Practice Pattern Variability in the Management of Regional Lymph Node Metastasis in Extremity and Trunk Soft Tissue Sarcoma: A Survey of the Society of Surgical Oncology and Musculoskeletal Tumor Society Membership.

BACKGROUND: Regional lymph node metastasis in extremity and trunk soft tissue sarcoma (ETSTS) is rare with no standardized management. We sought to determine management patterns for regional lymph node metastasis in ETSTS. METHODS: A survey regarding the management of ETSTS lymph node metastasis was distributed to the membership of the Musculoskeletal Tumor Society (MSTS) and the Society of Surgical Oncology (SSO) in January 2022. The survey queried the type of training (surgical oncology, orthopedic oncology), details of their practice setting, and management decisions of hypothetical ETSTS scenarios that involved potential or confirmed lymph node metastasis. RESULTS: The survey was distributed to 349 MSTS members (open rate of 63%, completion rate 21%) and 3026 SSO members (open rate of 55%, completion rate 4.7%) and was completed by 214 respondents, of whom 73 (34.1%) and 141 (65.9%) were orthopedic oncology and surgical oncology fellowship-trained, respectively. The majority of respondents practiced in an academic setting (n = 171, 79.9%) and treat >10 extremity sarcoma cases annually (n = 138, 62.2%). In scenarios with confirmed nodal disease for clear cell and epithelioid sarcoma, surgical oncologists were inclined to perform lymphadenectomy, while orthopedic oncologists were inclined to offer targeted lymph node excision with adjuvant radiation (p < 0.001). There was heterogeneity of responses regarding the management of nodal disease regardless of training background. CONCLUSION: Self-reported management of nodal disease in ETSTS was variable among respondent groups with differences and similarities based on training background. These data highlight the variability of practice for nodal disease management and the need for consensus-based guidelines.

What Is the Prosthetic Survival After Resection and Intercalary Endoprosthetic Reconstruction for Diaphyseal Bone Metastases of the Humerus and Femur?

BACKGROUND: Large metastatic lesions of the diaphysis can cause considerable pain and result in difficult surgical challenges. Resection and cemented intercalary endoprosthetic reconstruction offer one solution to the problem, but it is an extensive operation that might not be tolerated well by a debilitated patient. The risk of aseptic loosening and revision after intercalary endoprosthetic replacement has varied in previous reports, which have not examined the risk of revision in the context of patient survival. QUESTIONS/PURPOSES: (1) In a small case series from one institution, what is the survivorship of patients after cemented intercalary endoprosthetic replacement for diaphyseal metastasis, and what is the cumulative incidence of revision for any reason? (2) What are the complications associated with cemented intercalary reconstruction? (3) What is the functional outcome after the procedure as assessed by the MSTS93 score? METHODS: We retrospectively studied 19 patients with diaphyseal long bone metastases who were treated with resection and cemented intercalary endoprosthetic reconstruction by five participating surgeons at one referral center from 2006 to 2017. There were 11 men and eight women with a median age of 59 years (range 46 to 80 years). The minimum follow-up required for this series was 12 months; however, patients who reached an endpoint (death, radiographic loosening, or implant revision) before that time were included. One of these 19 patients was lost to follow-up but was not known to have died. The median follow-up was 24 months (range 0 to 116 months). Eight of the 19 patients presented with pathologic fractures. Ten of 19 lesions involved the femur, and nine of 19 were in the humerus. The most common pathologic finding was renal cell carcinoma (in 10 of 19). Survival estimates of the patients were calculated using the Kaplan-Meier method. A competing risks estimator was used to evaluate implant survival, using death of the patient as the competing risk. We also estimated the cumulative incidence of aseptic loosening in a competing risk analysis. Radiographs were analyzed for radiolucency at the bone-cement-implant interfaces, fracture, integrity of the cement mantle, and component position stability. Complications were assessed using record review that was performed by an individual who was not involved in the initial care of the patients. Functional outcomes were assessed using the MSTS93 scoring system. RESULTS: Patient survivorship was 68% (95% CI 50% to 93%) at 1 year, 53% (95% CI 34% to 81%) at 2 years, and 14% (95% CI 4% to 49%) at 5 years; the median patient survival time after reconstruction was 25 months (range 0 to 116 months). In the competing risk analysis, using death as the competing risk, the cumulative incidence of implant revision was 11% (95% CI 2% to 29%) at 1 year and 16% (95% CI 4% to 36%) at 5 years after surgery; however, the cumulative incidence of aseptic loosening (with death as a competing risk) was 22% (95% CI 6% to 43%) at 1 year and 33% (95% CI 13% to 55%) at 5 years after surgery. Other complications included one patient who died postoperatively of cardiac arrest, one patient with delayed wound healing, two patients with bone recurrence, and one patient who experienced local soft tissue recurrence that was excised without implant revision. Total MSTS93 scores improved from a mean of 12.6 ± 8.1 (42% ± 27%) preoperatively to 21.5 ± 5.0 (72% ± 17%) at 3 months postoperatively (p < 0.001) and 21.6 ± 8.5 (72% ± 28%) at 2 years postoperatively (p = 0.98; 3 months versus 2 years). CONCLUSION: Resection of diaphyseal metastases with intercalary reconstruction can provide stability and short-term improvement in function for patients with advanced metastatic disease and extensive cortical destruction. Aseptic loosening is a concern, particularly in the humerus; however, the competing risk analysis suggests the procedure is adequate for most patients, because many in this series died of disease without undergoing revision. LEVEL OF EVIDENCE: Level IV, therapeutic study .

