Paediatric high-grade osteosarcoma and its prognostic factors: a 10-year retrospective study.

INTRODUCTION: This retrospective study was conducted to identify the characteristics of paediatric high-grade osteosarcoma and define its prognostic factors. METHODS: We identified paediatric patients (aged <19 years at diagnosis) diagnosed with high-grade osteosarcoma from 1 January 2009 to 31 December 2018 in two hospitals in Hong Kong, then retrospectively evaluated their medical records to identify prognostic factors. RESULTS: In total, 52 patients were included in this study (22 girls, 42.3%). Femoral tumour was the most common form of osteosarcoma. Most patients (78.8%) had localised disease at diagnosis. The lung was the most common site of metastasis. Almost half (n=23, 46.9%) of the patients showed a good response to chemotherapy (ie, chemonecrosis >90%). Most patients (n=40, 80%) underwent limb-salvage surgery. The event-free survival and overall survival rates were 55.8% and 71.2%, respectively. Prognostic factors independently associated with poor event-free survival and poor overall survival were the presence of metastasis at diagnosis, poor tumour chemonecrosis, and the need for amputation. CONCLUSION: This multicentre review of paediatric high-grade osteosarcoma showed that the baseline patient demographics, event-free survival, and overall survival in Hong Kong were similar to previous findings in other countries. Patients with metastatic disease at diagnosis and poor chemonecrosis had worse survival outcomes. Molecular analyses of genetic abnormalities may help to identify targeted therapies in future studies.

Improved risk stratification of nasopharyngeal cancer by targeted sequencing of Epstein-Barr virus DNA in post-treatment plasma.

BACKGROUND: Quantitative measurement of plasma Epstein-Barr virus (EBV) DNA by real-time PCR at the end of primary treatment is a robust prognostic marker for nasopharyngeal carcinoma (NPC) patients. However, up to 40% of patients who would later develop disease recurrence had undetectable post-treatment plasma EBV DNA. Targeted sequencing for the entire EBV genome potentially allows a more comprehensive and unbiased detection of plasma EBV DNA and enables the use of other parameters such as fragment size as biomarkers. Hence, we explored if plasma EBV DNA sequencing might allow more accurate prognostication of NPC patients. PATIENTS AND METHODS: Plasma samples collected from 769 patients with stage IIB-IVB NPC at 6-8 weeks after radiotherapy were analysed using targeted sequencing for EBV DNA. RESULTS: The sensitivities of the PCR-based analysis, at a cut-off of any detectable levels of plasma EBV DNA, for prediction of local and distant recurrences were 42.3% and 85.3%, respectively. The sequencing-based analysis (involving quantitation and size profiling) achieved better performance for both local and distant recurrences than PCR. Using a cut-off of the proportion of plasma EBV DNA deduced by sequencing at 0.01%, the sensitivities of the sequencing-based analysis for local and distant recurrences were 88.5% and 97.1%, with the resultant negative predictive values of 99.1% and 99.4%, respectively. Among patients with undetectable EBV DNA on quantitative PCR, sequencing could further define a subgroup that enjoyed superior survival outcomes based on the proportion of plasma EBV DNA, with a 5-year progression-free survival (PFS) approaching 90%. On multivariate analysis, sequencing-based quantitative level of plasma EBV DNA was the independent prognostic factor with the highest hazard ratio for prediction of overall survival and PFS. CONCLUSION: NPC prognostication using post-treatment plasma EBV DNA could be enhanced through sequencing.

Integrating postradiotherapy plasma Epstein-Barr virus DNA and TNM stage for risk stratification of nasopharyngeal carcinoma to adjuvant therapy.

