Publications by authors named "John H Healey"

231 Publications

Exposure-response analysis of efficacy and safety for pexidartinib in patients with tenosynovial giant cell tumor.

CPT Pharmacometrics Syst Pharmacol 2021 Sep 29. Epub 2021 Sep 29.

Department of Medical Oncology, Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy.

This analysis was conducted to assess exposure-response relationships for efficacy and safety of pexidartinib in patients with tenosynovial giant cell tumor. Efficacy was assessed categorically by overall response rate (ORR) with Response Evaluation Criteria in Solid Tumors version 1.1 and longitudinally (changes in tumor size and volume). Safety included hepatic parameters (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], and total bilirubin). Average pexidartinib concentration (C ) was identified as the primary exposure parameter correlated with response. In categorical and longitudinal analyses, higher C coincided with greater ORR and tumor size reduction, respectively, with smaller joint size having a greater impact. For safety, a significant relationship was observed between C and incidence of ALT-related and AST-related adverse events (AEs). With increased exposure, an increase in efficacy was predicted with near maximum effect at 800 mg/day. Higher initial dose (1000 mg/day) during the first 2 weeks did not improve efficacy. Higher doses were associated with an increased risk of ALT-related and AST-related AEs. These results support the US Food and Drug Administration-approved dose (400 mg two times/day without initial loading dose).
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http://dx.doi.org/10.1002/psp4.12712DOI Listing
September 2021

Computer-Assisted Surgical Navigation for Primary and Metastatic Bone Malignancy of the Pelvis: Current Evidence and Future Directions.

HSS J 2021 Oct 7;17(3):344-350. Epub 2021 Jul 7.

Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Computer-assisted navigation and robotic surgery have gained popularity in the treatment of pelvic bone malignancies, given the complexity of the bony pelvis, the proximity of numerous vital structures, and the historical challenges of pelvic bone tumor surgery. Initial interest was on enhancing the accuracy in sarcoma resection by improving the quality of surgical margins and decreasing the incidence of local recurrences. Several studies have shown an association between intraoperative navigation and increased incidence of negative margin bone resection, but long-term outcomes of navigation in pelvic bone tumor resection have yet to be established. Historically, mechanical stabilization of pelvic bone metastases has been limited to Harrington-type total hip arthroplasty for disabling periacetabular disease, but more recently, computer-assisted surgery has been employed for minimally invasive percutaneous fixation and stabilization; although still in its incipient stages, this procedure is potentially appealing for treating patients with bone metastases to the pelvis. The authors review the literature on navigation for the treatment of primary and metastatic tumors of the pelvic bone and discuss the best practices and limitations of these techniques.
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http://dx.doi.org/10.1177/15563316211028137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436340PMC
October 2021

Long-term competing risks for overall and cause-specific failure of rotating-hinge distal femoral arthroplasty for tumour reconstruction.

Bone Joint J 2021 Aug;103-B(8):1405-1413

Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Aims: Rotating-hinge knee prostheses are commonly used to reconstruct the distal femur after resection of a tumour, despite the projected long-term burden of reoperation due to complications. Few studies have examined the factors that influence their failure and none, to our knowledge, have used competing risk models to do so. The purpose of this study was to determine the risk factors for failure of a rotating-hinge knee distal femoral arthroplasty using the Fine-Gray competing risk model.

Methods: We retrospectively reviewed 209 consecutive patients who, between 1991 and 2016, had undergone resection of the distal femur for tumour and reconstruction using a rotating-hinge knee prosthesis. The study endpoint was failure of the prosthesis, defined as removal of the femoral component, the tibial component, or the bone-implant fixation; major revision (exchange of the femoral component, tibial component, or the bone-implant fixation); or amputation.

Results: Multivariate Fine-Gray regression analyses revealed different hazards for each Henderson failure mode: percentage of femoral resection (p = 0.001) and extent of quadriceps muscle resection (p = 0.005) for overall prosthetic failure; extent of quadriceps muscle resection (p = 0.002) and fixation of femoral component (p = 0.011) for type 2 failure (aseptic loosening); age (p = 0.009) and percentage of femoral resection (p = 0.019) for type 3 failure (mechanical failure); and type of joint resection (p = 0.037) for type 4 (infection) were independent predictors. A bone stem ratio of > 2.5 reliably predicted aseptic loosening.

Conclusion: We identified independent risk factors for overall and cause-specific prosthetic failure after rotating-hinge knee distal femoral arthroplasty using a competing risk Fine-Gray model. A bone stem ratio > 2.5 reliably predicts aseptic loosening. An accurate knowledge of the risks of distal femoral arthroplasty after resection for tumour assists surgical planning and managing patient expectations. Cite this article:  2021;103-B(8):1405-1413.
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http://dx.doi.org/10.1302/0301-620X.103B8.BJJ-2020-2323.R1DOI Listing
August 2021

CSF1/CSF1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-cell Infiltration in the Sarcoma Microenvironment.

Mol Cancer Ther 2021 Aug 4;20(8):1388-1399. Epub 2021 Jun 4.

Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, New York.

Colony-stimulating factor 1 (CSF1) is a primary regulator of the survival, proliferation, and differentiation of monocyte/macrophage that sustains the protumorigenic functions of tumor-associated macrophages (TAMs). Considering current advances in understanding the role of the inflammatory tumor microenvironment, targeting the components of the sarcoma microenvironment, such as TAMs, is a viable strategy. Here, we investigated the effect of PLX3397 (pexidartinib) as a potent inhibitor of the CSF1 receptor (CSF1R). PLX3397 was recently approved by the Food and Drug Administration (FDA) to treat tenosynovial giant cell tumor and reprogram TAMs whose infiltration correlates with unfavorable prognosis of sarcomas. First, we confirmed by cytokine arrays of tumor-conditioned media (TCM) that cytokines including CSF1 are secreted from LM8 osteosarcoma cells and NFSa fibrosarcoma cells. The TCM, like CSF1, stimulated ERK1/2 phosphorylation in bone marrow-derived macrophages (BMDMs), polarized BMDMs toward an M2 (TAM-like) phenotype, and strikingly promoted BMDM chemotaxis. administration of PLX3397 suppressed pERK1/2 stimulation by CSF1 or TCM, and reduced M2 polarization, survival, and chemotaxis in BMDMs. Systemic administration of PLX3397 to the osteosarcoma orthotopic xenograft model significantly suppressed the primary tumor growth and lung metastasis, and thus improved metastasis-free survival. PLX3397 treatment concurrently depleted TAMs and FOXP3 regulatory T cells and, surprisingly, enhanced infiltration of CD8 T cells into the microenvironments of both primary and metastatic osteosarcoma sites. Our preclinical results show that PLX3397 has strong macrophage- and T-cell-modulating effects that may translate into cancer immunotherapy for bone and soft-tissue sarcomas.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0591DOI Listing
August 2021

Patients with an increased time to treatment initiation have a poorer overall survival after definitive surgery for localized high-grade soft-tissue sarcoma in the extremity or trunk : report from the National Cancer Database.

