An end-to-end multi-task system of automatic lesion detection and anatomical localization in whole-body bone scintigraphy by deep learning.

SUMMARY: Limited by spatial resolution and visual contrast, bone scintigraphy interpretation is susceptible to subjective factors, which considerably affects the accuracy and repeatability of lesion detection and anatomical localization. In this work, we design and implement an end-to-end multi-task deep learning model to perform automatic lesion detection and anatomical localization in whole-body bone scintigraphy. A total of 617 whole-body bone scintigraphy cases including anterior and posterior views were retrospectively analyzed. The proposed semi-supervised model consists of two task flows. The first one, the lesion segmentation flow, received image patches and was trained in a supervised way. The other one, skeleton segmentation flow, was trained on as few as five labeled images in conjunction with the multi-atlas approach, in a semi-supervised way. The two flows joint in their encoder layers so each flow can capture more generalized distribution of the sample space and extract more abstract deep features. The experimental results show that the architecture achieved the highest precision in the finest bone segmentation task in both anterior and posterior images of whole-body scintigraphy. Such an end-to-end approach with very few manual annotation requirement would be suitable for algorithm deployment. Moreover, the proposed approach reliably balances unsupervised labels construction and supervised learning, providing useful insight for weakly labeled image analysis. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Insights from Structure-Based Simulations into the Persulfidation of Uridine Diphosphate-Glycosyltransferase71c5 Facilitating the Reversible Inactivation of Abscisic Acid.

The action of abscisic acid (ABA) is closely related to its level in plant tissues. Uridine diphosphate-glycosyltransferase71c5 (UGT71C5) was characterized as a major UGT enzyme to catalyze the formation of the ABA-glucose ester (ABA-GE), a reversible inactive form of free ABA in Arabidopsis thaliana (thale cress). UGTs function in a mode where the catalytic base deprotonates an acceptor to allow a nucleophilic attack at the anomeric center of the donor, achieving the transfer of a glucose moiety. The proteomic data revealed that UGT71C5 can be persulfidated. Herein, an experimental method was employed to detect the persulfidation site of UGT71C5, and the computational methods were further used to identify the yet unknown molecular basis of ABA glycosylation as well as the regulatory role of persulfidation in this process. Our results suggest that the linker and the U-shaped loop are regulatory structural elements: the linker is associated with the binding of uridine diphosphate glucose (UPG) and the U-shaped loop is involved in binding both UPG and ABA.It was also found that it is through tuning the dynamics of the U-shaped loop that is accompanied by the movement of tyrosine (Y388) that the persulfidation of cysteine (C311) leads to the catalytic residue histidine (H16) being in place, preparing for the deprotonation of ABA, and then reorientates UPG and deprotonated ABA closer to the 'Michaelis' complex, facilitating the transfer of a glucose moiety. Ultimately, the persulfidation of UGT71C5 is in favor of ABA glycosylation. Our results provide insights into the molecular details of UGT71C5 recognizing substrates and insights concerning persulfidation as a possible mechanism for hydrogen sulfide (H2S) to modulate the content of ABA, which helps us understand how modulating ABA level strengthens plant tolerance.

Does joint-sparing tumor resection jeopardize oncologic and functional outcomes in non-metastatic high-grade osteosarcoma around the knee?

BACKGROUND: We previously reported joint-sparing tumor resection for osteosarcoma with epiphyseal involvement in which transepiphyseal osteotomy went through the in situ ablated epiphysis. However, we do not know whether this is a safe approach when compared with joint-sacrificed tumor resection. Our objective was to compare oncologic and functional outcomes between patients who underwent joint preservation (JP) and joint replacement (JR) tumor resection. Furthermore, we identified the risk factors of local recurrence, metastasis and survival. METHODS: Eighty-nine patients with non-metastatic high-grade osteosarcoma around the knee were treated with limb-salvage surgery (JP in 47 and JR in 42). Age, gender, tumor location, pathologic fracture, plain radiographic pattern, limb diameter change, perivascular space alteration, surgical margin, local recurrence, metastasis, death, and the Musculoskeletal Tumor Society (MSTS)-93 scores were extracted from the records. Univariate analysis was performed to compare oncologic and functional outcomes. Binary logistic and cox regression models were used to identify predicted factors for local recurrence, metastasis, and survival. RESULTS: Local recurrence, metastasis and overall survival were similar in the JP and JR group (p = 0.3; p = 0.211; p = 0.143). Major complications and limb survival were also similar in the JR and JP group (p = 0.14; p = 0.181). The MSTS score of 27.06 ± 1.77 in the JP group was higher than that of 25.88 ± 1.79 in the JR group (p = 0.005). The marginal margin of soft tissue compared with a wide margin was the only independent predictor of local recurrence (p = 0.006). Limb diameter increase and perivascular fat plane disappearance during neoadjuvant chemotherapy were independent predictors for metastasis (p = 0.002; p = 0.000) and worse survival (p = 0.000; p = 0.001). CONCLUSIONS: Joint-sparing tumor resection with the ablative bone margin offers advantage of native joint preservation with favorable functional outcomes while not jeopardizing oncologic outcomes compared with joint-sacrificed tumor resection. Surgeon should strive to obtain adequate soft tissue surgical margin decreasing risk of local recurrence. Novel drug regimens might be reasonable options for patients with obvious limb diameter increase and perivascular fat disappearance during chemotherapy.

