Restoring walking ability in older adults with arm-in-arm gait training: study protocol for the AAGaTT randomized controlled trial.

CONTEXT: Falls are a significant problem among older adults. While balance and functional exercises have been shown to be effective, it remains unclear whether regular walking has specific effects on reducing the risk of falls. RATIONALE: Older people who fall frequently have impaired gait patterns. Recent studies have suggested using interpersonal synchronization: while walking arm-in-arm, an older person synchronizes steps with a younger person to reinstate a better gait pattern. This method of gait training may reduce the risk of falls. OBJECTIVE: The aim is to assess the efficacy of an arm-in-arm gait-training program in older people. DESIGN: The arm-in-arm gait training trial (AAGaTT) is a single-site, open label, two-arm, randomized controlled trial. PARTICIPANTS: We will enroll 66 dyads of older people and their younger "gait instructors". The older participants must be > 70 years old with adequate walking ability. They must have experienced a fall in the year prior to study entry. INTERVENTION: Dyads will walk an indoor course for 30 min either side-by-side without contact (control group) or arm-in-arm while synchronizing their gait (intervention group). The gait training will be repeated three times a week for four weeks. OUTCOMES: The main outcome will be the walking speed measured in five-minute walking trials performed at baseline and at the end of each intervention week (week 1 - week 4), and at week 7. Gait quality will be assessed using accelerometers. We will also assess perceived physical activity and health using questionnaires. Finally, we will monitor fall incidence over 18 months. We will evaluate whether outcomes are more improved in the intervention group compared to the control group. In addition, interviews will be conducted to assess the perception of the gait training. EXPECTED RESULTS: Recent advances in the neurophysiology of motor control have shown that synchronizing gait to external cues or to a human partner can increase the efficiency of gait training. The expected benefits of arm-in-arm gait training are: reduced risk of falls, safe treatment with no adverse effects, and high adherence. This gait training program could be a low-cost intervention with positive effects on the health and well-being of seniors. TRIAL REGISTRATION: ClinicalTrials.gov NCT05627453. Date of registration: 11.25.2022.

NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial.

BACKGROUND: Pathological complete response to preoperative treatment in adults with soft-tissue sarcoma can be achieved in only a few patients receiving radiotherapy. This phase 2-3 trial evaluated the safety and efficacy of the hafnium oxide (HfO2) nanoparticle NBTXR3 activated by radiotherapy versus radiotherapy alone as a pre-operative treatment in patients with locally advanced soft-tissue sarcoma. METHODS: Act.In.Sarc is a phase 2-3 randomised, multicentre, international trial. Adults (aged ≥18 years) with locally advanced soft-tissue sarcoma of the extremity or trunk wall, of any histological grade, and requiring preoperative radiotherapy were included. Patients had to have a WHO performance status of 0-2 and a life expectancy of at least 6 months. Patients were randomly assigned (1:1) by an interactive web response system to receive either NBTXR3 (volume corresponding to 10% of baseline tumour volume at a fixed concentration of 53·3 g/L) as a single intratumoural administration before preoperative external-beam radiotherapy (50 Gy in 25 fractions) or radiotherapy alone, followed by surgery. Randomisation was stratified by histological subtype (myxoid liposarcoma vs others). This was an open-label study. The primary endpoint was the proportion of patients with a pathological complete response, assessed by a central pathology review board following European Organisation for Research and Treatment of Cancer guidelines in the intention-to-treat population full analysis set. Safety analyses were done in all patients who received at least one puncture and injection of NBTXR3 or at least one dose of radiotherapy. This study is registered with ClinicalTrials.gov, number NCT02379845, and is ongoing for long-term follow-up, but recruitment is complete. FINDINGS: Between March 3, 2015, and Nov 21, 2017, 180 eligible patients were enrolled and randomly assigned and 179 started treatment: 89 in the NBTXR3 plus radiotherapy group and 90 in the radiotherapy alone group. Two patients in the NBTXR3 group and one patient in the radiotherapy group were excluded from the efficacy analysis because they were subsequently discovered to be ineligible; thus, a total of 176 patients were analysed for the primary endpoint in the intention-to-treat full analysis set (87 in the NBTXR3 group and 89 in the radiotherapy alone group). A pathological complete response was noted in 14 (16%) of 87 patients in the NBTXR3 group and seven (8%) of 89 in the radiotherapy alone group (p=0·044). In both treatment groups, the most common grade 3-4 treatment-emergent adverse event was postoperative wound complication (eight [9%] of 89 patients in the NBTXR3 group and eight [9%] of 90 in the radiotherapy alone group). The most common grade 3-4 adverse events related to NBTXR3 administration were injection site pain (four [4%] of 89) and hypotension (four [4%]) and the most common grade 3-4 radiotherapy-related adverse event was radiation skin injury in both groups (five [6%] of 89 in the NBTXR3 group and four [4%] of 90 in the radiotherapy alone group). The most common treatment-emergent grade 3-4 adverse event related to NBTXR3 was hypotension (six [7%] of 89 patients). Serious adverse events were observed in 35 (39%) of 89 patients in the NBTXR3 group and 27 (30%) of 90 patients in the radiotherapy alone group. No treatment-related deaths occurred. INTERPRETATION: This trial validates the mode of action of this new class of radioenhancer, which potentially opens a large field of clinical applications in soft-tissue sarcoma and possibly other cancers. FUNDING: Nanobiotix SA.

