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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. 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. 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. 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. The National Cancer Institute.

BackgroundRegional 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. MethodsA 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. ResultsThe 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.ConclusionSelf-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.

Background Soft tissue sarcomas are a heterogeneous and rare group of solid tumors of mesenchymal origin that can arise anywhere in the body. Although surgical resection is the mainstay of treatment for patients with localized disease, disease recurrence is common and 5-year overall survival is poor (~ 65%). Both radiation therapy and conventional chemotherapy are used to reduce local and distant recurrence. However, the utility of radiation therapy is often limited by disease location (in the case of retroperitoneal sarcomas, for instance) while systemic therapy with conventional lines of chemotherapy offer limited efficacy and are often poorly tolerated and associated with significant toxicity. Within the past decade, major advances have been made in the treatment of other malignancies including melanoma, renal cell carcinoma, and non-small cell lung carcinoma with the advent of immune-checkpoint inhibitors such as ipilimumab (anti-CTLA4), pembrolizumab (anti-PD1), and nivolumab (anti-PD1). The recently published SARC028 (NCT02301039), an open label, phase II, multicenter trial of pembrolizumab in patients with advanced bone and soft tissue sarcomas reported promising activity in select histologic subtypes of advanced STS, including undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. Methods There is a clear need for novel and effective adjuncts in the treatment of STS. We hypothesize that immune checkpoint blockade will be effective in patients with surgically resectable primary or locally recurrent dedifferentiated liposarcoma and undifferentiated pleomorphic sarcoma when administered in the neoadjuvant setting. The primary aim of this phase II, single-center, open label, randomized non-comparative trial is to determine the pathologic response to neoadjuvant nivolumab monotherapy and combination nivolumab/ipilimumab in patients with resectable dedifferentiated liposarcoma of the retroperitoneum or undifferentiated pleomorphic sarcoma of the trunk or extremity treated with concurrent standard of care neoadjuvant radiation therapy. Discussion This study will help define the role of single agent anti-PD1 and combination anti-CTLA4 and anti-PD1 therapy in patients with surgically resectable dedifferentiated liposarcoma and undifferentiated pleomorphic sarcoma. Trial registration ClinicalTrials.gov NCT03307616 , registered October 12, 2017.

Osteosarcoma occurs predominantly in children and young adults. High-grade tumors require multidisciplinary treatment consisting of chemotherapy in the neoadjuvant and adjuvant settings, along with surgical intervention. Despite this approach, death from respiratory failure secondary to the development and progression of pulmonary metastases remains a significant problem. Here, we identify the IL-11 receptor α subunit (IL-11Rα) as a cell surface marker of tumor progression that correlates with poor prognosis in patients with osteosarcoma. We also show that both IL-11Rα and its ligand, IL-11, are specifically up-regulated in human metastatic osteosarcoma cell lines; engagement of this autocrine loop leads to tumor cell proliferation, invasion, and anchorage-independent growth in vitro. Consistently, IL-11Rα promotes lung colonization by human metastatic osteosarcoma cells in vivo in an orthotopic mouse model. Finally, we evaluate the IL-11Rα–targeted proapoptotic agent bone metastasis-targeting peptidomimetic (BMTP-11) in preclinical models of primary intratibial osteosarcomas, observing marked inhibition of both tumor growth and lung metastases. This effect was enhanced when BMTP-11 was combined with the chemotherapeutic drug gemcitabine. Our combined data support the development of approaches targeting IL-11Rα, and establish BMTP-11 as a leading drug candidate for clinical translation in patients with high-risk osteosarcoma.

