Complete tumor necrosis after neoadjuvant chemotherapy defines good responders in patients with Ewing sarcoma.

BACKGROUND: Survival in patients who have Ewing sarcoma is correlated with postchemotherapy response (tumor necrosis). This treatment response has been categorized as the response rate, similar to what has been used in osteosarcoma. There is controversy regarding whether this is appropriate or whether it should be a dichotomy of complete versus incomplete response, given how important a complete response is for in overall survival of patients with Ewing sarcoma. The purpose of this study was to evaluate the impact that the amount of chemotherapy-induced necrosis has on (1) overall survival, (2) local recurrence-free survival, (3) metastasis-free survival, and (4) event-free survival in patients with Ewing sarcoma. METHODS: In total, 427 patients who had Ewing sarcoma or tumors in the Ewing sarcoma family and received treatment with preoperative chemotherapy and surgery at 10 international institutions were included. Multivariate Cox proportional-hazards analyses were used to assess the associations between tumor necrosis and all four outcomes while controlling for clinical factors identified in bivariate analysis, including age, tumor volume, location, surgical margins, metastatic disease at presentation, and preoperative radiotherapy. RESULTS: Patients who had a complete (100%) tumor response to chemotherapy had increased overall survival (hazard ratio [HR], 0.26; 95% CI, 0.14-0.48; p < .01), recurrence-free survival (HR, 0.40; 95% CI, 0.20-0.82; p = .01), metastasis-free survival (HR, 0.27; 95% CI, 0.15-0.46; p ≤ .01), and event-free survival (HR, 0.26; 95% CI, 0.16-0.41; p ≤ .01) compared with patients who had a partial (0%-99%) response. CONCLUSIONS: Complete tumor necrosis should be the index parameter to grade response to treatment as satisfactory in patients with Ewing sarcoma. Any viable tumor in these patients after neoadjuvant treatment should be of oncologic concern. These findings can affect the design of new clinical trials and the risk-stratified application of conventional or novel treatments.

Risk of Malignant Transformation of Giant Cell Tumors of Bone Is 8 Times Lower with Megavoltage vs. Orthovoltage Radiation Therapy.

Background: The first-line treatment for most giant cell tumors (GCTs) of bone is surgical; radiotherapy (RT) is reserved for inoperable or refractory cases. While RT techniques have undergone a dramatic change over the past few decades, with the higher energy megavoltage RT replacing orthovoltage RT, concerns for high rates of malignant transformation following RT have limited its use. Evidence suggests a lower incidence of secondary malignancy after treatment with megavoltage compared with orthovoltage RT, but this has not been studied in GCTs. Our main purpose was to compare the incidence of malignant transformation of GCTB between patients treated with orthovoltage vs. megavoltage RT. Methods: A literature review was performed to identify studies reporting GCTBs treated with RT from 01/1900 through 12/2019. Studies that did not report RT modality or separate orthovoltage and megavoltage results were excluded. Included in the analysis were 6 patients from our institution. Primary outcome was the incidence of malignant transformation; secondary outcomes were time to transformation and incidence of local recurrence. Fisher's exact tests and independent sample t-tests were used, and significance was set at p < 0.05. Results: Twenty-two studies were included, which reported on 168 GCTBs treated with orthovoltage and 393 treated with megavoltage RT. Transformation incidence was 14% (n = 24) for orthovoltage and 1.8% (n = 7) for megavoltage RT, an 8-fold difference (odds ratio (OR) 9.1, 95% confidence interval (CI) 3.9-22, p < 0.001). Mean time to transformation was 8.7 years for orthovoltage and 11.2 years for megavoltage RT (p=0.28). Incidence of local recurrence was 38% (63/167) for orthovoltage and 17% (66/393) for megavoltage RT (OR 3.3, 95% CI 2.0-4.6, p < 0.001). Conclusions: The risk of developing a malignancy after RT of GCTB is 8 times lower with megavoltage than with orthovoltage. Malignant transformation with megavoltage, while not zero, is lower than that in historical series. Use of modern RT techniques in inoperable or refractory GCTB may be appropriate.

Lymphadenopathy in Fungating Extremity Soft-Tissue Sarcoma: Metastasis or Reactive?