Brain Metastases and Place of Antiangiogenic Therapies in Alveolar Soft Part Sarcoma: A Retrospective Analysis of the French Sarcoma Group.

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare sarcoma characterized by a slow evolution, brain metastasis (BM), and resistance to doxorubicin. Antiangiogenic therapies (AAT) have shown clinical activity, but little is known about the optimal therapeutic strategy, specifically considering BM. SUBJECTS, MATERIALS, AND METHODS: We performed a retrospective analysis of all patients with ASPS treated in three referral centers of the French Sarcoma Group. We aimed to describe factors associated with overall survival (OS) and the impact of BM on outcome of patients treated by AAT. RESULTS: We identified 75 patients between 1971 and 2012 (median age = 23, range: 5-96 years). Median follow-up was 74 months. Patients with localized (n = 44, 59%) and metastatic (n = 31, 41%) diseases had a 10-year OS of 69% and 25%, respectively. Only surgical incomplete resection was associated with shorter OS in localized disease (hazard ratio [HR] = 5.2, 95% confidence interval [CI] 1.2-22.4, p = .02). Fifty-two (69%) patients developed lung metastasis (LM; baseline: n = 31, [41%]; de novo: n = 21, [28%]). Thirteen patients developed BM, all occurring after LM. Tumor size ≥5 cm was associated with poorer BM-free survival (HR = 8.4, 95% CI 2.1-33.9, p = .002). Median OS post-BM was 17 months (95% CI 15 to not assessable). Overall, 12 patients were treated with AAT (sunitinib n = 10): 5 patients had BM and achieved poor outcomes compared with patients without, with median progression-free-survivals of 2 versus 11 months, respectively. CONCLUSION: Baseline larger tumors were associated with increased risk of brain metastasis in patients with ASPS. Patients with BM seem to have little benefit from AAT, suggesting the need to develop antineoplastic agents with high central nervous system penetrance in this setting. IMPLICATIONS FOR PRACTICE: Alveolar soft part sarcoma (ASPS) is an extremely rare subtype of sarcoma that is particularly resistant to conventional therapies. Antiangiogenic therapies (AAT) have shown promising results. However, patients with ASPS still die of tumor evolution. This study highlights the prognostic shift induced by brain metastasis (BM), identifying this event as a major contributor to the death of patients with ASPS, and observes a striking lack of effectiveness of AAT in patients who had previously developed BM. This observation is of interest for the therapeutic development in ASPS, highlighting the need to develop strategies dedicated to BM, such as radiosurgery or high-central nervous system penetrance tyrosine kinase inhibitors.

Breast desmoid tumor management in France: toward a new strategy.

PURPOSE: Desmoid tumors (DTs) are rare tumors that originate from myofibroblastic tissue. Recently, initial wait and see was recommended (ESMO guidelines Ann Oncol 2017) in the most frequent locations. This study investigates the outcome of breast desmoid tumor (BDT) according to the initial strategy. METHOD: Data from all consecutive patients treated from a BDT in four referral centers were collected. Only intra-mammary desmoid tumors were included. A pathological review and a molecular analysis (CTNNB1 gene mutation) were performed (National re-reading network of sarcomas-RRePS). Patients were grouped according to initial strategy: surgery group (SG) and active surveillance group (ASG). RESULTS: A total of 63 patients (61 women, 2 men) met the inclusion criteria. Median age was 50 years (16-86). CTNNB1 mutation was found in 61% (n = 36). SG included 46 patients (73%) (41 partial mastectomies, 2 mastectomies, and 3 mastectomies associated to parietectomies). Surgical margins were positive in 15 patients (33.3%). Median follow-up of SG was 24.9 (0.5-209) months; and 4 patients (8.7%) developed recurrence. ASG included 17 patients (27%). Their median follow-up was 42.2 (0-214) months, and 15 patients (88.2%) did not require any additional treatment. Six patients (35%) had a spontaneous regression, 9 patients (52%) were stable, and 2 patients presented a significant progression that was treated by partial mastectomy. CONCLUSION: This study supports an initial nonsurgical approach to BDTs followed by surgery based on tumor growth in select cases, which is consistent with current ESMO recommendations.

