A single-cell atlas of conventional central chondrosarcoma reveals the role of endoplasmic reticulum stress in malignant transformation.

The transformation of benign lesions to malignant tumours is a crucial aspect of understanding chondrosarcomas, which are malignant cartilage tumours that could develop from benign chondroid lesions. However, the process of malignant transformation for chondroid lesions remains poorly understood, and no reliable markers are available to aid clinical decision-making. To address this issue, we conducted a study analysing 11 primary cartilage tumours and controls using single-cell RNA sequencing. By creating a single-cell atlas, we were able to identify the role of endoplasmic reticulum (ER) stress in the malignant transformation of conventional central chondrosarcomas (CCCS). Our research revealed that lower levels of ER stress promote chondrosarcoma growth in a patient-derived xenograft mouse model, while intensive ER stress reduces primary chondrosarcoma cell viability. Furthermore, we discovered that the NF-κB pathway alleviates ER stress-induced apoptosis during chondrosarcoma progression. Our single-cell signatures and large public data support the use of key ER stress regulators, such as DNA Damage Inducible Transcript 3 (DDIT3; also known as CHOP), as malignant markers for overall patient survival. Ultimately, our study highlights the significant role that ER stress plays in the malignant transformation of cartilaginous tumours and provides a valuable resource for future diagnostic markers and therapeutic strategies.

Plate-assisted bone segment transport: Novel application on distal tibia defect after tumour resection. A case report.

INTRODUCTION: Reconstruction of a large bone defect of the distal tibia after limb salvage surgery is difficult. The options include custom-made ankle endoprosthetic replacement, arthrodesis, and biological or metallic intercalary reconstructions. This report introduces a technique that provides the patient with a long-lasting biological reconstruction while preserving the native ankle. PRESENTATION OF CASE: We present the case of a 47-year-old man with osteosarcoma of the distal tibia. After neoadjuvant chemotherapy, wide excision was performed while preserving the ankle joint. Bone reconstruction by Plate-assisted bone segment transport (PABST) was performed with a non-invasive growing intramedullary nail. At 34 months of follow-up, there was solid union and the Musculoskeletal Tumour Society Score was 26/30. DISCUSSION: This is the first report of PABST after distal tibia tumour resection. It shows that this is a viable and safe method of reconstruction. Despite the use of adjuvant chemotherapy, regenerate was formed and union was achieved. CONCLUSION: PABST is a useful tool in the armamentarium to tackle difficult large bone defects.

Case report on metastatic pelvic bone tumor treated with frozen autograft by liquid nitrogen.

INTRODUCTION AND IMPORTANCE: Frozen autograft recycling has been used for biological reconstruction of bone defects following tumor excision, more commonly in extremities. We report on the histological outcome of a pelvic recycled frozen autograft. CASE PRESENTATION: We investigated the pelvic frozen autograft removed in 2 years and 8 months after surgery because of soft tissue recurrence in pelvic floor. The autograft bone showed no evidence of revitalization and was non-viable with patchy inflammation, and no residual tumor. There was only fibrous union but the autograft bone remained mechanically stable. CLINICAL DISCUSSION: We confirmed the clearance of tumor cells with the treatment with liquid nitrogen. The union at the host-graft junction might be affected by the previous radiotherapy, the presence of infection, the small contact area limited by the anatomy, and the inadequate compression across the osteotomy interface with the fixation. CONCLUSION: Frozen autograft treated by liquid nitrogen can be used safely for biological reconstructions after pelvic tumor excision.

Vascularised bone graft is an effective technique for extracortical bone bridging to combat cemented megaprosthesis loosening at the bone-implant junction.