BACKGROUND: Patients with fungating extremity soft-tissue sarcoma (STS) can develop lymphadenopathy, which can represent nodal metastasis or benign reactive adenopathy. METHODS: In 1787 patients with STS, 67 (3.7%) had fungating extremity STS. In the 62 patients who met our inclusion criteria, we evaluated prevalence and histopathology of lymphadenopathy, factors associated with lymphadenopathy and nodal metastasis, and prevalence of and factors associated with lung metastasis and survival time from fungation. Logistic regression and Cox proportional-hazards models were used to analyze node pathology, lung metastasis, and survival duration with α = 0.05. RESULTS: Lymphadenopathy occurred in 11 of 62 patients (18%), 6 with nodal metastasis and 5 with reactive adenopathy. The only factor associated with lymphadenopathy was location of primary tumor in the upper extremity (p = 0.02). No tumor characteristics were associated with nodal metastasis. In all five patients with reactive adenopathy, the condition was recognized within 3 days after tumor fungation. Lymphadenopathy recognized more than 3 days after tumor fungation was likely to be nodal metastasis. Forty-one percent of patients developed lung metastasis, which was not associated with presence of lymphadenopathy or any patient or tumor characteristic. Age, tumor size, and Black and Asian race were independently associated with greater risk of death. CONCLUSIONS: Eighteen percent of patients with fungating extremity STS developed lymphadenopathy. Approximately half of cases represented nodal metastasis, and half represented reactive adenopathy. Lymphadenopathy that develops within 3 days after tumor fungation should increase suspicion for reactive adenopathy versus nodal metastasis.

Administration of TGF-ß Inhibitor Mitigates Radiation-induced Fibrosis in a Mouse Model.

BACKGROUND: Radiation-induced fibrosis is a long-term adverse effect of external beam radiation therapy for cancer treatment that can cause pain, loss of function, and decreased quality of life. Transforming growth factor beta (TGF-ß) is believed to be critical to the development of radiation-induced fibrosis, and TGF-ß inhibition decreases the development of fibrosis. However, no treatment exists to prevent radiation-induced fibrosis. Therefore, we aimed to mitigate the development of radiation-induced fibrosis in a mouse model by inhibiting TGF-ß. QUESTION/PURPOSES: Does TGF-ß inhibition decrease the development of muscle fibrosis induced by external beam radiation in a mouse model? METHODS: Twenty-eight 12-week-old male C57BL/6 mice were assigned randomly to three groups: irradiated mice treated with TGF-ßi, irradiated mice treated with placebo, and control mice that received neither irradiation nor treatment. The irradiated mice received one 50-Gy fraction of radiation to the right hindlimb before treatment initiation. Mice treated with TGF-c (n = 10) received daily intraperitoneal injections of a small-molecule inhibitor of TGF-ß (1 mg/kg) in a dimethyl sulfoxide vehicle for 8 weeks (seven survived to histologic analysis). Mice treated with placebo (n = 10) received daily intraperitoneal injections of only a dimethyl sulfoxide vehicle for 8 weeks (10 survived to histologic analysis). Control mice (n = 8) received neither radiation nor TGF-ß treatment. Control mice were euthanized at 3 months because they were not expected to exhibit any changes related to treatment. Mice in the two treatment groups were euthanized 9 months after radiation, and the quadriceps of each thigh was sampled. Masson's trichome stain was used to assess muscle fibrosis. Slides were viewed at 10 × magnification using bright-field microscopy, and in a blinded fashion, five representative images per mouse were used to quantify fibrosis. The mean ± SD fibrosis pixel densities in the TGF-ßi and radiation-only groups were compared using Mann-Whitney U tests. The ratio of fibrosis to muscle was calculated using the mean fibrosis per slide in the TGF-ßi group to standardize measurements. Alpha was set at 0.05. RESULTS: The mean (± SD) percentage of fibrosis per slide was greater in the radiation-only group (1.2% ± 0.42%) than in the TGF-ßi group (0.14% ± 0.09%) (odds ratio 0.12 [95% CI 0.07 to 0.20]; p < 0.001). Among control mice, mean fibrosis was 0.05% ± 0.02% per slide. Mice in the radiation-only group had 9.1 times the density of fibrosis as did mice in the TGF-ßi group. CONCLUSION: Our study provides preliminary evidence that the fibrosis associated with radiation therapy to a quadriceps muscle can be reduced by treatment with a TGF-ß inhibitor in a mouse model. CLINICAL RELEVANCE: If these observations are substantiated by further investigation into the role of TGF-ß inhibition on the development of radiation-induced fibrosis in larger animal models and humans, our results may aid in the development of novel therapies to mitigate this complication of radiation treatment.