BACKGROUND: After curative radiotherapy (RT) or chemoradiation (CRT), there is no validated tool to accurately identify patients for adjuvant therapy in nasopharyngeal carcinoma (NPC). Post-RT circulating plasma Epstein-Barr virus (EBV) DNA can detect minimal residual disease and is associated with recurrence and survival independent of TNM (tumor-lymph node-metastasis) stage. We aimed to develop and validate a risk model for stratification of NPC patients after completion of RT/CRT to observation or adjuvant therapy. PATIENTS AND METHODS: The prospective multicenter 0502 EBV DNA screening cohort (Hong Kong NPC Study Group 0502 trial) enrolled from 2006 to 2015 (n = 745) was used for model development. For internal validation, we pooled independent patient cohorts from prospective clinical studies enrolled from 1997 to 2006 (n = 340). For external validation, we used retrospective cohort of NPC patients treated at Sun Yat-sen University Cancer Center from 2009 to 2012 (n = 837). Eligible patients had histologically confirmed NPC of Union for International Cancer Control (UICC) 7th Edition stage II-IVB who completed curative RT/CRT with or without neoadjuvant chemotherapy, had post-RT EBV DNA tested within 120 days after RT and received no adjuvant therapy. The primary end point was overall survival (OS). We used recursive-partitioning analysis (RPA) to classify patients into groups of low, intermediate, and high risk of death. RESULTS: Combining post-RT EBV DNA level (0, 1-49, 50-499, and ≥500 copies/ml) and TNM stage (II, III, IVAB), RPA model classified patients into low-, intermediate-, and high-risk groups with 5-year OS of 89.4%, 78.5% and 37.2%, respectively. The RPA low-risk group had comparable OS to TNM stage II (5-year OS 88.5%) but identified more patients (64.8% versus stage II 28.1%) that could potentially be spared adjuvant therapy toxicity. The RPA model (c-index 0.712) showed better risk discrimination than either the TNM stage (0.604) or post-RT EBV DNA alone (0.675) with improved calibration and consistence. These results were validated in both internal and external cohorts. CONCLUSION: Combining post-RT EBV DNA and TNM stage improved risk stratification in NPC.

The Use of Post-ablation Stimulated Thyroglobulin in Predicting Clinical Outcomes in Differentiated Thyroid Carcinoma - What Cut-off Values Should We Use?

AIMS: Recently published international guidelines recommended using the stimulated thyroglobulin (sTg) post-radioactive iodine (RAI) ablation, in conjunction with tumour stage, as a risk stratification factor. The choice of cut-off values for sTg, namely 1 and 10 ng/ml, was, however, largely based on the functional sensitivities of the assays used, with relatively few published data addressing the prognostic impact of alternative cut-off values. Our study aims to provide data on the prognostic value of sTg at different levels of sensitivities and specificities. MATERIALS AND METHODS: We conducted a retrospective review of all adult cases of differentiated thyroid carcinoma receiving RAI ablation at our centre from 2008 to 2010. All patients had sTg measured at around 6 months post-ablation. The functional sensitivity of our assay was 0.5 ng/ml. The outcome was adverse clinical event, defined as cancer-related death, persistent macroscopic disease demonstrable on imaging (including radioisotope scan) and/or receiving further treatment for persistent or recurrent disease. A receiver operating characteristic (ROC) analysis was carried out. RESULTS: We identified 140 patients treated in the review period, with 106 of them suitable for further analysis. The reasons for exclusion included the presence of anti-thyroglobulin antibodies and medullary or anaplastic histological subtypes. Most (54.7%) had intermediate-risk disease as per the American Thyroid Association classification (2009). The median follow-up duration was 6.4 years; the minimum, excluding deaths, was 5.0 years. ROC analysis showed that the optimal cut-off value of sTg for predicting adverse clinical events was >1.0 ng/ml, associated with a sensitivity of 90.9%, a specificity of 81.0%, a positive predictive value of 55.6% and a negative predictive value of 97.1%. CONCLUSION: Based on ROC analysis of sensitivities and specificities, our data showed that a post-ablation sTg value of 1 ng/ml is the optimal cut-off in prognostication of adverse clinical events.

Evidence for Endovascular Simulation Training: A Systematic Review.

