High-risk Extremity Research Articles

Does topical vancomycin prevent fracture-related infections in closed fractures undergoing open reduction and internal fixation? A randomised controlled trial

PurposeThe role of topical vancomycin in fracture-related infection (FRI) is debatable. Very few studies have reported their efficacy in open and high-risk extremity fractures. This study aimed to assess topical vancomycin's role in reducing FRI in closed fractures undergoing open surgical intervention with an implant. MethodsThis prospective randomized cohort study was carried out between February 2021 to January 2022. Patients with isolated closed fractures, who were planned for open reduction and internal fixation within 2 weeks from the time of injury were included for this study. The data collected included age, gender, socioeconomic status, mechanism of injury, diagnosis, Tscherne classification, and time interval to take up for surgery. Patients were randomized into the intervention and control groups using the block randomization technique. The control group received only systemic antibiotic prophylaxis, whereas the intervention group received topical application of vancomycin powder in the surgical wound alongside systemic antibiotic prophylaxis. The primary outcome measure was the incidence of FRI among these individuals. Clinical and radiological findings and culture reports (in cases with infection) were recorded during the post-operative period and at 6 weeks of follow-up. All relevant statistical calculations were done using STATA statistical/data analysis-parallel edition version 16.0 (StataCorp LLC). The quantitative variables like age and duration of the surgery were assessed for normalcy by Shapiro-Wilk W test. An independent samples t-test with equal variances was applied to the age data. Fisher's exact test was used for the analysis of the primary outcome measure (presence of FRI following surgery), and “Risk of FRI” and “Risk difference” between the 2 groups was calculated. The strength of the association between qualitative variables was assessed using the Fisher's exact and Chi-square tests, respectively. ResultsThere were 88 patients included in this study. No statistical significance was found about FRI between both groups (p = 0.494). At 6 weeks following surgery, no incidence of infection was observed in the intervention group. Two infections (4.5%) were found in the control group, with positive cultures reported in one of them but none in the treatment group. Radiologically, 15.9% of patients in the control group showed lysis around the implant compared to 2.3% in the intervention group. Impaired fracture healing was observed in 22.7% of patients in the intervention group compared to 15.9% in the control group. ConclusionApplying topical vancomycin in closed fractures undergoing open reduction and internal fixation does not significantly reduce the incidence of FRI until the end of 6 weeks following surgery.

Preoperative radiation therapy increases adherence in patients with high-risk extremity soft tissue sarcoma

BackgroundSurgery and radiation therapy remain the standard of care for patients with high-grade extremity soft tissue sarcoma that are >5 cm. Radiation therapy is time and labor-intensive for patients, and social determinants of health may affect adherence. The aim of this study was to define demographic, clinical, and treatment factors associated with the completion of radiation therapy and determine if preoperative radiation therapy improved adherence compared to postoperative radiation therapy. MethodsThe cohort included patients in the National Cancer Database with high-grade extremity soft tissue sarcoma >5 cm without nodal or distant metastases who received limb-sparing surgery and radiation therapy with microscopically negative R0 margins. Multivariable logistic regression analyses identified factors associated with radiation therapy sequencing and adherence (defined as completion of 50 Gy preoperative radiation therapy or at least 60 Gy postoperative radiation therapy). A multivariable Cox Proportional Hazards model assessed overall survival. ResultsAmong 2,145 patients, 47.1% received preoperative radiation therapy (n = 1,010), and 52.9% (n = 1135) received postoperative radiation therapy. A greater proportion of patients treated with preoperative (77.2%) versus postoperative radiation therapy (64.9%, P < .0001) received the recommended dose. More patients with private insurance (49.8% vs 35.3% Medicaid vs 44.9% Medicare, P = .011) and patients treated at an academic medical center (52.6% vs 47.4%, P < .001) received preoperative radiation therapy. Patients who received preoperative radiation therapy had lower odds of receiving insufficient doses of radiation therapy (odds ratio 0.34 [95% CI 0.27–0.47]). Neither radiation therapy adherence nor sequencing were independent predictors of overall survival. ConclusionsPatients who received preoperative radiation therapy were more likely to complete therapy and receive an optimal dose than patients treated with postoperative radiation therapy. Preoperative radiation therapy improves adherence and should be widely considered in patients with high-grade extremity soft tissue sarcoma, particularly in patients at risk for not completing therapy.