Genomic and transcriptomic comparison of post-radiation versus sporadic sarcomas.

Post-radiation sarcomas are rare secondary cancers arising from radiation therapies. To date, few genetic specificities have been described for such malignancies and the oncogenesis of sarcomas with complex genetics (both sporadic and post-radiation) remains largely misunderstood. We performed genomic and transcriptomic analyses on 77 post-radiation sarcomas using DNA-array and RNA sequencing. Consequently, we were able to investigate changes in copy number variations, transcriptome profiling, fusion gene expression, and mutational landscapes. We compare these data to a reference cohort of 93 sporadic sarcomas. At genomic level, similar chromosomal complexity was observed both in post-radiation and sporadic sarcomas with complex genetics. We found more frequent CDKN2A and CDKN2B (coding for p14/p16 and p15 proteins, respectively; at 9p21.3) losses in post-radiation (71%) than in sporadic tumors (39%; P = 6.92e-3). Among all detected fusion genes and punctual variations, few specificities were observed between these groups and such alterations are not able to drive a strong and specific oncogenesis. Recurrent MYC amplifications (96%) and KDR variants (8%) were detected in post-radiation angiosarcomas, in agreement with the literature. Transcriptomic analysis of such angiosarcomas revealed two distinct groups harboring different genomic imbalances (in particular gains of 17q24.2-17qter) with different clinical courses according to patient's vital status. Differential gene expression analysis permitted to focus on the immune response as a potential actor to tumor aggressiveness. Histochemistry validated a lower inflammation and lower immune infiltrate at tumor periphery for highly aggressive angiosarcomas. Our results provide new genomic and transcriptomic information about post-radiation sarcomas. The techniques we used (RNA-seq and DNA-arrays) did not highlight major differences in sarcomas with complex genetics depending on the radiation context, revealing similar patterns of transcriptomic profiles and chromosomal copy number variations. Additional characterizations, particularly whole genome sequencing, could measure changes in DNA following radiation therapy in such malignancies and may precise their oncogenesis.

Distal extremities soft tissue sarcomas: Are they so different from other limb localizations?

BACKGROUND AND OBJECTIVES: Soft tissue sarcoma localization in distal extremities (DESTS) of the limbs (hand/fingers, and foot/toes) is unusual. The literature is scarce about their behavior and this study was designed to assess their epidemiological characteristics, outcomes, and prognosis compared to other limb localizations (OLSTS). METHODS: From 1980 to 2010, adult DESTS and OLSTS in 22 centers were included. Demographics, tumor type, treatment modalities, and latest follow-up status were collected. Primary endpoints were overall survival and local/metastatic recurrence incidences. RESULTS: Two hundred five DESTS and 3001 OLSTS were included. The patients were younger, with more female and smaller tumors in DESTS. There were more clear cell/epithelioid sarcomas, synovial sarcomas, and myxoid liposarcomas vs more dedifferentiated liposarcomas in OLSTS. DESTS tumors were less irradiated and more often amputated (24.3% vs 3.4%). The five-year survival rate was 78.2% compared to 68.6% in OLSTS and after multivariate analysis, STS localization did not impact survival or local/metastatic recurrence. CONCLUSION: Though rare and smaller than other limb localizations, DESTS are to be considered as aggressive. Despite a higher amputation rate, the prognosis remains the same as in OLSTS. Limb sparing vs amputation should be carefully assessed in DESTS, especially if grade 3 or of a poor prognosis histological subtype.

Influencing walking behavior can increase the physical activity of patients with chronic pain hospitalized for multidisciplinary rehabilitation: an observational study.