Bisphosphonate Therapy for Treating Osteonecrosis in Pediatric Leukemia Patients: A Systematic Review.

BACKGROUND: Despite improved outcomes in children with leukemia, complications such as osteonecrosis are common. We conducted a systematic review to investigate the role of bisphosphonates in reducing pain, improving mobility, and stabilizing lesions in pediatric leukemia survivors. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched the PubMed, Embase, Cochrane, Web of Science, Scopus, CINAHL, and ClinicalTrials.gov databases. Five of 221 articles retrieved met our inclusion criteria. RESULTS: Bisphosphonates, especially when combined with dietary calcium and vitamin D supplements and physical therapy (supplements/PT) were associated with improved pain and mobility in 54% and 50% of patients, respectively. A significantly greater proportion of patients treated with bisphosphonates (83%) reported mild/moderate pain or no pain compared with those with supplements/PT alone (36%) (P<0.001). Sixty-six percent of patients treated with bisphosphonates achieved improved/full mobility compared with 27% of those treated with supplements/PT alone (P=0.02). However, 46% of patients showed progressive joint destruction despite bisphosphonate therapy. No adverse events were reported, except for acute phase reactions to intravenous therapies. CONCLUSIONS: Bisphosphonates, when combined with supplements/PT, were associated with less pain and improved mobility, but not prevention of joint destruction in pediatric leukemia patients with osteonecrosis.

Healing of Pathologic Humeral Fractures in Patients with Metastatic Disease: Consideration for Operative Fixation in Patients.

We compared short-term outcomes after operative versus nonoperative treatment of pathologic humeral fractures. We hypothesized that patients who underwent operative fixation would heal faster and have better pain control. A retrospective review was conducted of 25 patients who underwent operative fixation and 6 who received nonoperative treatment from 2005-2017. Operative patients healed significantly earlier than nonoperative patients (p = 0.02). At 16-week follow-up, radiographs showed evidence of healing in 24 of 25 operatively treated patients and 2 of 6 nonoperatively treated patients (p < 0.01). Pain improved during the inpatient stay in 24 of 25 operatively treated patients and none of the nonoperatively treated patients (p < 0.01). All operatively treated patients returned to self-reported baseline motor function by final follow-up, whereas none of the nonoperatively treated patients returned to baseline (p = 0.01). Operative treatment was associated with earlier healing, pain control and return to function compared with nonoperative treatment of pathologic humeral fractures. Level of Evidence: 3. (Journal of Surgical Orthopaedic Advances 29(3):177-181, 2020).

Natural history of Ollier disease and Maffucci syndrome: Patient survey and review of clinical literature.

Ollier disease (OD) and Maffucci syndrome (MS) are characterized by multiple enchondromas. Patients with MS also have benign vascular overgrowths that become malignant in 8.5% of cases. OD is characterized by multiple enchondromas, typically unilateral in distribution with a predilection for the appendicular skeleton. MS is characterized by multiple enchondromas bilaterally distributed in most of the cases. Both disorders feature multiple swellings on the extremity, deformity around the joints, limitations in joint mobility, scoliosis, bone shortening, leg-length discrepancy, gait disturbances, pain, loss of function, and pathological fractures. About 50% of patients with OD or MS develop a malignancy, such as chondrosarcoma, glioma, and ovarian juvenile granulosa cell tumor. To better understand the natural history of OD and MS, we reviewed 287 papers describing patients with OD and MS. We also created a survey that was distributed directly to 162 patients through Facebook. Here, we compare the review of the cases described in the literature to the survey's responses. The review of the literature showed that: the patients with OD are diagnosed at a younger age; the prevalence of chondrosarcomas among patients with OD or MS was ~30%; in four patients, vascular anomalies were identified in internal organs only; and, the prevalence of cancer among patients with OD or MS was ~50%. With these data, health care providers will better understand the natural history, severity, and prognosis of these diseases and the prevalence of malignancies in these patients. Here, we recommend new guidelines for the care of patients with OD and MS.