National evaluation of patterns and predictors of underuse of multimodal therapy for high-risk extremity soft tissue sarcoma

BackgroundTreatment of high-risk extremity soft tissue sarcomas remains widely varied. Despite growing support for a multimodal approach for treatment of these rare and aggressive neoplasms, its dissemination remains underused. This national study aimed to evaluate variations in treatment patterns and uncover factors predictive of underuse of multimodal therapy in high-risk extremity soft tissue sarcomas. MethodsThe 2010 to 2015 National Cancer Database was used to evaluate trends in 3 common treatment patterns: surgery alone, surgery + adjuvant therapy, and neoadjuvant therapy + surgery. Demographic-, sarcoma-, hospital-, and treatment-level factors of 6,725 surgically treated patients with stage II or III intermediate- to high-grade extremity soft tissue sarcomas were evaluated by types of treatment modality. Stepwise multivariable logistic regression was performed to identify factors predictive of each treatment modality. ResultsWhen compared to surgery alone (34.6%) and adjuvant therapy (41.2%), use of neoadjuvant therapy + surgery for high-risk extremity soft tissue sarcomas remained low (25.3%). However, time trend analysis demonstrated that neoadjuvant therapy + surgery has significantly increased by 7% per year, whereas surgery alone decreased by 4% every year (P < .05 for both). Factors predictive of surgery alone were older age, nonprivate insurance, increasing travel distance, and multimorbidity (P < .05). Conversely, factors associated with neoadjuvant therapy + surgery were private insurance, higher education, and care at academic or high-volume institutions (for all, P < .05). Tumor-related factors predictive for neoadjuvant therapy + surgery included size <5 cm and higher-grade tumors (P < .05). ConclusionAdoption of multimodality therapy for high-risk extremity soft tissue sarcomas remains low and gradual in the United States. Dissemination of multimodality therapy will require attention to access and hospital factors to maximize these therapies for high-risk extremity soft tissue sarcomas.

A Population-based Analysis of Lymph Node Metastasis in Extremity Soft Tissue Sarcoma: An Update

BackgroundSoft tissue sarcomas (STSs) are mesenchymal tumors that may rarely metastasize to lymph nodes. This investigation sought to evaluate regional lymph node metastasis (RLNM) in extremity STS using a national cohort. Materials and methodsThis study was a retrospective review of the Surveillance, Epidemiology, and End Results database from 1975 to 2016. A Cox proportional hazards model was used to identify prognostic factors associated with disease-specific survival (DSS). ResultsRLNM was present in 3.7% (n = 547) of extremity STS. The rate of RLNM was highest in rhabdomyosarcoma (26.7%), clear cell sarcoma (18.8%), epithelioid sarcoma (14.5%), angiosarcoma (8.1%), spindle cell sarcoma (5.0%), and synovial sarcoma (3.2%). The 5-year DSS probability without RLNM was 69% (standard error: 1.3%) compared to 26% (standard error: 3.6%) with RLNM (P < 0.001). For the historically high-risk extremity STS, advanced age (hazard ratio (HR), 1.036; 95% confidence interval (CI), 1.0-1.04; P < 0.001), higher grade tumors (HR, 1.979; 95% CI, 1.3-3.0; P < 0.001), tumor size greater than 10 cm (HR, 1.892; 95% CI, 1.3-2.7; P < 0.001), primary site surgery (HR, 0.529; 95% CI, 0.3-0.8; P = 0.006), distant metastasis (HR, 4.585; 95% CI, 3.0-6.8; P < 0.001), and RLNM (HR, 2.153; 95% CI, 1.3-3.5; P = 0.003) were each independent disease-specific prognostic factors. ConclusionsThe prognosis of RLNM in historically high-risk extremity STS is poor with a 5-year DSS of 26%. These data support a staging system of STS inclusive of nodal involvement and contribute to the growing body of evidence that characterizes the rates of RLNM in STS.