Is the Capanna Technique a Reliable Method for Revision Surgery after Failure of Previous Limb-Salvage Surgery?

BACKGROUND: Reconstruction of a massive bone defect caused by previous failed limb-salvage surgery in patients with bone sarcoma is challenging. Many procedures have been used, but they all have their inherent disadvantages. The Capanna technique has demonstrated good functional outcomes and a low incidence of complications in primary reconstructive surgery of massive bone defect. However, few studies have focused on its usage in revision surgery after failed primary limb-salvage surgery. METHODS: Between June 2011 and January 2017, 13 patients underwent revision surgery with the Capanna technique for reconstruction of a secondary segmental bone defect caused by a previous failed surgical procedure. The demographics, operating procedures, graft union, functional outcomes, oncologic outcomes, and postoperative complications of each patient were recorded. RESULTS: The current study investigated 13 patients. The rate of limb salvage was 100 %. Bone union was achieved for all patients during a mean time of 8.54 ± 2.15 months (range 4-11 months) at the fibula-host bone junction and 14.92 ± 2.33 months (range 12-21 months) at the allograft-host bone junction. The postoperative complications included wound healing issues and internal fixation loosening. Allograft fracture, nonunion, and infection were not observed. All the patients achieved good functional outcomes, with a Musculoskeletal Tumor Society (MSTS) score of 0.86 ± 0.03 at the latest follow-up visit. CONCLUSIONS: The Capanna technique is a reliable alternative method for revision reconstruction of a segmental bone defect caused by a previous failed surgical procedure. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Use of Vascularized Fibular Epiphyseal Transfer with Massive Bone Allograft for Proximal Humeral Reconstruction in Children with Bone Sarcoma.

BACKGROUND: The vascularized fibula epiphyseal transfer provides a reconstructive option for longitudinal growth after oncologic resection of the proximal humerus in pediatric patients. However, postoperative fractures and poor shoulder function are common. The purpose of this review was to introduce a composite approach in oncologic reconstruction of the proximal humerus and assess its clinical outcomes. METHODS: We retrospectively investigated five children (3 osteosarcoma and 2 Ewing's sarcoma) who underwent biological reconstruction with combination of vascularized fibula epiphyseal transfer and massive bone allograft after oncologic resection of the proximal humerus. The mean follow-up was 46.8 months. RESULTS: All patients were alive at the last follow-up. There was no graft fracture, hardware failure, or infection. The mean time of osseous union was 2.9 months at fibula-humerus junction and 6.2 months at allograft-humerus junction. Hypertrophy and axial growth were evident in all, except one patient who has avascular necrosis of the fibula head. The mean hypertrophy index was 51.5%, and the mean growth was 4.4 mm per annum. The mean arm discrepancy was 4.6 cm. All reconstruction was in situ with the average abduction of 113° and forward flexion of 69°. The mean Musculoskeletal Tumor Society (MSTS) score was 85.4% at the final follow-up. All patients experienced dropped foot and resolved spontaneously. CONCLUSIONS: The combination of vascularized fibula epiphyseal transfer with massive allograft bone provides a reliable oncologic reconstruction of proximal humerus in children. It not only offers the ability of longitudinal growth, hypertrophy, and osseous union but also diminishes reconstructive complications and improves shoulder function. LEVEL OF EVIDENCE: Therapeutic Level IV.