Bone Joint J 2021 Jun;103-B(6):1142-1149

Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Aims: Time to treatment initiation (TTI) is generally defined as the time from the histological diagnosis of malignancy to the initiation of first definitive treatment. There is no consensus on the impact of TTI on the overall survival in patients with a soft-tissue sarcoma. The purpose of this study was to determine if an increased TTI is associated with overall survival in patients with a soft-tissue sarcoma, and to identify the factors associated with a prolonged TTI.

Methods: We identified 23,786 patients from the National Cancer Database who had undergone definitive surgery between 2004 and 2015 for a localized high-grade soft-tissue sarcoma of the limbs or trunk. A Cox proportional hazards model was used to examine the relationship between a number of factors and overall survival. We calculated the incidence rate ratio (IRR) using negative binomial regression models to identify the factors that affected TTI.

Results: Patients in whom the time to treatment initiation was prolonged had poorer overall survival than those with a TTI of 0 to 30 days. These were: 31 to 60 days (hazard ratio (HR) 1.08, p = 0.011); 61 to 90 days (HR 1.11, p = 0.044); and 91 days (HR 1.22; p = 0.003). The restricted cubic spline showed that the hazard ratio increased substantially with a TTI longer than 50 days. Non-academic centres (vs academic centres; IRR ranging from 0.64 to 0.86; p < 0.001) had a shorter TTI. Those insured by Medicaid (vs private insurance; IRR 1.34), were uninsured (vs private insurance; IRR 1.17), or underwent a transition in care (IRR 1.62) had a longer TTI.

Conclusion: A time to treatment initiation of more than 30 days after diagnosis was independently associated with poorer survival. The hazard ratio showed linear increase, especially if the TTI was more than 50 days. We recommend starting treatment within 30 days of diagnosis to achieve the highest likelihood of cure for localized high-grade soft-tissue sarcomas in the limbs and trunk, even when a patient needs to be referred to a specialist centre. Cite this article:  2021;103-B(6):1142-1149.
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http://dx.doi.org/10.1302/0301-620X.103B6.BJJ-2020-2087.R1DOI Listing
June 2021

Anti-tumor effects of an ID antagonist with no observed acquired resistance.

NPJ Breast Cancer 2021 May 24;7(1):58. Epub 2021 May 24.

Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

ID proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. ID proteins inhibit basic-HLH transcription factors often blocking differentiation and sustaining proliferation. A small-molecule, AGX51, targets ID proteins for degradation and impairs ocular neovascularization in mouse models. Here we show that AGX51 treatment of cancer cell lines impairs cell growth and viability that results from an increase in reactive oxygen species (ROS) production upon ID degradation. In mouse models, AGX51 treatment suppresses breast cancer colonization in the lung, regresses the growth of paclitaxel-resistant breast tumors when combined with paclitaxel and reduces tumor burden in sporadic colorectal neoplasia. Furthermore, in cells and mice, we fail to observe acquired resistance to AGX51 likely the result of the inability to mutate the binding pocket without loss of ID function and efficient degradation of the ID proteins. Thus, AGX51 is a first-in-class compound that antagonizes ID proteins, shows strong anti-tumor effects and may be further developed for the management of multiple cancers.
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http://dx.doi.org/10.1038/s41523-021-00266-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144414PMC
May 2021

Pexidartinib improves physical functioning and stiffness in patients with tenosynovial giant cell tumor: results from the ENLIVEN randomized clinical trial.

Acta Orthop 2021 Aug 12;92(4):493-499. Epub 2021 May 12.

Department of Orthopaedic Surgery, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA.

Background and purpose - The ENLIVEN trial showed that, after 25 weeks, pexidartinib statistically significantly reduced tumor size more than placebo in patients with symptomatic, advanced tenosynovial giant cell tumor (TGCT) for whom surgery was not recommended. Here, we detail the effect of pexidartinib on patient-reported physical function and stiffness in ENLIVEN.Patients and methods - This was a planned analysis of patient-reported outcome data from ENLIVEN, a double-blinded, randomized phase 3 trial of adults with symptomatic, advanced TGCT treated with pexidartinib or placebo. Physical function was assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS)-physical function (PF), and worst stiffness was assessed using a numerical rating scale (NRS). A mixed model for repeated measures was used to compare changes in PROMIS-PF and worst stiffness NRS scores from baseline to week 25 between treatment groups. Response rates for the PROMIS-PF and worst stiffness NRS at week 25 were calculated based on threshold estimates from reliable change index and anchor-based methods.Results - Between baseline and week 25, greater improvements in physical function and stiffness were experienced by patients receiving pexidartinib than patients receiving placebo (change in PROMIS-PF = 4.1 [95% confidence interval (CI) 1.8-6.3] vs. -0.9 [CI -3.0 to 1.2]; change in worst stiffness NRS = -2.5 [CI -3.0 to -1.9] vs. -0.3 [CI -0.9 to 0.3]). Patients receiving pexidartinib had higher response rates than patients receiving placebo for meaningful improvements in physical function and stiffness. Improvements were sustained after 50 weeks of pexidartinib treatment.Interpretation - Pexidartinib treatment provided sustained, meaningful improvements in physical function and stiffness for patients with symptomatic, advanced TGCT.
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http://dx.doi.org/10.1080/17453674.2021.1922161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382018PMC
August 2021

The diffuse-type tenosynovial giant cell tumor (dt-TGCT) patient journey: a prospective multicenter study.

Orphanet J Rare Dis 2021 04 29;16(1):191. Epub 2021 Apr 29.

Department of Orthopaedic Surgery, Leiden University Medical Center, Leiden, The Netherlands.

Background: Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm arising from the synovium of joints, bursae, and tendon sheaths affecting small and large joints. It represents a wide spectrum ranging from minimally symptomatic to massively debilitating. Most findings to date are mainly from small, retrospective case series, and thus the morbidity and actual impact of this rare disease remain to be elucidated. This study prospectively explores the management of TGCT in tertiary sarcoma centers.

Methods: The TGCT Observational Platform Project registry was a multinational, multicenter, prospective observational study involving 12 tertiary sarcoma centers in 7 European countries, and 2 US sites. This study enrolled for 2 years all consecutive ≥ 18 years old patients, with histologically diagnosed primary or recurrent cases of diffuse-type TGCT. Patient demographic and clinical characteristics were collected at baseline and every 6 months for 24 months. Quality of life questionnaires (PROMIS-PF and EQ-5D) were also administered at the same time-points. Here we report baseline patient characteristics.

Results: 166 patients were enrolled between November 2016 and March 2019. Baseline characteristics were: mean age 44 years (mean age at disease onset: 39 years), 139/166 (83.7%) had prior treatment, 71/166 patients (42.8%) had ≥ 1 recurrence after treatment of their primary tumor, 76/136 (55.9%) visited a medical specialist ≥ 5 times, 66/116 (56.9%) missed work in the 24 months prior to baseline, and 17/166 (11.6%) changed employment status or retired prematurely due to disease burden. Prior treatment consisted of surgery (i.e., arthroscopic, open synovectomy) (128/166; 77.1%) and systemic treatments (52/166; 31.3%) with imatinib (19/52; 36.5%) or pexidartinib (27/52; 51.9%). Treatment strategies at baseline visits consisted mainly of watchful waiting (81/166; 48.8%), surgery (41/166; 24.7%), or targeted systemic therapy (37/166; 22.3%). Patients indicated for treatment reported more impairment compared to patients indicated for watchful waiting: worst stiffness NRS 5.16/3.44, worst pain NRS 6.13/5.03, PROMIS-PF 39.48/43.85, and EQ-5D VAS 66.54/71.85.

