Synchrotron radiation X-ray diffraction computed tomography (XRDCT): a new tool in cultural heritage and stone conservation for 3D non-destructive probing and phase analysis of inorganic re-treatments.

The issue of preserving carbonatic stones of cultural heritage (CH) restored in the past that have undergone new decay phenomena is strongly emerging and conservation science has not yet found a reliable solution. In this paper, we propose the application of synchrotron radiation X-ray diffraction computed tomography (XRDCT) to explore the effects of using inorganic-mineral products (ammonium oxalate; ammonium phosphate) in sequence as a novel, compatible and effective re-treatment approach to consolidate decayed carbonatic stones already treated with inorganic-mineral treatments. High-quality XRDCT datasets were used to qualitatively/quantitatively investigate and 3D localize the complex mixture of crystalline phases formed after the conservation re-treatments within a porous carbonatic stone substrate. The XRDCT reconstruction images and the structural refinements of XRD patterns with the Rietveld methods showed that the phase composition of reaction products, their volume distribution, and weight fraction vary as a function of the treatment sequence and penetration depth. The high potential of XRDCT allows (i) assessment of peculiar trends of each treatment/treatment sequence; (ii) exploration of the reaction steps of the sequential treatments and (iii) demonstration of the consolidating effect of inorganic re-treatments, non-destructively and at the micron scale. Above all, our study (i) provides new analytical tools to support the conservation choices, (ii) showcases new analytical possibilities for XRDCT in conservation science, including in investigations of CH materials and decay processes, and (iii) opens up new perspectives in analytical chemistry and material characterisation for the non-destructive and non-invasive analysis of reactions within heterogeneous polycrystalline systems.

Local treatment in initially unresected non-rhabdomyosarcoma soft-tissue sarcomas of children and adolescents: A retrospective single-center experience.

BACKGROUND: Pediatric non-rhabdomyosarcoma soft-tissue sarcomas (NRSTS) are a heterogeneous group of aggressive tumors. Patients with locally advanced/initially unresected disease represent a subset of patients with unsatisfactory outcome: limited data are available on the best treatment approach, in particular regarding local therapy. METHODS: This retrospective analysis concerned 71 patients < 21 years old with nonmetastatic, initially unresected adult-type NRSTS, treated at a referral center for pediatric sarcomas from 1990 to 2021. Patients were treated using a multimodal approach, based on the protocols adopted at the time of their diagnosis. RESULTS: The series included a selected group of patients with unfavorable clinical characteristics, i.e., most cases had high-grade and large tumors, arising from axial sites in 61% of cases. All patients received neoadjuvant chemotherapy, 58 (82%) had delayed surgery (R0 in 45 cases), and 50 (70%) had radiotherapy. Partial response to chemotherapy was observed in 46% of cases. With a median follow-up of 152 months (range, 18-233), 5-year event-free survival (EFS) and overall survival (OS) were 39.9% and 56.5%, respectively. Survival was significantly better for patients who responded to chemotherapy, and those who had a delayed R0 resection. Local relapse at 5 years was 7.7% for patients who did not undergo delayed surgery. CONCLUSIONS: Our series underscores the unsatisfactory outcome of initially unresected NRSTS patients. Improving the outcome of this patient category requires therapeutic strategies able to combine novel effective systemic therapies with a better-defined local treatment approach to offer patients the best chances to have R0 surgery.

Six Surgical Stages in the Resection of Primary Right Retroperitoneal Liposarcoma: A Standardized Comprehensive Approach.