BACKGROUND: Simulation training in endovascular surgery provides opportunities for trainees to practice and learn from non-patient based experience. Several types of endovascular simulators are available commercially. Previous studies on endovascular simulation training can be categorized into trials in which only a simulator was used when measuring performance metrics or "trials within simulation"; patient specific procedure rehearsals; and randomized, controlled trials (RCTs) or translational studies. OBJECTIVES: To examine whether endovascular simulation training can improve surgeon techniques and patient outcomes in real clinical settings. METHODS: A literature review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. All searches were done via PubMed and Embase. Review articles, and papers that were not related to endovascular surgery and not within the scope of interest were excluded. References of review articles were further screened according to the exclusion criteria. RESULTS: In total, 909 records were identified and 290 duplicates were removed. Thirty-one were included in the qualitative analysis. Twenty-three were trials within simulation and most of them found statistically significant improvements in procedure time, fluoroscopy time, and contrast volume. Five were patient specific procedure rehearsals and showed that simulation significantly affected the fluoroscopy angle and improved performance metrics. Three were RCTs and revealed mainly positive results on a Global Rating Scale and procedure specific rating scale. CONCLUSIONS: Contemporary evidence shows that performance metrics within endovascular simulations improve with simulation training. Successful translation to in vivo situations is observed in patient specific procedure rehearsals and RCTs on real procedures. However, there is no level I evidence to show that predictive validity of simulation can definitively improve patient outcomes. Current literature supports the idea that there is a beneficial role of simulation in endovascular training. Future studies are needed to confirm the efficacy of simulation in endovascular surgical training and to see if simulation is superior to traditional training in the operating theatre.

One-step reconstruction with a 3D-printed, biomechanically evaluated custom implant after complex pelvic tumor resection.

Resection of a pelvic tumor is challenging because of its complex three-dimensional (3D) anatomy and deep-seated location with nearby vital structures. The resection is technically demanding if a custom implant is used for reconstruction of the bone defect as the surgeon needs to ensure the resection margin is sufficiently wide and the orientation of intended resection planes must match that of the custom implant. We describe a novel workflow of performing a partial acetabular resection in a patient with pelvic chondrosarcoma and reconstruction with a custom pelvic implant in a one-step operation. A multi-planar bone resection was virtually planned. A computer-aided design implant that both matched the bone defect and biomechanically evaluated was prefabricated with 3D printing technology. The 3D-printed patient-specific instruments (PSIs) were used to reproduce the same planned resection. The histology of the tumor specimen showed a clear resection margin. The errors of the achieved resection and implant position were deviating (1-4 mm) from the planned. The patient could walk unaided with a good hip function. No tumor recurrence and implant loosening were noted at 11 months after surgery. The use of this novel CT-based method for surgical planning, the engineering software for implant design and validation, together with 3D printing technology for implant and PSI fabrication makes it possible to generate a personalized, biomechanically evaluated implant for accurate reconstruction after a pelvic tumor resection in a one-step operation. Further study in a larger population is needed to assess the clinical efficacy of the workflow in complex bone tumor surgery.

Xanthogranulomatous inflammation of terminal ileum: report of a case with small bowel involvement.

Xanthogranulomatous inflammation is a rare pathological condition most frequently detected in the kidney and gallbladder. Reported herein is a case of xanthogranulomatous inflammation in a 51-year-old male presenting as a mass-forming lesion in the terminal ileum with mucosal ulceration. Diagnostic laparoscopy followed by ileocecectomy was performed due to intra-operative suspicion of carcinoma of appendix. This is a report of the condition involving the terminal ileum with mucosal ulceration and full-thickness involvement of bowel wall which are uncommon features of xanthogranulomatous inflammation in previously reported lower gastro-intestinal tract lesions.

Dosimetric advantages and superior treatment delivery efficiency of RapidArc over conventional intensity-modulated radiotherapy in high-risk prostate cancer involving seminal vesicles and pelvic nodes.

