Development of deep learning algorithms to discriminate giant cell tumors of bone from adjacent normal tissues by confocal Raman spectroscopy.

Raman spectroscopy is a non-destructive analysis technique that provides detailed information about the chemical structure of tumors. Raman spectra of 52 giant cell tumors of bone (GCTB) and 21 adjacent normal tissues of formalin-fixed paraffin embedded (FFPE) and frozen specimens were obtained using a confocal Raman spectrometer and analyzed with machine learning and deep learning algorithms. We discovered characteristic Raman shifts in the GCTB specimens. They were assigned to phenylalanine and tyrosine. Based on the spectroscopic data, classification algorithms including support vector machine, k-nearest neighbors and long short-term memory (LSTM) were successfully applied to discriminate GCTB from adjacent normal tissues of both the FFPE and frozen specimens, with the accuracy ranging from 82.8% to 94.5%. Importantly, our LSTM algorithm showed the best performance in the discrimination of the frozen specimens, with a sensitivity and specificity of 93.9% and 95.1% respectively, and the AUC was 0.97. The results of our study suggest that confocal Raman spectroscopy accomplished by the LSTM network could non-destructively evaluate a tumor margin by its inherent biochemical specificity which may allow intraoperative assessment of the adequacy of tumor clearance.

Simvastatin Possesses Antitumor and Differentiation-Promoting Properties That Affect Stromal Cells in Giant Cell Tumor of Bone.

Giant cell tumor of bone (GCTB) is a locally aggressive destructive bone lesion. The management of pulmonary metastasis and local recurrence after the surgical treatment of GCTB remains a challenge. Pathologically, stromal cells in GCTB are known as primary neoplastic cells and are recognized as incompletely differentiated preosteoblasts. Therefore, inducing GCTB stromal cells to differentiate into cells with a mature osteoblastic phenotype may stop tumor growth and recurrence. In this study, we aimed to investigate how simvastatin, a clinically approved and commonly used statin that has been known to promote the maturation of cells of the osteogenic lineage, affects GCTB stromal cells. We found that simvastatin effectively inhibited cell viability by suppressing proliferation and by inducing apoptosis in GCTB stromal cells. Moreover, simvastatin treatment upregulated the expression of genes related to osteogenic maturation, such as runt-related transcription factor 2, osteopontin, and osteocalcin, and increased the mineralization of the extracellular matrix in GCTB stromal cells. Ingenuity pathway analysis was used to discover that the vitamin D receptor pathway was involved in the simvastatin-induced osteogenic differentiation of GCTB stromal cells by upregulating the 1,25-dihydroxyvitamin D metabolism. Taken together, this in vitro study demonstrates the antitumor and differentiation-promoting effects of simvastatin on GCTB stromal cells and suggests the possibility of using simvastatin as an adjuvant therapy for GCTB. These findings support further clinical investigation of the efficacy of using simvastatin as an adjuvant therapy for GCTB to reduce recurrence and distant metastasis after surgical treatment. © 2019 Orthopedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:297-310, 2020.

Lifestyle intervention using an internet-based curriculum with cell phone reminders for obese Chinese teens: a randomized controlled study.

OBJECTIVES: Obesity is an increasing public health problem affecting young people. The causes of obesity are multi-factorial among Chinese youth including lack of physical activity and poor eating habits. The use of an internet curriculum and cell phone reminders and texting may be an innovative means of increasing follow up and compliance with obese teens. The objectives of this study were to determine the feasibility of using an adapted internet curriculum and existing nutritional program along with cell phone follow up for obese Chinese teens. DESIGN AND METHODS: This was a randomized controlled study involving obese teens receiving care at a paediatric obesity clinic of a tertiary care hospital in Hong Kong. Forty-eight subjects aged 12 to 18 years were randomized into three groups. The control group received usual care visits with a physician in the obesity clinic every three months. The first intervention (IT) group received usual care visits every three months plus a 12-week internet-based curriculum with cell phone calls/texts reminders. The second intervention group received usual care visits every three months plus four nutritional counselling sessions. RESULTS: The use of the internet-based curriculum was shown to be feasible as evidenced by the high recruitment rate, internet log-in rate, compliance with completing the curriculum and responses to phone reminders. No significant differences in weight were found between IT, sLMP and control groups. CONCLUSION: An internet-based curriculum with cell phone reminders as a supplement to usual care of obesity is feasible. Further study is required to determine whether an internet plus text intervention can be both an effective and a cost-effective adjunct to changing weight in obese youth. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-TRC-12002624.