INTRODUCTION: The bone-implant junction is a potential site for aseptic loosening. Extracortical bone bridging at the bone-implant junction is advocated to improve implant fixation by forming a biological seal. We propose a novel technique with vascularised bone graft (VBG) to form an extracortical bone bridge at the bone-implant junction to enhance implant stability. We compared the clinical and radiological outcomes for tumour megaprostheses performed (1) with and without bone graft and (2) with non-vascularised versus VBG technique. METHODS: Forty-six tumour megaprosthesis procedures from 1 June 2007 to 31 October 2017 were identified from hospital records. Twenty-eight operations incorporated bone graft at the bone-implant junction, and 18 did not. Of these 28 bone graft procedures, 13 involved VBG, and 15 did not (non-VBG). The VBG technique involves resecting a short segment of healthy bone beyond the oncological margin with its preserved blood supply, splitting it, then securing it over the junction. Clinical outcomes assessed included loosening, fracture and recurrence. Extracortical bone growth at the bone-implant junction was quantified radiologically at intervals 0-24 months post-operatively. The mean follow-up was 4.27 years. RESULTS: There were five incidences (27.8%) of loosening in the non-bone graft group compared to zero in the bone graft group (p = 0.03). There was a higher radiological score of extracortical bone growth in the bone graft group compared to no bone graft at 3-24 months post-operatively (p < 0.05). Within the bone graft group, the VBG group fared superior at 6 and 12 months post-operatively compared to non-VBG (p < 0.05), as well as a lower rate of radiological junctional resorption (p = 0.04). CONCLUSIONS: We recommend bone grafting for its merits of less implant loosening. We propose the VBG technique to combat early aseptic loosening in megaprosthesis replacement as there was a higher radiological score compared to non-VBG.

What Is the 10-year Survivorship of Cemented Distal Femoral Endoprostheses for Tumor Reconstructions and What Radiographic Features Are Associated with Survival?

BACKGROUND: Aseptic loosening is one of the most common causes of revision of distal femoral endoprostheses and is considered a mid- to long-term complication. There are not many reports of 10-year survivorship free from aseptic loosening and all-cause survivorship in cemented stems. To our knowledge, there are no reports on radiographic features that are associated with aseptic loosening of these implants. QUESTIONS/PURPOSES: (1) What is the 5- and 10-year survivorship free from aseptic loosening in patients undergoing reconstruction with a cemented distal femoral endoprosthesis after a tumor resection? (2) What is the all-cause 5- and 10-year survivorship at in these patients? (3) What radiographic features are associated with aseptic loosening at long-term follow-up? METHODS: We performed a multicenter retrospective study reviewing aseptic loosening in cemented prostheses to determine radiographic features associated with long-term implant survivorship. Patients who underwent a cemented distal femoral reconstruction with a modular endoprosthesis after resection of a musculoskeletal tumor between 1997 and 2017 were reviewed. A total of 246 patients were identified from five institutions and met initial inclusion criteria. Of those, 21% (51) were lost to follow-up before 2 years, leaving 195 patients available for us to evaluate and analyze the survivorship and radiologic features associated with long-term implant survival. The mean (range) follow-up was 78 months (22 to 257). At the time of this analysis, 69% (135 of 195) of the patients were alive. Osteosarcoma was the most common diagnosis in 43% of patients (83 of 195), followed by metastatic carcinoma 13% (25 of 195). Fifty-six percent (110 of 195) of patients received chemotherapy; 15% (30 of 195) had radiation therapy. Aseptic loosening was diagnosed radiographically and was defined as a circumferential radiolucent line on all views, or subsidence around the stem in the absence of infection. We present 5- and 10-year Kaplan-Meier survivorship free from aseptic loosening, 5- and 10-year all-cause survivorship, and a qualitative assessment of radiographic features potentially associated with aseptic loosening (including the junctional radiolucent area, and cortical expansion remodeling). The junctional radiolucent area was defined as a radiolucent area of the bone starting at the bone-endoprosthesis junction to the tip of the femoral stem, and cortical expansion remodeling was defined as an increased cortical thickness at the stem tip. Although we wished to statistically analyze radiographic factors potentially associated with aseptic loosening, we did not have enough clinical material to do so (only nine patients developed loosening). Instead, we will report a few preliminary qualitative observations, which necessarily are preliminary, and which will need to be confirmed or refuted by future studies. We urge caution in interpreting these findings because of the very small numbers involved. RESULTS: Kaplan-Meier survivorship free from aseptic loosening of the femoral component at 5 and 10 years were 95% (95% CI 89 to 98) and 93% (95% CI 86 to 97), respectively. Kaplan-Meier survivorship free from revision for any cause at 5 and 10 years were 74% (95% CI 65 to 79) and 64% (95% CI 49 to 70), respectively. Although the numbers were too small to analyze statistically, all patients with aseptic loosening had a junctional radiolucent area more than 20% of the total length of the stem without cortical expansion remodeling at the stem tip. No aseptic loosening was observed if there was cortical ex remodeling, a junctional radiolucent area less than 20%, or curved stems that were 13 mm or greater in diameter. The numbers of patients with aseptic loosening in this series were too small to analyze statistically. CONCLUSIONS: Cemented distal femoral endoprostheses have a relatively low rate of aseptic loosening and acceptable projected first-decade survivorship. The presence of a radiolucent area more than 20% without cortical expansion remodeling at the stem tip may lead to aseptic loosening in patients with these implants. Close radiographic surveillance and revision surgery may be considered for progressive lucencies and clinical symptoms of pain. If revision is contemplated, we recommend using larger diameter curved cemented stems. These are preliminary and provisional observations based on a low number of patients with aseptic loosening; future studies with greater numbers of patients are needed to validate or refute these findings. LEVEL OF EVIDENCE: Level III, therapeutic study.

