Pain Relief After Total Knee Arthroplasty with Intravenous and Periarticular Corticosteroid: A Randomized Controlled Trial.

BACKGROUND: Total knee arthroplasty (TKA) is a cost-effective procedure, but it is also associated with substantial postoperative pain. The present study aimed to compare pain relief and functional recovery after TKA among groups that received intravenous corticosteroids, periarticular corticosteroids, or a combination of both. METHODS: This randomized, double-blinded clinical trial in a local institution in Hong Kong recruited 178 patients who underwent primary unilateral TKA. Six of these patients were excluded because of changes in surgical technique; 4, because of their hepatitis B status; 2, because of a history of peptic ulcer; and 2, because they declined to participate in the study. Patients were randomized 1:1:1:1 to receive placebo (P), intravenous corticosteroids (IVS), periarticular corticosteroids (PAS), or a combination of intravenous and periarticular corticosteroids (IVSPAS). RESULTS: The pain scores at rest were significantly lower in the IVSPAS group than in the P group over the first 48 hours (p = 0.034) and 72 hours (p = 0.043) postoperatively. The pain scores during movement were also significantly lower in the IVS and IVSPAS groups than in the P group over the first 24, 48, and 72 hours (p ≤ 0.023 for all). The flexion range of the operatively treated knee was significantly better in the IVSPAS group than in the P group on postoperative day 3 (p = 0.027). Quadriceps power was also greater in the IVSPAS group than in the P group on postoperative days 2 (p = 0.005) and 3 (p = 0.007). Patients in the IVSPAS group were able to walk significantly further than patients in the P group in the first 3 postoperative days (p ≤ 0.003). Patients in the IVSPAS group also had a higher score on the Elderly Mobility Scale than those in the P group (p = 0.036). CONCLUSIONS: IVS and IVSPAS yielded similar pain relief, but IVSPAS yielded a larger number of rehabilitation parameters that were significantly better than those in the P group. This study provides new insights into pain management and postoperative rehabilitation following TKA. LEVEL OF EVIDENCE: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

Transgender health and the impact of aging and menopause.

Gender affirming hormone therapy (GAHT) is used by many transgender people to reduce gender incongruence and improve psychological functioning. As GAHT shares many similarities with menopausal hormone therapy, clinicians supporting people through menopause are ideally placed to manage GAHT. This narrative review provides an overview of transgender health and discusses long-term effects of GAHT to consider when managing transgender individuals across the lifespan. Menopause is less relevant for transgender individuals who take GAHT (often given lifelong) to achieve sex steroid concentrations generally in the range of the affirmed gender. For people using feminizing hormone therapy, there is an elevated risk of venous thromboembolism, myocardial infarction, stroke and osteoporosis relative to cisgender individuals. For trans people using masculinizing hormone therapy, there is an increased risk of polycythemia, probable higher risk of myocardial infarction and pelvic pain which is poorly understood. Proactive mitigation of cardiovascular risk factors is important for all transgender people and optimization of bone health is important for those using feminizing hormones. With a lack of research to guide GAHT in older age, a shared decision-making approach is recommended for the provision of GAHT to achieve individual goals whilst minimizing potential adverse effects.

Are clinical outcomes affected by laminoplasty method and K-line in patients with cervical ossification of posterior longitudinal ligament? A multicenter study.