BACKGROUND: Surgery is the treatment mainstay in retroperitoneal sarcoma (RPS), a frontline comprehensive approach based on tumor removal en bloc with adherent viscera is mandatory especially for liposarcoma, where the normal retroperitoneal fat is undistinguishable from the well-differentiated tumor component.1-5 In this video, a reproducible and standardized six-stage approach to a primary right retroperitoneal liposarcoma is presented. PATIENT AND METHODS: A 23-cm right retroperitoneal, well-differentiated liposarcoma was diagnosed in a 68-year-old female patient in December 2021. The tumor involved the right kidney and adrenal gland; displacing anteriorly the right colon, the duodenum, and the pancreatic head; and invading part of the ipsilateral psoas muscle. After the publication of the STRASS trial and STREXIT results,6,7 neoadjuvant radiotherapy was delivered to a total dose of 50.4 Gy in 28 fractions with stable disease. Virtual 3D reconstruction of regional anatomy by Visible Patient was performed preoperatively. RESULTS: The patient underwent right retroperitoneal mass resection en bloc with ipsilateral kidney and adrenal gland, colon, psoas muscle, and portion of ipsilateral diaphragm. Of note, the resection of the psoas muscle was performed to obtain a safe posterior margin and accomplish a better clearance of fat of the posterior abdominal wall. This can be limited to the psoas fascia whenever the tumor is not adherent to it. A six-stage approach was performed, as described in the supplementary video file. CONCLUSIONS: RPS resection is complex and requires a broad range of surgical expertise. A staged approach that can be followed in virtually all cases is highly recommended to achieve an optimal tumor resection.

Organ Infiltration and Patient Risk After Multivisceral Surgery for Primary Retroperitoneal Liposarcomas.

BACKGROUND: The extent of histological organ involvement (HOI) to organs and structures of a retroperitoneal liposarcoma may have prognostic implications. This study investigated incidence, characteristics, and risk association of HOI in these patients. PATIENTS AND METHODS: Data of patients who underwent multivisceral resection for primary liposarcoma (2009-2014) were retrospectively analyzed. HOI was the variable of interest and was classified into four degrees: absent (HOI-0), perivisceral (HOI-1), initial (HOI-2), and advanced (HOI-3). Primary endpoint was overall survival (OS). Secondary endpoint was disease-free survival (DFS). The prognostic value of HOI was adjusted for preoperative treatment and the Sarculator nomogram score. RESULTS: A total of 109 patients were included. HOI-0, HOI-1, HOI-2, and HOI-3 were detected in 9 (8.3%), 11 (10.1%), 43 (39.4%), and 46 (42.2%) patients. Median follow-up was 8.4 years [interquartile range (IQR) 7.2-9.6 years]. There were 68 recurrences and 50 patient deaths observed, resulting in a 10-year OS and DFS of 51.1% [95% confidence interval (CI) 41.9-62.1%] and 34.1% (95% CI 25.2-46.1%), respectively. Clinically relevant HOIs (HOI-2 and HOI-3) were found in 35/45 (77.8%) and 54/64 (84.4%) cases of well- and de-differentiated liposarcomas, respectively. On multivariable survival analysis, patients with HOI-3 had significantly shorter OS (HOI-3 vs HOI-0/HOI-1 HR 2.92; p = 0.012) and DFS (HOI-3 vs HOI-0/HOI-1 HR 2.23; p = 0.045), independently of the nomogram score (OS: HR 2.93; p < 0.001; DFS: HR 1.78; p = 0.003). CONCLUSIONS: Initial and advanced HOIs are frequently detected in both well-differentiated and de-differentiated liposarcomas, supporting that multivisceral resection may be needed. HOI stratifies the risk of patients with primary retroperitoneal liposarcoma.

The Chromatin Landscape around DNA Double-Strand Breaks in Yeast and Its Influence on DNA Repair Pathway Choice.

DNA double-strand breaks (DSBs) are harmful DNA lesions, which elicit catastrophic consequences for genome stability if not properly repaired. DSBs can be repaired by either non-homologous end joining (NHEJ) or homologous recombination (HR). The choice between these two pathways depends on which proteins bind to the DSB ends and how their action is regulated. NHEJ initiates with the binding of the Ku complex to the DNA ends, while HR is initiated by the nucleolytic degradation of the 5'-ended DNA strands, which requires several DNA nucleases/helicases and generates single-stranded DNA overhangs. DSB repair occurs within a precisely organized chromatin environment, where the DNA is wrapped around histone octamers to form the nucleosomes. Nucleosomes impose a barrier to the DNA end processing and repair machinery. Chromatin organization around a DSB is modified to allow proper DSB repair either by the removal of entire nucleosomes, thanks to the action of chromatin remodeling factors, or by post-translational modifications of histones, thus increasing chromatin flexibility and the accessibility of repair enzymes to the DNA. Here, we review histone post-translational modifications occurring around a DSB in the yeast Saccharomyces cerevisiae and their role in DSB repair, with particular attention to DSB repair pathway choice.

