Improved nationwide survival of sarcoma patients with a network of reference centers.

BACKGROUND: We investigated the impact of the implementation of a network of reference centers for sarcomas (NETSARC) on the care and survival of sarcoma patients in France since 2010. PATIENTS AND METHODS: NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor boards (MDTBs), funded by the French National Cancer Institute (INCa) since 2010. Its aims are to improve the quality of diagnosis and care of sarcoma patients. Patients' characteristics, treatments, and outcomes are collected in a nationwide database. The objective of this analysis was to compare the survival of patients in three periods: 2010-2012 (non-exhaustive), 2013-2015, and 2016-2020. RESULTS: A total of 43 975 patients with sarcomas, gastrointestinal stromal tumors (GISTs), or connective tissue tumors of intermediate malignancy were included in the NETSARC+ database since 2010 (n = 9266 before 2013, n = 12 274 between 2013 and 2015, n = 22 435 in 2016-2020). Median age was 56 years, 50.5% were women, and 13.2% had metastasis at diagnosis. Overall survival was significantly superior in the period 2016-2020 versus 2013-2015 versus 2010-2012 for the entire population, for patients >18 years of age, and for both metastatic and non-metastatic patients in univariate and multivariate analyses (P < 0.0001). Over the three periods, we observed a significantly improved compliance to clinical practice guidelines (CPGs) nationwide: the proportion of patients biopsied before surgery increased from 62.9% to 72.6%; the percentage of patients presented to NETSARC MDTBs before first surgery increased from 31.7% to 44.4% (P < 0.0001). The proportion of patients with R0 resection on first surgery increased (from 36.1% to 46.6%), while R2 resection rate decreased (from 10.9% to 7.9%), with a better compliance and improvement in NETSARC centers. CONCLUSIONS: The implementation of the national reference network for sarcoma was associated with an improvement of overall survival and compliance to guidelines nationwide in sarcoma patients. Referral to expert networks for sarcoma patients should be encouraged, though a better compliance to CPGs can still be achieved.

[Predictive factors assessment of pathological response to neoadjuvant radiotherapy of soft tissue sarcomas]. / Évaluation de facteurs prédictifs de réponse pathologique à la radiothérapie néoadjuvante des sarcomes des tissus mous.

PURPOSE: Conserving surgery combined with radiotherapy in presence of local recurrence risk factors is standard treatment of soft tissue sarcomas, a group of rare and heterogeneous tumours. Radiotherapy is performed before or after surgery. In neoadjuvant setting, late radiation-induced toxicity is reduced and pathological response to radiotherapy could be achieved. A complete pathological response to radiotherapy has recently been shown to predict better survival. Our study aims at identifying predictive factors of pathological response to neoadjuvant radiotherapy (clinical, radiological or histological) of soft tissue sarcomas. PATIENTS AND METHODS: Clinical, imaging (MRI: perilesional oedema, necrosis, tumour heterogeneity, vasculonervous relationships) and pathological (pathological subtype, tumour grade, anticipated/obtained resection quality) data were retrospectively collected. Tumour response (imaging and pathological), patient outcome, acute and late radiation-induced toxicity, predictive factors of pathological response to neoadjuvant radiotherapy were studied. The 2-test or exact-Fisher test (qualitative variables) and by Student's t-test or Kruskal-Wallis test (quantitative variables) were used for statistical analysis. RESULTS: From April 2017 to April 2021, neoadjuvant radiotherapy (50Gy in 25 fractions) followed by surgical excision was performed to 36 consecutive patients with liposarcomas (n=17/36), or undifferentiated sarcomas (n=8/36). MRI response was complete in 1 patient, partial in 9 patients (n=9/36, 25%), stable in 21 patients (n=21/36, 58%) or in progression in 5 patients (n=5/36, 14%). Pathological response was observed in 22 patients (61%). No grade 3-4 acute radiation-induced toxicity was observed. Regarding late toxicity, 28% of patients had grade 1-2 oedema (n=10/36), 39% had a grade 1 fibrosis (n=14/36), and 30% grade 1 pain (n=11/36). No predictive factors of response to radiotherapy was statistically significant. CONCLUSIONS: Neoadjuvant radiotherapy is well-tolerated. No clinical, radiological or pathological predictive factors was identified for radiotherapy tumour response.