Prophylactic Versus Postfracture Stabilization for Metastatic Lesions of the Long Bones: A Comparison of 30-day Postoperative Outcomes.

INTRODUCTION: The goals of orthopaedic treatment for most patients with osseous metastases are to control pain, maintain function, and maximize quality of life and time at home. The aim of this study was to determine differences in 30-day postoperative morbidity and mortality between patients who underwent prophylactic versus postfracture stabilization for metastatic lesions of long bones. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried for patients who underwent prophylactic fixation (n = 461) or postfracture stabilization (n = 856) for pathologic fractures because of metastatic lesions of long bones from 2006 to 2016. The groups were compared with respect to several potential confounders using Student t, Kruskal-Wallis, and χ tests. Logistic and Poisson regression models (inclusion threshold of P < 0.1) were used to assess the associations of functional status with outcomes. The alpha level was set at 0.05. RESULTS: Prophylactic fixation was associated with a lower risk of major medical complications (odds ratio = 0.64; 95% confidence interval [CI], 0.45 to 0.93; P = 0.02), discharge to a care facility rather than home (odds ratio = 0.48; 95% CI, 0.36 to 0.63; P < 0.01), and lower risk of a longer hospital stay (incidence risk ratio = 0.86; 95% CI, 0.74 to 0.96; P = 0.01) compared with postfracture stabilization. No significant difference was found in the risk of unplanned revision surgery or 30-day postoperative mortality between the two groups. CONCLUSION: Although prevention of pathologic fractures caused by metastatic disease may not always be possible, patients who underwent prophylactic stabilization had a lower risk of major complications within 30 days postoperatively and shorter hospital stays compared with patients who underwent postfracture stabilization. LEVEL OF EVIDENCE: Level IV, retrospective cohort.

Osteonecrosis in pediatric cancer survivors: Epidemiology, risk factors, and treatment.

Several treatment regimens for childhood malignancies have been associated with the development of osteonecrosis, including radiation therapy, glucocorticoid medications, immunotherapy (including anti-angiogenic agents), and several chemotherapeutic agents. Adolescents older than 10 years are at greatest risk of developing osteonecrosis within 1 year of initiating therapy. Screening with magnetic resonance imaging in this high-risk population may be a useful method for detecting osteonecrosis. Surgery may be required for lesions that have progressed substantially despite nonoperative interventions.

Preoperative Patient Functional Status Is an Independent Predictor of Outcomes After Primary Total Hip Arthroplasty.

This study was designed to determine whether preoperative functional status of patients with osteoarthritis predicts outcomes after primary total hip arthroplasty. The American College of Surgeons National Surgical Quality Improvement Program database was queried for records of patients who underwent primary total hip arthroplasty for a principal diagnosis of osteoarthritis from 2009 to 2013 (N=43,179). Patients were categorized as dependent or independent according to their preoperative functional status. The groups were compared regarding several potential confounders using Student's t and chi-square tests. Logistic and Poisson regression models (inclusion threshold of P<.1) were used to assess the associations of functional status with outcomes. The alpha level was set at 0.05. Compared with independent patients, dependent patients were likely to be older (mean, 70 vs 66 years, P<.01) and to have more preoperative comorbidities. After controlling for potential confounders, preoperative dependent functional status was predictive of major complications (odds ratio, 2.34; 95% confidence interval, 1.67-3.28), nonroutine discharge (odds ratio, 2.80; 95% confidence interval, 2.35-3.34), and longer hospital stay (incidence risk ratio, 1.19; 95% confidence interval, 1.12-1.27). Rates of unplanned reoperation were similar between groups on multivariate analysis. Compared with preoperative independent functional status, preoperative dependent functional status was independently associated with worse outcomes after primary total hip arthroplasty for osteoarthritis. [Orthopedics. 2019; 42(3):e326-e330.].