Hypofractionated, 3-week, preoperative radiotherapy for patients with soft tissue sarcomas (HYPORT-STS): a single-centre, open-label, single-arm, phase 2 trial.

BACKGROUND: The standard preoperative radiotherapy regimen of 50 Gy delivered in 25 fractions for 5 weeks for soft tissue sarcomas results in excellent local control, with major wound complications occurring in approximately 35% of patients. We aimed to investigate the safety of a moderately hypofractionated, shorter regimen of radiotherapy, which could be more convenient for patients. METHODS: This single-centre, open-label, single-arm, phase 2 trial (HYPORT-STS) was done at a single tertiary cancer care centre (MD Anderson Cancer Center, Houston, TX, USA). We administered preoperative radiotherapy to a dose of 42·75 Gy in 15 fractions of 2·85 Gy/day for 3 weeks (five fractions per week) to adults (aged ≥18 years) with non-metastatic soft tissue sarcomas of the extremities or superficial trunk and an Eastern Cooperative Oncology Group performance status of 0-3. The primary endpoint was a major wound complication occurring within 120 days of surgery. Major wound complications were defined as those requiring a secondary operation, or operations, under general or regional anaesthesia for wound treatment; readmission to the hospital for wound care; invasive procedures for wound care; deep wound packing to an area of wound measuring at least 2 cm in length; prolonged dressing changes; repeat surgery for revision of a split thickness skin graft; or wet dressings for longer than 4 weeks. We analysed our primary outcome and safety in all patients who enrolled. We monitored safety using a Bayesian, one-arm, time-to-event stopping rule simulator comparing the rate of major wound complications at 120 days post-surgery among study participants with the historical rate of 35%. This trial is registered with ClinicalTrials.gov, NCT03819985, recruitment is complete, and follow-up continues. FINDINGS: Between Dec 18, 2018, and Jan 6, 2021, we assessed 157 patients for eligibility, of whom 120 were enrolled and received hypofractionated preoperative radiotherapy. At no time did the stopping rule computation indicate that the trial should be stopped early for lack of safety. Median postoperative follow-up was 24 months (IQR 17-30). Of 120 patients, 37 (31%, 95% CI 24-40) developed a major wound complication at a median time of 37 days (IQR 25-59) after surgery. No patient had acute radiation toxicity (during radiotherapy or within 4 weeks of the radiotherapy end date) of grade 3 or worse (Common Terminology Criteria for Adverse Events [CTCAE] version 4.0) or an on-treatment serious adverse event. Four (3%) of 115 patients had late radiation toxicity (≥6 months post-surgery) of at least grade 3 (CTCAE or Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme): femur fractures (n=2), lymphoedema (n=1), and skin ulceration (n=1). There were no treatment-related deaths. INTERPRETATION: Moderately hypofractionated preoperative radiotherapy delivered to patients with soft tissue sarcomas was safe and could therefore be a more convenient alternative to conventionally fractionated radiotherapy. Patients can be counselled about these results and potentially offered this regimen, particularly if it facilitates care at a sarcoma specialty centre. Results on long-term oncological, late toxicity, and functional outcomes are awaited. FUNDING: The National Cancer Institute.

Certain risk factors for patients with desmoid tumors warrant reconsideration of local therapy strategies.