Learning curve for robotic-assisted total mesorectal excision: a multicentre, prospective study.

AIM: Robotic-assisted surgery (RAS) is becoming increasingly important in colorectal surgery. Recognition of the short, safe learning curve (LC) could potentially improve implementation. We evaluated the extent and safety of the LC in robotic resection for rectal cancer. METHOD: Consecutive rectal cancer resections (January 2018 to February 2021) were prospectively included from three French centres, involving nine surgeons. LC analyses only included surgeons who had performed more than 25 robotic rectal cancer surgeries. The primary endpoint was operating time LC and the secondary endpoint conversion rate LC. Interphase comparisons included demographic and intraoperative data, operating time, conversion rate, pathological specimen features and postoperative morbidity. RESULTS: In 174 patients (69% men; mean age 62.6 years) the mean operating time was 334.5 ± 92.1 min. Operative procedures included low anterior resection (n = 143) and intersphincteric resection (n = 31). For operating time, there were two or three (centre-dependent) LC phases. After 12-21 cases (learning phase), there was a significant decrease in total operating time (all centres) and an increase in the number of harvested lymph nodes (two centres). For conversion rate, there were two or four LC phases. After 9-14 cases (learning phase), the conversion rate decreased significantly in two centres; in one centre, there was a nonsignificant decrease despite the treatment of significantly more obese patients and patients with previous abdominal surgery. There were no significant differences in interphase comparisons. CONCLUSION: The LC for RAS in rectal cancer was achieved after 12-21 cases for the operating time and 9-14 cases for the conversion rate. RAS for rectal cancer was safe during this time, with no interphase differences in postoperative complications and circumferential resection margin.

DNA demethylation and hypermethylation are both required for late nodule development in Medicago.

Plant epigenetic regulations are involved in transposable element silencing, developmental processes and responses to the environment1-7. They often involve modifications of DNA methylation, particularly through the DEMETER (DME) demethylase family and RNA-dependent DNA methylation (RdDM)8. Root nodules host rhizobia that can fix atmospheric nitrogen for the plant's benefit in nitrogen-poor soils. The development of indeterminate nodules, as in Medicago truncatula, involves successive waves of gene activation9-12, control of which raises interesting questions. Using laser capture microdissection (LCM) coupled to RNA-sequencing (SYMbiMICS data11), we previously identified 4,309 genes (termed NDD) activated in the nodule differentiation and nitrogen fixation zones, 36% of which belong to co-regulated genomic regions dubbed symbiotic islands13. We found MtDME to be upregulated in the differentiation zone and required for nodule development, and we identified 474 differentially methylated regions hypomethylated in the nodule by analysing ~2% of the genome4. Here, we coupled LCM and whole-genome bisulfite sequencing for a comprehensive view of DNA methylation, integrated with gene expression at the tissue level. Furthermore, using CRISPR-Cas9 mutagenesis of MtDRM2, we showed the importance of RdDM for CHH hypermethylation and nodule development. We thus proposed a model of DNA methylation dynamics during nodule development.

Cutaneous sensitivity modulation by Aquaphilus dolomiae extract-G3 on in vitro models of neuro-inflammation.