Conclusion: This study confirms that diffuse-type TGCT can highly impact quality of life. A prospective observational registry in rare disease is feasible and can be a tool to collect curated-population reflective data in orphan diseases. Name of registry: Tenosynovial Giant Cell Tumors (TGCT) Observational Platform Project (TOPP).

Trial Registration Number: NCT02948088. Date of registration: 10 October 2016. URL of Trial registry record: https://clinicaltrials.gov/ct2/show/NCT02948088?term=NCT02948088&draw=2 .
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http://dx.doi.org/10.1186/s13023-021-01820-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086070PMC
April 2021

Anti-IL17 antibody Secukinumab therapy is associated with ossification in giant cell tumor of bone: a case report of pathologic similarities and therapeutic potential similar to Denosumab.

BMC Musculoskelet Disord 2021 Apr 1;22(1):320. Epub 2021 Apr 1.

Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY, 10065, USA.

Background: Giant cell tumor of bone is a benign, locally aggressive neoplasm. Surgical resection is the preferred treatment method. However, for cases in which resection poses an increased risk to the patient, denosumab (anti-RANKL monoclonal antibody) is considered. Secukinumab is an anti-IL-17 antibody that is used in psoriatic arthritis to reduce bone resorption and articular damage.

Case Presentation: One case of giant cell tumor of bone (GCTB) in a patient treated with secukinumab for psoriatic arthritis demonstrated findings significant for intra-lesional calcifications. Histologic examination showed ossification, new bone formation, and remodeling. A paucity of osteoclast type giant cells was noted. Real-time quantitative polymerase-chain-reaction (qRT-PCR) analysis revealed decreased osteoclast function compared to treatment-naive GCTB.

Conclusions: Secukinumab may play a role in bone remodeling for GCTB. Radiologists, surgeons, and pathologists should be aware of this interaction, which can cause lesional ossification. Further research is required to define the therapeutic potential of this drug for GCTB and osteolytic disease.
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http://dx.doi.org/10.1186/s12891-021-04182-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015053PMC
April 2021

Postradiation Fractures after Combined Modality Treatment in Extremity Soft Tissue Sarcomas.

Sarcoma 2021 15;2021:8877567. Epub 2021 Mar 15.

Department of Surgery, Orthopedic Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA.

Soft tissue sarcoma (STS) of the extremities is typically treated with limb-sparing surgery and radiation therapy; with this treatment approach, high local control rates can be achieved. However, postradiation bone fractures, fractures occurring in the prior radiation field with minimal or no trauma, are a serious late complication that occurs in 2-22% of patients who receive surgery and radiation for STS. Multiple risk factors for sustaining a postradiation fracture exist, including high radiation dose, female sex, periosteal stripping, older age, femur location, and chemotherapy administration. The treatment of these pathological fractures can be difficult, with complications including delayed union, nonunion, and infection posing particular challenges. Here, we review the mechanisms, risk factors, and treatment challenges associated with postradiation fractures in STS patients.
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http://dx.doi.org/10.1155/2021/8877567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984930PMC
March 2021

Minimal clinically important differences in SF-36 global score: Current value in orthopedic oncology.

J Orthop Res 2021 Oct 20;39(10):2116-2123. Epub 2020 Dec 20.

Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

The SF-36 is widely used to evaluate the health-related quality of life (HRQoL) of patients with musculoskeletal tumors. Instead of typical methods, calculating the SF-36 Global Score has recently become an increasingly common reporting approach. However, numerical changes lack clear clinical relevance. The minimal clinically important difference (MCID) is useful for interpreting changes in functional scores by defining the smallest change patients may perceive as clinically meaningful. The aim of this study is to determine the MCID of the SF-36 Global Score in orthopedic oncology patients, which has not been reported to date. Three-hundred ten patients who underwent surgery and completed two surveys during postoperative follow-up were reviewed. The two most common methods for calculating the SF-36 Global Score were used: (1) anchor-based methods and receiver operating characteristic analysis based on one-half of the SD of change score and standard error of measurement at baseline and; (2) distribution-based methods. Using anchor-based methods, the MCIDs of SF-36 Global Scores #1 and #2 were 2.7 (area under the curve [AUC] = 0.85) and 2.5 (AUC = 0.79) for improvement, and -1.5 (AUC = 0.81) and -0.6 (AUC = 0.83) for deterioration, respectively. Using distribution-based methods, the MCIDs of SF-36 Global Scores #1 and #2 were 4.1 and 4.4 by half SD, and 4.1 and 4.5 by standard error of measurement, respectively. Our findings provide benchmark values, which can serve as a reference for future studies in musculoskeletal tumor patients using the SF-36 Global Score as a single measure for HRQoL.
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http://dx.doi.org/10.1002/jor.24944DOI Listing
October 2021

Compliant Compression Reconstruction of the Proximal Femur Is Durable Despite Minimal Bone Formation in the Compression Segment.

Clin Orthop Relat Res 2021 Jul;479(7):1577-1585

Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, affiliated with Weill Medical College of Cornell University, New York, NY, USA.

Background: Compliant compression fixation was developed to promote permanent bone-prosthesis osteointegration while preserving bone stock in patients needing endoprosthetic reconstructions. This has demonstrated durability in the distal femur, with reliable cortical hypertrophy adjacent to the implant. However, the extent of bone formation and prosthetic survivorship of proximal femoral replacements with compliant compression fixation has not been established.

Questions/purposes: (1) How much bone formation occurs across the compression segment in patients treated with a proximal femoral replacement implant using compliant compression fixation? (2) What were the Musculoskeletal Tumor Society (MSTS) scores at minimum 24-month follow-up of patients who received this reconstruction? (3) What is the implant survivorship free from implant removal or revision for any reason at final follow-up?

Methods: From 2006 to 2018, we performed 213 proximal femoral replacements in patients with oncologic conditions of the proximal femur where the trochanters could not be preserved. Of these, 6% (12 of 213) were performed with an implant that used compliant compression fixation. We used this device in primary oncologic reconstructions in patients younger than 65 years of age without metastases who had nonirradiated bone with the requisite ≥ 2.5 mm of cortical thickness in the hope that it would provide more durable fixation and bone stock preservation than conventional reconstructions. All patients were followed for longer than 2 years except one who died in that interval. Median (range) follow-up was 6 years (2 to 10 years). Seven patients received diagnosis-specific chemotherapy in a consistent manner based on Children's Oncology Group chemotherapy protocols. Using the NIH-developed ImageJ open-access software, we measured the area of bone under compression on 3-, 6-, 9-, 12-, 18-, and 24-month radiographs and the length of the traction bar potential-compression distance, reconciling independent measures from two investigators using the identical method as published for the distal femur with compression fixation. The duration of prosthesis retention was evaluated using a competing risk analysis for the 11 surviving patients.