BACKGROUND: Open-door laminoplasty (ODL) and French-door laminoplasty (FDL) are the main laminoplasty techniques used to treat cervical ossification of the posterior longitudinal ligament (C-OPLL). However, few studies have compared the outcomes of ODL and modified FDL (mFDL) for C-OPLL. We explored the differences in outcomes between ODL and mFDL for C-OPLL and analyzed the technical efficacy of each procedure in patients with K-line (+) or (-) C-OPLL. METHODS: From January 2010 to December 2015, 202 patients with K-line (+) or (-) C-OPLL were retrospectively recruited from 4 institutions. Clinical outcomes were evaluated using the Japanese Orthopaedic Association (JOA) score, JOA score recovery rate, operative time, blood loss, and complications. Univariate analysis and binary logistic regression models were adjusted for confounding factors. RESULTS: Two hundred patients (mFDL, n = 69; ODL, n = 131) with a median follow-up of 42 months (range 36-54 months) were included. The postoperative JOA score significantly improved in both groups (P < 0.05). After adjusting for confounding factors, there was a statistically significant difference in blood loss (≥ 300 mL) between the two groups (P = 0.005), but there was no significant difference in the postoperative JOA score (≥ 14) (P = 0.062), JOA score recovery rate (≥ 0.82) (P = 0.187), or operative time (≥ 90 min) (P = 0.925). C5 palsy tended to occur more often in the mFDL group, although the difference was not significant (P > 0.05). The stratified analysis of the K-line status showed more blood loss in K-line (+) patients who underwent mFDL, but there was no significant difference in the postoperative JOA score, JOA score recovery rate, or operative time between the ODL and mFDL groups. Additionally, there was no significant difference in blood loss, postoperative JOA score, JOA score recovery rate, or operative time among all patients with K-line (+) or (-) C-OPLL in both groups. CONCLUSIONS: Both ODL and mFDL are effective for patients with C-OPLL. However, more blood loss tends to occur during mFDL. This study showed no significant difference in the operative time or incidence of complications between the two techniques. The efficacy of ODL and mFDL was not affected by the K-line status (+ or -) in patients with C-OPLL.

Update on the Recommendations on Breast Cancer Screening by the Cancer Expert Working Group on Cancer Prevention and Screening.

Breast cancer (BC) is the most common cancer among women in Hong Kong. The Food and Health Bureau commissioned The University of Hong Kong (HKU) to conduct the Hong Kong Breast Cancer Study (HKBCS) with the aim of identifying relevant risk factors for BC in Hong Kong and developing a locally validated BC risk assessment tool for Hong Kong Chinese women. After consideration of the most recent international and local scientific evidence including findings of the HKBCS, the Cancer Expert Working Group on Cancer Prevention and Screening (CEWG) has reviewed and updated its BC screening recommendations. Existing recommendations were preserved for women at high risk and slightly changed for women at moderate risk. The following major updates have been made concerning recommendations for other women in the general population: Women aged 44 to 69 with certain combinations of personalised risk factors (including presence of history of BC among first-degree relative, a prior diagnosis of benign breast disease, nulliparity and late age of first live birth, early age of menarche, high body mass index and physical inactivity) putting them at increased risk of BC are recommended to consider mammography screening every 2 years. They should discuss with their doctors on the potential benefits and harms before undergoing mammography screening. A risk assessment tool for local women (eg, one developed by HKU) is recommended to be used for estimating the risk of developing BC with regard to the personalised risk factors described above.

Relationships between resilience and quality of life in parents of children with cancer.

CLINICALTRIALS.GOV ID: NCT03631485.

Cancer Grade Model: a multi-gene machine learning-based risk classification for improving prognosis in breast cancer.

BACKGROUND: Prognostic stratification of breast cancers remains a challenge to improve clinical decision making. We employ machine learning on breast cancer transcriptomics from multiple studies to link the expression of specific genes to histological grade and classify tumours into a more or less aggressive prognostic type. MATERIALS AND METHODS: Microarray data of 5031 untreated breast tumours spanning 33 published datasets and corresponding clinical data were integrated. A machine learning model based on gradient boosted trees was trained on histological grade-1 and grade-3 samples. The resulting predictive model (Cancer Grade Model, CGM) was applied on samples of grade-2 and unknown-grade (3029) for prognostic risk classification. RESULTS: A 70-gene signature for assessing clinical risk was identified and was shown to be 90% accurate when tested on known histological-grade samples. The predictive framework was validated through survival analysis and showed robust prognostic performance. CGM was cross-referenced with existing genomic tests and demonstrated the competitive predictive power of tumour risk. CONCLUSIONS: CGM is able to classify tumours into better-defined prognostic categories without employing information on tumour size, stage, or subgroups. The model offers means to improve prognosis and support the clinical decision and precision treatments, thereby potentially contributing to preventing underdiagnosis of high-risk tumours and minimising over-treatment of low-risk disease.