Non-destructive Monitoring of Dye Depth Profile in Mesoporous TiO2 Electrodes of Solar Cells with Micro-SORS.

The dye distribution within a photo-electrode is a key parameter in determining the performances of dye-sensitized photon-to-electron conversion devices, such as dye-sensitized solar cells (DSSCs). A traditional, depth profiling investigation by destructive means including cross-sectional sampling is unsuitable for large quality control applications in manufacturing processes. Therefore, a non-destructive monitoring of the dye depth profile is required, which is the first step toward a non-destructive evaluation of the internal degradation of the device in the field. Here, we present a conceptual demonstration of the ability to monitor the dye depth profile within the light active layer of DSSCs by non-destructive means with high chemical specificity using a recently developed non-destructive/non-invasive Raman method, micro-spatially offset Raman spectroscopy (micro-SORS). Micro-SORS is able to probe through turbid materials, providing the molecular identification of compounds located under the surface, without the need of resorting to a cross-sectional analysis. The study was performed on the photo-electrode of DSSCs. This represents the first demonstration of the micro-SORS concept in the solar cell area as well as, more generally, the application of micro-SORS to the thinnest layer to date. A sample set has been prepared with varying concentrations of the dye and the thickness of the matrix consisting of a titanium dioxide layer. The results showed that micro-SORS can unequivocally discriminate between the homogeneous and inhomogeneous dye depth profiles. Moreover, micro-SORS outcomes have been compared with the results obtained with destructive time-of-flight secondary ion mass spectrometry measurements. The results of the two techniques are in good agreement, confirming the reliability of micro-SORS analysis. Therefore, this study is expected to pave the way for establishing a wider and more effective monitoring capability in this important field.

The "Historical Materials BAG": A New Facilitated Access to Synchrotron X-ray Diffraction Analyses for Cultural Heritage Materials at the European Synchrotron Radiation Facility.

The European Synchrotron Radiation Facility (ESRF) has recently commissioned the new Extremely Brilliant Source (EBS). The gain in brightness as well as the continuous development of beamline instruments boosts the beamline performances, in particular in terms of accelerated data acquisition. This has motivated the development of new access modes as an alternative to standard proposals for access to beamtime, in particular via the "block allocation group" (BAG) mode. Here, we present the recently implemented "historical materials BAG": a community proposal giving to 10 European institutes the opportunity for guaranteed beamtime at two X-ray powder diffraction (XRPD) beamlines-ID13, for 2D high lateral resolution XRPD mapping, and ID22 for high angular resolution XRPD bulk analyses-with a particular focus on applications to cultural heritage. The capabilities offered by these instruments, the specific hardware and software developments to facilitate and speed-up data acquisition and data processing are detailed, and the first results from this new access are illustrated with recent applications to pigments, paintings, ceramics and wood.

The Prognostic Role of ß-Catenin Mutations in Desmoid-type Fibromatosis Undergoing Resection Only: A Meta-analysis of Individual Patient Data.