BACKGROUND: The objective of this study was to evaluate treatment outcomes for patients with desmoid tumors (DTs) receiving local therapy with surgery alone, radiation therapy (RT) alone, or combined modality therapy (RT and surgery). METHODS: This was a cross-sectional cohort study of 412 patients with nonmesenteric DTs who received local therapy at the authors' institution between 1965 and 2018. RESULTS: The median follow-up time was 95 months (range, 1-509 months). Local recurrence occurred in 127 patients (31%) at a median time of 21 months (interquartile range, 12-38 months). The 5-year local control (LC) rate was 67%. Patient or tumor factors that were significantly associated with poorer 5-year LC in a multivariable analysis included an age ≤ 30 years (57% vs 75% for an age > 30 years; hazard ratio [HR], 1.73; P = .004), an extremity location (57% vs 71% for a nonextremity location; HR, 1.77; P = .004), and large tumors (59% for >10 cm [HR, 2.17; P = .004] and 65% for 5.1-10 cm [HR, 1.71; P = .02] vs 76% for ≤5 cm). Subset analyses of these high-risk patients revealed no local therapy strategy to be superior for young patients ≤ 30 years old (HR for surgery, 1.42; P = .33; HR for RT, 1.36; P = .38) or for large tumors > 10 cm (HR for surgery, 1.55; P = .46; HR for RT, 0.91; P = .91). However, for patients with extremity tumors, surgery alone was significantly associated with inferior LC (HR for surgery, 5.15; P < .001; HR for RT, 1.51; P = .38). CONCLUSIONS: Local therapy provides durable tumor control in the majority of patients with DTs. However, young patients, patients with an extremity location, and patients with large tumors are at increased risk of recurrence. When active treatment is indicated, systemic therapy should perhaps be considered as a first-line option in these high-risk subsets. Prospective multi-institutional studies evaluating this strategy are warranted.

Cancer Surgery Scheduling During and After the COVID-19 First Wave: The MD Anderson Cancer Center Experience.

OBJECTIVE: To summarize the multi-specialty strategy and initial guidelines of a Case Review Committee in triaging oncologic surgery procedures in a large Comprehensive Cancer Center and to outline current steps moving forward after the initial wave. SUMMARY OF BACKGROUND DATA: The impetus for strategic rescheduling of operations is multifactorial and includes our societal responsibility to minimize COVID-19 exposure risk and propagation among patients, the healthcare workforce, and our community at large. Strategic rescheduling is also driven by the need to preserve limited resources. As many states have already or are considering to re-open and relax stay-at-home orders, there remains a continued need for careful surgical scheduling because we must face the reality that we will need to co-exist with COVID-19 for months, if not years. METHODS: The quality officers, chairs, and leadership of the 9 surgical departments in our Division of Surgery provide specialty-specific approaches to appropriately triage patients. RESULTS: We present the strategic approach for surgical rescheduling during and immediately after the COVID-19 first wave for the 9 departments in the Division of Surgery at The University of Texas MD Anderson Cancer Center in Houston, Texas. CONCLUSIONS: Cancer surgeons should continue to use their oncologic knowledge to determine the window of opportunity for each surgical procedure, based on tumor biology, preoperative treatment sequencing, and response to systemic therapy, to safely guide patients through this cautious recovery phase.

Local recurrence of Ewing sarcoma: Is wide excision an acceptable treatment?

BACKGROUND AND OBJECTIVES: Local recurrence in Ewing sarcoma (ES) is associated with poor prognosis. The purpose of the study is to determine what factors affect overall survival after local recurrence and whether wide excision constitutes appropriate treatment. METHODS: From 1992 to 2017, 26 patients were treated for local recurrence of ES. Sixteen patients presented with local recurrence only while 10 had metastasis. The median follow-up was 23 months (range, 3-255 months). Overall survival was assessed with Kaplan-Meier analysis. RESULTS: At the last follow-up, seven of 26 (27%) patients were alive. Overall survival after local recurrence was 28% at 5 years. Later onset of local recurrence (P = .041), surgical treatment (P < .001), and complete eradication of all recurrent disease (P < .001) predicted better survival. Metastasis was associated with worse survival (P = .014). All three patients who survived more than 10 years were treated with wide local excision. A second local recurrence developed in seven patients (28%) but did not predict worse overall survival. CONCLUSIONS: Overall survival after local recurrence is better for patients with nonmetastatic disease treated surgically. Wide excision can be compatible with long survival. We do not advocate amputation on a routine basis for local recurrence. Complete eradication of all diseases is associated with better survival.

Is a Cephalomedullary Nail Durable Treatment for Patients With Metastatic Peritrochanteric Disease?