Transfer of the anterior gluteus maximus to address abductor deficiency following soft tissue tumour excision.

Hip abductor deficiency is most commonly encountered in the context of degeneration of the hip, and techniques for reconstruction pioneered by arthroplasty surgeons. We adopted a local muscle transfer technique utilizing the anterior half of the gluteus maximus for abductor reconstruction following soft tissue tumour excision in a young female patient. The patient of concern had a solitary fibrous tumour located between the right gluteus medius and minimus detected as an incidental finding. Marginal excision of the mass resulted in removal of the gluteus medius. The anterior half of the gluteus maximus was transferred and attached to the decorticated lateral greater trochanter by means of suture anchors and transosseous sutures. The patient initially demonstrated a Trendelenburg gait and limited abduction against gravity. By 1-year post-operation, there was return of normal gait and recovery of hip abductor power. This is the first report of anterior gluteus maximus transfer being successfully applied for soft tissue reconstruction around the hip subsequent to tumour excision.

Antibiotic-laden cement wrap: A simple but effective way of treating patients with megaprosthesis infection.

Infection is one of the commonest causes for megaprosthesis failure. The current treatment includes antibiotics but no surgery, debridement, prosthesis removal and joint fusion, prosthesis revision or amputation. Success in controlling infection may be less than 50% in implant revision. The overall risk of amputation is more than 20%. We believe that repeated debridement with antibiotic-laden cement wrap (ALCW) may be a reliable alternative for managing the megaprosthesis infection. The purposes of this article are to identify whether ALCW is an effective way of eradicating the megaprosthesis infection, the associated complications and the functional outcome after management by ALCW. METHODS: This was a retrospective study of patients with megaprosthesis infection. From January 2014 to June 2016, there were five patients with tumour megaprosthesis infection who had undergone the ALCW procedure. Ages ranged from 17 to 59 years of age. Male to female ratio was 4:1. The patients studied had humeral (1), proximal femoral (1), distal femoral (1) and proximal tibial (2) prostheses. All patients had follow-ups more than 1 year (21-52 months) after treatment. RESULTS: All patients recovered from their implant infection and the implants were retained in all patients. There was no sign of infection in the most recent follow-up. One patient died of osteosarcoma recurrence. One patient had a large block of cement causing plastic insert dislodgement in the shoulder joint 1 year after surgery. Another patient with a dislocated hip cup had revision carried out in the final debridement. The most recent Musculoskeletal Tumor society (MSTS) scores ranged from 21 to 30. All patients were satisfied with their treatment. CONCLUSIONS: In this preliminary report of a small number of patients, ALCW has achieved 100% infection control. ALCW may be an easy and effective alternative for managing the megasprosthesis infection. The complications associated can be avoidable. The functional outcome is excellent.

Prevalence and predictors of spontaneous bacterial peritonitis due to ceftriaxone-resistant organisms at a large tertiary centre in the USA.

OBJECTIVES: The epidemiology of spontaneous bacterial peritonitis (SBP) due to ceftriaxone-resistant organisms has not been well studied in the USA. The primary objective of this study was to assess the prevalence and predictors of ceftriaxone-resistant SBP at a large US tertiary-care centre. METHODS: This 1:1:4 case-case-control study included 141 adults with liver cirrhosis admitted from November 2011 to March 2016. Case group 1 were patients with SBP with a ceftriaxone-resistant organism (n=21). Case group 2 were patients with SBP with a ceftriaxone-susceptible organism (n=26). The control group were patients without SBP (n=94). Multiple logistic regression analysis was used to identify predictors of ceftriaxone-resistant SBP. RESULTS: Fifty isolates were identified from 47 patients with culture-positive SBP (case groups 1 and 2). Of these 50 isolates, 32 (64%) were Gram-negatives [mostly Enterobacteriaceae (91%)], 15 (30%) were Gram-positives and 3 (6%) were Candida spp. The prevalence of ceftriaxone resistance in patients with culture-positive SBP was 45% (21/47). The most common ceftriaxone-resistant organisms were ESBL-producing Enterobacteriaceae (45%). Independent predictors of ceftriaxone-resistant SBP included duration of ß-lactam therapy in the past 90days (aOR=1.07, 95% CI 1.01-1.13) and recent invasive gastrointestinal procedure (aOR=12.47, 95% CI 2.74-56.67). CONCLUSIONS: The prevalence of ceftriaxone-resistant SBP was significant at a US tertiary centre. Local epidemiological data and identification of risk factors associated with ceftriaxone-resistant SBP, e.g. increased usage of previous ß-lactam therapy and invasive gastrointestinal procedure, may help clinicians identify patients requiring alternative empirical antibiotics.