An emerging option for internal hemipelvectomy surgery is custom prosthesis reconstruction. This option typically recapitulates the resected pelvic bony anatomy with the goal of maximizing post-surgery walking function while minimizing recovery time. However, the current custom prosthesis design process does not account for the patient’s post-surgery prosthesis and bone loading patterns, nor can it predict how different surgical or rehabilitation decisions (e.g., retention or removal of the psoas muscle, strengthening the psoas) will affect prosthesis durability and post-surgery walking function. These factors may contribute to the high observed failure rate for custom pelvic prostheses, discouraging orthopedic oncologists from pursuing this valuable treatment option. One possibility for addressing this problem is to simulate the complex interaction between surgical and rehabilitation decisions, post-surgery walking function, and custom pelvic prosthesis design using patient-specific neuromusculoskeletal models. As a first step toward developing this capability, this study used a personalized neuromusculoskeletal model and direct collocation optimal control to predict the impact of ipsilateral psoas muscle strength on walking function following internal hemipelvectomy with custom prosthesis reconstruction. The influence of the psoas muscle was targeted since retention of this important muscle can be surgically demanding for certain tumors, requiring additional time in the operating room. The post-surgery walking predictions emulated the most common surgical scenario encountered at MD Anderson Cancer Center in Houston. Simulated post-surgery psoas strengths included 0% (removed), 50% (weakened), 100% (maintained), and 150% (strengthened) of the pre-surgery value. However, only the 100% and 150% cases successfully converged to a complete gait cycle. When post-surgery psoas strength was maintained, clinical gait features were predicted, including increased stance width, decreased stride length, and increased lumbar bending towards the operated side. Furthermore, when post-surgery psoas strength was increased, stance width and stride length returned to pre-surgery values. These results suggest that retention and strengthening of the psoas muscle on the operated side may be important for maximizing post-surgery walking function. If future studies can validate this computational approach using post-surgery experimental walking data, the approach may eventually influence surgical, rehabilitation, and custom prosthesis design decisions to meet the unique clinical needs of pelvic sarcoma patients.

Bone is the most common site of distant metastases from breast carcinoma. The presence of bone metastases affects a patient's prognosis, quality of life, and the planning of their treatment. We discuss recent innovations in bone imaging and present algorithms, based on the strengths and weaknesses of each technique, to facilitate the most successful and cost-effective choice of imaging studies for the detection of osseous metastases. Skeletal scintigraphy (bone scan) is very sensitive in the detection of osseous metastases and is recommended as the first imaging study in patients who are asymptomatic. Radiographs are recommended for the assessment of abnormal radionuclide uptake or the risk of pathological fracture and as initial imaging studies in patients with bone pain. MRI or PET–CT can be considered for cases of abnormal radionuclide uptake that are not addressed by radiography. Osseous metastases can lead to emergent situations, such as spinal-cord compression or impending fracture of a weight-bearing bone, and imaging guidelines are essential for early detection and initiation of appropriate therapy. The imaging method used in non-emergent situations, such as assessment of the ribs, sternum, pelvis, hips, and joints, should be guided by the strengths and limitations of each technique.

Custom implants used for pelvic reconstruction in pelvic sarcoma surgery face a high complication rate due to mechanical failures of fixation screws. Consequently, patient-specific finite element (FE) models have been employed to analyze custom pelvic implant durability. However, muscle forces have often been omitted from FE studies of the post-operative pelvis with a custom implant, despite the lack of evidence that this omission has minimal impact on predicted bone, implant, and fixation screw stress distributions. This study investigated the influence of muscle forces on FE predictions of fixation screw pullout and fatigue failure in a custom pelvic implant. Specifically, FE analyses were conducted using a patient-specific FE model loaded with seven sets of personalized muscle and hip joint contact force loading conditions estimated using a personalized neuromusculoskeletal (NMS) model. Predictions of fixation screw pullout and fatigue failure—quantified by simulated screw axial forces and von Mises stresses, respectively—were compared between analyses with and without personalized muscle forces. The study found that muscle forces had a considerable influence on predicted screw pullout but not fatigue failure. However, it remains unclear whether including or excluding muscle forces would yield more conservative predictions of screw failures. Furthermore, while the effect of muscle forces on predicted screw failures was location-dependent for cortical screws, no clear location dependency was observed for cancellous screws. These findings support the combined use of patient-specific FE and NMS models, including loading from muscle forces, when predicting screw pullout but not fatigue failure in custom pelvic implants.