OBJECTIVE: This meta-analysis (PROSPERO CRD42018100653) uses individual patient data (IPD) to assess the association between recurrence and CTNNB1 mutation status in surgically treated adult desmoid-type fibromatosis (DTF) patients. SUMMARY OF BACKGROUND DATA: The majority of sporadic DTF tumors harbor a CTNNB1 (ß-catenin) mutation: T41A, S45F, and S45P or are wild-type (WT). Results are conflicting regarding the recurrence risk after surgery for these mutation types. METHODS: A systematic literature search was performed on June 6th, 2018. IPD from eligible studies was used to analyze differences in recurrence according to CTNNB1 mutation status using Cox proportional hazards analysis. Predictive factors included: sex, age, mutation type, tumor site, tumor size, resection margin status, and cohort. The PRISMA-IPD guideline was used. RESULTS: Seven studies, describing retrospective cohorts were included and the IPD of 329 patients were used of whom 154 (46.8%) had a T41A mutation, 66 (20.1%) a S45F mutation, and 24 (7.3%) a S45P mutation, whereas 85 (25.8%) patients had a WT CTNNB1. Eighty-three patients (25.2%) experienced recurrence. Multivariable analysis, adjusting for sex, age, and tumor site yielded a P-value of 0.011 for CTNNB1 mutation. Additional adjustment for tumor size yielded a P-value of 0.082 with hazard ratio's of 0.83 [95% confidence interval (CI) 0.48-1.42), 0.37 (95% CI 0.12-1.14), and 0.44 (95% CI 0.21-0.92) for T41A, S45P and WT DTF tumors compared to S45F DTF tumors. The effect modification between tumor size and mutation type suggests that tumor size is an important mediator for recurrence. CONCLUSIONS: Primary sporadic DTFs harboring a CTNNB1 S45F mutation have a higher risk of recurrence after surgery compared to T41A, S45P, and WT DTF, but this association seems to be mediated by tumor size.

Time-Resolved ATR-FTIR Spectroscopy and Macro ATR-FTIR Spectroscopic Imaging of Inorganic Treatments for Stone Conservation.

In this study, the novel application of ATR-FTIR spectroscopy and macro ATR-FTIR spectroscopic imaging overcame an analytical challenge in conservation science: the time-resolved, chemical, and spatial investigation of the reaction of inorganic treatments for stone conservation (ammonium oxalate, AmOx; ammonium phosphate, DAP) occurring in water-based solutions. The aim was to (1) assess the composition and localization of reaction products and their phase variation during the reaction in real time and directly in an aqueous environment and (2) investigate the reaction of AmOx and DAP with calcite and the transformations induced to the substrate with a time-resolved approach. The new analytical results showed that for both treatments, the formation of new crystalline phases initiated at the early stages of the reaction. Their composition changed during the treatment and led to more stable phases. The reactivity of the stone substrate to the treatments varied as a function of the stone material features, such as the specific surface area. A clear influence of post-treatment rinsing on the final composition of reaction phases was observed. Above all, our research demonstrates the actual feasibility, practicality, and high potential of an advanced ATR-FTIR spectroscopic approach to investigate the behavior of conservation treatments and provided new analytical tools to address the choices of conservation in pilot worksites. Lastly, this study opens novel analytical perspectives based on the new possible applications of ATR-FTIR spectroscopic imaging in the field of conservation science, materials science, and analytical chemistry.

Inoperable Primary Retroperitoneal Sarcomas: Clinical Characteristics and Reasons Against Resection at a Single Referral Institution.

BACKGROUND: The outcome of patients with retroperitoneal sarcomas (RPS) depends mainly on tumor biology and completeness of surgical resection. However, some patients are deemed not resectable for various reasons. This study analyzed a series of primary RPS patients to describe rate and reasons of primary inoperability at a large referral center. METHODS: All consecutive patients affected by primary localized RPS referred for surgical treatment at our institution between January 1, 2013 and December 31, 2017 were analyzed. Patients were split in two groups: those who underwent surgical resection with curative intent, and those who were not resected. RESULTS: A total of 322 patients were available for the current analysis: 285 (88.5%) underwent resection with curative intent, and 37 (11.5%) did not. Twenty of 322 (6.2%) patients who did not undergo resection had a technically unresectable tumor, whereas the remaining 18 of 322 (5.6%) were not amenable to a major surgical procedure due to comorbidities/poor performance status. The dominant technical reason was involvement of the celiaco-mesenteric vessels. At a median follow-up from the diagnosis of 34 months, 24 of 37 (64.9%) nonoperated and 48 of 285 (16.8%) operated patients died. The corresponding 4-year overall survival were 10.3% and 83.4%, respectively (p < 0.001). CONCLUSIONS: Roughly, 10% of patients who presented with localized primary RPS at a large referral institution were not resected. An attempt to standardize the definition of resectability for primary localized RPS should be made considering anatomic, biologic, and patient-related factors.