AIMS: To compare the dosimetry and treatment delivery efficiency of RapidArc with conventional intensity-modulated radiotherapy (IMRT) in the treatment of high-risk prostate cancer. MATERIALS AND METHODS: Fifteen patients with high-risk localised prostate cancer were studied. Sequential treatment was used. The initial planning target volume (PTV-L) included the prostate, seminal vesicles and pelvic lymphatics, whereas the prostate boost PTV (PTV-P) included the prostate and seminal vesicles only. The total prescription dose was 76 Gy (44 Gy to PTV-L, 32 Gy to PTV-P; 2 Gy/fraction). Two separate planning techniques were generated for each patient: seven static-field IMRT versus two-arc RapidArc. Dose-volume parameters for the organs at risk, conformity index and homogeneity index for the PTVs, the calculated monitor units and treatment delivery time for both techniques were compared. RESULTS: RapidArc gave more conformal plans than IMRT for both PTVs. RapidArc gave a higher homogeneity index to the PTV-P and a similar homogeneity index to the PTV-L. The two techniques gave similar dosimetric results for the rectum, bladder and femoral heads. The mean dose (Dmean) and the maximum dose (Dmax) of the bowel space were reduced by 3.06 and 2.83%, respectively, with RapidArc. The V20 Gy, V30 Gy and V40 Gy for healthy tissues were reduced by 7.77, 14.25 and 17.55%, respectively, with RapidArc. The calculated treatment delivery time and monitor units were reduced by 74.09%/60.93% and 68.32%/48.06% for the PTV-L/PTV-P, respectively, with RapidArc. CONCLUSION: RapidArc is better than conventional IMRT in terms of dosimetry and delivery efficiency for high-risk prostate cancer.

Use of a patient-specific CAD/CAM surgical jig in extremity bone tumor resection and custom prosthetic reconstruction.

Computer navigation has recently been introduced for bone tumor surgery in the orthopedic field, with the aim of achieving increased accuracy and precision in tumor resection and in custom prosthetic reconstruction. However, the technique requires bulky navigation facilities, the presence of a system operator in the operating room, and surgeons with prior experience in navigated surgery. We describe a new and simple method of using a patient-specific computer-aided design/computer-aided modeling (CAD/CAM) surgical jig to realize the preoperative planning in the surgical field. The accuracy of the proposed method was first tested in a cadaver trial. It took one minute to set the location of the jig prior to the bone resection and three minutes to perform the bone resections via the cutting slits of the jig. The dimensional difference between the achieved and planned bone resection was <1 mm on validation with the help of a junctional plate and a navigation system. The technique was then applied successfully to a patient with a low-grade osteosarcoma of the femur. An intercalated tumor resection was performed using a patient-specific surgical jig, and a custom CAD prosthesis reconstruction matched accurately to the skeletal defect. Further assessment in a larger population is necessary to determine the clinical efficacy of the technique.

Aggressive surgical palliation for advanced girdle tumours.

BACKGROUND: The surgical management of advanced, incurable, malignant disease presents particular ethical and technical challenges. The clear goal is palliation and the surgical futility must be avoided. This case series presents some particular challenges in end-of-life surgery. MATERIALS AND METHODS: Fifteen patients referred with advanced malignant disease involving a limb girdle were reviewed. RESULTS: In one case, a patient pleaded for surgery after initially requesting a delay to seek treatment from a Chinese Traditional Herbalist. The increase in tumour bulk led to problems with surgery and the patient died in a hospital a few weeks later. This case illustrates 'futility' not recognized and encountered. The remaining 14 patients exhibited positive palliation with improved quality of dying and appreciation expressed by patients, relatives and staff. CONCLUSION: In selected cases, with a skilled and experienced surgical team, patients with advanced malignant disease can still benefit from aggressive surgical palliation. The margin of error is small between palliation being attempted and futility being achieved. This considerably adds to the challenge of end-of-life surgery.

Integration of CAD/CAM planning into computer assisted orthopaedic surgery.

Modern Computer Aided Design/Modeling (CAD/CAM) software allows complex surgical simulations, but it is often difficult to transfer and execute precisely the planned scenarios during actual operations. We describe a new method of integrating CAD/CAM surgical plans directly into a computer surgical navigation system, and demonstrate its use to guide three complex orthopaedic surgical procedures: a periacetabular osteotomy of a dysplastic hip, a corrective osteotomy of a post-traumatic tibial deformity, and a multi-planar resection of a distal femoral tumor followed by reconstruction with a CAD custom prosthesis.

Navigation Endoscopic Assisted Tumor (NEAT) surgery for benign bone tumors of the extremities.