Results: Bone hypertrophy in the compression segment was scant. At the final analysis, cortical bone formation was a median (range) of 4 (-7 to 14) above baseline. The median (range) MSTS score was 27 (19 to 30). One implant failed after trauma, and the patient underwent revision of the implant.

Conclusion: Despite scant bone formation across the compression segment and drastically less formation than reported for distal femoral replacements, compliant compression fixation of the proximal femur demonstrated good survivorship in patients 65 years or younger with localized sarcoma and nonirradiated, adequate bone stock in this small, retrospective series. Patients achieved good functional outcomes at final follow-up. The potential benefit of this reconstruction method should be weighed against the initial period of limited weightbearing and the life expectancy of the patient.

Level Of Evidence: Level IV, cohort study.
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http://dx.doi.org/10.1097/CORR.0000000000001663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208447PMC
July 2021

Interlocking reconstruction-mode stem-sideplates preserve at-risk hips with short residual proximal femora.

Bone Joint J 2021 Feb;103-B(2):398-404

Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Aims: We have evaluated the survivorship, outcomes, and failures of an interlocking, reconstruction-mode stem-sideplate implant used to preserve the native hip joint and achieve proximal fixation when there is little residual femur during large endoprosthetic reconstruction of the distal femur.

Methods: A total of 14 patients underwent primary or revision reconstruction of a large femoral defect with a short remaining proximal femur using an interlocking, reconstruction-mode stem-sideplate for fixation after oncological distal femoral and diaphyseal resections. The implant was attached to a standard endoprosthetic reconstruction system. The implant was attached to a standard endoprosthetic reconstruction system. None of the femoral revisions were amenable to standard cemented or uncemented stem fixation. Patient and disease characteristics, surgical history, final ambulatory status and Musculoskeletal Tumor Society (MSTS) score were recorded. The percentage of proximal femur remaining was calculated from follow-up radiographs.

Results: All 14 at-risk native hip joints were preserved at a mean final follow-up of 6.0 years (SD 3.7), despite a short residual femur, often after proximal osteotomies through the lesser trochanter. Overall, 13 of 14 stems had long-term successful fixation. Eight patients required no reoperation. Three patients required reoperation due to implant-related issues, and three patients required reoperation for wound healing problems or infection. There were no dislocations or fractures. At final follow-up the mean MSTS score was 24.9 (SD 4.1). Nine patients required no ambulation aids, and only one had a Trendelenburg gait.

Conclusion: This interlocking, reconstruction-mode stem-sideplate reliably preserves native hip joint anatomy and function after large femoral resection with a short remaining proximal femur, both in the primary and revision setting. This is particularly important for preventing or delaying total femoral arthroplasty in young patients after oncological reconstruction. Hip abductor strength and function could be maintained by this method, and the risk of dislocation eliminated. The success of this technique in this modest series should be verified in a larger collaborative study and will be of interest to revision surgeons and oncologists. Cite this article: 2021;103-B(2):398-404.
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http://dx.doi.org/10.1302/0301-620X.103B2.BJJ-2020-0654.R1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926295PMC
February 2021

The critical difference in the DASH (Disabilities of the Arm, Shoulder, and Hand) outcome measure after essential upper extremity tumor surgery.

J Shoulder Elbow Surg 2021 Sep 20;30(9):e602-e609. Epub 2021 Jan 20.

Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Background: The DASH (Disabilities of the Arm, Shoulder, and Hand) is a scored questionnaire that is widely used to evaluate the health-related quality of life of patients with upper limb musculoskeletal disorders. However, numerical changes in the measure scores lack clinical significance without meaningful threshold change values of outcome measures that are diagnostically specific. The minimal clinically important difference (MCID) is useful for the interpretation of scores by defining the smallest change that a patient would perceive. However, the MCIDs of the scores in orthopedic oncology patients has not been reported. We aimed to determine the MCIDs of the measure in orthopedic oncology patients.

Methods: Data from our health-related quality of life database from 1999 to 2005 were retrospectively reviewed after institutional review board approval. Seventy-eight patients who underwent surgery and completed 2 surveys during postoperative follow-up were evaluated. Two different methods were used to estimate the MCIDs: distribution-based and anchor-based approaches (the latter used receiver operating characteristic analysis).

Results: Using distribution-based methods, the MCIDs of the DASH questionnaire were 7.4 and 8.3 by half standard deviation and the 90% interval of minimal detectable change, respectively. By anchor-based method (receiver operating characteristic analysis), the MCID was 8.3.

Conclusion: The MCID values calculated by each method validates that the results for upper extremity oncology patients were similar to those reported in other orthopedic conditions. These results identify the threshold for meaningful improvements in DASH scores in orthopedic oncology patients and establish the reference to evaluate health-related quality of life and the outcomes of upper extremity oncology surgery. These data should be further refined for disease- and reconstruction-specific analyses.
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http://dx.doi.org/10.1016/j.jse.2020.11.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289920PMC
September 2021

Finn/Orthopaedic Salvage System Distal Femoral Rotating-Hinge Megaprostheses in Oncologic Patients: Long-Term Complications, Reoperations, and Amputations.

J Bone Joint Surg Am 2021 04;103(8):705-714

Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, NY.

Background: There is a lack of evidence regarding long-term outcomes of rotating-hinge knee prostheses with distal femoral replacement in a large oncologic patient series. In this study, we investigated the proportion of patients experiencing complications requiring surgery in the long term, as well as the cumulative incidence of implant removal/revision and amputation at 5, 10, 15, and 20 years through competing risk analyses.

Methods: We retrospectively studied 214 patients treated with a Finn/Orthopaedic Salvage System (OSS) knee prosthesis (Zimmer Biomet) after distal femoral resection from 1991 to 2017. The study end points were postoperative complications requiring surgery. Reoperations were classified as major when there was (1) removal of the metal-body femoral component, the tibial component, or the bone-implant fixation; (2) major revision (exchange of the metal-body femoral component, the tibial component, or the bone-implant fixation); or (3) amputation. Minor reoperations were defined as all other reoperations. Competing risk analysis was used to estimate the cumulative incidence of implant removal/revision or amputation.

Results: There were 312 reoperations in 113 patients (98 major reoperations in 68 patients and 214 minor reoperations). Seventeen patients (8%) required ≥5 additional operations, and 21 patients (10%) required >1 major reoperation. Although the number of reoperations decreased over time, major and minor reoperations continuously accrued after 10 years. The cumulative incidences of implant removal or revision for any reason at 5, 10, 15, and 20 years were 22.6%, 30.1%, 34.3%, and 42.5%, respectively. Although most implant removals/revisions occurred in the first 10 years, the risk persisted after 10 years, at a mean of 1.24%/year, mainly due to deep infection (1.06%/year).

Conclusions: The long-term outcomes of treatment with a Finn/OSS distal femoral rotating-hinge knee prosthesis showed it to be a durable reconstruction technique. The rate of implant removal/revisions after 10 years was gradual (1.24%/year). Deep infection remains a major late-failure mechanism, and lifetime surveillance for prosthetic problems is needed.