A Prospective Observational Study of Multivisceral Resection for Retroperitoneal Sarcoma: Clinical and Patient-Reported Outcomes 1 Year After Surgery.

BACKGROUND: Primary retroperitoneal sarcoma (RPS) may require multivisceral resection (MVR). Clinical outcome (morbidity and renal function) and quality of life (QoL) are not as well reported as the oncologic outcome. METHODS: Patients with primary RPS who underwent surgery between 2014 and 2016 were prospectively enrolled in an observational longitudinal study. At baseline, then at 4 and 12 months, the study measured Clavien-Dindo morbidity, estimated glomerular filtration rate (EGFR), EORTC QLQ-C30, QLQ-CR29, DN4 (neuropathic pain [NP]), lower-extremity functional scale (LEFS), and the brief pain inventory. The primary end point was the difference in global health status (GHS/QoL). The secondary end points were EGFR changes, difference in other QLQ-C30 scales, pain intensity, NP, and LEFS. The study is registered at ClinTrials.gov (NCT03480399). RESULTS: Of 74 patients, 58 were evaluable. Morbidity grade 3 or higher was 24.1%, and mortality was 1.3%. After nephrectomy, the mean 1-year EGFR change was -33.9%. The GHS/QoL at baseline was 58.6 and had increased of 6.9 points at 1 year, comparable with that of the general population. A transient worsening in pain and diarrhea had recovered at 12 months. Average pain was mild and did not differ at 12 months. However, NP was found in 41.4% of the patients and was significantly associated with resection of the psoas muscle. At baseline, LEFS was already lower than the normative value, and worsening after surgery was not clinically relevant. CONCLUSION: A QoL measure after MVR in primary RPS is complex and requires multiple tools. Whereas overall MVR is safe and associated with an improvement in GHS/QoL, chronic NP is frequent and deserves specific attention. Pre-surgery rehabilitation tracks may help to prevent or reduce chronic NP.

Insight into the effects of moisture and layer build-up on the formation of lead soaps using micro-ATR-FTIR spectroscopic imaging of complex painted stratigraphies.

Metal soaps are formed in paint layers thorough the reaction of metal ions of pigments and fatty acids of organic binders. In this study, micro-ATR-FTIR spectroscopic imaging was used to analyse the formation of lead soaps in oil-based paint layers in relation to their exposure to moisture sources. The investigations were carried out on authentic samples of complex stratigraphies from cold painted terracotta statues (Sacred Mount, Varallo, UNESCO) and different IR-active lead white pigments, organic materials, and lead soaps were discriminated. The saponification of selected paint layers was correlated to the conservation history, the manufacturing technique, and the build-up of layers. The presence of hydrophilic layers within the stratigraphy and their role as a further water source are discussed. Furthermore, the modifications experienced by lead-based pigments from the core of an intact grain of pigment towards the newly formed decay phases were investigated via a novel approach based on shift of the peak for the corresponding spectral bands and their integrated absorbance in the ATR-FTIR spectra. Qualitative information on the spatial distribution from the chemical images was combined with quantitative information on the peak shift to evaluate the different manufacture (lead carbonate, basic lead carbonate) or the extent of decay undergone by the lead-based pigments as a function of their grain size, contiguous layers, and moisture source. Similar results, having a high impact on heritage science and analytical chemistry, allow developing up-to-date conservation strategies by connecting an advanced knowledge of the materials to the social and conservation history of artefacts.

How do cells sense DNA lesions?