Perioperative treatment of soft-tissue sarcoma

SummaryThe standard treatment of high-risk localized extremity and trunk soft-tissue sarcoma is wide local excision and radiation therapy, which can be delivered pre- or postoperatively. Improved care for sarcoma patients at expert centres with multidisciplinary tumour boards, specialized pathologists, surgeons, radio-oncologists, and medical oncologists, according to national or international guidelines, has improved outcomes. Yet, a substantial number of patients will experience disease recurrence with metastatic spread and ultimately die from their disease. In many solid tumours neo/adjuvant chemotherapy has become an accepted standard treatment, whereas in soft-tissue sarcoma discussions on the use of cytotoxic therapy in localized and resectable disease are ongoing. Some centres demonstrated the feasibility and now treat with concomitant neoadjuvant chemoradiotherapy as standard. Others argue that treatments should be given in the order of the accompanying evidence (surgery → radiotherapy → chemotherapy), which does not take biology of the disease into account and probably attempts to simplify complex decision making processes. It is important to enhance our ability to identify patients at highest risk of recurrence, and to generate data and develop tools to predict which patients will benefit from neo/adjuvant systemic therapy most.

Does the addition of chemotherapy to neoadjuvant radiotherapy impact survival in high-risk extremity and trunk soft tissue sarcoma?

11054 Background: Large, high-grade extremity/trunk (ET) non-rhabdomyosarcoma soft-tissue sarcoma (STS) is at high risk for distant recurrence and death. The integration of chemotherapy (C) to standard of care neoadjuvant radiotherapy (RT) remains controversial, even for these patients. This study examines the impact of adding C to neoadjuvant RT on overall survival (OS) in high risk ET-STS. Methods: The National Cancer Data Base (NCDB) was queried for patients ≥18 years with high risk (≥5 cm + high grade) non-rhabdomyosarcoma ET-STS (WHO histology) who received neoadjuvant RT and limb sparing surgery from 2006-2014. Patients were next stratified based upon receipt of C (RT and CRT cohorts). Overall survival (OS) for RT vs CRT cohorts was analyzed using the Kaplan-Meier (KM) method, log-rank test, and Cox proportional hazards models. Propensity score-matched analysis (PSM) was employed to account for potential treatment selection bias between cohorts. Results: A total of 848 (71.1%) and 344 (28.9%) patients received RT and CRT, respectively. Patient cohorts were well-balanced except for the CRT cohort having higher rates of treatment in the West (22.1% vs 10.6%) &amp; Midwest (28.3% vs 22.7%), Charlson-Deyo [CD] score 0 vs ≥1 (85.5% vs 79.4%), younger age (≤50) (45.9% vs 21.7%), synovial sarcoma histology (18.9% vs 3.2%), earlier year of diagnosis (2006-2010) (39.5% vs 32.3%), and positive lymphovascular invasion (2.0 vs 1.51%), (p &lt; 0.05 each). The KM 5-year OS was significantly higher in the CRT vs RT cohort: 69.2% vs 58.1% on univariate (p &lt; 0.0001) and multivariate analysis (Hazard Ratio [HR]: 0.66; 95% Confidence Interval [CI]: 0.52-0.85; p = 0.001) even after adjusting for age, race, income, CD score, histology, tumor size, tumor grade, and primary site (lower extremity; upper extremity; trunk). PSM identified evenly matched cohorts of 300 patients each with respect to age, income, CD score, histology, grade, tumor size, and primary site. The addition of neoadjuvant C remained prognostic for OS on PSM (HR: 0.74 [0.56-0.99], p = 0.042). Conclusions: The addition of C to neoadjuvant RT was associated with improved OS in patients with high risk non-rhabdomyosarcoma ET-STS in the NCDB. These hypothesis generating results support prospective evaluation.