Level Of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.2106/JBJS.20.00696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493615PMC
April 2021

Molded, Gamma-radiated, Argon-processed Polyethylene Components of Rotating Hinge Knee Megaprostheses Have a Lower Failure Hazard and Revision Rates Than Air-sterilized, Machined, Ram-extruded Bar Stock Components.

Clin Orthop Relat Res 2021 01;479(1):95-101

A. C. Belzarena, M. A. Elalfy, M. A. Yakoub, J. H. Healey, Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Megaprostheses are commonly used for reconstruction after distal femoral resection in orthopaedic oncology. The polyethylene bearings in these reconstructions experience wear and wear-related complications that may result in revision surgery. Improved manufacturing and processing of polyethylene has increased the durability of components commonly used for routine arthroplasty. Alterations in the manufacture of polyethylene is expected to reduce the revision risk of oncologic megaprostheses, resulting in fewer revision procedures, but this has not been proven.

Questions/purposes: Is there a difference in the hazard of polyethylene wear or breakage leading to prosthetic revision between differences in polyethylene manufacture and processing based on a competing risk analysis?

Methods: This was a single-center, observational, retrospective comparative study of 224 patients who had distal femur megaprostheses with identical rotating hinge articulations and knee kinematics after oncologic surgery from 1993 to 2015. No differences in surgical indications, joint articular components and kinematics, age, sex, diagnosis, BMI, use of chemotherapy, or tumor stage were seen with the patient numbers available. Prosthetic survivorship free from prosthetic revision surgery because of polyethylene wear-related revisions, defined as breakage, increased excursion on varus-valgus stress, or new locking or giving way was compared between two groups of patients: group 1 polyethylene (P1) (66 patients) who had air-sterilized machined ram-extruded bar stock or group 2 polyethylene (P2) (158 patients) molded gamma-radiated argon-processed polyethylene components. The mean follow-up duration for the P1 group (89 ± 55 months) was not different from that of patients with P2 polyethylene (79 ± 63 months; p = 0.24) including 27% (18 of 66) of patients in the P1 group and 25% (40 of 158) of patients in the P2 group followed for more than 10 years. More patients in the P2 group were lost to follow-up (9.2%, 16 of 174) than in the P1 group (5.7%, 4 of 70) but this was not statistically different (chi square; p = 0.37). The hazard of revision because of polyethylene wear or breakage was calculated with a competing risk analysis using the Fine-Gray subdistribution hazard model.

Results: The P1 implants had a higher hazard ratio for revision caused by polyethylene damage at 120 months than did the P2 polyethylene implants (P1 HR 0.24 [95% CI 0.13 to 0.36] versus HR 0.07 [95% CI 0.03 to 0.12]), which represents an estimated absolute risk reduction of 17% (95% CI 6.15 to 27.9).

Conclusion: Polyethylene damage can result in megaprosthetic revisions in patients undergoing oncologic procedures. The hazard of polyethylene failure resulting in revision surgery was lower in patients who received recent polyethylene than in patients with polyethylene produced by previous methods, enhancing the durability of distal femoral megaprosthetic reconstructions. Despite improvements in polyethylene manufacture and clinical results, revision solely because of polyethylene damage still occurs in 7% of patients by the 10-year timepoint; thus, more improvement is needed. Patients who receive these implants should be monitored for signs and symptoms of polyethylene damage.

Level Of Evidence: Level III, therapeutic study.
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http://dx.doi.org/10.1097/CORR.0000000000001439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899595PMC
January 2021

Pexidartinib Long-Term Hepatic Safety Profile in Patients with Tenosynovial Giant Cell Tumors.

Oncologist 2021 05 24;26(5):e863-e873. Epub 2020 Dec 24.

University Hospital Essen, University of Duisburg-Essen, Germany.

Background: Pexidartinib is approved in the U.S. for tenosynovial giant cell tumors (TGCTs). Herein, we assessed the hepatic safety profile of pexidartinib across patients with TGCTs receiving pexidartinib.

Materials, And Methods: Hepatic adverse reactions (ARs) were assessed by type and magnitude of liver test abnormalities, classified as (a) isolated aminotransferase elevations (alanine [ALT] or aspartate [AST], without significant alkaline phosphatase [ALP] or bilirubin elevations), or (b) mixed or cholestatic hepatotoxicity (increase in ALP with or without ALT/AST and bilirubin elevations, based on adjudication). Median follow-up from initial pexidartinib treatment was 39 months (range, 32-82) in 140 patients with TGCTs across clinical studies NCT01004861, NCT02371369, NCT02734433, and NCT03291288.

Results: In total, 95% of patients with TGCTs (133/140) treated with pexidartinib (median duration of exposure, 19 months [range, 1-76]), experienced a hepatic AR. A total of 128 patients (91%) had reversible, low-grade dose-dependent isolated AST/ALT elevations without significant ALP elevations. Five patients (4%) experienced serious mixed or cholestatic injury. No case met Hy's law criteria. Onset of hepatic ARs was predominantly in the first 2 months. All five serious hepatic AR cases recovered 1-7 months following pexidartinib discontinuation. Five patients from the non-TGCT population (N = 658) experienced serious hepatic ARs, two irreversible cases.

Conclusion: This pooled analysis provides information to help form the basis for the treating physician's risk assessment for patients with TCGTs, a locally aggressive but typically nonmetastatic tumor. In particular, long-term treatment with pexidartinib has a predictable effect on hepatic aminotransferases and unpredictable risk of serious cholestatic or mixed liver injury.

Implications For Practice: This is the first long-term pooled analysis to report on the long-term hepatic safety of pexidartinib in patients with tenosynovial giant cell tumors associated with severe morbidity or functional limitations and not amenable to improvement with surgery. These findings extend beyond what has been previously published, describing the observed instances of hepatic toxicity following pexidartinib treatment across the clinical development program. This information is highly relevant for medical oncologists and orthopedic oncologists and provides guidance for its proper use for appropriate patients within the Pexidartinib Risk Evaluation and Mitigation Safety program.
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http://dx.doi.org/10.1002/onco.13629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100574PMC
May 2021

Impact of Magnetic Resonance Imaging (MRI) Findings on Management of Symptomatic Patients Following Radiofrequency Ablation (RFA) of Osteoid Osteoma (OO).

SN Compr Clin Med 2020 Nov 14;2:2170-2177. Epub 2020 Sep 14.

Memorial Sloan Kettering Cancer Center, Department of Surgery, Orthopedic Oncology Service, 1275 York Ave, New York, NY 10065.

Object: To assess the impact of MRI findings on management of symptomatic patients following RFA of OO.

Materials & Methods: Retrospective review of 43 patients with RFA for OO between June 2010 and June 2017 was performed. Patient, nidus and ablation data were reviewed. Pre- and 6-8 weeks post-procedural MRI (n=32) were compared for coverage of nidus by ablation zone, bone marrow edema, nidus hyperintensity and other findings. Baseline pain levels and analgesic use were compared with post-procedural follow-up visit at 6-8 weeks. Three groups of clinical and MRI outcomes of complete (CR), partial (PR) and no response (NR) were defined. A weighted-kappa statistic was used to assess for agreement.