BACKGROUND: Inflammatory skin disorders, including atopic dermatitis (AD), associated pruritus and sensitive skin, have a complex multifactorial pathogenesis including neurogenic inflammation involving the release in blood and skin of neurotransmitters such as substance P (SP). AIMS AND METHODS: In vitro models evaluated the effect of the original biological extract of Aquaphilus dolomiae extract-G3 (ADE-G3) on cutaneous neurogenic inflammation. RESULTS: ADE-G3 significantly inhibited SP-stimulated release of IL-1ß and TNF-α from normal human epidermal keratinocytes; significantly and dose-dependently inhibited SP-stimulated activation of human mast cells; significantly inhibited veratridine-stimulated release of SP from human sensory neurons; modulated expression of genes involved in lipid synthesis, innate immunity, corneocyte scaffolding and epidermal differentiation in a histamine-sensitized reconstructed human epidermis model; and, when applied topically to ex vivo human explants, inhibited IL-8 and histamine release. CONCLUSIONS: Topically applied ADE-G3, once formulated, may improve neuro-inflammation in patients with inflammatory skin disorders.

Pre- or postoperative radiotherapy for soft tissue sarcomas.

Sarcomas are rare tumours arising from mesenchymal tissue. A multimodal management in an expert centre combining surgery and radiotherapy is the current standard of care for localized soft-tissue sarcomas of the extremities, to enable limb-sparing strategies. The delivery of pre- radiotherapy or postoperative radiotherapy offers similar local control and survival rates but the toxicity profile is quite different: preoperative radiotherapy increases the risk of wound complications and postoperative radiotherapy affects long-term functional outcomes. While postoperative radiotherapy has long been the rule, especially in Europe, technical improvements with image-guided- and intensity-modulated radiotherapy associated with a better management of postoperative wounds has tended to change practices with more frequent preoperative radiotherapy. More recently the possibilities of a hypofractionated regimen or potentiation by nanoparticles to increase the therapeutic index plead in favour of a preoperative delivery of radiotherapy. The aim of this paper is to report pros and cons of pre- and post-operative radiotherapy for soft-tissue sarcomas.

Non-medical caregivers and the use of intraperitoneal chemotherapy in the operating theatre: A survey on the perception of safety.

BACKGROUND: In the last two decades, intraperitoneal(IP) chemotherapy during surgery achieved recognition in the management of peritoneal metastases. Occupational hazard became a concern leading to standardized safety measures. The aim of this study is to evaluate the perceived level of information and protection among the non-medical caregivers involved in HIPEC and PIPAC in a high-volume center. METHODS: All non-medical caregivers in the operating theatre of our institution were asked to answer a questionnaire between April and May 2018. The questionnaire included multiple choice questions and open questions structured in four parts: demographic variables, perceived level of information, perceived level of protection, interest in further education. RESULTS: Forty-nine caregivers agreed to answer the questionnaire. All identified IP chemotherapy as an occupational risk. Thirty-eight persons (77.55%) trusted the protective value of safety measures during HIPEC compared to 32 (65.3%) during PIPAC. A total of 29 persons (59.18%) used some of the measures while 16 (32.65%) used all of them. Main reasons of non-use were slips and lapses (7 persons) and lack of comfort (4 persons). A total of 34 caregivers considered the level of information about safety protocols as good or very good (69%). A total of 46 persons considered the level of protection as satisfying or excellent (93.87%). A total of 36 (73.47%) interviewees expressed the need of receiving more information. CONCLUSIONS: The present study shows that non-medical caregivers in the operating theatres are aware of the occupational hazards related to the use of IP chemotherapy. The use of protective measures is associated with decreased level of perceived risk. However there is a high need of continuous education on this subject for the involved personnel.

Can we cure patients with abdominal Desmoplastic Small Round Cell Tumor? Results of a retrospective multicentric study on 100 patients.