BACKGROUND: Physical therapy and exercising are key components of biopsychosocial rehabilitation for chronic pain. Exercise helps reduce pain and improve physical functions. In addition, a high level of physical activity benefits quality of life and emotional well-being. However, the degree to which hospitalization for extensive rehabilitation effectively increases physical activity has not yet been studied. Therefore, we investigated the physical activity level and the walking behavior of inpatients with musculoskeletal pain. The objectives were 1) to compare physical activity level and walking with or without rehabilitation, 2) to evaluate whether pain site influences physical activity level, and 3) to measure the association between physical activity and pain-related interference with physical functioning. METHODS: During a rehabilitation stay, 272 inpatients with lower limb, spine, or upper limb pain wore an accelerometer over 1 week. We assessed the daily duration of the practice of moderate physical activity and walking. Weekend days, during which the participants went home (days off), were used as a reference for habitual activities. We also evaluated 93 patients before the hospitalization to validate the use of days off as a baseline. Pain interference was measured with the brief pain inventory questionnaire. Generalized linear mixed models analyzed the association between physical activity and walking levels, and 1) rehabilitation participation, 2) pain sites, and 3) pain interference. RESULTS: Weekend days during the stay have similar physical activity level as days measured before the stay (73 min / day at the clinic, versus 70 min / day at home). Rehabilitation days had significantly higher physical activity levels and walking durations than days off (+ 28 min [+ 37%] and + 32 min [+ 74%], respectively). Mixed models revealed 1) a negative association between physical activity and pain interference, and 2) no effect of pain sites. Overall, patients increased their physical activity level independently of reported pain interference. CONCLUSIONS: Despite their painful condition, the inpatients were able to engage themselves in a higher level of physical activity via increased participation in walking activities. We conclude that walking incentives can be a valid solution to help patients with chronic pain be more physically active.

Influence of single and dual tasks on gait stability and gait speed in the elderly : An explorative study.

BACKGROUND: Gait stability during dual tasks is important for elderly persons, especially for elderly individuals in need of care. A study was conducted to assess gait stability by using Lyapunov exponents (λS) during single task and dual task conditions in independently living elderly people (Go-Goes) and elderly people in need of care (No-Goes). MATERIAL AND METHODS: This study was conducted with 26 participants (average age 82 ± 9.4 years) who were allocated to the Go-Goes or No-Goes group. Outcomes were mediolateral and vertical Lyapunov exponents (λS) from accelerometer data and gait speed under single task and dual task conditions. RESULTS: In both groups significantly higher mediolateral and vertical Lyapunov exponent values as well as significantly lower walking speeds under dual task conditions were found in both groups. The effect sizes were small to moderate for mediolateral λS and large for vertical λS and these differences remained when the analyses were adjusted for walking speed. CONCLUSION: Elderly people showed lower gait stability and gait speed under dual task conditions compared to single task conditions.

Presentation and outcome of frequent and rare sarcoma histologic subtypes: A study of 10,262 patients with localized visceral/soft tissue sarcoma managed in reference centers.

BACKGROUND: The objective of this study was to describe characteristics at diagnosis and outcomes of adults with soft tissue sarcoma. METHODS: The authors conducted a retrospective multicenter study of 12,262 patients who were treated between January 1980 and 31 December 2013 in French Sarcoma Group centers and enrolled in the "Conticabase." Diagnoses were systematically reviewed by expert pathologists, and entities were classified according to the 2013 World Health Organization classification. Diagnostic characteristics, treatments, and outcomes are described for the entire cohort, for the subgroup of patients with translocation-related sarcomas, and for 9 different histologic subtypes. RESULTS: The results stressed the magnitude of heterogeneity among adult sarcomas. For example, compared with other sarcomas, translocation-related sarcomas (2143 tumors; 20.8%) were associated with a younger age at presentation (40.6 vs 60.0 years; P < .0001), a low rate of predisposing conditions (0.01% vs 22.3%; P < .0001), a higher rate of lymph node involvement (4.7% vs 1.3%; P < .0001), and a higher rate of synchronous metastasis (11.9% vs 6.7%; P < .001); and complete (R0) resection (41.6% vs 31.9%; P < .0001), receipt of (neo)adjuvant radiation therapy (62.6% vs 42.2%; P < .0001), and receipt of (neo)adjuvant chemotherapy (36.6% vs 22.3%; P < .0001) were significantly more frequent. Overall, translocation-related sarcomas were associated with a lower rate of local relapse (18.1% vs 26.0%; P < .0001) but a higher rate of metastatic relapse (42.0% vs 30.7%; P < .0001). CONCLUSIONS: Collaborative efforts are urgently needed to better assess the natural history and management options for every histologic subtype of sarcoma. Cancer 2018;124:1179-87. © 2017 American Cancer Society.

Evaluation of eight melanocytic and neural crest-associated markers in a well-characterised series of 124 malignant peripheral nerve sheath tumours (MPNST): useful to distinguish MPNST from melanoma?

