be the first line of defense against AIDS (UNAIDS, 2006). Using protection motivation theory (Rogers, 1983), this research aims to first understand the factors affecting condom usage intention among homosexual and heterosexual men in Singapore, and then to utilize those findings to assess the efficacy of HIV-directed health communications. We collected survey data from 484 men and analyzed the data using hierarchical regression and structural equation modeling. We found self-efficacy to be a significant predictor for both groups of men, together with perceived severity for homosexuals and response efficacy for heterosexuals. Next, we analyzed HIV-directed condom usage communication materials and found that the use of threat appeal themes is more common than themes promoting self-efficacy. Implications for health communications and policy are discussed.