Relationships among hope, psychological well-being and health-related quality of life in childhood cancer survivors.

This cross-sectional study examined the level of hope among Hong Kong childhood cancer survivors and investigated the relationships among hope, depressive symptoms, self-esteem and health-related quality of life. We recruited 176 survivors aged 10-16 years who underwent medical follow-ups at the outpatient clinic. This study revealed that lower levels of hope were associated with an increase in depressive symptoms and reductions in self-esteem and health-related quality of life. Our results contribute to novel findings by demonstrating that hope may be a significant factor associated with health-related quality of life. This understanding could increase healthcare professionals' awareness about the psychological needs of childhood cancer survivors.

Dissemination and implementation of national physical activity, sedentary behaviour, and/or sleep guidelines among community-dwelling adults aged 18 years and older: a systematic scoping review and suggestions for future reporting and research.

Strategies for dissemination (purposive distribution of a guideline to specific audiences) and implementation (actions to support the general public in meeting guideline recommendations/behavioural benchmarks) of national movement guidelines (physical activity (PA), sedentary behaviour, and sleep) have yet to be synthesized. The purpose of this systematic scoping review was to identify strategies for dissemination and implementation of national PA, sedentary behaviour, and/or sleep guidelines among community-dwelling adults (aged >18 years) and/or stakeholders in Canada and analogous countries. Five search approaches (e.g., published literature, grey literature, targeted web-based, custom Google, and content expert consultation) identified records (e.g., empirical studies, organizational reports, website pages, or guideline messages) that discussed and/or evaluated dissemination or implementation strategies for a prespecified list of guidelines. A modified strategy classification system was developed to chart the data. Forty-seven reports met inclusion criteria. Dissemination strategies (n = 42) were more frequently reported than implementation strategies (n = 24). Implementation strategies were more frequently evaluated (n = 13 vs. 7 dissemination strategies) and associated with positive outcomes. The 13 studies that evaluated strategies were at high or serious risk of bias. We identified limited information about the dissemination and implementation of national movement guidelines and identified strategies were rarely evaluated. Greater efforts are required to increase the impact of guidelines among the general public and stakeholders and to build the evidence base in this field. (Open Science Framework registration: https://osf.io/4tyw3.) Novelty An adapted movement guideline dissemination and implementation strategy classification framework is provided. Knowledge translation efforts should be documented and evaluated to advance science and practice in the movement guideline field.

Preoperative optimization to prevent periprosthetic joint infection in at-risk patients.

Periprosthetic joint infection (PJI) remains an important complication with devastating consequences after total joint arthroplasties. With the increasing number of arthroplasties worldwide, the number of PJI will increase correspondingly with a significant economic burden to our healthcare system. It is likely impossible to completely eradicate PJI; hence, assessment and optimization of its risk factors to preventing such a disastrous complication will be the key. There are many strategies to prevent PJI in the preoperative, intraoperative, or postoperative phases. The preoperative assessment provides a unique opportunity to screen and diagnose underlying comorbidities and optimize modifiable risk factors before elective surgeries. In this review, we will focus on current literature in preoperative assessment of various modifiable risk factors and share the experience and practical approach in our institution in preoperative optimization to reduce PJI in total joint arthroplasties.

Universal haemoglobin A1c screening reveals high prevalence of dysglycaemia in patients undergoing total knee arthroplasty.