DNA is exposed to both endogenous and exogenous DNA damaging agents that chemically modify it. To counteract the deleterious effects exerted by DNA lesions, eukaryotic cells have evolved a network of cellular pathways, termed DNA damage response (DDR). The DDR comprises both mechanisms devoted to repair DNA lesions and signal transduction pathways that sense DNA damage and transduce this information to specific cellular targets. These targets, in turn, impact a wide range of cellular processes including DNA replication, DNA repair and cell cycle transitions. The importance of the DDR is highlighted by the fact that DDR inactivation is commonly found in cancer and causes many different human diseases. The protein kinases ATM and ATR, as well as their budding yeast orthologs Tel1 and Mec1, act as master regulators of the DDR. The initiating events in the DDR entail both DNA lesion recognition and assembly of protein complexes at the damaged DNA sites. Here, we review what is known about the early steps of the DDR.

Malnutrition and Perioperative Nutritional Support in Retroperitoneal Sarcoma Patients: Results from a Prospective Study.

INTRODUCTION: Retroperitoneal soft tissue sarcomas (RPSs) are mesenchymal neoplasms. The prevalence of protein energetic malnutrition (PEM) and its impact in RPS patients who were candidates for surgery is unknown. MATERIALS AND METHODS: A prospective feasibility study enrolled 35 patients with primary RPS who were candidates for extended multivisceral resection. PEM was screened at enrollment. Preoperative high protein ß-hydroxy-ß-methyl butyrate oral nutritional support (ONS) was provided according to the degree of PEM. After surgery, nutritional support followed standard practice, targeting at least 1 g/kg/day protein and 20 kcal/kg/day caloric intake within the third postoperative day (POD). PEM was re-evaluated before surgery on POD 10, and at 4 and 12 months after surgery. Primary outcomes were the patient's compliance to preoperative ONS and the physician's compliance to postoperative nutritional targets. RESULTS: PEM was documented in 46% of patients at baseline; ONS met a 91% adherence (overall well tolerated). After ONS, PEM reduced to 38% (p = 0.45). The postoperative caloric target was reached on day 4.1 (standard error ± 2.7), with a protocol adherence rate of 52%. On POD 10, 91% of patients experienced PEM, the worsening of which was greater after resection of four or more organs (p = 0.06). At 4 and 12 months after surgery, almost all patients had fully recovered. A significant correlation between PEM at surgery and postoperative complications was found (p = 0.04). CONCLUSIONS: Relevant PEM prevalence in RPS is documented for the first time. PEM correlates with greater morbidity. In this setting, preoperative ONS was feasible and well-tolerated. Disease-related factors for PEM and the ideal perioperative caloric target in the context of extended multivisceral resection need to be further investigated. Nutritional support should be included in enhanced recovery after surgery programs for RPS. TRIAL REGISTRY: ClinicalTrials.gov identifier: NCT03877588.

NR4A3 fusion proteins trigger an axon guidance switch that marks the difference between EWSR1 and TAF15 translocated extraskeletal myxoid chondrosarcomas.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma histotype with uncertain differentiation. EMC is hallmarked by the rearrangement of the NR4A3 gene, which in most cases fuses with EWSR1 or TAF15. TAF15-translocated EMC seem to feature a more aggressive course compared to EWSR1-positive EMCs, but whether the type of NR4A3 chimera impinges upon EMC biology is still largely undefined. To gain insights on this issue, a series of EMC samples (7 EWSR1-NR4A3 and 5 TAF15-NR4A3) were transcriptionally profiled. Our study unveiled that the two EMC variants display a distinct transcriptional profile and that the axon guidance pathway is a major discriminant. In particular, class 4-6 semaphorins and axonal guidance cues endowed with pro-tumorigenic activity were more expressed in TAF15-NR4A3 tumors; vice versa, class 3 semaphorins, considered to convey growth inhibitory signals, were more abundant in EWSR1-NR4A3 EMC. Intriguingly, the dichotomy in axon guidance signaling observed in the two tumor variants was recapitulated in in vitro cell models engineered to ectopically express EWSR1-NR4A3 or TAF15-NR4A3. Moreover, TAF15-NR4A3 cells displayed a more pronounced tumorigenic potential, as assessed by anchorage-independent growth. Overall, our results indicate that the type of NR4A3 chimera dictates an axon guidance switch and impacts on tumor cell biology. These findings may provide a framework for interpretation of the different clinical-pathological features of the two EMC variants and lay down the bases for the development of novel patient stratification criteria and therapeutic approaches. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Intraperitoneal Invasion of Retroperitoneal Sarcomas: A Risk Factor for Dismal Prognosis.