Regional deep hyperthermia: quantitative evaluation of predicted and direct measured temperature distributions in patients with high-risk extremity soft-tissue sarcoma

Background: Temperature distributions resulting from hyperthermia treatment of patients with high-risk soft-tissue sarcoma (STS) were quantitatively evaluated and globally compared with thermal simulations performed by a treatment planning system. The aim was to test whether the treatment planning system was able to predict correct temperature distributions.Methods: Five patients underwent computed tomography (CT) fluoroscopy-guided placement of tumor catheters used for the interstitial temperature measurements. For the simulations, five 3 D patient models were reconstructed by segmenting the patient CT datasets into different tissues. The measured and simulated data were evaluated by calculating the temperature change (), T90, T50, T20, Tmean, Tmin and Tmax, as well as the 90th percentile thermal dose (CEM43T90). In order to measure the agreement between both methods quantitatively, the Bland–Altman analysis was applied.Results: The absolute difference between measured and simulated temperatures were found to be 2°, 6°, 1°, 4°, 5° and 4 °C on average for Tmin, Tmax, T90, T50, T20 and Tmean, respectively. Furthermore, the thermal simulations exhibited relatively higher thermal dose compared to those that were measured. Finally, the results of the Bland–Altman analysis showed that the mean difference between both methods was above 2 °C which is considered to be clinically unacceptable.Conclusion: Given the current practical limitations on resolution of calculation grid, tissue properties, and perfusion information, the software SigmaHyperPlan™ is incapable to produce thermal simulations with sufficient correlation to typically heterogeneous tissue temperatures to be useful for clinical treatment planning.

1614PD - A phase II study of preoperative chemoradiation plus sorafenib (S) for high-risk extremity soft tissue sarcomas (STS)

1614PD - A phase II study of preoperative chemoradiation plus sorafenib (S) for high-risk extremity soft tissue sarcomas (STS)

The sarculator predicted risk of distant metastasis and overall survival in patients with high-risk soft tissue sarcoma treated with perioperative chemotherapy in a randomised controlled trial

Patients with high-risk extremity and trunk wall soft tissue sarcoma (STS, i.e. high malignancy grade and size > 5cm) have a wide survival range depending on histologic subtype and size. The Sarculator is a freely online-available accurate prognostic nomogram for patients with STS that improves current prognostic staging. We tested this tool for stratifying incidence of distant metastasis (DM) and overall survival (OS) rates in patients with high-risk STS enrolled in a randomised controlled trial (RCT) investigating neoadjuvant/adjuvant chemotherapy.

Neoadjuvant Chemotherapy, Concurrent Chemoradiation, and Adjuvant Chemotherapy for High-Risk Extremity Soft Tissue Sarcoma.

Standard treatment of large intermediate- and high-grade extremity soft tissue sarcoma (ESTS) typically includes wide excision and radiation therapy. Many patients do well with this approach, but for those with unfavorable features, risk for distant recurrence and, ultimately, mortality can exceed 50%. Unfortunately, universally accepted data elucidating effective treatments to prevent recurrences and improve survival for such high-risk patients are lacking. Accordingly, opinions about the appropriate role of systemic therapy for patients with high-risk localized ESTS vary. This article reviews the current literature pertaining to neoadjuvant chemotherapy, concurrent chemoradiation, and adjuvant chemotherapy for high-risk ESTS. All of these approaches are feasible and reasonable to consider. Ultimately, the decision to incorporate chemotherapy into the treatment regimen is best reached by discussion among an experienced multidisciplinary sarcoma team and should be tailored to the individual patient risk profile.