INTRODUCTION: Diabetes mellitus is an established modifiable risk factor for periprosthetic joint infection (PJI). Haemoglobin A1c (HbA1c) is a glycaemic marker that correlates with diabetic complications and PJI. As diabetes and prediabetes are frequently asymptomatic, and there is increasing evidence to suggest a correlation between dysglycaemia and osteoarthritis, it is reasonable to provide HbA1c screening before total knee arthroplasty (TKA). The aim of the present study was to determine the prevalence of dysglycaemia in patients who underwent TKA and investigate whether HbA1c screening and optimisation of glycaemic control before TKA affects the incidence of PJI after TKA. METHODS: Patients who underwent primary TKA before and after routine HbA1c screening was introduced in our unit were reviewed. Prediabetes and diabetes were defined according to the American Diabetes Association. Patients with HbA1c ≥7.5% were referred to an endocrinologist for optimisation of glycaemic control before TKA. The incidence PJI, defined according to the Musculoskeletal Infection Society criteria, was recorded. RESULTS: A total of 729 patients (934 knees) had HbA1c screening before TKA. Of them, 17 (2.3%) and 184 (25.2%) patients had known prediabetes and diabetes, respectively, and 265 (36.4%) and 12 (1.6%) had undiagnosed prediabetes and diabetes, respectively. The incidence of PJI was significantly lower in all patients who received HbA1c screening compared with those who did not (0.2% vs 1.02%, P=0.027). CONCLUSION: Screening for HbA1c before TKA provides a cost-effective opportunity to identify undiagnosed dysglycaemia. Patients identified as having dysglycaemia receive modified treatment, significantly reducing the rate of PJI when compared with historical controls.

Whole Brain Radiotherapy Versus Stereotactic Radiosurgery in Poor-Prognosis Patients with One to 10 Brain Metastases: A Randomised Feasibility Study.

AIMS: A significant proportion of patients with brain metastases have a poor prognosis, with a life expectancy of 3-6 months. To determine the optimal radiotherapeutic strategy for brain metastases in this population, we conducted a randomised feasibility study of whole brain radiotherapy (WBRT) versus stereotactic radiosurgery (SRS). MATERIALS AND METHODS: Patients with a life expectancy of 3-6 months and between one and 10 brain metastases with a diameter ≤4 cm were enrolled at six Canadian cancer centres. Patients were randomly assigned (1:1) to receive either WBRT (20 Gy in five fractions) or SRS (15 Gy in one fraction). The primary end point was the rate of accrual per month. Secondary feasibility and clinical end points included the ratio of accrued subjects to screened subjects. This trial is registered with ClinicalTrials.gov (number NCT02220491). RESULTS: In total, 210 patients were screened to enrol 22 patients into the trial; 20 patients were randomised between the two arms. Two patients did not receive treatment because one patient died and another patient withdrew consent after being enrolled. Patients were accrued between January 2015 and November 2017; the accrual rate was 0.63 patients/month. The most common reasons for exclusion were anticipated median survival outside the required range (n = 40), baseline Karnofsky Performance Score below 70 (n = 28) and more than 10 brain metastases (n = 28). The median follow-up was 7.0 months and the median survival was 7.0 months for all patients in the trial. The median intracranial progression-free survival was 1.8 months in the SRS arm and 9.2 months in the WBRT arm. There were five grade 3+ toxicities in the SRS arm and one grade 3+ toxicity in the WBRT arm; no grade 5 toxicities were observed. The cumulative rates of retreatment were 40% in the SRS arm and 40% in the WBRT arm. CONCLUSIONS: A randomised trial evaluating WBRT versus SRS in patients with one to 10 metastases and a poor prognosis is feasible. A slower than expected accrual rate and difficulties with accurate prognostication were identified as issues in this feasibility study. A larger phase III randomised trial is planned to determine the optimal treatment in this patient population.

Recommendations on prevention and screening for colorectal cancer in Hong Kong.

Colorectal cancer is the commonest cancer in Hong Kong. The Cancer Expert Working Group on Cancer Prevention and Screening was established in 2002 under the Cancer Coordinating Committee to review local and international scientific evidence, assess and formulate local recommendations on cancer prevention and screening. At present, the Cancer Expert Working Group recommends that average-risk individuals aged 50 to 75 years and without significant family history consult their doctors to consider screening by: (1) annual or biennial faecal occult blood test, (2) sigmoidoscopy every 5 years, or (3) colonoscopy every 10 years. Increased-risk individuals with significant family history such as those with a first-degree relative diagnosed with colorectal cancer at age ≤60 years; those who have more than one first-degree relative diagnosed with colorectal cancer irrespective of age at diagnosis; or carriers of genetic mutations associated with familial adenomatous polyposis or Lynch syndrome should start colonoscopy screening earlier in life and repeat it at shorter intervals.