Soft-Tissue Metastases From Esophageal Cancer.

BACKGROUND: Metastatic carcinoma to skeletal muscle and/or subcutaneous fat is a rare event. Only 27 cases of esophageal cancer to soft tissue have been described in the English-language literature. PURPOSE: Our goal was to describe the prevalence and clinical characteristics of soft-tissue metastasis among patients with primary esophageal cancer at a single institution. METHODS: We performed a retrospective review of all patients with primary esophageal cancer. Data points analyzed included histologic subtype, anatomic location, metastasis pattern, treatment, and survival. Kaplan-Meier curves were used to estimate survival time, and log-rank tests were used for comparisons. For all analyses, P < 0.05 was considered significant. RESULTS: Of 1341 patients with primary esophageal cancer, 25 (1.9%) had metastases to soft tissue. Soft-tissue metastases were diagnosed at a median age of 64 years, a median 9.6 months after esophageal cancer diagnosis. Adenocarcinoma was the predominant histopathological type, and soft-tissue metastasis was most common in the lower extremity. Local intervention was used for 10 symptomatic patients with favorable prognoses. Chemotherapy was the only treatment modality in 18 patients. Median survival time after diagnosis of soft-tissue metastasis was 8.9 months and was longer in patients with metastasis in soft tissue only (24.6 months, P = 0.007) and in those who received local intervention (11.1 months vs those who did not, P = 0.020). CONCLUSION: We estimate the prevalence of soft-tissue metastasis to be 1.9% among patients with esophageal cancer. Local intervention may be beneficial for patients in otherwise good health with symptomatic soft-tissue lesions.

Reconstructive limb-salvage surgery after lower extremity soft tissue sarcoma resection: A 20-year experience.

BACKGROUND: Reconstructive surgery is often required following lower extremity soft tissue sarcoma resection. The relationship between the method of plastic surgery reconstruction and postoperative wound healing or functional oncologic outcomes in this patient population is poorly understood. METHODS: We performed a retrospective review on all adult patients that underwent soft tissue reconstruction following resection of lower extremity soft tissue sarcomas between 1996 and 2016 at our institution. RESULTS: One hundred and thirty-six patients were identified. Wound complications occurred within 6-months postoperatively in 72 patients (52.9%). Average time to heal was 13.0 weeks. Limb survival was 94.9%. 16.9% and 36.8% of patients had evidence of local recurrence or metastatic disease, respectively. There was no significant difference in the incidence of overall wound complications, time to heal, limb survival, local recurrence, or metastatic disease between the different reconstructive methods. CONCLUSIONS: In our cohort, the utilization of different reconstructive techniques did not correlate with a difference in postoperative wound complications or oncologic outcomes. Local flaps can effectively reconstruct the majority of lower extremity sarcoma defects that cannot be closed primarily. However, alternative reconstructive techniques may be utilized when indicated without a significant increase in postoperative morbidity in this patient population.

Osseous Metastatic Disease to the Hands and Feet.

Osseous metastases to the hands and feet (acrometastases) are exceedingly rare. Historically, the most common primary cancer observed has been lung carcinoma, treated either nonoperatively or with amputation. The aim of this study was to describe the clinical characteristics associated with acrometastases. This was a retrospective review of 28 patients with histologically proven osseous metastatic disease to the hands and feet. Variables recorded included primary cancer histology, age at diagnosis of primary and acrometastases, location of acrometastases, burden of disease, treatment, and age at death. Kaplan-Meier curves were used to estimate survival, and log-rank tests were used for comparison. The median age at acrometastases diagnosis was 61.5 years, and the most common associated primary cancer was lung carcinoma (n=9). Sixteen patients had acrometastases to the foot, and 12 had acrometastases to the hand. In the foot, most acrometastases were located in the tarsal bones (n=11), followed by the metatarsals (n=4) and the phalanges (n=3). In the hand, most were in the metacarpals and the phalanges (n=6 each), and 2 were in the carpals. The most common treatment was resection or curettage only (n=7). The median duration of survival after acrometastases diagnosis was 9.7 months. Despite advances in cancer treatment and shifting patterns of metastatic disease, there has been little change in the distribution of primary malignancies responsible for acrometastases, with lung carcinoma remaining the most common. Ablative procedures are rarely required, with limb-salvage interventions predominating. [Orthopedics. 2019; 42(2):e197-e201.].