Genetic and clonal dissection of osteosarcoma progression and lung metastasis.

Osteosarcoma is a primary malignant bone tumor that has a high potential to metastasize to lungs. Little is known about the mechanisms underlying the dissemination of OS cancer cells to lungs. We performed whole exome sequencing of 13 OS primary tumors, with matched lung metastases and normal tissues. Phylogenetic analyses revealed that lung metastatic tumors often harbor clones that are nonexistent or rare in the matched primary OS tumors. Spatially and temporally separated lung metastases were from parallel seeding events with a polyphyletic pattern. Loss of TP53 or RB1 is among the early events during OS tumorigenesis, while loss of PTEN is involved at the later stages associated with lung metastases. Finally, KEAP1 was identified as a novel biomarker for increased metastatic risk. Patients whose primary tumors harbored KEAP1 amplification have significantly poorer lung-metastasis free survival. This finding was validated in two independent datasets. Further, in vitro experiments exhibited that KEAP1 depletion suppressed the invasion of OS cells. Our findings uncover the patterns of clonal evolution during OS progression and highlight KEAP1 as a novel candidate associated with the risk of lung metastasis in OS patients.

Bacteremia in Patients With Liver Cirrhosis: Prevalence and Predictors of Multidrug Resistant Organisms.

GOALS: The objective of this study was to assess the prevalence and predictors of multidrug resistant organisms (MDRO) in cirrhotic patients with bacteremia at a large tertiary center in the United States. BACKGROUND: The epidemiology of bacteremia in patients with liver cirrhosis has not been well studied in the United States. STUDY: This case-case control study included 180 adults with liver cirrhosis hospitalized from 2011 to 2015. Case group 1 were patients with bacteremia due to a MDRO (n=30). Case group 2 were patients with bacteremia due to a non-MDRO (n=60). Control group comprised patients without bacteremia (n=90). MDRO was defined as bacteria that was nonsusceptible to ≥1 agent in ≥3 antimicrobial categories. RESULTS: Of the 90 bacteremia episodes, 44% were because of gram-positive bacteria, 50% were because of gram-negative bacteria, and 6% were polymicrobial. MDROs caused 30 of 90 (33%) bacteremia episodes, including methicillin-resistant Staphylococcus species [12% (11/90)], fluoroquinolone-resistant Enterobacteriaceae [10% (9/90)], and Enterococcus faecium [3% (3/90)]. Eight percent of Enterobacteriaceae produced extended-spectrum ß-lactamases. Four independent predictors of MDROs were identified: nonwhite race [adjusted odds ratio (aOR), 3.35; 95% confidence interval (CI), 1.19-9.38], biliary cirrhosis (aOR, 11.75; 95% CI, 2.08-66.32), blood cultures obtained >48 hours after hospital admission (aOR, 6.02; 95% CI, 1.70-21.40), and recent health care exposure (aOR, 9.81; 95% CI, 2.15-44.88). CONCLUSIONS: A significant proportion of bacteremia in cirrhotic patients was due to MDROs at a large US tertiary care center. Local epidemiology data and identification of risk factors associated with MDROs may help with optimal empiric antibiotic selection.

Is It Possible and Safe to Perform Acetabular-preserving Resections for Malignant Neoplasms of the Periacetabular Region?