Myxoid liposarcoma: local relapse and metastatic pattern in 43 patients

BackgroundLiposarcomas are the second most common type of soft tissue sarcomas, 30–50% of these are of myxoid subtype. The aim of this retrospective study was to analyze the local control rate, the metastatic pattern and survival of patients in a consecutive single-institution series.MethodsFrom 1983 to 2015, 43 patients with myxoid liposarcoma of the extremities and trunk wall underwent resections. The margin was defined as R0 (wide) or R1 (marginal). Patients were followed for evidence of local recurrence or distant metastasis. Overall and recurrence-free survival was calculated.ResultsThe mean age was 48.6 years. The lower extremity was involved in 40 cases, the mean tumour size was 12 cm. In 31 cases a wide and in 12 cases a marginal resection was performed. Grading was G1 in 14, G2 in 25 and G3 in 4 cases.Nine patient died in follow-up, 4 of them with metastatic disease, all nonpulmonary. 5-year local recurrence (LR) free survival was 82%. 4 (9.3%) patients developed LR (all R1). Overall survival (OS) was 81% after 5 and 72% after 10 years. In multivariate analysis age and Grading proved to be significant on OS. According to univariate analysis, only age over 48 years and distant metastasis had a significant impact on overall survival.ConclusionsPatients with myxoid liposarcomas have a good prognosis. Myxoid liposarcoma has a distinct pattern of nonpulmonary metastatic disease. Therefore, patients with high-risk extremity myxoid liposarcoma should undergo imaging studies of the chest, abdomen, spine and pelvis as part of their staging and follow-up examinations preferably with whole body MRI, or CT scans and MRI of the spine and pelvic region for detection of suspected metastatic disease.

Neoadjuvant chemotherapy in localised soft-tissue sarcomas: where do we go from here?

In The Lancet Oncology, Alessandro Gronchi and colleagues report a phase 3 trial 1 Gronchi A Ferrari S Quagliuolo V et al. Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial. Lancet Oncol. 2017; 18: 812-822 Summary Full Text Full Text PDF PubMed Scopus (292) Google Scholar randomly assigning 287 patients with localised, high-risk extremity and trunk wall soft-tissue sarcomas to receive three cycles of histotype-tailored chemotherapy versus a standard control of full-dose chemotherapy with epirubicin plus ifosfamide. With a median follow-up of 12·3 months (IQR 2·75–28·20), the trial was closed prematurely after the third interim analysis for futility because superiority for the histotype-tailored chemotherapy group was not to be expected for both the primary endpoint disease-free survival and the secondary endpoint overall survival. Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trialIn a population of patients with high-risk soft-tissue sarcoma, we did not show any benefit of a neoadjuvant histotype-tailored chemotherapy regimen over the standard chemotherapy regimen. The benefit seen with the standard chemotherapy regimen suggests that this benefit might be the added value of neoadjuvant chemotherapy itself in patients with high-risk soft-tissue sarcoma. Full-Text PDF

Neoadjuvant sequential chemoradiotherapy versus radiotherapy alone for treatment of high-risk extremity soft tissue sarcoma: a single-institution experience.

