The effect of transfusion on survival in head and neck cancer after free tissue reconstruction.

Objective: To examine if perioperative blood transfusion affects overall survival (OS) and recurrence-free survival (RFS) in head and neck cancer patients who undergo free tissue reconstruction. Design: Retrospective cohort study. Methods: The medical records of free tissue flaps between 2007 and 2010 were reviewed. Differences in demographics and clinical factors based on the level of transfused packed red blood cells (PRBC) were examined using chi-squared tests, Kruskal-Wallis tests, and/or ANOVA tests. Survival time was compared using a Cox proportional hazard model. Results: Data were available for 183 patients. Patients who had PRBC transfusion significantly differed from the non-transfused group by flap type, flap with bone, Charlson Comorbidity Index (CCI), and hemoglobin and hematocrit. When stratified into three groups based on units of PRBC; flap type, flap with bone, CCI, preoperative hemoglobin, and hematocrit were found to differ significantly. The 2-year Kaplan-Meier plot demonstrated improved OS for those who did not receive any PRBC transfusion. The use of more than 3 units of blood decreased 2-year OS significantly when compared to the non-transfused group. Finally, after adjusting for CCI using a Cox proportional hazard model, survival was significantly affected by CCI. Conclusion: After controlling for patient age, oncologic stage, cancer subsite, histology, type of free flap, vascularized bone-containing flap, recurrence type, CCI, and preoperative hemoglobin and hematocrit, patients who received 3 or more units of PRBC in the perioperative period had significantly decreased OS. RFS did not differ between the transfused versus non-transfused groups. Level of Evidence: Level 4.

Giant-cell-poor giant cell tumor of bone: report of two cases and literature review.

Giant cell tumor of bone (GCTB) is a locally aggressive tumor that shows predilection for the metaphysis/epiphysis of long bones, with an incidence of 4-5% of primary bone tumors. GCTB shows two main populations of cells: mononuclear cells and non-neoplastic multi-nucleated giant cells, with or without fibrous background. On the other hand, giant-cell-poor GCTB are rare with only few reports in the literature. These cases offer a diagnostic challenge, given the absence of giant cells and such cases have consistently been shown to harbor the H3F3A gene mutation by sequencing. The H3.3 G34W mutation-specific monoclonal antibody has shown high specificity in the diagnosis of GCTB. Two cases of giant-cell-poor GCTB are presented in this study, in which giant cells were absent or sparse and the diagnosis of GCTB was confirmed by the expression of H3.3 G34W monoclonal antibody in the mononuclear cells by immunohistochemistry. Whether this represents a histologic variant of GCTB or partial involution of GCTB is not yet fully understood; however, an immune response, infectious/inflammatory reaction, and/or anti-tumor cytokine production have been purported to be factors inciting disease regression in GCTB.

Cathepsin protease expression in infiltrative soft tissue sarcomas: cathepsin-K correlates with infiltrative tumor growth and clinical outcomes.

Cathepsin proteases, activated in the lysosomes, are upregulated in many cancers. Intraoperative detection systems of microscopic residual tumor using cathepsin-mediated release of fluorescent nanoparticles may guide surgical excisions to improve local control. We sought to define the genetic and proteomic expression of cathepsins and their clinicopathological correlates in myxofibrosarcoma and undifferentiated pleomorphic sarcoma (UPS)-soft tissue sarcomas with high rates of positive resection margins and local recurrence-and to establish a cellular justification for cathepsin-dependent systems to identify residual cancer in the resection bed. Real-time quantitative polymerase chain reaction analysis of 58 fresh-frozen tumor specimens revealed that 56 (97%) had elevated mRNA expression of ≥1 cathepsin, including cathepsin-B (79%), cathepsin-K (59%), cathepsin-L (71%), and -S (71%). Immunohistochemical analysis of these fresh-frozen specimens revealed that 98% of tumors were positive for one or more of cathepsin-B (85%), cathepsin-K (50%), cathepsin-L (63%), and -S (10%). Strong cathepsin-K expression was associated with greater risks of local recurrence (hazard ratio, 3.78; p = 0.044) and disease-specific mortality (hazard ratio, 3.70; p = 0.025). Immunohistochemical analysis of 33 formalin-fixed paraffin-embedded block samples revealed that 97% were positive for cathepsin-B (88%), cathepsin-K (76%), cathepsin-L (52%), or -S (52%) at the tumor periphery; cathepsin-K positivity correlated with a radiographic tail-like sign (p = 0.004) and microscopic infiltrative growth (p = 0.020). We conclude that cathepsins are broadly overexpressed in myxofibrosarcoma and UPS, and cathepsin-K may be an immunohistochemical marker of local infiltration and poorer prognosis that could be used to guide precision surgery.

Quantitative preoperative patient assessments are related to survival and procedure outcome for osseous metastases.

Aims: Our objective was to determine if preoperative patient-reported assessments are associated with survival after surgery for stabilization of skeletal metastases. Patients and Methods: All patients with metastatic cancer to bone and indications for skeletal stabilization surgery were approached to participate in a prospective cohort study at a tertiary care center from 2012 to 2017. Of the 208 patients who were eligible, 195 (94%) completed the 36-item Short Form Health Survey (SF-36) preoperatively and underwent surgical treatment of skeletal metastases with complete or impending fractures; the sample encompassed a range of cancer diagnoses and included cases of both internal fixation and endoprosthetic replacement. Cox proportional hazards models were used to identify associations between SF-36 scores and survival. Results: In a model adjusted for clinical factors, patients' mental and physical SF-36 component summary scores were significantly associated with survival, as was their SF-36 composite score (P = 0.004, P = 0.015, and P < 0.001, respectively). Scores in the general health, vitality, and mental health domains were each strongly associated with survival (P < 0.001). Conclusions: Patients' preoperative assessments of their health status are associated with their survival after surgery for skeletal metastases. Patient-reported assessments have the potential to contribute unique information to models that estimate patient survival, as part of efforts to provide optimal, individualized care and make informed decisions about the type and magnitude of surgery for metastatic bone disease that will last the patient's lifetime.

Neoplastic synovial lining cells that coexpress podoplanin and CD90 overproduce CSF-1, driving tenosynovial giant cell tumor.

Tenosynovial giant cell tumor (TCGT) is a rare neoplasm affecting the synovium of joints, bursae, and tendon sheaths. The overproduction of colony-stimulating factor-1 (CSF-1) by a minority of the tumor population works in a paracrine fashion to drive tumor growth. Pathology of the reactive, monocytic component has been well elucidated, whereas the populations of neoplastic cells and all the sources of CSF-1 overproduction are incompletely characterized. Podoplanin (PDPN), or gp38, is a cell surface glycoprotein that is expressed on fibroblast-like synovial cells and upregulated in rheumatoid arthritis and many cancers; it governs cell mobility, epithelial-mesenchymal transition, and other functions and is associated with lymphangiogenesis and poor prognosis in many solid tumors, which underscores its local and possible systemic effects. We found higher PDPN expression in TGCT than in internal controls of patients' healthy synovium. Flow cytometry partitioned PDPNhigh cells into PDPNhigh CD90+ and PDPNhigh CD14+ populations. Quantitative real-time polymerase chain reaction analysis of the PDPNhigh CD90+ cells revealed that CSF-1 expression was 10-fold higher than in PDPNhigh CD14+ cells. Therefore, we conclude that the lining fibroblast-like synovial cells, which express PDPNhigh CD90+ , are responsible for the overproduction of CSF-1 and for driving tumor growth.

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

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. In vitro 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.

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

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.

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

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

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

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.

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

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.

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.

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.

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

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.