Evidence of virtual patients as a facilitative learning tool on an anesthesia course.

Virtual patients are computerised representations of realistic clinical cases. They were developed to teach clinical reasoning skills through delivery of multiple standardized patient cases. The anesthesia course at The Chinese University of Hong Kong developed two novel types of virtual patients, formative assessment cases studies and storyline, to teach its final year medical students on a 2 week rotational course. Acute pain management cases were used to test if these two types of virtual patient could enhance student learning. A 2 × 2 cross over study was performed in academic year 2010-2011 on 130 students divided into four groups of 32-34. Performance was evaluated by acute pain management items set within three examinations; an end of module 60-item multiple choice paper, a short answer modified essay paper and the end of year final surgery modified essay paper. The pain management case studies were found to enhanced student performance in all three examinations, whilst the storyline virtual patient had no demonstrable effect. Student-teaching evaluation questionnaires showed that the case studies were favored more than the storyline virtual patient. Login times showed that students on average logged onto the case studies for 6 h, whereas only half the students logged on and used the storyline virtual patient. Formative assessment case studies were well liked by the students and reinforced learning of clinical algorithms through repetition and feedback, whereas the educational role of the more narrative and less interactive storyline virtual patient was less clear .

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.

Effect of water-soluble P-chitosan and S-chitosan on human primary osteoblasts and giant cell tumor of bone stromal cells.

Water-soluble phosphorylated chitosan (P-chitosan) and disodium (1 → 4)-2-deoxy-2-sulfoamino-ß-D-glucopyranuronan (S-chitosan) are two chemically modified chitosans. In this study, we found that P-chitosan significantly promotes cell proliferation of both human primary osteoblasts (OBs) and the OB like stromal cell component of the giant cell tumor of bone (GCTB) cells at the concentration from 125 to 1000 µg ml⁻¹ at all time points of 1, 3, 5 and 7 days after treatment. Further investigation of the osteogenic effect of the P-chitosan suggested that it regulates the levels of osteoclastogenic factors, receptor activator of nuclear factor kappa B ligand and osteoprotegerin expression. An interesting finding is that S-chitosan at lower concentration (100 µg ml⁻¹) stimulates cell proliferation while a higher dose (1000 µg ml⁻¹) of S-chitosan inhibits it. The inhibitory effect of S-chitosan on human primary GCT stromal cells was greater than that of OBs (p < 0.05). Taken together, our findings elucidated the osteogenic effect of P-chitosan and the varying effects of S-chitosan on the proliferation of human primary OBs and GCT stromal cells and provided us the rationale for the construction of novel bone repair biomaterials with the dual properties of bone induction and bone tumor inhibition.

Pamidronate, farnesyl transferase, and geranylgeranyl transferase-I inhibitors affects cell proliferation, apoptosis, and OPG/RANKL mRNA expression in stromal cells of giant cell tumor of bone.

Giant cell tumor (GCT) is the most common nonmalignant primary bone tumor reported in Hong Kong. It usually affects young adults between the ages of 20 and 40. This tumor is well known for its potential to recur following treatment. To date no effective adjuvant therapy exists for GCT. Our project aimed to study the effects of pamidronate (PAM), farnesyl transferase inhibitor (FTI-277), geranylgeranyl transferase inhibitor (GGTI-298), and their combinations on GCT stromal cells (SC). Individual treatment with PAM, FTI-277, and GGTI-298, inhibited the cell viability and proliferation of GCT SC in a dose-dependent way. Combination of FTI-277 with GGTI-298 caused synergistic effects in reducing cell viability, and its combination index was 0.49, indicating a strong synergism. Moreover, the combination of FTI-277 with GGTI-298 synergistically enhanced cell apoptosis and activated caspase-3/7, -8, and -9 activities. PAM induced cell-cycle arrest at the S-phase. The combination of PAM with GGTI-298 significantly increased OPG/RANKL mRNA ratio and activated caspase-3/7 activity. Our findings support that the combination of bisphosphonates with GGTIs or FTIs with GGTIs may be used as potential adjuvants in the treatment of GCT of bone.