BACKGROUND: Although cephalomedullary nail fixation is often used for metastatic peritrochanteric lesions of the femur, there is concern regarding the durability of the implant in comparison to endoprosthetic reconstruction. Previous studies have reported the proportion of patients who undergo reoperation for loss of stability, but the adequacy of the construct has not been critically evaluated in a competing risk analysis that incorporates death of the patient in the calculation. QUESTIONS/PURPOSES: (1) What is the cumulative incidence of reoperation of cephalomedullary nails with death as a competing risk for metastatic lesions of the proximal femur? (2) What is the survival of patients with metastases to the proximal femur after cephalomedullary nailing? (3) What clinical factors are associated with implant stability in these patients? METHODS: Between 1990 and 2009, 11 surgeons at one center treated 217 patients with cephalomedullary nails for metastatic proximal femoral lesions. This represented 40% (217 of 544) of the patients undergoing surgery for metastases in this location during the study period. In general, we used cephalomedullary nails when there was normal bone in the femoral head, no fracture in the neck, and a moderate-sized lesion; we favored bipolar hemiarthroplasty for femoral neck fractures and disease affecting the femoral head; finally, we used proximal femoral endoprosthetic replacement for large lesions with severe bone destruction. A retrospective study was conducted of 199 patients with cephalomedullary nails for peritrochanteric metastases from 1990 to 2009. Pathologic fracture, defined as a breach in cortex with a clear fracture line either with or without displacement, was present in 61 patients. The most common primary cancers were breast (42 of 199 patients [21%]), lung (37 of 199 patients [18%]), and renal cell (34 of 199 patients [17%]). A competing risk analysis was performed to describe the cumulative incidence of implant revision. Patient overall survival was assessed by Kaplan-Meier survivorship. A univariate analysis was performed to determine whether there was an association between revision surgery and various patient factors, including tumor histology, pathologic fracture, cementation, and radiation. RESULTS: Loss of implant stability necessitating revision surgery occurred in 19 of 199 patients (10%). In a competing risk analysis with death of the patient as the competing event, the cumulative incidence of revision surgery was 5% (95% confidence interval [CI], 3%-9%) at 12 months and 9% (95% CI, 5%-13%) at 5 years. Using Kaplan-Meier analysis, the overall patient survival was 31% (95% CI, 25%-37%) at 12 months and 5% (95% CI, 3%-9%) at 60 months. Patients with lung cancer had the shortest overall survival of 11% (95% CI, 1%-21%) at 12 months, and patients with multiple myeloma had the longest overall survival of 71% (95% CI, 49%-94%) at 12 months (p < 0.001). Duration of patient survival beyond the median 7 months was the only factor associated with a greater likelihood of revision surgery. Factors not associated with revision included tumor histology, pathologic fracture, closed versus open nailing, cementation, gender, age, and postoperative radiation. CONCLUSIONS: The competing risk analysis demonstrates a relatively low cumulative incidence of reoperation and suggests that cephalomedullary nailing is reasonable for patients with moderate-sized proximal femoral metastasis not affecting the femoral head. For the large majority of patients, the construct achieves the goal of stabilizing the femur for the duration of the patient's life. Longer patient survival was associated with greater risk of revision surgery, but no particular tumor histology was found to have a greater cumulative incidence of reoperation. Future work with a larger number of patients and stricter surgical indications may be needed to corroborate these findings. LEVEL OF EVIDENCE: Level III, therapeutic study.

Is It Appropriate to Treat Sarcoma Metastases With Intramedullary Nailing?

BACKGROUND: Patients with primary bone and soft tissue sarcoma are at risk for skeletal metastases. Although uncommon, these metastases can result in impending or pathologic fractures. Intramedullary nailing traditionally has been an accepted form of palliative treatment for patients with metastatic carcinoma, but we could find no studies that report specifically on intramedullary nailing of metastatic sarcoma lesions. QUESTIONS/PURPOSES: We asked: (1) What is the survival of patients with an impending or pathologic fracture from a sarcoma metastasis? (2) What proportion of patients treated with intramedullary nailing subsequently underwent a revision procedure or nail removal during their lifetimes? METHODS: Between 1996 and 2014, we performed 40 intramedullary nailing procedures in 34 patients with multifocal metastases from sarcomas who showed signs or symptoms of impending fracture or who presented with a pathologic fracture. All of these patients are accounted for, either through the time of death or to the present, and all are included at a mean of 13 months (range, 0.3-86 months) in this retrospective study. During the study period, we generally applied the same surgical indications for patients with nailing of metastatic sarcoma lesions as we did for patients with metastatic carcinoma; in general, we used intramedullary nailing (with or without cement) rather than resection for diaphyseal lesions with less cortical destruction and no substantial soft tissue mass or metadiaphyseal lesions that could be adequately supplemented with cementation. The goal was to use this approach when it would allow immediate weightbearing, or in patients whose medical conditions were such that a more-extensive procedure seemed unsafe. During the same period, an additional 58 patients underwent resection procedures for metastatic sarcomas to long bones because they either did not meet the above indications, had a solitary resectable metastasis, or because of surgeon preference; these patients were excluded from this study. The median age of the patients was 52 years (range, 27-81 years). Eleven patients with 11 impending or pathologic fractures were documented to have received either preoperative or postoperative radiation therapy and 29 patients received some form of chemotherapy. RESULTS: Thirty (88%) patients died during the period of observation, at a median of 5 months (range, 0.3-80 months) after surgery. Twenty-nine patients (85%) underwent no additional surgery and retained their original intramedullary nail. One patient (3%) underwent nail removal for infection, and four patients (12%) underwent further surgical revision secondary to local progression. CONCLUSIONS: Patients with an impending or pathologic fracture from multifocal metastatic sarcoma to a long bone have a dismal prognosis, but they may gain short-term benefit from surgical fixation with the goal of reducing pain and maintaining mobility. Although we have no group for comparison, such as treating with radiotherapy alone or resection and an endoprosthesis, our findings suggest that use of intramedullary nails is helpful for providing fixation that in most instances lasts for the lifetime of patients with multifocal bone metastases from sarcomas. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Cas9-Guide RNA Directed Genome Editing in Soybean.