BACKGROUND: Despite being associated with a very poor prognosis, long-term survivors across all series of Desmoplastic Small Round Cell Tumor (DSRCT) have been reported. AIM OF THE STUDY: To analyze patients 'characteristics associated with a prolonged survival after DSRCT diagnosis. METHODS: All consecutive patients treated for DSRCT in nine French expert centers between 1991 and 2018 were retrospectively analyzed. Patients with a follow-up of less than 2 years were excluded and cure defined as being disease-free at least 5 years. RESULTS: 100 pts were identified (median age 25 years, 89% male). 27 had distant metastases at diagnosis and 80 pts underwent upfront chemotherapy (CT). 71 pts were operated, 20 pts without prior CT). Surgery was macroscopically complete (CC0/1) in 50 pts. Hyperthermic intraperitoneal Chemotherapy (HIPEC) was administered during surgery in 15 pts 54 pts had postoperative CT and 26 pts had postoperative whole abdomino-pelvic RT (WAP-RT). After a median follow-up of 103 months (range 23-311), the median overall survival (OS) was 25 months. The 1- year, 3-year and 5-year OS rates were 90%, 35% and 4% respectively. 5 patients were considered cured after a median disease-free interval of 100 months (range 22-139). Predictive factors of cure were female sex (HR = 0.49, p = 0.014), median PCI<12 (HR = 0.32, p = 0.0004), MD Anderson stage I (HR = 0.25, p < 0.0001), CC0/1 (HR = 0.34, p < 0.0001), and WAP-RT (HR = 0.36, p = 0.00013). HIPEC did not statistically improve survival. CONCLUSION: Cure in DSRCT is possible in 5% of patients and is best achieved combining systemic chemotherapy, complete cytoreductive surgery and WAP-RT. Despite aggressive treatment, recurrence is common and targeted therapies are urgently needed.

Survival Benefit of the Surgical Management of Retroperitoneal Sarcoma in a Reference Center: A Nationwide Study of the French Sarcoma Group from the NetSarc Database.

BACKGROUND: Guidelines recommend that retroperitoneal sarcoma (RPS) be managed in a reference sarcoma center (RSC), but the benefit remains to be demonstrated. This study investigated the impact of initial surgery performed within the NetSarc network on overall survival (OS). METHODS: NetSarc is a network of 26 RSCs with specialized multidisciplinary tumor boards (MDTs) that is funded by the French NCI. Since 2010, presentation to an MDT and second pathological review are mandatory for sarcoma patients, and data have been collected in a nationwide database. We extracted data for all patients who received surgery in or outside the network and who presented at a NetSarc center (NSC) for primary nonmetastatic RPS between 2010 and 2017. RESULTS: A total of 2945 patients were included: 1078 (36.6%) underwent the first surgery in an NSC, and 1867 (63.4%) in an out-of-network center. The median number of operations at an NSC during the study period was 23 (range: 3-209), and the corresponding median was 1 (range: 1-2) at out-of-network centers. The diagnostic procedures followed significantly more clinical practice guidelines within NetSarc, where there were significantly more first R0 resections [452 (41.9%) vs. 230 (12.3%)]. The OS was significantly superior for patients treated within NetSarc, with a 2-year OS of 87% vs. 70% (p < 0.001). In the multivariate analysis, surgery within an NSC was an independent predictor of OS, with a twofold lower odds ratio of death. CONCLUSIONS: In this national study, surgery for primary RPS within an NSC was associated with a better OS.

Surgery in reference centers improves survival of sarcoma patients: a nationwide study.

BACKGROUND: NETSARC (netsarc.org) is a network of 26 sarcoma reference centers with specialized multidisciplinary tumor boards (MDTB) aiming to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB and expert pathological review are mandatory for sarcoma patients nationwide. In the present work, the impact of surgery in a reference center on the survival of sarcoma patients investigated using this national NETSARC registry. PATIENTS AND METHODS: Patients' characteristics and follow-up are prospectively collected and data monitored. Descriptive, uni- and multivariate analysis of prognostic factors were conducted in the entire series (N = 35 784) and in the subgroup of incident patient population (N = 29 497). RESULTS: Among the 35 784 patients, 155 different histological subtypes were reported. 4310 (11.6%) patients were metastatic at diagnosis. Previous cancer, previous radiotherapy, neurofibromatosis type 1 (NF1), and Li-Fraumeni syndrome were reported in 12.5%, 3.6%, 0.7%, and 0.1% of patients respectively. Among the 29 497 incident patients, 25 851 (87.6%) patients had surgical removal of the sarcoma, including 9949 (33.7%) operated in a NETSARC center. Location, grade, age, size, depth, histotypes, gender, NF1, and surgery outside a NETSARC center all correlated to overall survival (OS), local relapse free survival (LRFS), and event-free survival (EFS) in the incident patient population. NF1 history was one of the strongest adverse prognostic factors for LRFS, EFS, and OS. Presentation to an MDTB was associated with an improved LRFS and EFS, but was an adverse prognostic factor for OS if surgery was not carried out in a reference center. In multivariate analysis, surgery in a NETSARC center was positively correlated with LRFS, EFS, and OS [P < 0.001 for all, with a hazard ratio of 0.681 (95% CI 0.618-0.749) for OS]. CONCLUSION: This nationwide registry of sarcoma patients shows that surgical treatment in a reference center reduces the risk of relapse and death.