What are the Oncologic and Functional Outcomes After Joint Salvage Resections for Juxtaarticular Osteosarcoma About the Knee?

BACKGROUND: Joint salvage surgery for patients with juxtaarticular osteosarcoma remains challenging, especially when the tumor invades the epiphysis. Because patients are surviving longer with current chemotherapy regimens, it is advantageous to retain native joints if possible, especially in young patients. However, the results using joint-preserving tumor resections in this context have not been well characterized. QUESTIONS/PURPOSES: (1) What are the functional outcomes after limb salvage surgery at a minimum of 3 years? (2) What are the oncologic outcomes? (3) Is joint salvage surgery for epiphyseal tumors associated with an increased risk of local recurrence compared with metaphyseal tumors not invading the epiphysis? (4) What are the complications associated with joint salvage surgery? METHODS: Between 2004 and 2013, we treated 117 patients with juxtaarticular osteosarcoma; of those, 43 (38%) were treated with joint salvage surgery, and 41 (95%) of the 43 patients are included in our study. The other two (5%) were lost to followup before 3 years (mean, 4.4 years; range, 3-11 years,). During the period in question, we generally performed joint salvage surgery in these patients when they had a favorable response to chemotherapy, did not have a pathologic fracture or extrusion of the tumor into the joint, and did not have a whole-epiphyseal osteolytic lesion, a large mass, or obvious neurovascular involvement. This report is a followup of an earlier study; the current study includes an additional nine patients, and additional followup of a mean of 19 months for the patients included in the earlier report. We ascertained overall survival and survival free from local recurrence which was estimated using the Kaplan-Meier method, functional status of the limb which was evaluated using the Musculoskeletal Tumor Society (MSTS)-93 scoring system, and recorded reconstructive complications including infection, fracture, skin necrosis, and nonunion. We compared oncologic and functional outcomes between patients with (n = 28) and without tumor extension to epiphysis (n =13). We also compared oncologic and functional outcomes among patients with different adjuvant treatments including microwave ablation (n = 11), cryoablation (n = 12), and navigation-assisted osteotomy (n = 5). Complications were tallied using records from our institutional database. RESULTS: The overall Kaplan-Mayer survival rate was 82% (95% CI, 104-128 months) at 5 years. The overall Kaplan-Meier survivorship from local recurrence was 91% at 5 years (95% CI, 115-133 months). Three patients had a local recurrence, but none had local recurrence in or close to the remaining epiphysis. The MSTS scores ranged from 22 to 30 points, with a median of 28. There were no differences in survival rate, local recurrence, or MSTS scores between patients with a tumor that did not invade the epiphysis and those in whom the tumor did invade the epiphysis. There were differences in MSTS scores among patients with epiphyseal tumor extension in which different adjuvant techniques, including microwave ablation, cryoablation, and navigation-assisted osteotomy, were used. Additional surgical procedures were recorded for 10 patients (24%). Osteonecrosis of the residual epiphysis was detected 13 patients (31%). CONCLUSIONS: Our findings suggest it is possible to salvage joints in selected patients with juxtaarticular osteosarcoma around the knee. The patients who have a favorable response to chemotherapy are the best candidates for this approach. Future studies might explore the role of adjuvant techniques of microwave ablation and cryoablation, particularly when the tumor invades the epiphysis, and whether resections can be facilitated with navigation. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Individualized chemotherapy for osteosarcoma and identification of gene mutations in osteosarcoma.

The study aims to identify novel gene mutations in osteosarcoma and to guide individualized preoperative chemotherapy for osteosarcoma based on the analysis of expression and mutations of the drug-metabolism-related genes. Twenty-eight osteosarcoma patients received individualized preoperative chemotherapy regimens. Expression levels and mutations of chemotherapy-related genes in samples collected from the patients were determined using real-time PCR and DNA sequencing, respectively. Patient sensitivity to chemotherapeutic agents was evaluated by systematic analysis of the PCR and sequencing results. Novel mutations were identified via high-throughput sequencing of 339 genes in 10 osteosarcoma samples. Individualized preoperative chemotherapy outcomes were valid for nine patients (n = 9/28, 32.1%). Chemosensitivity assays showed that all 28 patients were sensitive to ifosfamide, whereas 46.4 and 39.2% were sensitive to docetaxel and platinum, respectively. More importantly, patients receiving highly chemosensitive chemotherapy agents had better prognosis and treatment outcomes than those receiving less chemosensitive agents (P < 0.05). In addition, 39 gene mutations were detected in at least five osteosarcoma tumor samples. Analysis of the expression and mutation of drug-metabolism-related genes will aid in the design of effective individualized preoperative chemotherapy regimens for osteosarcoma. Determining the chemosensitivity of individual tumors to chemotherapeutic agents will facilitate the development of better therapeutic approaches. Individualized treatment of osteosarcoma may improve chemotherapy efficacy and the survival rate of osteosarcoma patients. High-throughput genotyping allows mapping of osteosarcoma mutations, and novel gene mutations offered new candidates for diagnosis and therapeutic targeting.