Introduction of virtual patients onto a final year anesthesia course: Hong Kong experience.

e-Learning has revolutionized the way in which undergraduate medical education is delivered. One e-learning tool of note is the virtual patient (VP), a type of computer software that simulates real-life clinical scenarios, in which the learner emulates the role of health care provider to obtain the history, conduct examination, and make diagnoses and management decisions. VPs have been in use since 1993. Early designs were based on serial screen-cards of patient history, examination, investigations, diagnoses, treatment, and outcome, which the learner explored. With the development of web technology, VPs can now be accessed via the Internet and are more versatile, supporting different structural designs to suit a variety of learning objectives, and they can branch via different routes through a case. Using VPs has a number of advantages: 1) VPs improve access to learning material, 2) VPs help learners to acquire higher order cognitive skills like strategic thinking and decision making, 3) VPs provide a safe environment to practice, 4) VPs help to teach interdisciplinary care, and 5) VPs can be used instead of patients for examination. A number of well-known VP player systems are in use today: CASUS, CAMPUS, web-based Simulation of Patients, OpenLabyrinth, and vpSim. At the Chinese University of Hong Kong, we have also developed a web-based VP authoring and player system called Formative Assessment Case Studies (FACS), which is run by our Teaching and Learning Resources Centre. FACS has been integrated into Year-5 Anesthesia teaching since 2006. Three VP products have been developed: Anaesthesia FACS (six cases) that teaches preoperative assessment, Acute Pain Management FACS, and an eight-part longitudinal VP which tells the story of a patient's stay, and anesthesia care, for routine gynecological surgery. Students spend about 3 hours on each during a 2-week clinical attachment. Our VPs have been well received and have overcome problems of providing adequate clinical exposure.

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.

Achilles tendon rupture and tendinopathy: management of complications.

Ailments of the Achilles tendon are on the increase and present in athletic and sedentary patients. The management of tendinopathy and rupture is not codified; Achilles tendon rupture and tendinopathy can be managed conservatively or surgically. Tackling the complications that arise from the management of these conditions provides a formidable challenge to the surgeon. Rupture, rerupture, disordered scarring with potential keloid formation, nerve damage (especially the sural nerve), poor healing, infection, bleeding and hematoma formation, wound dehiscence, deep vein thrombosis (DVT), and loss of function have been reported. This article gives an up-to-date account on our personal views of managing complications following Achilles tendon rupture, tendinopathy, and delayed rupture.

Thapsigargin potentiates TRAIL-induced apoptosis in giant cell tumor of bone.

TNF-related apoptosis-inducing ligand (TRAIL) is capable of causing apoptosis in tumor cells but not in normal cells; however, it has been shown that certain types of tumor cells are resistant to TRAIL-induced apoptosis. In this study, we examined the potentiation of TRAIL-induced apoptosis in the stromal-like tumor cells of giant cell tumor of bone (GCT). We show that both mRNA and protein of TRAIL receptors-death receptors (DR4, DR5) and decoy receptors (DcR1, DcR2) are present in GCT stromal tumor cells. However, the expression profiles in all GCT clones tested do not readily correlate with their differential sensitivity to TRAIL. To this end, we selected thapsigargin (TG), an agent known to cause perturbations in intracellular Ca(2+) homeostasis to enhance the apoptotic action of TRAIL. When added alone, neither TRAIL nor TG induces a therapeutically important magnitude of cell death in GCT tumor cells. Interdependently, scheduled treatment of the cultures with TG followed by subsequent addition of TRAIL resulted in a significant synergistic apoptotic activity, while in contrast, no obvious augmentation was seen when TRAIL was added before TG. This effect was in accord with our observation that TG predominantly up-regulated both mRNA and protein expression of DR5, as well as DR4 mRNA while down-regulating DcR1 protein in GCT stromal-like tumor cells. Taken together, our findings suggest that TG is able to sensitize tumor cells of GCT to TRAIL-induced cell death, perhaps in part through up-regulating the death receptor DR5 and down-regulating the decoy receptor DcR1. These findings provide an additional insight into the design of new treatment modalities for patients suffering from GCT.