Recently discovered bacteria and archaea adaptive immune system consisting of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) endonuclease has been explored in targeted genome editing in different species. Streptococcus pyogenes Cas9-guide RNA (gRNA) was successfully applied to generate targeted mutagenesis, gene integration, and gene editing in soybean (Glycine max). Two genomic sites, DD20 and DD43 on chromosome 4, were mutagenized with frequencies of 59% and 76%, respectively. Sequencing randomly selected transgenic events confirmed that the genome modifications were specific to the Cas9-gRNA cleavage sites and consisted of small deletions or insertions. Targeted gene integrations through homology-directed recombination were detected by border-specific polymerase chain reaction analysis for both sites at callus stage, and one DD43 homology-directed recombination event was transmitted to T1 generation. T1 progenies of the integration event segregated according to Mendelian laws and clean homozygous T1 plants with the donor gene precisely inserted at the DD43 target site were obtained. The Cas9-gRNA system was also successfully applied to make a directed P178S mutation of acetolactate synthase1 gene through in planta gene editing.

Patellar Height Decreasing After Distal Femur Endoprosthesis Reconstruction Does Not Affect Functional Outcome.

INTRODUCTION: The patellar height can influence extensor mechanism and the knee function. Thus, during knee arthroplasty, the surgeon seeks to maintain the correct patellar height. However, it is more difficult to define and maintain the correct patella height in megaprosthesis reconstructions after tumor resections. The objective of this study was to evaluate patellar height after distal femur endoprosthesis reconstruction and its association to knee function. METHODS: This retrospective analysis included 108 patients who underwent distal femur resections and endoprosthesis reconstruction. The minimum follow-up was 1 year or until the patients underwent patellar resurfacing or endoprosthesis revision. Patellar height was calculated using Insall-Salvati ratio (ISR) and Insall-Salvati patellar tendon insertion ratio (PTR) at 2 different times: postoperatively and at the final follow-up. The postoperative ratio was calculated using the best postoperative radiograph taken at least 1 month after the procedure. The final measures were based on the radiograph available at the last follow-up consultation. The ISR and PTR were associated to anterior knee pain (AKP), range of motion (ROM), and extension lag (EXL). RESULTS: The average follow-up was 4.5years. The mean postoperative ISR was 1.02, and the mean ISR at final follow-up was 0.95 (P<.0001). The mean postoperative PTR was 1.45, and the mean PTR at final follow-up was 1.40 (P=.016). There was no association between patellar height and AKP, ROM, and EXL. Patellar height decreases significantly after distal femur resections but does not affect AKP, ROM, and EXL.

Tissue-specific expression of a soybean hypersensitive-induced response (HIR) protein gene promoter.

A Glycine max gene encoding a putative protein similar to hypersensitive-induced response proteins (HIR) was identified as a gene with preferred expressions in flowers and developing seeds by whole transcriptome gene expression profiling. Its promoter gm-hir1 was cloned and revealed to strongly express a fluorescence reporter gene primarily in integuments, anther tapetum, and seed coat with unique tissue-specificity. Expression in the inner integument was apparent prior to pollination, while expression in the outer integument started to develop from the micropylar end outward as the embryo matured. A 5'-deletion study showed that the promoter can be truncated to 600 bp long relative to the translation start site without affecting expression. A positive regulatory element was identified between 600 and 481 bp that controls expression in the inner integument, with no noticeable effect on expression in the outer integument or tapetum. Additionally, removal of the 5'UTR intron had no effect on levels or location of gm-hir1 expression while truncation to 370 bp resulted in a complete loss of expression suggesting that elements controlling both the outer integument and tapetum expression are located within the 481-370 bp region.

Intramedullary nailing of femoral diaphyseal metastases: is it necessary to protect the femoral neck?