Giant cell tumor of axial vertebra: surgical experience of five cases and a review of the literature.

BACKGROUND: Due to the complex anatomy of the upper cervical spinal column region and the variable aggressiveness of giant cell tumors (GCTs), there exists no standard treatment for GCTs of axial vertebra. To the best of our knowledge, there are only a few case reports in the literature and no large sum numbers of clinical trials about the treatment of, or research into, axial vertebra GCTs. METHODS: Between 2009 and 2013, five patients pathologically diagnosed with axial vertebra GCTs were treated at our hospital. We performed intralesional excision and odontoid process reconstructive surgery to preserve the odontoid process, followed with adjuvant radiation therapy after surgery. RESULTS: For those with an intact bone shell, part of the ß-TCP (beta tricalcium phosphate) artificial bone could be seen clearly after surgery and became blurred three months after surgery, as seen on a radiograph. One year later, the part of ß-TCP artificial bone was fused as a block. Subsequently, autogenous bone regenerated successfully and artificial bone degraded thoroughly. For those with a defective cortical bone, partial fusion of the odontoid process, autograft ilium and third vertebra body could be seen three months after surgery, and complete fusion was seen nine months later. The odontoid process was preserved successfully, and the upper cervical spine was reconstructed effectively, without implant failure or infection. CONCLUSIONS: In this study, the odontoid process and function of upper cervical vertebra was preserved successfully through lesion curettage, combined with reconstruction with bone grafting, and adjuvant radiation therapy after surgery. During the follow-up periods, no recurrence or complications was observed.

Precise resection and biological reconstruction under navigation guidance for young patients with juxta-articular bone sarcoma in lower extremity: preliminary report.

BACKGROUND: It is a challenge to perform a joint-preserving resection for young patients with juxta-articular bone sarcomas. We determined whether osteotomy under image-guided navigation make joint-saving resection possible for juxta-articular lesions while adhering oncological principles. METHODS: Between June 2008 and July 2010, joint-preserving limb salvage surgeries were performed on 9 patients with juxta-articular bone sarcomas under navigation guidance. Computed tomography/magnetic resonance imaging fusion images were used for real-time navigation. Eight lesions located around the knee and 1 in hip. Six tumors extend to and 3 beyond the epiphyseal line. Planned osteotomy under image-guided navigation was employed for achieving clear surgical margin while maximizing host tissue preservation. All tumors were en bloc removed and intercalary defect were reconstructed by combination of allograft with vascularized fibula graft. All specimens were examined for resection margin. Patients were followed up for an average of 25.2 months for evaluating of functional and oncology outcomes. RESULTS: Entire joint were preserved in 6 patients and part of joint were saved in another 3 patients. The mean registration error for navigation was 0.40 mm (range, 0.31 to 0.62 mm). Clear surgical margin was obtained in all specimens. The average closest distance between the osteotomy line and tumor edge was 9.6 mm (range, 6 to 14 mm). Entire joint cartilage was preserved in 6 patients and portion of joint were saved in 3 patients (2 in proximal tibia, 1 in distal femur). No patient experienced local recurrence. Two patients developed lung metastasis. One died of disease and the other underwent metastasectomy and had no evidence of disease at the most recent follow-up. All reconstruction was in situ with the Musculoskeletal Tumor Society average score of 26.7 at final follow-up. CONCLUSIONS: With careful patient selection, image navigation-assisted surgery made it possible to resect the bone exactly as planned in length and orientation in the magnetic resonance imaging image, yielding a clear margin and preserving the entire or part of the articular cartilage in joint-sparing limb salvage procedures for treating skeletally immature patients with juxta-articular bone sarcomas. LEVEL OF EVIDENCE: Level IV--therapeutic study.