AIMS: The diagnosis of malignant peripheral nerve sheath tumour (MPNST) may be challenging, especially in the sporadic setting. Owing to the lack of specific histological criteria, immunohistochemical and molecular diagnostic markers, several differential diagnoses must be considered, especially melanoma. Indeed, although S100 protein usually stains melanoma, other melanocytic markers are often negative, especially in spindle cell/desmoplastic types. This pattern of immunoreactivity resembles that of some nerve-derived tumours such as MPNST. Owing to their different clinical behaviours and therapeutic implications, accurate identification of these two different tumours is crucial. METHODS AND RESULTS: S100, SOX10, KBA62, MITF, HMB45, Melan-A, tyrosinase PNL2 and BRAF-V600E immunostaining was performed in a pathologically and genetically well-characterised cohort of primary MPNST (n = 124), including 66 (53%) NF1-associated tumours. Sox10 and KBA62 expression were found, respectively, in 102 (84%) and in 101 (83%) MPNST, whereas S100 was expressed in 64 cases (52%). We observed an increased loss of S100 with increasing histological grade (P = 0.0052). We found Melan-A expression in 14% (n = 17) of all MPNST, occurring in 82% (n = 14) of cases in an NF1 context. Six per cent (n = 8) of MPNST showed tyrosinase positivity, including seven (87%) NF1-associated. MITF expression was found in 10 (8%) MPNST. None expressed PNL2, HMB45 or BRAF-V600E. CONCLUSION: MPNST (in NF1 and a sporadic setting) can quite often be positive for Melan-A, tyrosinase and MITF. Pathologists should be cognisant of these exceptions to prevent confusion with melanoma.

Management of locoregional recurrence after radical resection of a primary nonmetastatic retroperitoneal soft tissue sarcoma: The Gustave Roussy experience.

BACKGROUND: Despite surgery, many patients experience locoregional recurrence (LR), the optimum treatment of which is still debated. METHODS: All 297 consecutive patients operated for a nonmetastatic primary retroperitoneal soft tissue sarcoma (RPS) between 1994 and 2017 were retrospectively analyzed to report our experience in treating LR. RESULTS: After a median follow-up of 97 months, 55 patients (19%) developed LR. The first site of recurrence was locoregional in 100% with associated peritoneal metastases in 45% and distant metastases in 5%. After LR treatment, the 1-, 3-, and 5-year overall survival (OS) rates were 71%, 46%, and 33%. Low tumor grade, disease-free interval above 24 months, exclusive LR, and well-differentiated liposarcoma were predictive of better OS. The treatment strategy (best supportive care, chemotherapy radiotherapy, and/or surgery) was not statistically significant. Fourteen patients underwent initial surveillance (strategic delay) for low-grade LR and eventually required treatment in 86% after a median delay of 20 months during which no patient developed distant metastases. CONCLUSIONS: The management of LR in RPS is complex. An initial surveillance may not alter survival in asymptomatic low-grade and slow-growing LR. An LR decision scheme is proposed.

Germline CDKN2A/P16INK4A mutations contribute to genetic determinism of sarcoma.

BACKGROUND: Sarcomas are rare mesenchymal malignancies whose pathogenesis is poorly understood; both environmental and genetic risk factors could contribute to their aetiology. METHODS AND RESULTS: We performed whole-exome sequencing (WES) in a familial aggregation of three individuals affected with soft-tissue sarcoma (STS) without TP53 mutation (Li-Fraumeni-like, LFL) and found a shared pathogenic mutation in CDKN2A tumour suppressor gene. We searched for individuals with sarcoma among 474 melanoma-prone families with a CDKN2A-/+ genotype and for CDKN2A mutations in 190 TP53-negative LFL families where the index case was a sarcoma. Including the initial family, eight independent sarcoma cases carried a germline mutation in the CDKN2A/p16INK4A gene. In five out of seven formalin-fixed paraffin-embedded sarcomas, heterozygosity was lost at germline CDKN2A mutations sites demonstrating complete loss of function. As sarcomas are rare in CDKN2A/p16INK4A carriers, we searched in constitutional WES of nine carriers for potential modifying rare variants and identified three in platelet-derived growth factor receptor (PDGFRA) gene. Molecular modelling showed that two never-described variants could impact the PDGFRA extracellular domain structure. CONCLUSION: Germline mutations in CDKN2A/P16INK4A, a gene known to predispose to hereditary melanoma, pancreatic cancer and tobacco-related cancers, account also for a subset of hereditary sarcoma. In addition, we identified PDGFRA as a candidate modifier gene.

Patterns of care and outcomes of patients with METAstatic soft tissue SARComa in a real-life setting: the METASARC observational study.