INTRODUCTION: Retroperitoneal sarcomas (RPS) lie in the retroperitoneal space and are covered by a peritoneal layer. However, some RPS have an intraperitoneal component (IPC), which invades into the peritoneal cavity. The significance of such a clinical presentation is unknown. METHODS: We retrospectively analyzed our prospectively maintained institutional database of RPS, along with intraoperative photographs taken to document the primary tumor extent at laparotomy. The effects of IPC on overall survival (OS), local recurrence (LR), and distant metastasis (DM) were evaluated. RESULTS: IPC was present in 81 of 493 patients (16.4%). It was significantly associated with older age (64 vs. 59, p = 0.008), gender (67% vs. 33% males, p = 0.005), and multifocality (11.1% vs. 0.5%; p < 0.0001). IPC was not associated with size or any specific histology, while it showed a weak association with high malignancy grade (40.7% vs. 28.6% in G3 tumors; p = 0.076). At a median follow-up of 32 months IPC was associated with worse 5-year OS (54% vs. 74%, p < 0.001) and crude cumulative incidence (CCI) of LR (5-year CCI of LR: 38% vs. 19%, p = 0.001), but not to CCI of DM. However, multivariable models showed that IPC's effect on OS (HR: 1.52, 95% CI 0.92-2.49, p = 0.1) and LR (HR: 1.34, 95% CI 0.8-2.26, p = 0.27) could be sufficiently explained by other known risk factors. CONCLUSIONS: IPC is associated with increased LR and decreased survival. However, the effect of IPC on prognosis is predominantly related to other tumor characteristics already included in published nomograms. IPC should not be a contraindication to a proper surgical resection.

Management of complicated tumor response to tyrosine-kinase inhibitors in gastrointestinal stromal tumors.

BACKGROUND: The aim was to describe complicated tumor response (CTR) to tyrosine-kinase inhibitors (TKI) in gastrointestinal stromal tumors (GIST) patients. METHODS: From 2001 to 2017, data from patients with metastatic (group A) or locally advanced (group B) GIST who received TKI at our institution were collected. We defined CTR as bleeding, abscess, or perforation as surgical complications of TKI. Patients who had progressive disease were excluded. Clinical characteristics were assessed, and time of occurrence and mortality rate recorded. RESULTS: Among 470 patients, 30 developed CTR (6.4%), 26 in group A (6.8%) and four in group B (4.5%) (P = 0.43). Bleeding, abscess, and perforation, respectively, were observed in 17 (56.7%), 8 (26.7%), and 5 (16.7%) patients. A conservative approach was possible in 17 (56.7%) cases; four (13.3%) patients received percutaneous drainage, while nine (30%) underwent emergency surgery. The overall rate of mortality was 13.3%. CTR occurred after 1.6 months (median time) from the imatinib mesylate onset in group B and 14 months in group A. CONCLUSIONS: While the risk of CTR in early metastatic patients is virtually nil, patients with locally advanced disease should be monitored carefully. CTR as a consequence of TKI therapy do not prevent patients receiving a potentially curative surgery.

Completion surgery of residual disease after primary inadequate surgery of retroperitoneal sarcomas can salvage a selected subgroup of patients-A propensity score analysis.