Fine hippocampal morphology analysis with a multi-dataset cross-sectional study on 2911 subjects.

CA1 subfield and subiculum of the hippocampus contain a series of dentate bulges, which are also called hippocampus dentation (HD). There have been several studies demonstrating an association between HD and brain disorders. Such as the number of hippocampal dentation correlates with temporal lobe epilepsy. And epileptic hippocampus have a lower number of dentation compared to contralateral hippocampus. However, most studies rely on subjective assessment by manual searching and counting in HD areas, which is time-consuming and labor-intensive to process large amounts of samples. And to date, only one objective method for quantifying HD has been proposed. Therefore, to fill this gap, we developed an automated and objective method to quantify HD and explore its relationship with neurodegenerative diseases. In this work, we performed a fine-scale morphological characterization of HD in 2911 subjects from four different cohorts of ADNI, PPMI, HCP, and IXI to quantify and explore differences between them in MR T1w images. The results showed that the degree of right hippocampal dentation are lower in patients with Alzheimer's disease than samples in mild cognitive impairment or cognitively normal, whereas this change is not significant in Parkinson's disease progression. The innovation of this paper that we propose a quantitative, robust, and fully automated method. These methodological innovation and corresponding results delineated above constitute the significance and novelty of our study. What's more, the proposed method breaks through the limitations of manual labeling and is the first to quantitatively measure and compare HD in four different brain populations including thousands of subjects. These findings revealed new morphological patterns in the hippocampal dentation, which can help with subsequent fine-scale hippocampal morphology research.

[Therapeutic evaluation of the polylactic acid gel (PLA-G) used for preventing skin flap adhesion in modified radical mastectomy].

The present preliminary study was to observe the feasibility of the use of polylactic acid gel (PLA-G) in modified radical mastectomy and the ability of the PLA-G in the prevention of flap adhesion after operation. Sixty-eight patients were diagnosed with breast cancer, and received modified radical mastectomy from Jan. 2004 to Dec. 2006. The patients were divided randomly into a treatment group and a control group (with 34 cases each). The PLA-G was used under the surface of the auxiliary operative wound in the treatment group, and nothing was used in the control group. The wound healing, the wound complication, the amount of drainage solution, the indwelling time of the drainage tube and the auxiliary skin adhesion were evaluated after operation in both groups. There were no statistical difference on wound healing between the first intension (29:27) and the second intention (5:7), and the wound dehiscence after taking the stitches out (0:0) between the two intensions, the hematoma (0:1) and the effusion of the wound (5:6), and the flap necrosis (1:2) between two groups. There were also no statistical difference on the amount of drainage solution per day (6 +/- 3) and indwelling time of the drainage tube (6 +/- 4) after operation between the two groups (P > 0.5). After the operation, the case load with no flap adhesion in the treatment group was significant higher compared with the control group (22:8). The case load with complete acquired skin flap adhesion in the treatment group was visibly lower than in the control group (3:19), which proved that there was a significant statistical difference between the two groups (P < 0.05). This study suggested that the using of PLA-G in the breast cancer modified radical mastectomy could prevent skin flap adhesion without any harmful effects in the wound healing.

A classification system of joint-salvage tumor resection in osteosarcoma of the knee: A retrospective cohort study.

BACKGROUND: Joint-preserving surgery is possible for patients with juxta-articular osteosarcoma of the knee, even when the tumor invades the epiphysis. Oncologic and functional outcomes may vary due to the extent of tumor invasion, the amount of epiphysis preservation, and reconstruction methods. We aimed to introduce a novel classification facilitating clinical evaluation of different surgical treatments. METHODS: We identified 52 patients with osteosarcoma of the knee undergoing joint-preserving tumor resection and intercalary reconstruction. We classified procedures into two types and six subtypes based on the tumor location and adjuvant treatment employed. Oncologic outcomes, limb function and complications were compared among different types. RESULTS: None of the patients had a local recurrence in the preserved epiphysis apart from three (5.7 %) who had local recurrence in soft tissue. Overall survival rate of the patients was 82.7 % at 5 and 10 years. There was no difference in survival rate (P = 0.909), local recurrence (P = 0.642) between type I (tumor not invading epiphysis) and type II (tumor invading epiphysis). In addition to one skin necrosis in the 3D-printed prosthesis reconstruction and one infection in Capanna reconstruction, all complications necessitating additional surgery occurred in allograft. The Musculoskeletal Tumor Society (MSTS) scores ranged from 21 to 30 with a median of 26. There were differences in the MSTS scores among six subgroups (P = 0.015), with the highest in type Ia and the lowest in type IIc. The less of the viable epiphysis retained, the worse the knee function was at long-term follow up. CONCLUSIONS: The suggested classification can guide surgical strategy and is convenient for comparison of the functional results.