A novel technique of using both a navigation system and an endoscope in intra-lesional curettage of benign bone tumors enables safe and adequate tumor removal via a minimal access approach. We performed curettage of benign bone tumors in five consecutive patients (4 female, 1 male, mean age 31.4 years) using a commercial CT-based navigation system supplemented by visual guidance through a shoulder arthroscope. The bone defect was filled with bone cement in four patients and with artificial bone substitute in one patient. Mean follow-up time was 8.8 months (range: 7-12 months). Mean duration of surgery was 144 min (range: 120-165 min). Mean wound length of each portal site was 19.5 mm (range: 15-25 mm). All patients could achieve a full range of joint movement and walk unaided at 4 weeks post-surgery. No local recurrence was noted.

Initial presentation and management of osteosarcoma, and its impact on disease outcome.

OBJECTIVE: To evaluate the initial presenting symptoms and management of osteosarcoma in Hong Kong Chinese children, in relation to any possible impact on disease outcomes. DESIGN: Retrospective study. SETTING: A tertiary referral centre of bone cancer in a university teaching hospital in Hong Kong. PATIENTS: All children aged younger than 18 years with a diagnosis of osteosarcoma who received treatment from March 1994 to October 2005. RESULTS: A total of 51 children were studied. The median age of onset was 13 (range, 3-20) years; 61% were males. The tumours were located in the distal femur and proximal tibia, which accounted for 45% and 22% of the cases, respectively; 24% of patients had metastatic disease at presentation. Swelling (76%) and pain (90%) were the most common presenting complaints. Approximately one third of the patients had a preceding history of trauma. The median duration of initial symptoms to first medical consultation of any sort was 30 (range, 0-360) days. The median time from the first consultation to a definitive diagnosis was 21 (range, 0-350) days; 25% were diagnosed more than 52 days after presentation. Bonesetters were initially consulted by 37% of these patients. From presentation to diagnosis, the median duration was 61 (range, 4-361) days. Analysis of the duration of pre-diagnosis symptoms did not correlate significantly with the development of metastatic disease, response to chemotherapy, feasibility of limb salvage surgery, relapse rates, or survival rates. CONCLUSIONS: In Hong Kong, initial consultation to bonesetters was common. A relatively long delay in between symptom onset and diagnosis of osteosarcoma was encountered. The public and medical practitioners should be made aware of this disease, especially in adolescents.

Characteristics of ovarian cancer in women residing in Aotearoa, New Zealand: 1993-2004.

BACKGROUND: Few studies have compared ovarian cancer rates between different ethnic groups in the same country. The aim of this study was to describe ethnic patterns in the incidence and mortality of ovarian cancer in New Zealand, and to investigate ethnic and socioeconomic differences in the grade and stage of ovarian cancer. METHODS: Data on all women registered with ovarian cancer on the New Zealand Cancer Registry (1993-2004) were analysed. Population data were taken from the 1996 and 2001 census. Logistic regression was used to estimate associations between ethnicity, deprivation and tumour characteristics. RESULTS: Age-standardised incidence rates were highest in Pacific women, intermediate in Maori women, and lowest in non-Maori, non-Pacific women. Age-standardised mortality rates showed the same pattern. Ovarian cancer subtypes differed by ethnic group. There was no significant association between socioeconomic deprivation and tumour grade or stage. Age-adjusted models showed that Maori women were more likely to have well-differentiated tumours and less likely to present at a later stage compared to non-Maori, non-Pacific women. These patterns were partly explained by socioeconomic deprivation, and were not apparent for Pacific women. CONCLUSIONS: Pacific and Maori women experience higher incidence of ovarian cancer and mortality, compared to non-Maori, non-Pacific women. Maori women seemed to have better prognostic factors (local stage and well-differentiated tumours) than non-Maori, non-Pacific women. More work is needed to improve current cancer prevention strategies, particularly in Pacific women.

Differential fadE28 expression associated with phenotypic virulence of Mycobacterium tuberculosis.