Results: Clinical responses were CR in 34/43 (79.1%, 95%CI: 64.0-90.0%), PR in 8/43 (18.6%) and NR in 1/43 (2.3%) patients. All 19/32 patients with MRI CR experienced clinical CR. One patient with MRI NR had clinical NR. All 7/32 patients with clinical PR had MRI PR. All 4/43 complications were in MRI PR or NR groups. Substantial agreement was observed between MRI and clinical outcomes (kappa:0.69, 95%CI:0.45-0.95). MRI helped determine etiologies in all symptomatic patients and their management (n=8).

Conclusions: MRI is recommended for symptomatic patients after ablation.
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http://dx.doi.org/10.1007/s42399-020-00514-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681937PMC
November 2020

Long-term outcomes of pexidartinib in tenosynovial giant cell tumors.

Cancer 2021 03 16;127(6):884-893. Epub 2020 Nov 16.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: The objective of this study was to report on the long-term effects of pexidartinib on tenosynovial giant cell tumor (TGCT).

Methods: This was a pooled analysis encompassing 3 pexidartinib-treated TGCT cohorts: 1) a phase 1 extension study (NCT01004861; 1000 mg/d; n = 39), 2) ENLIVEN patients randomized to pexidartinib (1000 mg/d for 2 weeks and then 800 mg/d; n = 61), and 3) ENLIVEN crossover patients (NCT02371369; 800 mg/d; n = 30). Eligible patients were 18 years old or older and had a histologically confirmed TGCT that was unresectable and symptomatic. Efficacy endpoints included the best overall response (complete or partial response) and the duration of response (DOR) by the Response Evaluation Criteria in Solid Tumors (RECIST) and the tumor volume score (TVS). The safety assessment included the frequency of treatment-emergent adverse events (TEAEs) and hepatic laboratory abnormalities (aminotransferase elevations and mixed/cholestatic hepatotoxicity). The data cutoff was May 31, 2019.

Results: One hundred thirty patients with TGCT received pexidartinib (median treatment duration, 19 months; range, 1 to 76+ months); 54 (42%) remained on treatment at the end of the analysis (26 months after initial data cut of March 2017). The RECIST overall response rate (ORR) was 60%; the TVS ORR was 65%. The median times to response were 3.4 (RECIST) and 2.8 months (TVS), with 48 of the responding patients (62%) achieving a RECIST partial response by 6 months and with 72 (92%) doing so by 18 months. The median DOR was reached for TVS (46.8 months). Reported TEAEs were mostly low-grade, with hair color changes being most frequent (75%). Most liver abnormalities (92%) were aminotransferase elevations; 4 patients (3%) experienced mixed/cholestatic hepatotoxicity (all within the first 2 months of treatment), which was reversible in all cases (recovery spanned 1-7 months).

Conclusions: This study demonstrates the prolonged efficacy and tolerability of long-term pexidartinib treatment for TGCT.
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http://dx.doi.org/10.1002/cncr.33312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946703PMC
March 2021

Management of Tenosynovial Giant Cell Tumor: A Neoplastic and Inflammatory Disease.

J Am Acad Orthop Surg Glob Res Rev 2020 11;4(11):e20.00028

From the Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, NY (Healey); Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Santa Monica, CA (Bernthal); and Department of Orthopedics, Leiden University Medical Center, Leiden, Netherlands (van de Sande).

Background: Patients with diffuse tenosynovial giant cell tumor (TGCT) face a high risk of recurrence, progression, and disability. This systematic review assesses the recent evidence of surgical, adjuvant, and systemic treatments for TGCT.

Methods: We searched PubMed and Ovid with the terms "Giant cell tumor of tendon sheath" OR "pigmented villonodular synovitis" OR "tenosynovial giant cell" AND "treatment" OR "surgery."

Inclusion Criteria: published 2013 to present; prospective or retrospective design; English language; > 20 patients with histopathological confirmed diagnosis of TGCT; and ≥ 1 efficacy and/or safety outcome from surgery, systemic drug therapy, or adjuvant yttrium radiosynoviorthesis.

Results: Of the 434 studies identified, 25 met the inclusion criteria. Of 11 studies in patients with disease in the knee, nine examined surgical treatment approaches, and two evaluated adjuvant yttrium radiosynoviorthesis. Of 11 studies in patients with mixed sites of disease, six assessed surgical treatment approaches, and five evaluated systemic drug therapies. Three studies assessed surgery in patients with TGCT in the hand, hip, and ankle or foot.

Discussion: The high rates of recurrence and risks associated with surgery emphasize the need for novel treatments in patients with symptomatic, advanced TGCT. Systemic therapy may be valuable as part of a multidisciplinary approach.
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http://dx.doi.org/10.5435/JAAOSGlobal-D-20-00028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643913PMC
November 2020

Population Pharmacokinetic Analysis of Pexidartinib in Healthy Subjects and Patients With Tenosynovial Giant Cell Tumor or Other Solid Tumors.

J Clin Pharmacol 2021 04 11;61(4):480-492. Epub 2020 Oct 11.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Pexidartinib is a kinase inhibitor that induces tumor response and improvements in symptoms and functional outcomes in adult patients with symptomatic tenosynovial giant cell tumor (TGCT). A population pharmacokinetic (PK) model for pexidartinib and its metabolite, ZAAD, was developed, and effects of demographic and clinical factors on the PK of pexidartinib and ZAAD were estimated. The analysis included pooled data from 7 studies in healthy volunteers (N = 159) and 2 studies in patients with TGCT or other solid tumors (N = 216). A structural 2-compartment model with sequential zero- and first-order absorption and lag time, and linear elimination from the central compartment adequately described pexidartinib and ZAAD PKs. Clearance of pexidartinib was estimated at 5.83 L/h in a typical patient with reference covariates (male, non-Asian, weight = 80 kg, creatinine clearance ≥90 mL/min, aspartate aminotransferase ≤80 U/L, and total bilirubin ≤20.5 μmol/L). In the covariate analysis, Asians and healthy subjects had modestly lower pexidartinib exposure (21% decrease each) in terms of steady-state area under the curve values from 0 to 24 hours (AUC ). Effects of body weight, sex, and hepatic function parameters on pexidartinib AUC were generally <20%. Patients with TGCT with mild renal impairment were predicted to have approximately 23% higher AUC than those with normal renal function. The effects of covariates on ZAAD exposure were similar to those on pexidartinib. These results indicate small and generally clinically nonmeaningful effects of patient demographic and clinical characteristics on pexidartinib and ZAAD PK profiles.
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http://dx.doi.org/10.1002/jcph.1753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969430PMC
April 2021

Epithelioid hemangioma of bone harboring FOS and FOSB gene rearrangements: A clinicopathologic and molecular study.

Genes Chromosomes Cancer 2021 01 9;60(1):17-25. Epub 2020 Oct 9.