Fine scale hippocampus morphology variation cross 552 healthy subjects from age 20 to 80.

The cerebral cortex varies over the course of a person's life span: at birth, the surface is smooth, before becoming more bumpy (deeper sulci and thicker gyri) in middle age, and thinner in senior years. In this work, a similar phenomenon was observed on the hippocampus. It was previously believed the fine-scale morphology of the hippocampus could only be extracted only with high field scanners (7T, 9.4T); however, recent studies show that regular 3T MR scanners can be sufficient for this purpose. This finding opens the door for the study of fine hippocampal morphometry for a large amount of clinical data. In particular, a characteristic bumpy and subtle feature on the inferior aspect of the hippocampus, which we refer to as hippocampal dentation, presents a dramatic degree of variability between individuals from very smooth to highly dentated. In this report, we propose a combined method joining deep learning and sub-pixel level set evolution to efficiently obtain fine-scale hippocampal segmentation on 552 healthy subjects. Through non-linear dentation extraction and fitting, we reveal that the bumpiness of the inferior surface of the human hippocampus has a clear temporal trend. It is bumpiest between 40 and 50 years old. This observation should be aligned with neurodevelopmental and aging stages.

Evaluation of Anlotinib Combined with Adriamycin and Ifosfamide as Conversion Therapy for Unresectable Soft Tissue Sarcomas.

(1) Background: This study investigated the safety and efficiency of adriamycin and ifosfamide combined with anlotinib (AI/AN) as a neoadjuvant conversion therapy in uSTS. (2) Methods: Patients with uSTS were eligible to receive AI/An, including adriamycin (20 mg/m2/d) and ifosfamide (3 g/m2/d) for the first to the third day combined with anlotinib (12 mg/d) for 2 weeks on/1 week off, all of which combine to comprise one cycle. Surgery was recommended after four cycles of treatment. (3) Results: A total of 28 patients were enrolled from June 2018 to December 2020. The best tumor responses included eight patients with partial responses and 20 with a stable disease. Patients with synovial sarcoma and liposarcoma had a significant decrease in the number of tumors compared with fibrosarcoma (p = 0.012; p = 0.042). The overall response rate and disease control rate were 28.57% and 100%, respectively. In total, 24 patients received surgery, while the rates of limb salvage and R0 resection were 91.67% (n = 22/24) and 87.50% (n = 21/24), respectively. Until the last follow-up visit, the mean PFS and RFS were 21.70 and 23.97 months, respectively. During drug administration, 67.87% of patients had grade ≥3 AEs. No treatment-related death occurred. (4) Conclusions: AI/AN followed by surgery showed favorable efficiency and manageable safety in patients with uSTS. A randomized controlled study with a large cohort should be performed for further investigations.

Predicting chemosensitivity based on mini patient-derived xenografts in osteosarcoma patients: A retrospective study.

Context: The survival of patients diagnosed with osteosarcoma has not improved in the past three decades because of chemoresistance. Aim: This study aimed to improve the prognosis of patients with osteosarcoma. Settings and Design: From January 1, 2018, to June 30, 2019, a total of 14 patients with osteosarcoma were enrolled who underwent mini patient-derived xenograft (mini-PDX) assay in our hospital. Methods and Materials: We recruited 14 patients with osteosarcoma having acquirable lesions to establish PDX models and examine the sensitivity of nine drugs, including methotrexate (MTX), ifosfamide (IFO), epirubicin, and etoposide. Drug sensitivity was evaluated using the tumor relative proliferation rate (TRPR), and the patients' responses were assessed according to the RECIST 1.1 guidelines. Statistical Analysis Used: The difference in TRPR was analyzed using a paired t-test, while progression-free survival (PFS) was analyzed using the Kaplan-Meier method. Results: The mini-PDX results revealed that IFO had a lower tumor proliferation rate than MTX, indicating that IFO was more sensitive in patients with osteosarcoma (38.3% vs. 84.3%, P = 0.031). Thus, the regimen where IFO alternates with doxorubicin and cisplatin was recommended as adjuvant chemotherapy. MTX could replace IFO if the TRPR was better. Finally, 11 patients received adjuvant chemotherapy. A comparison of PFS revealed that sensitive patients with TRPR of <40% had a better prognosis (9.4 months vs. 3.7 months, P = 0.0324). Conclusions: Chemotherapy based on mini-PDX can improve the survival of patients with osteosarcoma whose TRPR was <40%, and that chemotherapy without MTX could be an alternative for osteosarcoma.