Cytochemical and ultrastructural changes in the osteoclast-like giant cells of giant cell tumor of bone following bisphosphonate administration.

Giant cell tumor of bone (GCT) is a local aggressive neoplasm of bone characterized by expansive osteolytic lesions at the epiphysis of long bones. Bisphosphonates have been used to prevent bone resorption in secondary osteolytic tumors because of their strong anti-osteoclastic action. The authors studied the apoptosis and ultrastructural changes induced in osteoclast-like giant cells of GCT, following treatment with the aminobisphosphonate pamidronate in 16 patients with GCT of bone. Transmission electron microscopy (TEM) was used to identify ultrastructural changes, indicative of apoptosis, in the cytoplasm and the nucleus of the giant cells. Significant changes were observed in tumor samples from all 16 patients. In the cytoplasm these changes were characterized by abundant large tubular vesicles containing a central electrodense core scattered through the cytoplasm. In addition, mitochondria in the sections from pamidronate-treated patients appeared to be edematous when compared with sections from untreated patients. Nuclear changes in the giants cells were characterized by the formation of dense chromatin material scattered throughout the nucleus. The TUNEL labeling assay indicated that the mean pretreatment apoptotic index of 7.8% increased to 53% following pamidronate treatment. This was statistically significant (p<.001) and correlated well with the ultrastructural changes noted on TEM. The formation of abundant tubular vesicles in giant cells following bisphosphonate treatment may reflect disturbed vesicular trafficking and may affect the bone resorbing activity of giant cells.

Expression and localization of extracellular matrix metalloproteinase inducer in giant cell tumor of bone.

Matrix metalloproteinases (MMPs) are regarded as a significant regulator in tumor invasion and metastasis. Previous studies have shown that extracellular matrix metalloproteinase inducer (EMMPRIN) in tumor cells induces the synthesis of MMPs. EMMPRIN is abundantly present on the surface of tumor cells and stimulate adjacent stromal cells to synthesize MMPs to induce tumor progression. Giant cell tumor (GCT) of bone is a benign but locally aggressive primary neoplasm of bone. The spindle-shaped mononuclear stromal cells are considered to be the tumor components of GCT, which are capable of inducing osteoclast formation by recruiting the circulating monocyte and macrophage. In this study, we proposed that EMMPRIN is associated with the biological progression and aggressiveness of GCT. We have conducted semi-quantitative RT-PCR to determine the correlation of EMMPRIN expression with the clinical stage of GCT. We have also examined the cellular localization of EMMPRIN in GCT using in-situ hybridization (ISH) and Immunohistochemistry (IH). The results showed that EMMPRIN was present in GCT and its mRNA levels were associated with the clinical stage of GCT. Higher expression level of EMMPRIN was observed in GCT with advanced stage (stage III). There was a great significance (P < 0.05) of EMMPRIN expression between stage I & II and stage III GCTs. Both ISH and IH demonstrated that EMMPRIN is present at the multinuclear osteoclast-like giant cells of GCT, with strong immunostaining on the cell membrane. The stromal-like tumor cells were also positively stained but the intensity was weaker. Interestingly, the production of EMMPRIN in osteoclast-like cells of GCT seems to be regulated by stromal-like tumor cells. Receptor activator of NF-kappaB ligand (RANKL), which has been previously shown to be produced by the stromal-like tumor cells for the recruitment of osteoclast-like giant cells in GCT, enhanced the expression of EMMPRIN mRNA during the differentiation of macrophage-like RAW(264.7) cells into osteoclasts. In short, our studies suggest that EMMPRIN may be an important regulatory factor involved in the biological behaviors of GCT.

Imaging of musculoskeletal tuberculosis: a new look at an old disease.

There are certain imaging features that help to differentiate tuberculosis from other bone and joint disorders with a similar presentation. The current authors discuss these distinguishing imaging features particularly with respect to ultrasound, computed tomography, and magnetic resonance imaging. The judicious and appropriate use of these newer imaging modalities coupled with aspiration or biopsy can lead to earlier recognition of musculoskeletal tuberculosis before the onset of debilitating disease.