Aim of the studyPatients with large and high-grade extremity soft-tissue sarcoma are at significant risk for distant metastasis and sarcoma-related death. There is no randomized trial comparing chemoradiotherapy to radiotherapy in the neoadjuvant setting for high risk extremity soft-tissue sarcoma. The aim of this study is to evaluate the outcomes of patients treated with two different modalities (neoadjuvant sequential chemoradiotherapy vs. radiotherapy alone) in a single center.Material and methodsData of 67 patients were analyzed retrospectively. Thirty-four patients received neoadjuvant sequential chemoradiotherapy (2–3 cycles of doxorubicin (75 mg/m2) and ifosfamide (6 g/m2) followed by radiotherapy of 28 Grays (Gy) administered as 8 fractions of 35 Gy) and 33 patients received radiotherapy alone. R0 resection rates and 3-year survival estimates were evaluated.ResultsMedian follow-up time was 37 months. The estimated 3-year overall and disease-free survival rates for the whole patient group were 79% (95% CI: 67.0–86.4) and 57.9% (95% CI: 46.3–69.0), respectively. The most common side effects were nausea and leucopenia. Three-year overall, disease-free, local recurrence-free and distant recurrence-free survival rates did not differ significantly. All patients except one underwent wide excision or compartmental resection. R0 resection rate for the whole patient group was 92.5% (n = 62). Sites of progression were similar across both treatment arms.ConclusionsPreoperative hypofractionated radiotherapy alone or sequentially with chemotherapy result in high rates of limb salvage and acceptable toxicity. Our study results did not show a statistically significant treatment effect regarding survival and patterns of failure.

Long-Term Results of Neoadjuvant Chemotherapy and Preoperative Hypofractionated Radiation Therapy in the Management of High-Risk Extremity Sarcomas

Long-Term Results of Neoadjuvant Chemotherapy and Preoperative Hypofractionated Radiation Therapy in the Management of High-Risk Extremity Sarcomas

CORR Insights(®): Do Surgical Margins Affect Local Recurrence and Survival in Extremity, Nonmetastatic, High-grade Osteosarcoma?

W hile there is certainly no consensus as to how wide a margin of resection should be [1], surgeons agree that oncologic outcome must take priority over functional results when performing surgery for patients with osteosarcoma. The debate begins with the understanding that the patient’s survival can be affected by the hands of the surgeon, despite the enormous benefits of chemotherapy and the confusing effects of local recurrence on survival. In a study of patients with locally recurrent osteosarcoma published almost a decade ago by Nathan et al. [5], it is noted that six of 13 patients with positive margins and 14 of 389 with negative margins developed local recurrence. The strongest correlation with poor survival was local recurrence within the first year after primary resection [5]. It would seem from this study alone that positive margins and local recurrence should be avoided at all cost. However, a study by Rougraff and colleagues [6] found that despite having no local recurrences after hip disarticulation for osteosarcoma of the femur, there was no difference in duration of survival or of disease-free survival when compared to patients undergoing limb-salvage surgery or above knee amputations in spite of higher local recurrence rates in these groups. One of the reasons for this, the authors speculate, is that the small percentage difference in local control, confounded by nearly 50% of the patients dying, represents such a small discrepancy that it did not affect the overall survival statistics. The literature can be confusing when considering margins, local recurrence, and survival. Readers should consider how words like ‘‘only’’ or ‘‘small’’ may influence decisions about margins. A study by Kong and colleagues [3], with the title, ‘‘Local Recurrence Has Only a Small Effect on Survival in High-risk Extremity Osteosarcoma’’ might allow us as surgeons to let down our guard a bit, relax, or push the envelope when the margin is ‘‘close.’’ In the current study, Bertrand and his colleagues showed that after controlling for relevant confounding variables, the presence of a positive This CORR Insights is a commentary on the article ‘‘Do Surgical Margins Affect Local Recurrence and Survival in Extremity, Nonmetastatic, High-grade Osteosarcoma?’’ by Bertrand and colleagues available at: DOI: 10.1007/s11999-015-4359-x. The author certifies that he, or any member of his immediate family, has no funding or commercial associations (eg, consultancies, stock ownership, equity interest, patent/ licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research editors and board members are on file with the publication and can be viewed on request. The opinions expressed are those of the writers, and do not reflect the opinion or policy of CORR or The Association of Bone and Joint Surgeons. This CORR Insights comment refers to the article available at DOI: 10.1007/s11999-0154359-x. K. S. Beebe MD (&) Musculoskeletal Oncology and Limb Salvage, Rutgers-New Jersey Medical School, 140 Bergen St., Newark, NJ 07101-1709, USA e-mail: kathleen.beebe@rutgers.edu CORR Insights Published online: 20 June 2015 The Association of Bone and Joint Surgeons1 2015

Phase I study of neoadjuvant gemcitabine combined with radiation therapy for patients with high-risk extremity and trunk soft tissue sarcomas.