BACKGROUND: Intramedullary nailing is the accepted form of treatment for impending or pathologic fractures of the femoral diaphysis. Traditional teaching promotes the use of a cephalomedullary nail so that stabilization is provided for the femoral neck in the event that a future femoral neck metastasis develops. However, that approach may add cost, surgical time, blood loss, and added radiation exposure to staff members, and there is limited evidence in the literature that supports this practice. QUESTIONS/PURPOSES: The purpose of our study was to evaluate the incidence of femoral neck metastases in patients who underwent femoral nailing of diaphyseal metastases. PATIENTS AND METHODS: Retrospective analysis of our Musculoskeletal Oncology database identified 145 femoral nailings performed for metastatic disease, myeloma, or lymphoma of the femoral diaphysis between 2001 and 2011. Average patient age was 59 years. One hundred forty-one patients underwent 145 femoral nailings (four were bilateral). One hundred forty-four of the nails used were cephalomedullary implants and one was a flexible nail. Thirty-six (25%) femurs had sustained a pathologic fracture and 109 (75%) femurs were treated as impending fractures. Eighty-four patients received either preoperative or postoperative radiation therapy. Average radiographic followup was 13 months and average postoperative survival was 16 months. Of the 141 patients in this series, 121 (86%) are known to have died at a median of 9 months (range, 0.1-133 months) after surgery. The latest followup radiographs were obtained at a median of 5 months after the femoral nailing (range, 0-119 months). Of the 90 patients with documented dates of death and radiographic followup greater than zero months, 76 (84%) had radiographs available within a year of death. Thirty-one patients had zero months radiographic followup. The median survival for this group of patients was only 0.9 months (range, 0.1-12 months). RESULTS: No patients (0%) in this series had femoral neck metastases develop postoperatively. CONCLUSION: Despite traditional teaching that supports the use of cephalomedullary implants when treating metastatic disease of the femur, we were unable to identify a single patient who had femoral neck metastasis after surgery on the femur. Our findings do not support the use of cephalomedullary implants in this patient population for the sole purpose of prophylactic femoral neck stabilization; however, this series was relatively small, and the experiences of other centers will be needed to come to a more-complete sense of the frequency of what in all likelihood is a rare event.

What are the factors that affect survival and relapse after local recurrence of osteosarcoma?

BACKGROUND: Despite improvements in treatment of primary osteosarcoma, treatment of patients who have local recurrence is not well defined. QUESTIONS/PURPOSES: We asked: (1) What are the 5- and 10-year overall survival rates of patients with osteosarcoma who have a local recurrence? (2) What factors are associated with better survival after a local recurrence? (3) Does chemotherapy affect overall survival after local recurrence? (4) What are the rates of rerecurrence after amputation and with limb salvage? METHODS: We reviewed 45 patients with nonmetastatic conventional high-grade osteosarcoma who had local recurrence between 1985 and 2007, during which time 461 patients were treated for the same disease. Seven patients with known local recurrence were lost to followup and not included in our study. The median age of the patients was 18 years, and minimum followup was 2 months (median, 39 months; range, 2-350 months). The primary tumor was located in the extremity in 36 patients and the pelvis in nine. The median time from initial surgery for resection or amputation of the primary tumor to local recurrence was 18 months (range, 2-149 months). Ten recurrences developed in bone and 35 in soft tissue. In 21 of the latter cases, the soft tissue recurrence was undetectable on conventional radiographs. Prognostic factors for overall patient survival after recurrence were evaluated by Kaplan-Meier survival and Cox multivariate analyses. RESULTS: Overall postrecurrence patient survival was 30% at 5 years and 13% at 10 years. Cox multivariate analysis revealed that concurrent metastasis (relative risk = 4, p = 0.003) and recurrent tumor size 5 cm or larger (relative risk = 13, p < 0.0001) were independent predictors of worse survival. With the numbers available, treatment with chemotherapy after local recurrence was not associated with better survival (p = 0.54). Nine patients had a second local recurrence, and the actuarial risk of rerecurrence was 34% at 5 years. There was no difference in the frequency of rerecurrence between patients treated by amputation and wide local excision (p = 0.23). CONCLUSIONS: The long-term prognosis of patients who have local recurrence of osteosarcoma is poor. Followup beyond 5 years is essential, because the disease can have a protracted course. Most recurrences develop in soft tissue and are difficult to see on plain radiographs alone. The size of the recurrence and presence of metastasis were independent prognostic factors, suggesting that early detection may be important. Chemotherapy did not have a significant effect on survival, and surgical eradication of recurrence with wide margins may be critical to maximizing the chances for survival.

Operative management of metastatic melanoma in bone may require en bloc resection of disease.