Acceptor Engineering Produces Ultrafast Nonradiative Decay in NIR-II Aza-BODIPY Nanoparticles for Efficient Osteosarcoma Photothermal Therapy via Concurrent Apoptosis and Pyroptosis.

Small-molecule photothermal agents (PTAs) with intense second near-infrared (NIR-II, 1,000 to 1,700 nm) absorption and high photothermal conversion efficiencies (PCEs) are promising candidates for treating deep-seated tumors such as osteosarcoma. To date, the development of small-molecule NIR-II PTAs has largely relied on fabricating donor-acceptor-donor (D-A-D/D') structures and limited success has been achieved. Herein, through acceptor engineering, a donor-acceptor-acceptor (D-A-A')-structured NIR-II aza-boron-dipyrromethene (aza-BODIPY) PTA (SW8) was readily developed for the 1,064-nm laser-mediated phototheranostic treatment of osteosarcoma. Changing the donor groups to acceptor groups produced remarkable red-shifts of absorption maximums from first near-infrared (NIR-I) regions (~808 nm) to NIR-II ones (~1,064 nm) for aza-BODIPYs (SW1 to SW8). Furthermore, SW8 self-assembled into nanoparticles (SW8@NPs) with intense NIR-II absorption and an ultrahigh PCE (75%, 1,064 nm). This ultrahigh PCE primarily originated from an additional nonradiative decay pathway, which showed a 100-fold enhanced decay rate compared to that shown by conventional pathways such as internal conversion and vibrational relaxation. Eventually, SW8@NPs performed highly efficient 1,064-nm laser-mediated NIR-II photothermal therapy of osteosarcoma via concurrent apoptosis and pyroptosis. This work not only illustrates a remote approach for treating deep-seated tumors with high spatiotemporal control but also provides a new strategy for building high-performance small-molecule NIR-II PTAs.

Reconstructing avascular necrotic femoral head through a bioactive ß-TCP system: From design to application.

A variety of techniques have been used for treating avascular necrosis of the femoral head (ANFH), but have frequently failed. In this study, we proposed a ß-TCP system for the treatment of ANFH by boosting revascularization and bone regeneration. The angio-conductive properties and concurrent osteogenesis of the highly interconnected porous ß-TCP scaffold were revealed and quantified through an in vivo model that simulated the ischemic environment of ANFH. Mechanical test and finite element analysis showed that the mechanical loss caused by tissue necrosis and surgery was immediately partially compensated after implantation, and the strength of the operated femoral head was adaptively increased and eventually returned to normal bone, along with continuous material degradation and bone regeneration. For translational application, we further conducted a multi-center open-label clinical trial to assess the efficacy of the ß-TCP system in treating ANFH. Two hundred fourteen patients with 246 hips were enrolled for evaluation, and 82.1% of the operated hips survived at a 42.79-month median follow-up. The imaging results, hip function, and pain scores were dramatically improved compared to preoperative levels. ARCO stage Ⅱ disease outperformed stage Ⅲ in terms of clinical effectiveness. Thus, bio-adaptive reconstruction using the ß-TCP system is a promising hip-preserving strategy for the treatment of ANFH.

Irregular osteotomy in limb salvage for juxta-articular osteosarcoma under computer-assisted navigation.