Ability to persist in human macrophages is central to the virulence of Mycobacterium tuberculosis and is not invariable among various strains. Differential gene expression that is associated with phenotypic virulence may provide additional information of virulent genes involved in the pathogenesis of M. tuberculosis, which is not fully elucidated. Three hypervirulent strains of M. tuberculosis isolated from patients suffering with tuberculous meningitis were shown to grow more rapidly inside human macrophages in a previous study. In the current investigation, expression of 7 mycobacterial genes (fadE28, mce1A, mymA, acr, sigA, sugC, and Rv3723) of these strains during ex vivo macrophage challenge and in vitro acid shock was quantified by real-time PCR. Using rrs gene as a normalisation gene, fadE28 gene exhibited differential gene expression that is associated with phenotypic virulence, whereas the other 6 genes showed indistinguishable expression patterns. Up-regulation of fadE28 gene in the hypervirulent strains may account for virulence by increasing the efficiency of beta-oxidation, which is important for the persistence in macrophages as M. tuberculosis uses fatty acids preferably inside phagosome of macrophages. The fadE28 gene, together with its adjacent genes may also be critical in the process of lipid modification that could facilitate parasitism in human macrophages.

Cardiovascular risk profile of patients with psoriatic arthritis compared to controls--the role of inflammation.

OBJECTIVE: To examine the distribution of traditional and novel risk factors of cardiovascular disease (CVD) in patients with PsA compared with healthy controls. METHODS: We compared risk factors for CVD between 102 consecutive PsA patients and 82 controls, adjusting for BMI. We also assessed the role of inflammation on the CVD risk factor by using a BMI and high-sensitivity CRP (hsCRP)-adjusted model. RESULTS: The BMI of PsA patients were significantly higher than healthy controls. After adjusting for the BMI, PsA patients still have a higher prevalence of diabetes mellitus (DM) [odds ratio (OR) 9.27, 95% CI 2.09, 41.09) and hypertension (OR 3.37, 95% CI 1.68, 6.72), but a lower prevalence of low high density lipoprotein (HDL) cholesterol (OR 0.16, 95% CI 0.07, 0.41). PsA patients have significantly increased systolic and diastolic blood pressures, insulin resistance and inflammatory markers (hsCRP and white cell count) compared to controls. PsA patients have higher HDL cholesterol and apolipoprotein (Apo) A1 levels; and lower total cholesterol (TC) and low density lipoprotein cholesterol levels; and a lower TC/HDL ratio. However, the Apo B level (P < 0.05), and the Apo B/Apo A1 ratio (P = 0.07) were higher in PsA patients. Further adjustment for hsCRP level rendered the differences in the prevalence of hypertension and DM; the TC, and sugar levels; and white cell count non-significant between the two groups; while the differences in other parameters remained significant. CONCLUSION: These data support the hypothesis that PsA may be associated with obesity, hypertension, dyslipidaemia and insulin resistance because of the shared inflammatory pathway.

Molecular characterization of clinical isolates of Mycobacterium tuberculosis and their association with phenotypic virulence in human macrophages.

Among 125 clinical isolates of Mycobacterium tuberculosis collected in Hong Kong and Shanghai, China, between 2002 and 2004, IS6110 typing revealed that 71 strains (57%) belonged to the Beijing family. The intracellular growth of the strains in human peripheral blood monocyte-derived macrophages was measured ex vivo on days 0, 3, 6, and 10. Among all tested strains, three hypervirulent strains showed significant increases in intracellular growth after 10 days of incubation. With an initial bacterial load of 10(4) CFU, most of the clinical isolates and H37Ra (an avirulent strain) exhibited no intracellular survival on day 10, while the three hypervirulent strains together with H37Rv (a virulent strain) showed on average a two- to fourfold rise in CFU count. These three hypervirulent strains belonging to a non-Beijing family were isolated from patients suffering from tuberculosis meningitis. Cytokines secreted by gamma interferon-activated macrophages were measured daily after challenge with selected strains of M. tuberculosis. The levels of tumor necrosis factor alpha were elevated after 24 h of infection among all strains, but the levels were significantly lower among the three hypervirulent strains, whereas interleukin 10 (IL-10) and IL-12 were not detected. Results were concordant with the differential expression of the corresponding cytokine genes in activated macrophages, as monitored by real-time PCR. Our findings highlighted that these three hypervirulent strains may possess an innate mechanism for escaping host immunity, which accounts for their characteristic virulence in patients presenting with a more severe form of disease.