10571 Background: Gemcitabine is used in many solid tumors as a sensitizer for radiation therapy. We sought to determine the maximum tolerated dose (MTD) of gemcitabine when given concurrently with preoperative external beam radiation (EBRT) for patients with high-risk extremity and trunk soft tissue sarcoma (STS). Methods: Fifty gray of EBRT was given in 25 daily fractions over 5 weeks. Gemcitabine was administered on days 1, 8, 22, 29, 43, and 50 at a starting dose of 400 mg/m2. Dose escalation between cohorts by increments of 100 mg/m2 was done using a toxicity severity weight method (TSWM), incorporating 6 different toxicities (Table). This method is a Bayesian procedure that repeatedly assesses the data to find the drug dose having a posterior total toxicity burden closest to a predetermined clinician-defined target (Bekele and Thall, 2004). Clinicopathologic and outcome data were also collected. Results: Thirty-six patients completed the study. Mean tumor size was 6.3 cm and 67% of patients had high...

Limb-sparing management with surgical resection, external-beam and intraoperative electron-beam radiation therapy boost for patients with primary soft tissue sarcoma of the extremity

A joint analysis of data from three contributing centres within the intraoperative electron-beam radiation therapy (IOERT) Spanish program was performed to investigate the main contributions of IORT to the multidisciplinary treatment of high-risk extremity soft tissue sarcoma (STS). Patients with an histologic diagnosis of primary extremity STS, with absence of distant metastases, undergoing limb-sparing surgery with radical intent, external beam radiotherapy (median dose 45 Gy) and IOERT (median dose 12.5 Gy) were considered eligible for participation in this study. From 1986-2012, a total of 159 patients were analysed in the study from three Spanish institutions. With a median follow-up time of 53 months (range 4-316 years), 5-year local control (LC) was 82 %. The 5-year IOERT in-field control, disease-free survival (DFS) and overall survival (OS) were 86, 62 and 72 %, respectively. On multivariate analysis, only microscopically involved margin (R1) resection status retained significance in relation to LC (HR 5.20, p < 0.001). With regard to IOERT in-field control, incomplete resection (HR 4.88, p = 0.001) and higher IOERT dose (≥ 12.5 Gy; HR 0.32, p = 0.02) retained a significant association in multivariate analysis. From this joint analysis emerges the fact that an IOERT dose ≥ 12.5 Gy increases the rate of IOERT in-field control, but DFS remains modest, given the high risk of distant metastases. Intensified local treatment needs to be tested in the context of more efficient concurrent, neo- and adjuvant systemic therapy.

Phase I Trial of Preoperative Chemoradiation plus Sorafenib for High-Risk Extremity Soft Tissue Sarcomas with Dynamic Contrast-Enhanced MRI Correlates

We conducted a phase I trial of the addition of sorafenib to a chemoradiotherapy regimen in patients with high-risk (intermediate/high grade, >5 cm) extremity soft tissue sarcoma undergoing limb salvage surgery. We conducted a correlative study of quantitative dynamic contrast-enhanced MRI (DCE-MRI) to assess response to treatment. Patients were treated at increasing dose levels of sorafenib (200 mg daily, 400 mg daily, 400 mg twice daily) initiated 14 days before three preoperative and three postoperative cycles of epirubicin/ifosfamide. Radiation (28 Gy) was administered during cycle 2 with epirubicin omitted. The primary objective was to determine the maximum tolerated dose (MTD) of sorafenib. DCE-MRI was conducted at baseline, after 2 weeks of sorafenib, and before surgery. The imaging data were subjected to quantitative pharmacokinetic analyses. Eighteen subjects were enrolled, of which 16 were evaluable. The MTD of sorafenib was 400 mg daily. Common grade 3-4 adverse events included neutropenia (94%), hypophosphatemia (75%), anemia (69%), thrombocytopenia (50%), and neutropenic fever/infection (50%). Of note, 38% developed wound complications requiring surgical intervention. The rate of ≥95% histopathologic tumor necrosis was 44%. Changes in DCE-MRI biomarker ΔK(trans) after 2 weeks of sorafenib correlated with histologic response (R(2) = 0.67, P = 0.012) at surgery. The addition of sorafenib to preoperative chemoradiotherapy is feasible and warrants further investigation in a larger trial. DCE-MRI detected changes in tumor perfusion after 2 weeks of sorafenib and may be a minimally invasive tool for rapid assessment of drug effect in soft tissue sarcoma.