BACKGROUND: Well-designed observational studies of individuals with rare tumors are needed to improve patient care, clinical investigations, and the education of healthcare professionals. METHODS: The patterns of care, outcomes, and prognostic factors of a cohort of 2225 patients with metastatic soft tissue sarcomas who were diagnosed between 1990 and 2013 and documented in the prospectively maintained database of the French Sarcoma Group were analyzed. RESULTS: The median number of systemic treatments was 3 (range, 1-6); 27% of the patients did not receive any systemic treatment and 1054 (49%) patients underwent locoregional treatment of the metastasis. Half of the patients who underwent chemotherapy (n = 810) received an off-label drug. Leiomyosarcoma was associated with a significantly better outcome than the other histological subtypes. With the exception of leiomyosarcomas, the benefit of a greater than third-line regimen was very limited, with a median time to next treatment (TNT) and overall survival (OS) ranging between 2.3 and 3.7 months and 5.4 and 8.5 months, respectively. The TNT was highly correlated with OS. Female sex, leiomyosarcoma histology, locoregional treatment of metastases, inclusion in a clinical trial, and treatment with first-line polychemotherapy were significantly associated with improved OS in the multivariate analysis. CONCLUSIONS: The combination of doxorubicin with a second drug, such as ifosfamide, represents a valid option, particularly when tumor shrinkage is expected to provide clinical benefits. After failure of the second-line therapy, best supportive care should be considered, particularly in patients with non-leiomyosarcoma histology who are not eligible to participate in a clinical trial. Locoregional treatment of metastasis should always be included in the therapeutic strategy when feasible. TNT may represent a useful surrogate endpoint for OS in clinical studies.

Loss of H3K27 trimethylation is not suitable for distinguishing malignant peripheral nerve sheath tumor from melanoma: a study of 387 cases including mimicking lesions.

The diagnosis of malignant peripheral nerve sheath tumor remains challenging, especially in the sporadic setting. Malignant peripheral nerve sheath tumor is a rare malignancy, and owing to the lack of specific histological criteria, immunohistochemical and molecular diagnostic markers, several differential diagnoses must be considered, in particular melanoma. Recently, inactivation of the polycomb repressive complex 2 (PRC2), induced by inactivating mutations in two of its critical constituents SUZ12 and EED, was reported in a large subset of malignant peripheral nerve sheath tumors. Homozygous PRC2 inactivation induces complete loss of trimethylation at lysine 27 of histone 3 (H3K27me3). Recent studies suggest that complete loss of H3K27me3 is highly specific for malignant peripheral nerve sheath tumor and may be a useful immunohistochemical diagnostic marker. Therefore, to determine the specificity of the complete loss of H3K27me3 expression in the context of the differential diagnosis of malignant peripheral nerve sheath tumor from melanoma (its major potential mimic), we performed H3K27me3 immunohistochemistry in a pathologically and genetically well-characterized cohort of primary (neurofibromatosis type 1 (NF1), radiation-associated and sporadic context) malignant peripheral nerve sheath tumors (n=122) and in a cohort or primary (desmoplastic) and metastatic melanomas (n=265). In total, 88 (72%) malignant peripheral nerve sheath tumors, including 46 (71%) NF1-associated, 4 (100%) radiation-associated, and 38 (72%) sporadic tumors, showed complete loss of H3K27me3. We observed increased loss of H3K27me3 with increasing histological grade. Interestingly, we found complete loss of H3K27me3 in 37% (n=98) of all melanomas, including 25% (n=9) of primary desmoplastic melanomas. Moreover, partial loss ('mosaic' pattern) was observed in 23 (19%) of all malignant peripheral nerve sheath tumors and in 136 (51%) of all melanomas. Complete loss of H3K27me3 detected by immunohistochemistry is not specific for malignant peripheral nerve sheath tumor and cannot be used safely when distinguishing malignant peripheral nerve sheath tumor from melanoma.

Primary Extremity Soft Tissue Sarcomas: Does Local Control Impact Survival?

BACKGROUND: The objective of this study was to evaluate the adequate margin in the local treatment of extremity soft tissue sarcomas (ESTS) and understand the relationship between local control and overall survival (OS). METHODS: All consecutive patients treated for a primary ESTS at a single center from 1993 to 2012 were reviewed. RESULTS: In all, 531 patients were included. Twelve (2 %) underwent a first-line amputation. The resections were R0/R1/not available in 434 (82 %), 92 (17 %), and 5 patients (1 %). The median tumor size was 8 cm, and the tumor grades were 1 (n = 132), 2 (n = 201), and 3 (n = 195). The median size of the minimal margin was 2 mm on fixed specimen. Preop or postop chemotherapy was administered to 222 patients, and 414 received radiotherapy. With a median follow-up period of 7 years, the 5-year actuarial local recurrence (LR) rate and OS were 8 % (95 % CI, 6-11 %) and 80 % (95 % CI, 76-83 %). Predictors of worse OS were grade 3, leiomyosarcoma, male gender, and age >60 years, whereas tumor size, margin status, and LR were not. Among patients requiring re-excision (n = 252), the presence of residual cells correlated with OS but not LR. After preoperative treatment, a percentage of residual cells ≥10 % correlated with OS but not LR. In the multivariate analysis, specific subtypes (epithelioid sarcoma and myxofibrosarcoma) and margin size <1 mm correlated with LR, whereas grade and the tissue constituting the surgical margins did not. CONCLUSIONS: Specific subtypes and surgical margin size <1 mm were correlated with a higher LR. Neither the margin status nor LR affect OS.