[What is the best management for a spermatic cord sarcoma in 2018?] / Quelle prise en charge optimale pour un sarcome du cordon spermatique en 2018 ?

Spermatic cord sarcomas are rare tumors for which the most important is the initial diagnostic procedure. They are frequently misdiagnosed after surgery for inguinal hernia, inguinal lymphadenectomy or testicular malignancy. Any clinical suspicion has to lead to perform imaging with MRI and a core needle biopsy in order to obtain an accurate preoperative diagnosis. Liposarcoma and leiomyosarcoma are the most common histological subtypes in elderly adults, rhabdomyosarcoma in children or in young adults. A CT scan will precede the treatment in order to look for distant metastasis and abdominal involvement. The therapeutic strategy as well as the surgical planning are then adapted to the histological, morphological and prognostic factors. Surgery is the cornerstone for the treatment of spermatic cord sarcoma. The minimum requirements for the surgical procedure are a wide excision of the tumor en bloc with radical orchidectomy, excision of the ipsilateral scrotum and high spermatic cord ligation. It could be enlarged to the anterior abdominal wall and adjacent organs some required a soft tissue flap. Spermatic cord sarcoma and trunk wall sarcoma have the same prognosis for which local recurrence could significantly decrease survival. Consequently, surgeon in charge with these tumors has to be familiar with soft tissue sarcoma and the management of these patients must be carried out under the supervision of a multidisciplinary team within the Netsarc network.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei of appendicular and extra-appendicular origin.

BACKGROUND: The prognostic value of the primary neoplasm responsible for pseudomyxoma peritonei (PMP) remains poorly studied. The aim of this study was to determine the prognosis for patients with extra-appendicular PMP (EA-PMP) treated optimally with complete cytoreductive surgery (CCRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: All patients treated for PMP with CCRS and HIPEC between 1994 and 2016 were selected retrospectively from a French multicentre database. Patients with EA-PMP had pathologically confirmed non-neoplastic appendices and were matched in a 1 : 4 ratio with patients treated for appendicular PMP (A-PMP), based on a propensity score. RESULTS: Some 726 patients were identified, of which 61 (EA-PMP group) were matched with 244 patients (A-PMP group). The origins of primary tumours in the EA-PMP group included the ovary (45 patients), colon (4), urachus (4), small bowel (1), pancreas (1) and unknown (6). The median peritoneal carcinomatosis index was comparable in EA-PMP and A-PMP groups (15·5 versus 18 respectively; P = 0·315). In-hospital mortality (3 versus 2·9 per cent; P = 1·000) and major morbidity 26 versus 25·0 per cent; P = 0·869) were also similar between the two groups. Median follow-up was 66·9 months. The 5-year overall survival rate was 87·8 (95 per cent c.i. 83·2 to 92·5) per cent in the A-PMP group and 87 (77 to 96) per cent in the EA-PMP group. The 5-year disease-free survival rate was 66·0 (58·7 to 73·4) per cent and 70 (53 to 83) per cent respectively. CONCLUSION: Overall and disease-free survival following treatment with CCRS and HIPEC is similar in patients with pseudomyxoma peritonei of appendicular or extra-appendicular origin.