Case report: Broad insertion of a large subscapularis tendon in association with congenital absence of the long head of the biceps tendon.

Congenital absence of the long head of the biceps (LHB) tendon is a rare variation in shoulder anatomy. The authors present a case of congenital absence of the long head of the biceps tendon associated with a large insertion of the subscapularis muscle. The patient initially presented with shoulder pain on overhead activity. Shoulder examination was negative for signs of a torn biceps tendon. MRI revealed congenital absence of the LHB tendon, a rim rent tear of the supraspinatus, and a large insertion of the subscapularis muscle. This is the first reported case describing a large insertion of the subscapularis muscle associated with absence of the LHB tendon.5.

Predictors of survival after intramedullary nail fixation of completed or impending pathologic femur fractures from metastatic disease.

BACKGROUND: Surgical decision-making can be challenging when treating patients with osseous metastases. Numerous factors, including expected duration of survival, must be considered to ensure optimal operative stabilization of the affected bone. However, life expectancy of patients with metastatic carcinoma is often difficult to estimate. The goal of our study was to assess the associations of various clinical and demographic factors with survival time after intramedullary nail fixation of impending or completed pathologic femur fractures. METHODS: One hundred thirty-eight consecutive patients treated with intramedullary nail fixation for impending or completed pathologic femur fractures between 2005 and 2017 were included in this study. Factors related to patient survival were assessed with Cox multivariate survival analysis. For all analyses, p < 0.05 was considered significant. RESULTS: The median overall postoperative survival time was 8.4 months. Lower hemoglobin concentration (p = 0.001), lower albumin concentration (p = 0.002), and having a group 2 primary cancer (p = 0.001) were associated with shorter survival on multivariate analysis. When considering the subgroup of 88 prophylactically stabilized patients, lower hemoglobin concentration (p = 0.005), lower albumin concentration (p = 0.015), and having a group 2 primary cancer (p = 0.037) were predictive of shorter survival. CONCLUSION: Several factors are associated with shorter survival after intramedullary nail fixation of pathologic femur fractures. These factors should be considered by orthopedic surgeons when educating patients and determining appropriate treatment.

Increased Plasma Levels of Select Deoxy-ceramide and Ceramide Species are Associated with Increased Odds of Diabetic Neuropathy in Type 1 Diabetes: A Pilot Study.

Plasma deoxy-sphingoid bases are elevated in type 2 diabetes patients and correlate with the stage of diabetic distal sensorimotor polyneuropathy; however, associations between deoxy-sphingolipids (DSL) and neuropathy in type 1 diabetes have not been examined. The primary aim of this exploratory pilot study was to assess the associations between multiple sphingolipid species including DSL and free amino acids and the presence of symptomatic neuropathy in a DCCT/EDIC type 1 diabetes subcohort. Using mass spectroscopy, plasma levels of DSL and free amino acids in DCCT/EDIC type 1 diabetes participants (n = 80), with and without symptoms of neuropathy, were investigated. Patient-determined neuropathy was based on 15-item self-administered questionnaire (Michigan Neuropathy Screening Instrument) developed to assess distal symmetrical peripheral neuropathy in diabetes. Patients who scored ≥4, or reported inability to sense their feet during walking or to distinguish hot from cold water while bathing were considered neuropathic. Plasma levels of ceramide, sphingomyelin, hexosyl- and lactosylceramide species, and amino acids were measured and analyzed relative to neuropathy status in the patient. Deoxy-C24-ceramide, C24- and C26-ceramide were higher in patients with neuropathy than those without neuropathy. Cysteine was higher in patients with neuropathy. No differences in other sphingolipids or amino acids were detected. The covariate-adjusted Odds Ratios of positive patient-reported neuropathy was associated with increased levels of deoxy-C24-, and deoxy-C24:1-ceramide; C22-, C24-, and C26-ceramide; and cysteine. Plasma deoxy-ceramide and ceramide species may have potential diagnostic and prognostic significance in diabetic neuropathy.