BACKGROUND: Primary malignant tumors located near the acetabulum are usually managed by resection of the tumor with wide margins that include the acetabulum. These resections are deemed P2 resections by the Enneking and Dunham classification. There are various methods to perform the subsequent hip reconstruction. Unfortunately, there is no consensus as to the best management. In general, patients undergoing resection at this level will have substantial levels of pain and disability as measured by the Musculoskeletal Tumor Society (MSTS) scoring system. We believe there is a subset of patients whose tumors in this location can be resected while preserving all or most of the weightbearing acetabulum using navigation and careful surgical planning. QUESTIONS/PURPOSES: (1) What complications were associated with this resection; (2) what oncological outcomes (histological margins and local recurrence) were achieved; and (3) what is the function achieved by these patients? METHODS: This was a retrospective study of patients with periacetabular primary malignancy. From 2008 to 2014, we treated 12 patients who had periacetabular primary malignant tumors and in five, we performed resection with the weightbearing portion spared. During this period, our general indications to perform a resection that spared the acetabulum were the tumor with its resection margin not involving the weightbearing portion of the acetabulum. However, we did not perform this procedure in patients who had more cranial lesion involving the weightbearing portion or whose hip stability might be in question after the tumor excision. Three patients were women and the other two were men. Four were chondrosarcomas, whereas the other one was synovial sarcoma. Ages ranged from 46 to 60 years (average, 53 years). Minimum followup was 14 months (median, 37 months; range, 14-88 months); no patients were lost to followup before a 1-year minimum was achieved, and all patients have been seen within the last 9 months. RESULTS: There were no intraoperative or early postoperative complications. None of the five patients had a positive margin by histological assessment. No local recurrences were detected. The median functional score by MSTS was 28 out of 30 (range, 27-30). CONCLUSIONS: The roof of the acetabulum is the weightbearing portion of the acetabulum. It also maintains the stability of the hip. With precise preoperative planning of the resection and accurate execution of the procedure, the hip-sparing approach through partial acetabular resection can be performed in selected patients with malignant periacetabular neoplasms. Navigation makes it possible to minimize the amount of bone resection. In this preliminary report of a small number of patients, we had adequate short-term local tumor control. We believe the function is good, but we do not have a comparison group of patients to document improved function. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Direct thrombolytic therapy for thrombosis of a centrifugal flow left ventricular assist device.

In patients receiving left ventricular assistance for end-stage heart failure, pump-related thrombosis is a potentially fatal complication that may manifest as hemolysis and abnormally high pump power consumption. The optimal approach to treat this complication is unclear, especially in patients who are not heart transplant candidates or who have a high surgical risk. We report the successful use of direct thrombolytic therapy for recurrent hemolysis and thrombosis-related pump failure in a patient with the HeartWare ventricular assist device (HVAD), a third-generation, centrifugal flow pump. We know of only one previous case in which direct thrombolytic therapy has been used to treat the failure of a third-generation device. On the basis of our experience in the present case, we believe that direct thrombolytic therapy is a feasible option in these patients.

Impact of prior inappropriate fluconazole dosing on isolation of fluconazole-nonsusceptible Candida species in hospitalized patients with candidemia.

Prior use of fluconazole is a modifiable risk factor for the isolation of fluconazole-nonsusceptible Candida species. Optimization of the use of fluconazole by appropriate dose or duration may be able to minimize the risk of resistance. The objective of this study was to evaluate the effects of prior fluconazole therapy, including the dose and duration, on fluconazole susceptibility among Candida species isolated from hospitalized patients with candidemia. A retrospective cohort study of hospitalized patients with a first occurrence of nosocomial candidemia, from 2006 to 2009, was carried out. The relationships between the initial dose and duration of prior fluconazole therapy and the isolation of fluconazole-nonsusceptible Candida species were assessed. An initial fluconazole dose greater than 2 mg/kg and less than 6 mg/kg of body weight was considered suboptimal. A total of 177 patients were identified, of whom 133 patients aged 61 ± 16 years (56% male, 51% Caucasian, 51% with an APACHE II score of ≥ 15) had candidemia more than 2 days after the hospital admission day. Nine of 107 (8%) patients with fluconazole-susceptible Candida species and 9 of 26 (35%) patients with fluconazole-nonsusceptible Candida species had prior fluconazole exposure (risk ratio [RR], 3.03; 95% confidence interval [95% CI], 1.57 to 5.86; P, 0.0022). Preexposure with an initial dose of fluconazole greater than 2 mg/kg and less than 6 mg/kg occurred in 3 of 9 (33%) and 8 of 9 (89%) patients with fluconazole-susceptible and fluconazole-nonsusceptible Candida species, respectively (P, 0.0498). We conclude that patients with candidemia due to fluconazole-nonsusceptible Candida species were more likely to have received prior fluconazole therapy. Suboptimal initial dosing of prior fluconazole therapy was associated with candidemia with fluconazole-nonsusceptible Candida species.