Recommendations on prevention and screening for breast cancer in Hong Kong.

In Hong Kong, breast cancer is the most common cancer among women and poses a significant health care burden. The Cancer Expert Working Group on Cancer Prevention and Screening (CEWG) was set up in 2002 by the Cancer Coordinating Committee to review and assess local and international scientific evidence, and to formulate recommendations for cancer prevention and screening. After considering the local epidemiology, emerging scientific evidence, and local and overseas screening practices, the CEWG concluded that it was unclear whether population-based breast cancer screening did more harm than good in local asymptomatic women at average risk. The CEWG considers that there is insufficient evidence to recommend for or against population-based mammography screening for such individuals. Women who consider breast cancer screening should be adequately informed about the benefits and harms. The CEWG recommends that all women adopt primary preventive measures, be breast aware, and seek timely medical attention for suspicious symptoms. For women at high risk of breast cancer, such as carriers of confirmed BRCA1/2 deleterious mutations and those with a family history of breast cancer, the CEWG recommends that they seek doctor's advice for annual mammography screening and the age at which the process should commence. Additional annual screening by magnetic resonance imaging is recommended for confirmed BRCA1/2 mutation carriers or women who have undergone radiation therapy to the chest between the age of 10 and 30 years. Women at moderate risk of breast cancer should discuss with doctors the pros and cons of breast cancer screening before making an informed decision about mammography screening every 2 to 3 years.

Adventure-based training to promote physical activity and reduce fatigue among childhood cancer survivors: A randomized controlled trial.

BACKGROUND: Cancer-related fatigue is one of the most distressing symptoms reported by childhood cancer survivors. Despite the body of evidence that regular physical activity helps alleviate cancer-related fatigue, insufficient participation in physical activity is frequently observed among childhood cancer survivors. OBJECTIVES: This study examined the effectiveness of an adventure-based training programme in promoting physical activity, reducing fatigue, and enhancing self-efficacy and quality of life among Hong Kong Chinese childhood cancer survivors. DESIGN: A prospective randomised controlled trial. SETTINGS: A paediatric oncology outpatient clinic, a non-governmental organisation, and a non-profit voluntary organisation. PARTICIPANTS: Hong Kong Chinese childhood cancer survivors aged 9-16 years who reported symptoms of fatigue and had not engaged in regular physical exercise in the past 6 months. METHODS: The experimental group underwent a 4-day adventure-based training programme. The control group received a placebo intervention. The primary outcome was fatigue at 12 months. Secondary outcomes were physical activity levels, self-efficacy and quality of life at 12 months. Data collection was conducted at baseline, and 6 and 12 months after the intervention began. We performed intention-to-treat analyses. RESULTS: From 6 January, 2014 to 8 June, 2015, we randomly assigned 222 eligible childhood cancer survivors to either an experimental (n = 117) or a control group (n = 105). The experimental group showed statistically significantly lower levels of cancer-related fatigue (P < 0.001), higher levels of self-efficacy (P < 0.001) and physical activity (P < 0.001), and better quality of life (P < 0.01) than the control group at 12 months. CONCLUSIONS: This study provides evidence that adventure-based training is effective in promoting physical activity, reducing cancer-related fatigue, and enhancing self-efficacy and quality of life among Hong Kong Chinese childhood cancer survivors. These results may help inform parents and healthcare professionals that regular physical activity is crucial for the physical and psychological wellbeing and quality of life of childhood cancer survivors.

An automated quantitative DNA image cytometry system detects abnormal cells in cervical cytology with high sensitivity.