Departments of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

The diagnosis of epithelioid hemangioma (EH) remains challenging due to its rarity, worrisome histologic features, and locally aggressive clinical and radiographic presentation. Especially in the bone, EH can be misdiagnosed as a malignant vascular neoplasm due its lytic, often destructive or multifocal growth, as well as atypical morphology. The discovery of recurrent FOS and FOSB gene fusions in the pathogenesis of most EH has strengthened its stand-alone classification, distinct from other malignant epithelioid vascular lesions, such as epithelioid hemangioendothelioma or angiosarcoma. In this study we investigate a group of molecularly confirmed skeletal EH by the presence of FOS or FOSB gene rearrangements to better define its clinical and pathologic characteristics within a homogenous molecular subset. The cohort included 38 patients (25 males, 13 females), with a mean age at diagnosis of 38 years (range, 4-75). Regional, multifocal presentation was noted in 10 cases. Only six cases were correctly recognized as EH by the referring institutions, while most were misdiagnosed as other vascular tumors. Of the 17 patients with follow-up data available, five patients (29%) developed local recurrence after marginal en bloc excision (n = 3) or curettage (n = 2). Local recurrence-free survival rates were 84% at 3 years and 38% at 5 years. No metastasis or disease-related death was identified. Imaging studies exhibited no specific features, showing cortical bone destruction and soft-tissue extension in 14 (38%) cases. FOS gene rearrangements were detected in 28 (74%) of cases, while FOSB rearrangements in 10 (26%) cases. Our results highlight the significant challenges encountered in establishing a correct diagnosis exclusive of the molecular testing, mainly due to its overlap to other malignant epithelioid vascular tumors. Skeletal EH emerges as a genetically defined locally aggressive vascular neoplasm, with a high rate of local recurrence, but lacking the propensity for distant spread.
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http://dx.doi.org/10.1002/gcc.22898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739373PMC
January 2021

Editorial Comment: Selected Proceedings of the 2019 International Society of Limb Salvage Annual Meeting.

Authors:
John H Healey

Clin Orthop Relat Res 2020 11;478(11):2440-2441

Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, NY

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http://dx.doi.org/10.1097/CORR.0000000000001516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571908PMC
November 2020

Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers.

Cell 2020 08 13;182(4):1044-1061.e18. Epub 2020 Aug 13.

School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan.

There is an unmet clinical need for improved tissue and liquid biopsy tools for cancer detection. We investigated the proteomic profile of extracellular vesicles and particles (EVPs) in 426 human samples from tissue explants (TEs), plasma, and other bodily fluids. Among traditional exosome markers, CD9, HSPA8, ALIX, and HSP90AB1 represent pan-EVP markers, while ACTB, MSN, and RAP1B are novel pan-EVP markers. To confirm that EVPs are ideal diagnostic tools, we analyzed proteomes of TE- (n = 151) and plasma-derived (n = 120) EVPs. Comparison of TE EVPs identified proteins (e.g., VCAN, TNC, and THBS2) that distinguish tumors from normal tissues with 90% sensitivity/94% specificity. Machine-learning classification of plasma-derived EVP cargo, including immunoglobulins, revealed 95% sensitivity/90% specificity in detecting cancer. Finally, we defined a panel of tumor-type-specific EVP proteins in TEs and plasma, which can classify tumors of unknown primary origin. Thus, EVP proteins can serve as reliable biomarkers for cancer detection and determining cancer type.
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http://dx.doi.org/10.1016/j.cell.2020.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522766PMC
August 2020

Gold/alpha-lactalbumin nanoprobes for the imaging and treatment of breast cancer.

Nat Biomed Eng 2020 07 13;4(7):686-703. Epub 2020 Jul 13.

Center for Molecular Imaging and Nanotechnology (CMINT), Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Theranostic agents should ideally be renally cleared and biodegradable. Here, we report the synthesis, characterization and theranostic applications of fluorescent ultrasmall gold quantum clusters that are stabilized by the milk metalloprotein alpha-lactalbumin. We synthesized three types of these nanoprobes that together display fluorescence across the visible and near-infrared spectra when excited at a single wavelength through optical colour coding. In live tumour-bearing mice, the near-infrared nanoprobe generates contrast for fluorescence, X-ray computed tomography and magnetic resonance imaging, and exhibits long circulation times, low accumulation in the reticuloendothelial system, sustained tumour retention, insignificant toxicity and renal clearance. An intravenously administrated near-infrared nanoprobe with a large Stokes shift facilitated the detection and image-guided resection of breast tumours in vivo using a smartphone with modified optics. Moreover, the partially unfolded structure of alpha-lactalbumin in the nanoprobe helps with the formation of an anti-cancer lipoprotein complex with oleic acid that triggers the inhibition of the MAPK and PI3K-AKT pathways, immunogenic cell death and the recruitment of infiltrating macrophages. The biodegradability and safety profile of the nanoprobes make them suitable for the systemic detection and localized treatment of cancer.
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http://dx.doi.org/10.1038/s41551-020-0584-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255032PMC
July 2020

Editorial Comment: 2019 Musculoskeletal Tumor Society Proceedings.

Authors:
John H Healey

Clin Orthop Relat Res 2021 03;479(3):466-467

J. H. Healey, Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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http://dx.doi.org/10.1097/CORR.0000000000001365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899405PMC
March 2021

Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition.

Cancer Discov 2020 09 22;10(9):1352-1373. Epub 2020 Jun 22.

Department of Radiation Oncology, Perlmutter Cancer Center and NYU Langone Health, New York, New York.

A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine-limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is a major determinant of brain metastasis in multiple human cancer types and preclinical models. Enhanced serine synthesis proved important for nucleotide production and cell proliferation in highly aggressive brain metastatic cells. , genetic suppression and pharmacologic inhibition of PHGDH attenuated brain metastasis, but not extracranial tumor growth, and improved overall survival in mice. These results reveal that extracellular amino acid availability determines serine synthesis pathway dependence, and suggest that PHGDH inhibitors may be useful in the treatment of brain metastasis. SIGNIFICANCE: Using proteomics, metabolomics, and multiple brain metastasis models, we demonstrate that the nutrient-limited environment of the brain potentiates brain metastasis susceptibility to serine synthesis inhibition. These findings underscore the importance of studying cancer metabolism in physiologically relevant contexts, and provide a rationale for using PHGDH inhibitors to treat brain metastasis..
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http://dx.doi.org/10.1158/2159-8290.CD-19-1228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483776PMC
September 2020

What Are the Minimum Clinically Important Differences in SF-36 Scores in Patients with Orthopaedic Oncologic Conditions?

Clin Orthop Relat Res 2020 09;478(9):2148-2158

K. Ogura, M. A. Yakoub, A. B. Christ, T. Fujiwara, Z. Nikolic, P. J. Boland, J. H. Healey, Department of Surgery, Orthopaedic Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: The SF-36 is widely used to evaluate the health-related quality of life of patients with musculoskeletal tumors. The minimum clinically important difference (MCID) is useful for interpreting changes in functional scores because it defines the smallest change each patient may perceive. Since the MCID is influenced by the population characteristics, MCIDs of the SF-36 should be defined to reflect the specific conditions of orthopaedic oncology patients.