BACKGROUND: Bone metastasis is a poor prognostic indicator in melanoma. Some authors have advocated only palliative treatment for patients with osseous disease. QUESTIONS/PURPOSES: We determined (1) overall survival after surgery for bone metastasis in patients with malignant melanoma, (2) the rate of local relapse after surgery for bone metastasis, (3) whether certain patients might benefit from more extensive surgery to reduce the risk of local recurrence, and (4) whether there is an effect of prior radiation on survival and local progression. METHODS: We identified 37 patients who underwent 41 orthopaedic procedures for metastatic melanoma to bone in the pelvis or appendicular skeleton, including 20 for pathologic fracture, from our institutional orthopaedic database and performed a retrospective review of their charts and radiographs. The femur (n = 19) and humerus (n = 11) were the most common operative sites. Kaplan-Meier survivorship was used to determine overall survival and local progression-free survival. RESULTS: The median survival from surgery was 9 months (range, 1-135 months). Kaplan-Meier analysis showed overall survival of 30% at 12 months and 17% at 24 months. Local recurrence developed in seven of 41 lesions (17%). The local progression-free survival was 87% at 12 months and 67% at 24 months. Patients for whom prior radiation failed and patients who did not have excision of osseous metastases had higher rates of local recurrence. Two patients underwent amputation for uncontrolled local progression of disease. CONCLUSIONS: Osseous metastasis from melanoma behaves aggressively. The rate of local progression is substantial, and two of 37 patients in this series required amputation for progressive disease. Despite the poor overall prognosis, local control of bone disease is an important issue, and patients may benefit from resection of osseous metastases, particularly if prior radiation has failed.

Percutaneous Cementation for Improvement of Pain and Function for Osteolytic Pelvic Metastasis: A Systematic Review.

INTRODUCTION: Pelvic metastasis is a common presentation among patients presenting with skeletal metastasis. Image-guided percutaneous cementation of these lesions is becoming increasingly popular for the treatment of these lesions. The objective of this study was to conduct a systematic review that investigates clinical outcomes after percutaneous cementation for pelvic metastasis. METHODS: A systematic review was registered with International Prospective Register of Systematic Reviews and performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the PubMed, SCOPUS, and Ovid MEDLINE databases. All level I to IV clinical studies published in the English language investigating the clinical outcomes after percutaneous cementation for pelvic metastasis were included. RESULTS: Fourteen studies with 579 patients (278 men, 301 women) and 631 metastatic pelvic lesions were included in the study. The mean follow-up range was 0.7 to 26.4 months. Percutaneous cementation alone was performed in 441 patients (76.2%). Supplemental ablative procedures were performed in 77 patients (13.3%), and supplemental internal fixation using cannulated screws was performed in 107 patients (18.5%). Twelve studies with 430 patients (74.2%) reported pain-related and/or functional outcome scores, of which all studies reported overall clinically notable improvement at short-term follow-up. All studies reported periprocedural complications. Local cement leakage was the most common complication (162/631 lesions, 25.7%) followed by transient local pain (25/579 patients, 4.3%). There were no reported cases of major complications. Seven patients (1.2%) underwent re-intervention for persistent symptoms. CONCLUSIONS: Percutaneous cementation may be an effective method for treating pain and function related to pelvic metastasis. The most common complication was cement leakage surrounding the lesion. The rates of major complications were low, and most complications appeared minor and transient. Additional prospective studies are needed to further assess the efficacy of this procedure. LEVEL OF EVIDENCE: IV, systematic review of level I to IV therapeutic studies.

BIGH3 mediates apoptosis and gap junction failure in osteocytes during renal cell carcinoma bone metastasis progression.

Renal cell carcinoma (RCC) bone metastatis progression is driven by crosstalk between tumor cells and the bone microenvironment, which includes osteoblasts, osteoclasts, and osteocytes. RCC bone metastases (RCCBM) are predominantly osteolytic and resistant to antiresorptive therapy. The molecular mechanisms underlying pathologic osteolysis and disruption of bone homeostasis remain incompletely understood. We previously reported that BIGH3/TGFBI (transforming growth factor-beta-induced protein ig-h3, shortened to BIGH3 henceforth) secreted by colonizing RCC cells drives osteolysis by inhibiting osteoblast differentiation, impairing healing of osteolytic lesions, which is reversible with osteoanabolic agents. Here, we report that BIGH3 induces osteocyte apoptosis in both human RCCBM tissue specimens and in a preclinical mouse model. We also demonstrate that BIGH3 reduces Cx43 expression, blocking gap junction (GJ) function and osteocyte network communication. BIGH3-mediated GJ inhibition is blocked by the lysosomal inhibitor hydroxychloroquine (HCQ), but not osteoanabolic agents. Our results broaden the understanding of pathologic osteolysis in RCCBM and indicate that targeting the BIGH3 mechanism could be a combinational strategy for the treatment of RCCBM-induced bone disease that overcomes the limited efficacy of antiresorptives that target osteoclasts.