Highlights of This Issue

The CD20 antigen is an effective target in &gt;90% of B-cell lymphomas. To achieve more rapid, higher contrast imaging of B-cells, compared to the full antibody, Natarajan and colleagues developed a novel 10 kDa anti-CD20 fibronectin (FN3) binder to monitor therapy. 64Cu-FN3CD20 was evaluated in a humanized CD20 transgenic mouse model for PET imaging. This PET tracer shows high specificity and exhibited a target tissue-to-blood ratio of 13-fold at 4 h. At 4h, 64Cu-FN3CD20 shows ten-fold greater signal-to-background than the 64Cu-rituximab antibody radiotracer. Thus, 64Cu-FN3CD20 tracer shows significant clinical promise for imaging early after tracer injection of lymphoma patients.The failure of conventional chemotherapeutic agents on survival of patients with pancreatic cancer highlights an urgent need for novel treatment strategies. STAT3 plays a critical role in pancreatic cancer initiation and progression and represents a novel therapeutic target. However, STAT3 occupies a point of convergence for many signaling pathways; blockade of existed upstream signaling to STAT3 activation are not sufficient to abrogate STAT3 activation. This study identified HAb18G/CD147 as a novel upstream activator in STAT3-mediated pancreatic tumor development by forming signaling complex with CD44s. Furthermore, we showed that pancreatic cancer patients with high co-expression of HAb18G/CD147-CD44s-STAT3 had poor prognosis. This information is valuable for a better understanding of the relationship between inflammation and pancreatic cancer initiation and progression induced by STAT3. Our results also suggest HAb18G/CD147 as a novel therapeutic target for highly aggressive pancreatic cancer and as a surrogate marker in clinical trials of molecular therapy targeting STAT3.PDGFR, VEGF, and VEGF-R are overexpressed in soft tissue sarcomas and VEGF-R targeted therapies have shown activity in advanced disease. To explore the role of an antiangiogenic agent combined with chemoradiotherapy in patients with high-risk extremity soft tissue sarcomas, Meyer and colleagues designed a phase I trial of sorafenib in combination with epirubicin, ifosfamide, and hypofractionated radiation. The maximum tolerated dose of sorafenib was 400 mg daily. Dynamic contrast-enhanced MRI was investigated as an imaging modality to assess early response to therapy, which showed a correlation between the biomarker ΔKtrans and histologic necrosis at the time of surgery.The translation of preclinically validated biomarkers to the clinical setting to assess the activity of targeted therapy is of crucial importance for drug development. Yan and colleagues examined the impact of the catalytic Akt inhibitor GDC-0068 on preclinical models and derived a ten-biomarker set of Akt inhibition. The behavior of these biomarkers was tested in pre- and on-treatment tumor biopsies from patients treated with GDC-0068 and confirmed that GDC-0068 is biologically active at clinically achievable concentrations. The application of this approach may be useful for the clinical development of other targeted compounds.

Split Thickness Skin Grafts in High-Risk Extremity Wounds: Helpful or Heretical?

Split Thickness Skin Grafts in High-Risk Extremity Wounds: Helpful or Heretical?