Questions/purposes: (1) What is the MCID of SF-36 physical component summary (PCS) and mental component summary (MCS) scores in patients with orthopaedic oncologic conditions when calculated with distribution-based methods? (2) What is the MCID of SF-36 PCS and MCS scores in patients with orthopaedic oncologic conditions when calculated by anchor-based methods?

Methods: Of all 960 patients who underwent surgery from 1999 to 2005, 32% (310) of patients who underwent musculoskeletal oncologic surgery and completed two surveys during postoperative follow-up were reviewed. We evaluated a dataset that ended in 2005, completing follow-up of data accrued as part of the cooperative effort between the American Academy of Orthopaedic Surgeons and the Council of Musculoskeletal Specialty Societies to create patient reported quality of life instruments for lower extremity conditions. This effort, started in 1994 was validated and widely accepted by its publication in 2004. We believe the findings from this period are still relevant today because (1) this critical information has never been available for clinicians and researchers to distinguish real differences in outcome among orthopaedic oncology patients, (2) the SF-36 continues to be the best validated and widely used instrument to assess health-related quality of life, and unfortunately (3) there has been no significant change in outcome for oncology patients over the intervening years. SF-36 PCS and MCS are aggregates of the eight scale scores specific to physical and mental dimension (scores range from 0 to 100, with higher scores representing better health). Their responsiveness has been shown postoperatively for several surgical procedures (such as, colorectal surgery). Two different methods were used to calculate the MCID: the distribution-based method, which was based on half the SD of the change in score and standard error of the measurement at baseline, and anchor-based, in which a receiver operating characteristic (ROC) curve analysis was performed. The anchor-based method uses a plain-language question to ask patients how their individual conditions changed when compared with the previous survey. Answer choices were "much better," "somewhat better," "about the same," "somewhat worse," or "much worse." The ROC curve-derived MCIDs were defined as the change in scores from baseline, with sensitivity and specificity to detect differences in patients who stated their outcome was, about the same and those who stated their status was somewhat better or somewhat worse. This approach is based on each patient's perception. It considers that the definition of MCID is the minimal difference each patient can perceive as meaningful.

Results: Using the distribution-based method, we found that the MCIDs of the PCS and MCS were 5 and 5 by half the SD, and 6 and 5 by standard error of the measurement. In the anchor-based method, the MCIDs of the PCS and MCS for improvement/deterioration were 4 (area under the curve, 0.82)/-2 (area under the curve, 0.79) and 4 (area under the curve, 0.72)/ (area under the curve, 0.68), respectively.

Conclusions: Since both anchor-based and distribution-based MCID estimates of the SF-36 in patients with musculoskeletal tumors were so similar, we have confidence in the estimates we made, which were about 5 points for both the PCS and the MCS subscales of the SF-36. This suggests that interventions improving SF-36 by less than that amount are unlikely to be perceived by patients as clinically important. Therefore, those interventions may not justify exposing patients to risk, cost, or inconvenience. When applying new interventions to orthopaedic oncology patients going forward, it will be important to consider these MCIDs for evaluation purposes.

Level Of Evidence: Level III, diagnostic study.
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http://dx.doi.org/10.1097/CORR.0000000000001341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431256PMC
September 2020

The clinical heterogeneity of round cell sarcomas with EWSR1/FUS gene fusions: Impact of gene fusion type on clinical features and outcome.

Genes Chromosomes Cancer 2020 09 28;59(9):525-534. Epub 2020 May 28.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

The genetic hallmark of classic Ewing sarcoma is a recurrent fusion between EWSR1 and FUS gene with a member of the ETS transcription factor family. In contrast, tumors with non-ETS gene partners have been designated until recently "Ewing-like sarcoma," as a provisional molecular entity, as their clinical and pathologic features were still evolving. However, this group was reclassified as "round cell sarcoma with EWSR1-non-ETS fusions" in the latest 2020 WHO classification. Moreover, round cell sarcomas with either CIC or BCOR gene abnormalities, initially classified under Ewing family of tumors, are now regarded as stand-alone pathologic entities based on their distinct features. In this study we investigated the clinical characteristics of 226 confirmed Ewing sarcoma patients (EWSR1-FLI1 [n = 176], EWSR1/FUS-ERG [n = 35], EWSR1/FUS-FEV [n = 12], and EWSR1-ETV1/4 [n = 3]) and 14 round cell sarcoma patients with EWSR1-non-ETS fusion (EWSR1/FUS-NFATC2 [n = 10], EWSR1-PATZ1 [n = 3], and EWSR1-VEZF1 [n = 1]). The impact on overall survival (OS) was assessed in 90 patients with available follow-up, treated between 2011 and 2018. Patients with fusions involving FEV and NFATC2 genes showed an older median age at diagnosis, compared to those with EWSR1-FLI1 (P = .005), while extraskeletal location was more common in tumors with noncanonical EWSR1-FLI1 fusions (P = .001). Axial and pelvic primary sites were more common in patients with EWSR1-FLI1 (72%), while tumors with NFATC2 fusions were more frequent in the limb (78%, P = .006). The 3-year OS in patients with EWSR1-FLI1 was 91%, compared to only 60% in patients with alternative fusions (P = .037); the latter group showing a higher rate of metastases at presentation. However, this OS difference was not significant in patients with localized tumor (P = .585). Our study demonstrates significant correlations between fusion subtype and age at presentation, primary tumor sites, and OS, in both conventional Ewing sarcoma and round cell sarcoma with EWSR1-non ETS fusions patients. Larger studies are needed to determine survival differences in localized tumors.
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http://dx.doi.org/10.1002/gcc.22857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372700PMC
September 2020

Adamantinomatous tumors: Long-term follow-up study of 20 patients treated at a single institution.

J Surg Oncol 2020 Aug 25;122(2):273-282. Epub 2020 Apr 25.

Department of Surgery, Orthopaedic Service, Memorial Sloan-Kettering Cancer Center, New York, New York.

Background And Objectives: Adamantinomas are primary, low-grade malignant tumors of the bone that have metastatic potential to the lungs, lymph nodes, and other regions. The rarity of this disease and its nonspecific symptoms complicate diagnosis.

Materials And Methods: Records for 20 patients who underwent treatment for adamantinoma from 1975 to 2018 were reviewed for demographic, clinical, and pathological data, treatment details, postoperative complications, and outcomes.

Results: Patients presented at a median age of 22 years (1-79 years): 14 patients had a localized primary tumor, three presented with local recurrence, and three with metastatic disease. Median tumor size was 5.7 cm (0.5-15.5 cm). Wide excision was performed primarily in 15 cases; the remaining five patients underwent intralesional curettage. At a median follow-up of 7.3 years, 14 patients had no evidence of disease; two patients were alive with disease, and four patients died from the disease. Local recurrence and distant metastasis occurred at a median of 11.4 years (6 month-19 years) and 15.8 years (4 month-23 years) after diagnosis.

Conclusions: Adequate histopathological diagnosis is crucial to avoid misdiagnosis of this rare tumor. Local and distant recuAbs_Para_meprrence can occur more than 20 years after the initial diagnosis. Life-long follow-up with clinical examination and imaging is required.
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http://dx.doi.org/10.1002/jso.25950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547203PMC
August 2020
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