BACKGROUND: Patients with retroperitoneal sarcoma (RPSs) who undergo primary inadequate surgery before referral to specialized sarcoma centers may be considered for completion surgery (CS). We wanted to compare the outcome of these patients to those who underwent primary adequate surgery (PAS) at a single referral institution. METHODS: We identified 34 patients who were referred for CS after primary inadequate surgery. Using a propensity score based on validated RPS outcome risk factors, we managed to match 28 patients to patients with PAS. RESULTS: Median time lag between the first and second operation in CS patients was 5 months (2-15). Surgical extent was similar among groups (median number of organs resected = 3; P = 0.08), and macroscopically complete excision was achieved in all patients. The rate of severe complications did not differ between the groups (1 of 28 vs 3 of 28, respectively; P = 0.35) and no perioperative mortality was documented. Median follow-up was 43.5 months. Patients in the CS group had similar local recurrence-free survival (mean, 92.1 ± 9.7 vs 99.8 ± 12.4; P = 0.85) and relapse-free survival (mean, 88.7 ± 9.8 vs 80.9 ± 12.3; P = 0.3) to those with PAS. CONCLUSIONS: CS has short- and long-term outcomes comparable to PAS. While primary surgery should always be carried out at a referral institution, some of the patients who undergo an initial incomplete resection at a non specialist center can still be offered a salvage procedure at a referral institution with comparable results.

The RNA binding protein Npl3 promotes resection of DNA double-strand breaks by regulating the levels of Exo1.

Eukaryotic cells preserve genome integrity upon DNA damage by activating a signaling network that promotes DNA repair and controls cell cycle progression. One of the most severe DNA damage is the DNA double-strand break (DSB), whose 5΄ ends can be nucleolitically resected by multiple nucleases to create 3΄-ended single-stranded DNA tails that trigger DSB repair by homologous recombination. Here, we identify the Saccharomyces cerevisiae RNA binding protein Npl3 as a new player in DSB resection. Npl3 is related to both the metazoan serine-arginine-rich and the heterogeneous nuclear ribonucleo-proteins. NPL3 deletion impairs the generation of long ssDNA tails at the DSB ends, whereas it does not exacerbate the resection defect of exo1Δ cells. Furthermore, either the lack of Npl3 or the inactivation of its RNA-binding domains causes decrease of the exonuclease Exo1 protein levels as well as generation of unusual and extended EXO1 RNA species. These findings, together with the observation that EXO1 overexpression partially suppresses the resection defect of npl3Δ cells, indicate that Npl3 participates in DSB resection by promoting the proper biogenesis of EXO1 mRNA.

Novel intra-genic large deletions of CTNNB1 gene identified in WT desmoid-type fibromatosis.

A wait and see approach for desmoid tumors (DT) has become part of the routine treatment strategy. However, predictive factors to select the risk of progressive disease are still lacking. A translational project was run in order to identify genomic signatures in patients enrolled within an Italian prospective observational study. Among 12 DT patients (10 CTNNB1-mutated and 2 wild type) enrolled from our institution only two patients (17%) showed a progressive disease. Tumor biopsies were collected for whole exome sequencing. Overall, DT exhibited low somatic sequence mutation rate and no additional recurrent mutation was found. In the two wild type (WT) cases, two novel alterations were detected: a complex deletion of APC and a pathogenic mutation of LAMTOR2. Focusing on WT DT subtype, deep sequencing of CTNNB1, APC and LAMTOR2 was conducted on a retrospective series of 11 WT DT using a targeted approach. No other mutation of LAMTOR2 was detected, while APC was mutated in two cases. Low-frequency (mean reads of 16%) CTNNB1 mutations were discovered in five samples (45%) and two novel intra-genic deletions in CTNNB1 were detected in two cases. Both deletions and low frequency mutations of CTNNB1 were highly expressed. In conclusion, a minority of DT is WT for either CTNNB1, APC or any other gene involved in the WNT pathway. In this subgroup novel and hard to be detected molecular alterations in APC and CTNNB1 were discovered, contributing to explain a portion of the allegedly WT DT cases.