Trabectedin in advanced desmoplastic round cell tumors: a retrospective single-center series.

Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive malignancy that occurs with unpredictable chemosensitivity and limited treatment options in the advanced setting. Prognosis is poor, and exploring new treatment options for such diseases is difficult because of its rarity. Clinical activity of trabectedin for advanced DSRCT was scarcely reported in the literature. Here, we report a series of six patients treated with trabectedin for an unresectable DSRCT. After receiving trabectedin, two patients had stable disease with a time to progression of 3 and 3.5 months; four patients experienced disease progression after one cycle, two of them could receive one and two patients another line regiment. Four patients experienced grade 3-4 adverse events, two grade 3 thrombocytopenia, and one neutropenic fever. Prognosis was poor with a median overall survival of 4 (range: 2-14) months. In our experience, trabectedin had limited activity in advanced DSRCT. Further studies are warranted to find effective treatments.

Clinical effect of molecular methods in sarcoma diagnosis (GENSARC): a prospective, multicentre, observational study.

BACKGROUND: Advances in molecular genetics of sarcoma have enabled the identification of type-specific aberrations. We aimed to assess the clinical effect of systematic implementation of molecular assays to improve sarcoma misdiagnosis. METHODS: In this multicentre, observational study, we recruited patients from 32 centres of the French Sarcoma Group/Reference Network in Pathology of Sarcomas. Eligibility criteria included: biopsy or surgical resection; suspicion of: dermatofibrosarcoma protuberans (cohort 1), dedifferentiated liposarcoma (cohort 2), Ewing's sarcoma family of tumours (cohort 3), synovial sarcoma (cohort 4), alveolar rhabdomyosarcoma (cohort 5), and myxoid or round cell liposarcoma (cohort 6); review by one sarcoma-expert pathologist; availability of frozen material (except for cohort 1 of patients with dermatofibrosarcoma protuberans because anti-CD34 immunohistochemistry is performed on paraffin-embedded tissue); and patient information. For each case, the pathologist made one primary diagnosis followed by up to two differential diagnoses, based on histological characteristics only. Each diagnosis was classified as certain, probable, or possible. For each case to determine the molecular classification, we did fluorescence in-situ hybridisation on paraffin-embedded samples. We also did comparative genomic hybridisation and quantitative PCR (cohort 2) or reverse transcriptase PCR (cohorts 3-6) on frozen and paraffin-embedded samples. We made a final diagnosis based on the molecular results. The clinical effect of diagnosis correction was assessed by a board of experts. FINDING: Between June 22, 2009, and Oct 30, 2012, 395 patients were enrolled in the study, of which 384 were eligible for inclusion. The diagnosis was eventually modified by molecular genetics for 53 patients: eight (16%) of 50 patients with dermatofibrosarcoma (cohort 1), seven (23%) of 30 patients with dedifferentiated liposarcoma (cohort 2), 13 (12%) of 112 with Ewing's sarcoma family of tumours (cohort 3), 16 (16%) of 97 patients with synovial sarcoma (cohort 4), seven (15%) of 46 patients with alveolar rhabdomyosarcoma (cohort 5), and two (4%) of 49 patients with myxoid or round cell liposarcoma (cohort 6), with an effect on primary management or prognosis assessment in 45 cases. INTERPRETATION: Molecular genetic testing should be mandatory for diagnostic accuracy of sarcoma and appropriate clinical management, even when histological diagnosis is made by pathologist experts in this field. FUNDING: French National Cancer Institute and Nice University Hospital.

Uterine smooth muscle tumor analysis by comparative genomic hybridization: a useful diagnostic tool in challenging lesions.