[Radiotherapy for soft tissue sarcomas: Technical evolution and impact on clinical benefit]. / Radiothérapie des sarcomes des tissus mous des membres : évolution technique et impact sur le bénéfice clinique.

The standard treatment for extremity soft tissue sarcomas is based on the association of surgery and radiotherapy. This strategy allows local control improvement with the risk of increased toxicity. There is therefore a growing interest to identify those patients who will benefit from radiotherapy and those who will have the same local control with surgery alone. Furthermore, the development of toxicity has been correlated with the extension of the irradiated volume and the volume receiving high doses. Technological development as intensity modulated radiotherapy and image-guided radiotherapy allows limited irradiated volume improving the protection of the organs at risk leading to clinical benefit improvement. Moreover, efforts are being done to improve local control for the patients at high risk of local relapse. In this paper, we discuss all these mentioned aspects.

High-Quality Draft Genome Sequences of Two Xanthomonas Pathotype Strains Infecting Aroid Plants.

We present here the draft genome sequences of bacterial pathogens of the Araceae family, Xanthomonas axonopodis pv. dieffenbachiae LMG 695 and Xanthomonas campestris pv. syngonii LMG 9055, differing in host range. A comparison between genome sequences will help understand the mechanisms involved in tissue specificity and adaptation to host plants.

Draft Genome Sequence of Xanthomonas axonopodis pv. allii Strain CFBP 6369.

We report here the draft genome sequence of Xanthomonas axonopodis pv. allii strain CFBP 6369, the causal agent of bacterial blight of onion. The draft genome has a size of 5,425,942 bp and a G+C content of 64.4%.

[Impact of surgery in the management of pancreatic metastases of renal cell cancer]. / Place de la chirurgie dans la prise en charge des métastases pancréatiques des cancers du rein.

INTRODUCTION: Incidence of renal cell carcinoma (RCC) is increasing over the 25 last years. Pancreatic metastases of RCC are rare. The aim of this work was to study overall survival of patients operated for pancreatic metastases of RCC in Montpellier cancer institute. PATIENTS AND METHODS: Between 2000 and 2012, a retrospective monocentric study was performed at Montpellier cancer institute. We evaluated the outcomes of curative pancreatic metastases from renal primary and the impact of targeted therapies. RESULTS: Thirty-eight patients were treated in our center for pancreatic metastases of RCC. Twelve patients had a curative surgery of metachronous pancreatic metastases. Four patients were without recurrence after pancreatic resection (33.3%). None had adjuvant therapy. Six patients were treated by targeted therapies, because of metastatic progression. Five of 6 died, the sixth evolved with targeted therapies by thyrosine kinase inhibitor. Average deadline between appearance of metastases and death was 89.9 months for operated patients. Average deadline between appearance of c metastases and death was 33.1 months for the others (P=0.004). CONCLUSION: Surgical treatment of pancreatic metastases should increase life expectancy of patients. Others studies are necessary to prove the impact of targeted therapies in metastatics patients in this indication. LEVEL OF EVIDENCE: 5.

High-Quality Draft Genome Sequence of Xanthomonas alfalfae subsp. alfalfae Strain CFBP 3836.

We report the high-quality draft genome sequence of Xanthomonas alfalfae subsp. alfalfae strain CFBP 3836, the causal agent of bacterial leaf and stem spot in lucerne (Medicago sativa). Comparative genomics will help to decipher the mechanisms provoking disease and triggering the defense responses of this pathogen of the model legume Medicago truncatula.

High-Quality Draft Genome Sequences of Xanthomonas axonopodis pv. glycines Strains CFBP 2526 and CFBP 7119.

We report here the high-quality draft genome sequences of two strains of Xanthomonas axonopodis pv. glycines, the causal agent of bacterial pustule on soybeans. Comparison of these genomes with those of phylogenetically closely related pathovars of Xanthomonas spp. will help to understand the mechanisms involved in host specificity and adaptation to host plants.