BACKGROUND: Joint-preserving limb salvage surgery has been expected to have good functional outcomes. However, it is still a unsolved problem to perform a joint preserving resection for patients with juxta-articular osteosarcoma invading epiphyseal line. We determined whether irregular osteotomy under image-guided navigation make joint-saving resection possible for juxta-articular osteosarcoma while adhering oncological principles. METHODS: We performed joint-preserving limb salvage surgeries on six patients with juxta-articular osteosarcoma of the long bone. Three lesions located in humerus, two in tibia and one in femur. Two tumors extend to and four beyond the epiphyseal line. CT and MRI data fusion images were applied for intraoperative navigation. Planned irregular osteotomy under image-guided navigation was employed for obtaining clear surgical margin while maximizing host tissue preservation. All tumors were en bloc removed and intercalary defect were reconstructed by allograft in one and combination of allograft with vascularized fibula graft in five patients. All specimens were examined for resection margin. Patients were followed up for average of 17.5 months for evaluating of functional and oncology outcomes. RESULT: Entire joint were preserved in three patients and part of joint were saved in another three patients. Clear surgical margin was obtained in all specimens with a minimum of 6-mm distance between tumor and osteotomy line. No patient experienced a local recurrence. One patient developed lung metastasis and had no evidence of disease at the most recent follow-up. All allografts but one healed during the study period. The MSTS average score was 88.8% at final follow-up. CONCLUSIONS: With careful patient selection, the irregular osteotomy under navigation guidance was proved to be an effective and safe technique for precise tumor resection in joint preserving limb salvage procedures for treating patients with juxta-articular osteosarcomas.

Composite biological reconstruction following total calcanectomy of primary calcaneal tumors.

BACKGROUND: Advances in oncologic treatment modalities and wide resection have made limb salvage procedures in calcaneal malignancy or aggressive benign tumor increasingly possible. However, reconstructions of the calcaneus remain a major surgical challenge because of the rarity and specific anatomy of this condition. METHODS: we retrospectively reviewed 4 patients who had primary calcaneal tumors and underwent total calcanectomy and reconstructions with use of composite of allograft and vascularized osteocutaneous fibular grafts between 2007 and 2010. The diagnoses included chondrosarcoma in 1, fibrosarcoma in 1, aggressive osteoblastoma in 1, and giant-cell tumor in 1. Wide resection margins were achieved in all patients. The mean age at the time of the operation was 32.1 years. Patients were examined clinically and radiographically and were assessed functionally with Musculoskeletal Tumor Society (MSTS) score and American Orthopaedic Foot and Ankle Society (AOFAS) score. RESULTS: The median duration of follow-up was 24.5 months. No local recurrence occurred in this series and all patients had no evidence of disease at the time of final follow-up. Limb salvage was achieved in all patients. Revision surgery was necessary in two patients because of complications (skin flap necrosis and infection). The average MSTS 93 score and AOFAS score were 91.7% and 87.5 at the final follow-up, respectively. All fibular flaps survived and bone unions achieved successfully. The overall mean time for bone union was 9.5 months. The mean time to full-weight bearing was 7 months. CONCLUSIONS: Vascularized fibular flaps in combination with massive allografts provide an excellent option for biological reconstruction after total calcanectomy in tumor situation and have proven to be a successful limb salvage procedure, which result in earlier patient recovery and return of function. LEVEL OF EVIDENCE: Therapeutic Level IV.

Precise resection and biological reconstruction for patients with bone sarcomas in the proximal humerus.

BACKGROUND: It is a challenge to perform a joint-preserving resection for patients with bone sarcomas in the proximal humerus. We determined whether osteotomy under navigation guidance made joint-saving resection possible for juxtaarticular humeral sarcomas while adhering to oncological principles. METHOD: Between January 2008 and July 2010, joint-preserving surgeries were performed on six patients with proximal humeral sarcomas under navigation guidance. Five tumors extended to, and one extended beyond, the epiphyseal line. Planned osteotomy under image-guided navigation was employed to achieve a clear surgical margin while preserving the humeral head and rotator cuff. All tumors were removed en bloc and intercalary defects were reconstructed by a combination of allograft and vascularized fibula graft. All specimens were examined for resection margin. Patients were followed up for an average of 19.1 months. RESULTS: The entire glenohumeral joint was preserved in five patients and part of the humeral head was saved in one patient. Clear surgical margin was obtained in all specimens. The minimum closest distance between the osteotomy line and tumor edge was 7 mm. No patient experienced local recurrence. One patient developed lung metastasis and was alive with disease. The mean Musculoskeletal Tumor Society (MSTS) 93 score was 92.1%. All reconstruction was in situ at final follow-up. CONCLUSION: With careful patient selection, image navigation-assisted surgery made it possible to excise the bone exactly as seen in orientation in magnetic resonance imaging (MRI) image, yielding a clear margin and preserving all or part of the humeral head in limb salvage procedures for patients with juxtaarticular bone sarcomas in proximal humerus. LEVEL OF EVIDENCE: Therapeutic study; Level IV.