The diagnosis and management of uterine smooth muscle tumors with uncertain malignant potential (STUMP) is often challenging, and genomic data on these lesions as well as on uterine smooth muscle lesions are limited. We tested the hypothesis that genomic profile determination by array-CGH could split STUMP into a benign group with scarce chromosomal alterations akin to leiomyoma and a malignant group with high chromosomal instability akin to leiomyosarcoma. Array-CGH genomic profile analysis was conducted for a series of 29 cases of uterine STUMP. A group of ten uterine leiomyomas and ten uterine leiomyosarcomas served as controls. The mean age was 50 years (range, 24-85) and the follow-up ranged from 12 to 156 months (average 70 months). Since STUMP is a heterogenous group of tumors with genomic profiles that can harbor few to many chromosomal alterations, we compared genomic indices in leiomyomas and leiomyosarcomas and set a genomic index=10 threshold. Tumors with a genomic index <10 were classified as nonrecurring STUMPs and those with a genomic index >10 represented STUMPs with recurrences and unfavorable outcomes. Hence, the genomic index threshold splits the STUMP category into two groups of tumors with different outcomes: a group comparable to leiomyomas and another similar to leiomyosarcomas, but more indolent. In our STUMP series, genomic analysis by array-CGH is an innovative diagnostic tool for problematic smooth muscle uterine lesions, complementary to the morphological evaluation approach. We provide an improved classification method for distinguishing truly malignant tumors from benign lesions within the category of STUMP, especially those with equivocal morphological features.

Abdominal desmoplastic small round cell tumor: multimodal treatment combining chemotherapy, surgery, and radiotherapy is the best option.

BACKGROUND: With nearly 450 cases reported since 1991, desmoplastic small round cell tumor (DSRCT) is a rare abdominal tumor typically arising in adolescent and young adult white men. With no large series described, the best therapeutic strategy remains unclear. METHODS: All consecutive patients treated in our tertiary care center between January 1991 and December 2013 for a DSRCT were retrospectively studied. RESULTS: Thirty-eight patients with a median age of 27 years (range 13-57 years) were identified; 71 % were men. At the time of diagnosis, 47.4 % patients had extraperitoneal metastases (EPM): 78 % were located in the liver and 11 % were located in the lungs. Fourteen patients (37 %) were treated exclusively with systemic chemotherapy, with a median survival of 21.1 months. Twenty-three patients underwent surgery, 12 (52 %) experienced complete removal of all macroscopic disease, 5 (21.7 %) received additional intraperitoneal chemotherapy, and 7 (30 %) received postoperative whole abdominopelvic radiotherapy (WAP RT). With a median follow-up of 59.9 months, the median survival was 37.7 months, and the median disease-free survival was 15.5 months. The factors predictive of 3-year overall survival were the absence of EPM, complete surgical resection, postoperative WAP RT, and postoperative chemotherapy. The intraperitoneal chemotherapy had no impact on overall survival. CONCLUSIONS: DSRCT is a rare and aggressive disease. In patients without EPM, a multimodal treatment combining systemic chemotherapy, complete macroscopic resection, and postoperative WAP RT could enable prolonged survival. No benefit of surgery was demonstrated for patients with EPM. The value of associated hyperthermic intraperitoneal chemotherapy remains unproven.

Personalizing the approach to retroperitoneal soft tissue sarcoma: histology-specific patterns of failure and postrelapse outcome after primary extended resection.

PURPOSE: To explore patterns of failure and postrelapse outcome of patients with retroperitoneal sarcoma primarily treated by extended resection. METHODS: All consecutive patients with primary retroperitoneal sarcoma, treated between January 2002 and December 2011 at two European sarcoma centers were included. Five-year overall survival (OS) and crude cumulative incidence (CCI) of local recurrence (LR) and distant metastases (DM) were calculated. Multivariate analyses for OS and CCI of LR and DM were performed. Postrelapse OS was investigated. RESULTS: A total of 377 patients were identified. Median follow-up from the time of primary surgery was 44 months [interquartile range (IQR) 27-82]. Five-year OS was 64 % [95 % confidence interval (CI) 0.588, 0710]. CCI of LR and DM were 23.6 % (95 % CI 18.9, 29.4) and 21.9 % (95 % CI 17.6, 27.3), respectively. OS, CCI of LR and DM were 87, 18 % and 0 for well-differentiated liposarcoma; 54, 44 and 9 % for grade II dedifferentiated liposarcoma; 41,33, and 44 % for grade III dedifferentiated liposarcoma; 58, 5, and 55 % for leiomyosarcoma; and 85, 4, and 17 % for solitary fibrous tumor, respectively. Seventy-six patients developed LR. Median postrelapse follow-up was 27 months (IQR 10-58). Twenty-one patients (27 %) underwent a second surgical resection (complete in 18), while 55 (73 %) did not (22 multifocal, 17 inoperable, 16 other causes). Median postrelapse OS was 17 months (IQR 7-31). Well-differentiated liposarcoma histology and disease-free interval predicted postrelapse OS, while surgical resection did not. CONCLUSIONS: When primary extended surgery limits LR, histologic subtype and grade determine the outcome. At recurrence, a second surgery is of limited benefit.