Single-fraction radiation retreatment for bone metastases: role of a rapid access clinic.

OBJECTIVES: This study investigates retreatment rates in single-fraction radiation therapy (SFRT) for painful bone metastasis in patients with limited life expectancy. We compared retreatment-free survival (RFS) in patients from a rapid access bone metastases clinic (RABC) and non-RABC patients, identifying factors associated with retreatment. METHODS: In this observational study, we analysed RABC patients who received SFRT between April 2018 and November 2019, using non-RABC SFRT patients as a comparison group. Patients with prior or perioperative radiation therapy (RT) were excluded. The primary endpoint was same-site and any-site retreatment with RT or surgery. Patient characteristics were compared using χ2 and Student's t-tests, with RFS estimates based on a multistate model considering death as a competing risk using Aalen-Johansen estimates. RESULTS: We identified 151 patients (79 RABC, 72 non-RABC) with 225 treatments (102 RABC, 123 non-RABC) meeting eligibility criteria. Of the 22 (10.8%) same-site retreatments, 5 (22.7%) received surgery, 14 (63.6%) received RT and 3 (13.6%) received both RT and surgery. We found no significant differences in any-site RFS (p=0.97) or same-site RFS (p=0.11). CONCLUSIONS: RFS is high and similar comparable in the RABC and non-RABC cohorts. Retreatment rates are low, even in patients with low Eastern Cooperative Oncology Group scores.

A randomized, non-comparative phase 2 study of neoadjuvant immune-checkpoint blockade in retroperitoneal dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma.

Based on the demonstrated clinical activity of immune-checkpoint blockade (ICB) in advanced dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS), we conducted a randomized, non-comparative phase 2 trial ( NCT03307616 ) of neoadjuvant nivolumab or nivolumab/ipilimumab in patients with resectable retroperitoneal DDLPS (n = 17) and extremity/truncal UPS (+ concurrent nivolumab/radiation therapy; n = 10). The primary end point of pathologic response (percent hyalinization) was a median of 8.8% in DDLPS and 89% in UPS. Secondary end points were the changes in immune infiltrate, radiographic response, 12- and 24-month relapse-free survival and overall survival. Lower densities of regulatory T cells before treatment were associated with a major pathologic response (hyalinization > 30%). Tumor infiltration by B cells was increased following neoadjuvant treatment and was associated with overall survival in DDLPS. B cell infiltration was associated with higher densities of regulatory T cells before treatment, which was lost upon ICB treatment. Our data demonstrate that neoadjuvant ICB is associated with complex immune changes within the tumor microenvironment in DDLPS and UPS and that neoadjuvant ICB with concurrent radiotherapy has significant efficacy in UPS.

A long femoral stem is not always required in hip arthroplasty for patients with proximal femur metastases.

BACKGROUND: During hip arthroplasties for treating proximal femur metastases, a long femoral stem frequently is used, presumably protecting the entire femur against progression of the existing lesions or development of new lesions. However, it is unclear whether a long stem is really required. QUESTIONS/PURPOSES: We therefore determined in patients with proximal femur metastases (1) the reoperation rate related to different stem lengths after hip arthroplasty, (2) the risk of tumor progression in the same femur (the progression of preexisting lesions and the development of new distal femur lesions), and (3) complications. METHODS: We retrospectively reviewed 203 patients (206 femurs) with proximal femur metastases treated with hip arthroplasty. These femurs were divided into three groups based on femoral stem length: short stem (SS), 12 to 14 cm; medium stem (MS), 20 to 24 cm; and long stem (LS), 25 to 35 cm. We reviewed reoperations, disease progression in the same femur, and complications. Minimum followup was 2 days (median, 487 days; range, 2-4853 days), with most patients followed to their death. RESULTS: Only three femurs were revised owing to tumor progression, with no difference among the SS, MS, and LS groups. Two SS prostheses were revised for nononcologic reasons. Tumor progression in the same femur was uncommon during the patient's survival, with 11 femurs showing progression of the proximal lesion and five femurs showing new distal lesions. The complication rate was higher in the LS group (28%) than the combined rate in the MS and SS groups (16%), especially acute cardiopulmonary complications (18% versus 7.5%). CONCLUSIONS: Reoperation after hip arthroplasty for proximal femur metastases is uncommon and not correlated with femoral stem length. Considering the high complication rate associated with a LS hip prosthesis, we do not believe its routine use is justified.