OBJECTIVE: To evaluate the performance of an automated DNA-image-cytometry system as a tool to detect cervical carcinoma. METHODS: Of 384 liquid-based cervical cytology samples with available biopsy follow-up were analyzed by both the Imager System and a high-risk HPV test (Cobas). RESULTS: The sensitivity and specificity of Imager System for detecting biopsy proven high-grade squamous intraepithelial lesion (HSIL, cervical intraepithelial neoplasia [CIN]2-3) and carcinoma were 89.58% and 56.25%, respectively, compared to 97.22% and 23.33% of HPV test but additional HPV 16/18 genotyping increased the specificity to 69.58%. The sensitivity and specificity of the Imager System for predicting HSIL+ (CIN2-3+) lesions among atypical squamous cells of undetermined significance samples were 80.00% and 70.53%, respectively, compared to 100% and 11.58% of HPV test whilst the HPV 16/18 genotyping increased the specificity to 77.89%. Among atypical squamous cells-cannot exclude HSIL, the sensitivity and specificity of Imager System for predicting HSIL+ (CIN2-3+) lesions upon follow up were 82.86% and 33.33%%, respectively, compared to 97.14% and 4.76% of HPV test and the HPV 16/18 genotyping increased the specificity to 19.05%. Among low-grade squamous intraepithelial lesion cases, the sensitivity and specificity of the Imager System for predicting HSIL+ (CIN2-3+) lesions were 66.67% and 35.71%%, respectively, compared to 66.67% and 29.76% of HPV test while HPV 16/18 genotyping increased the specificity to 79.76%. The overall results of imager and high-risk HPV test agreed in 69.43% (268) of all samples. CONCLUSIONS: The automated imager system and HPV 16/18 genotyping can enhance the specificity of detecting HSIL+ (CIN2-3+) lesions.

Atypical femur fractures: a survey of current practices in orthopedic surgery.

The results of a self-administered online survey demonstrate that orthopedic surgeons' management practices for AFF are variable. These data will inform the development of clinical practice guidelines. INTRODUCTION: We aimed to determine current AFF treatment practices of orthopedic surgeons to inform clinical practice guideline development. METHODS: A self-administered online survey was developed and sequentially posted on the Orthopaedic Trauma Association (OTA) website from July to August 2015 and the Canadian Orthopaedic Association (COA) website from December 2015 to January 2016. Level of confidence in diagnosis and treatment as well as treatment preferences between respondents who self-identified as trauma surgeons vs. non-trauma surgeons were compared. RESULTS: A total of 172 completed surveys were obtained (OTA, N = 100, 58%; COA, N = 72, 8%). Seventy-eight percent of respondents had treated ≥1 AFF in the previous 6 months. Seventy-six percent reported feeling extremely or very confident in diagnosing AFF (trauma 84% vs. non-trauma surgeons 70%, p = 0.04), and 63% reported feeling extremely or very confident in treating AFF (trauma 82%, non-trauma surgeons 50%, p < 0.01). Preferred management for complete and symptomatic incomplete AFFs was surgical fixation with a cephalomedullary nail (CMN) by 88 and 79%, respectively, while close follow-up was preferred for asymptomatic incomplete AFFs in 72% of respondents. Trauma surgeons used the CMN more frequently than non-trauma surgeons (90 vs. 76% p = 0.03). In patients with bilateral AFFs, with one side surgically treated, 56% were extremely likely to surgically treat the contralateral side, if symptomatic. Most felt guidelines (81%) and educational resources (73%) would be valuable. CONCLUSIONS: Current orthopedic treatment practices for AFFs are variable. The results of this survey will inform the development of practice guidelines and educational resources.

Healthy Eating for Life English as a second language curriculum: applying the RE-AIM framework to evaluate a nutrition education intervention targeting cancer risk reduction.