Introduction: Three-dimensional (3D)-printed custom pelvic implants have become a clinically viable option for patients undergoing pelvic cancer surgery with resection of the hip joint. However, increased clinical utilization has also necessitated improved implant durability, especially with regard to the compression screws used to secure the implant to remaining pelvic bone. This study evaluated six different finite element (FE) screw modeling methods for predicting compression screw pullout and fatigue failure in a custom pelvic implant secured to bone using nine compression screws. Methods: Three modeling methods (tied constraints (TIE), bolt load with constant force (BL-CF), and bolt load with constant length (BL-CL)) generated screw axial forces using functionality built into Abaqus FE software; while the remaining three modeling methods (isotropic pseudo-thermal field (ISO), orthotropic pseudo-thermal field (ORT), and equal-and-opposite force field (FOR)) generated screw axial forces using iterative physics-based relationships that can be implemented in any FE software. The ability of all six modeling methods to match specified screw pretension forces and predict screw pullout and fatigue failure was evaluated using an FE model of a custom pelvic implant with total hip replacement. The applied hip contact forces in the FE model were estimated at two locations in a gait cycle. For each of the nine screws in the custom implant FE model, likelihood of screw pullout failure was predicted using maximum screw axial force, while likelihood of screw fatigue failure was predicted using maximum von Mises stress. Results: The three iterative physics-based modeling methods and the non-iterative Abaqus BL-CL method produced nearly identical predictions for likelihood of screw pullout and fatigue failure, while the other two built-in Abaqus modeling methods yielded vastly different predictions. However, the Abaqus BL-CL method required the least computation time, largely because an iterative process was not needed to induce specified screw pretension forces. Of the three iterative methods, FOR required the fewest iterations and thus the least computation time. Discussion: These findings suggest that the BL-CL screw modeling method is the best option when Abaqus is used for predicting screw pullout and fatigue failure in custom pelvis prostheses, while the iterative physics-based FOR method is the best option if FE software other than Abaqus is used.

Introduction: Surgical planning and custom prosthesis design for pelvic cancer patients are challenging due to the unique clinical characteristics of each patient and the significant amount of pelvic bone and hip musculature often removed. Limb-sparing internal hemipelvectomy surgery with custom prosthesis reconstruction has become a viable option for this patient population. However, little is known about how post-surgery walking function and neural control change from pre-surgery conditions. Methods: This case study combined comprehensive walking data (video motion capture, ground reaction, and electromyography) with personalized neuromusculoskeletal computer models to provide a thorough assessment of pre- to post-surgery changes in walking function (ground reactions, joint motions, and joint moments) and neural control (muscle synergies) for a single pelvic sarcoma patient who received internal hemipelvectomy surgery with custom prosthesis reconstruction. Pre- and post-surgery walking function and neural control were quantified using pre- and post-surgery neuromusculoskeletal models, respectively, whose pelvic anatomy, joint functional axes, muscle-tendon properties, and muscle synergy controls were personalized using the participant’s pre-and post-surgery walking and imaging data. For the post-surgery model, virtual surgery was performed to emulate the implemented surgical decisions, including removal of hip muscles and implantation of a custom prosthesis with total hip replacement. Results: The participant’s post-surgery walking function was marked by a slower self-selected walking speed coupled with several compensatory mechanisms necessitated by lost or impaired hip muscle function, while the participant’s post-surgery neural control demonstrated a dramatic change in coordination strategy (as evidenced by modified time-invariant synergy vectors) with little change in recruitment timing (as evidenced by conserved time-varying synergy activations). Furthermore, the participant’s post-surgery muscle activations were fitted accurately using his pre-surgery synergy activations but fitted poorly using his pre-surgery synergy vectors. Discussion: These results provide valuable information about which aspects of post-surgery walking function could potentially be improved through modifications to surgical decisions, custom prosthesis design, or rehabilitation protocol, as well as how computational simulations could be formulated to predict post-surgery walking function reliably given a patient’s pre-surgery walking data and the planned surgical decisions and custom prosthesis design.