Medically underserved US immigrants are at an increased risk for death from preventable or curable cancers due to economic, cultural, and/or linguistic barriers to medical care. The purpose of this study was to describe the evaluation of the pilot study of the Healthy Eating for Life (HE4L) English as a second language curriculum. The Reach, Effectiveness Adoption, Implementation, Maintenance (RE-AIM) model was used to design a mixed-methods approach to the evaluation of the HE4L curriculum. Successful implementation was dependent upon enthusiastic teacher and manager support of the curriculum, teachers' ability to flexibly apply the curriculum to meet student needs, and researcher provision of curriculum workbooks. HE4L can be implemented successfully in various adult education settings to teach healthy eating behaviors and English language principles. Scale-up of HE4L may depend on the development of an online version of the curriculum to avoid the costs associated with printing and distributing curriculum materials.

MicroRNA-377 suppresses initiation and progression of esophageal cancer by inhibiting CD133 and VEGF.

Esophageal cancer is one of the most lethal cancers worldwide with poor survival and limited therapeutic options. The discovery of microRNAs created a new milestone in cancer research. miR-377 is located in chromosome region 14q32, which is frequently deleted in esophageal squamous cell carcinoma (ESCC), but the biological functions, clinical significance and therapeutic implication of miR-377 in ESCC are largely unknown. In this study, we found that miR-377 expression was significantly downregulated in tumor tissue and serum of patients with ESCC. Both tumor tissue and serum miR-377 expression levels were positively correlated with patient survival. Higher serum miR-377 expression was inversely associated with pathologic tumor stage, distant metastasis, residual tumor status and chemoradiotherapy resistance. The roles of miR-377 in suppressing tumor initiation and progression, and the underlying molecular mechanisms were investigated. Results of in vitro and in vivo experiments showed that miR-377 overexpression inhibited the initiation, growth and angiogenesis of ESCC tumors as well as metastatic colonization of ESCC cells, whereas silencing of miR-377 had opposite effects. Mechanistically, miR-377 regulated CD133 and VEGF by directly binding to their 3' untranslated region. Moreover, systemic delivery of formulated miR-377 mimic not only suppressed tumor growth in nude mice but also blocked tumor angiogenesis and metastasis of ESCC cells to the lungs without overt toxicity to mice. Collectively, our study established that miR-377 plays a functional and significant role in suppressing tumor initiation and progression, and may represent a promising non-invasive diagnostic and prognostic biomarker and therapeutic strategy for patients with ESCC.

Detecting intratumoral heterogeneity of EGFR activity by liposome-based in vivo transfection of a fluorescent biosensor.

Despite decades of research in the epidermal growth factor receptor (EGFR) signalling field, and many targeted anti-cancer drugs that have been tested clinically, the success rate for these agents in the clinic is low, particularly in terms of the improvement of overall survival. Intratumoral heterogeneity is proposed as a major mechanism underlying treatment failure of these molecule-targeted agents. Here we highlight the application of fluorescence lifetime microscopy (FLIM)-based biosensing to demonstrate intratumoral heterogeneity of EGFR activity. For sensing EGFR activity in cells, we used a genetically encoded CrkII-based biosensor which undergoes conformational changes upon tyrosine-221 phosphorylation by EGFR. We transfected this biosensor into EGFR-positive tumour cells using targeted lipopolyplexes bearing EGFR-binding peptides at their surfaces. In a murine model of basal-like breast cancer, we demonstrated a significant degree of intratumoral heterogeneity in EGFR activity, as well as the pharmacodynamic effect of a radionuclide-labeled EGFR inhibitor in situ. Furthermore, a significant correlation between high EGFR activity in tumour cells and macrophage-tumour cell proximity was found to in part account for the intratumoral heterogeneity in EGFR activity observed. The same effect of macrophage infiltrate on EGFR activation was also seen in a colorectal cancer xenograft. In contrast, a non-small cell lung cancer xenograft expressing a constitutively active EGFR conformational mutant exhibited macrophage proximity-independent EGFR activity. Our study validates the use of this methodology to monitor therapeutic response in terms of EGFR activity. In addition, we found iNOS gene induction in macrophages that are cultured in tumour cell-conditioned media as well as an iNOS activity-dependent increase in EGFR activity in tumour cells. These findings point towards an immune microenvironment-mediated regulation that gives rise to the observed intratumoral heterogeneity of EGFR signalling activity in tumour cells in vivo.