Surgical Outcome in Retroperitoneal Sarcoma Surgery: Accuracy of P-POSSUM, ACS-NSQIP, and Inflammatory Biomarkers Prognostic Index (IBPI) Risk-Calculators for Prediction of Severe and Overall Morbidity.

INTRODUCTION: Retroperitoneal sarcoma often requires comprehensive resection, leading to severe postoperative morbidity. The lack of disease-procedure specific tools for morbidity risk and the questionable accuracy of existing tools (ACS-NSQIP and P-POSSUM) in RPS surgery drove this study to assess these calculators' accuracy. METHODS: Retrospective analysis of primary RPS cases undergoing surgery at two sarcoma-referral centers was conducted. Predicted morbidity/mortality rates at 90 days postsurgery, classified by Clavien-Dindo (CD) and Comprehensive Complication Index (CCI), were compared with observed data. Accuracy was assessed by Brier Score and area under the curve (AUC). Inflammatory Biomarkers Prognostic Index (IBPI) also was tested. RESULTS: A total of 567 patients (median age 62 years; 53.6% male) with a median of four resected organs were included. 59% experienced surgical complications by 90 days postoperation, graded CD ≥ 3 in 30.5%, median CCI 20.9, with a mortality rate of 1.6% (8/567). Reoperation was required in 68 of 567 patients (12%). Thirty-day mortality was 1.1%. Severe complications occurred after 30th postoperative day in 3.5% cases. ACS-NSQIP predicted below-average complication for 65.1%, average for 16.9%, and above-average for 18% of patients. P-POSSUM predicted a 66% rate of morbidity and 4% mortality. None of the prediction tools were accurate, with Brier scores ranging 0.155-0.231 and no AUC ≥ 0.7. IBPI accuracy for predicting severe infective complication was low (AUC 0.58, Brier 0.161). CONCLUSIONS: The significant morbidity burden after MVR necessitates reliable evaluation, especially in frail patients. Given the limitations of ACS-NSQIP and P-POSSUM, a dedicated prediction tool for perioperative events in RPS candidates for MVR needs urgent development.

Circulating Tumor DNA in Patients with Desmoid Fibromatosis during Active Surveillance.

BACKGROUND: Sporadic desmoid fibromatosis (DF) is a rare locally aggressive tumor characterized by mutation in exon 3 of CTNNB1 (T41A, S45F, and S45P). Standard of care is active surveillance (AS), but 30% require treatment. DF clinical course is unpredictable and identification of prognostic markers is needed to tailor strategy. In this prospective study, we investigated the consistency between mutation detected in tumor biopsies with that detected in plasma by digital droplet PCR (ddPCR) and the association between circulating tumor DNA (ctDNA) abundancy with clinical outcome. PATIENTS AND METHODS: A total of 56 patients and 10 healthy donors were included. CTNNB1 mutation status of DF biopsies was determined by Sanger and in case of WT CTNNB1 with NGS. In matched plasma samples at enrollment and during AS at specific timepoints, we evaluated cfDNA quantity and ctDNA. RESULTS: ctDNA levels were measured in 46 patients with CTNNB1 mutation. Detection rate for T41A, S45F and S45P was 68%, 42% and 100%, respectively. S45P variant has been detected in all patients with S45P mutation. Longitudinal assessment of ctDNA during AS in nine patients (four with regression and five with progression as first event according to RECIST) showed a concordance between the event and ctDNA level change in six out of nine patients tested (4/5 with progression and 2/4 with regression). CONCLUSIONS: Results of ctDNA analysis support its potential clinical implementation as diagnostic tool in specific clinical scenarios where biopsy can be challenging. A prospective clinical trial needs to be performed to evaluate the potential role of ctDNA as predictive biomarker.

Pleomorphic Liposarcoma of the Extremity and Trunk: Multimodality Therapy for Some but Not All?

BACKGROUND: Pleomorphic liposarcoma (PLPS) is an ultra-rare malignancy distinct from well-differentiated/dedifferentiated and myxoid liposarcoma. In this study, we sought to (1) assess outcomes after surgery for primary, non-metastatic PLPS and (2) explore potential indications for multimodality therapy. METHODS: Clinicopathologic data were retrospectively collected for patients treated from 2002 to 2019 at our sarcoma referral center. Descriptive data were summarized and Kaplan-Meier plots were constructed for overall survival (OS) and crude cumulative incidences (CCI) of disease-specific death (DSD), local recurrence (LR), and distant metastasis (DM). Univariable models were performed to assess the association of specific variables of interest on outcome. RESULTS: Forty-four pathology-verified PLPS cases were included in this study. Median tumor size was 8.5 cm; 75% were FNCLCC Grade 3. All patients underwent complete resection, including 15 patients (34%) who required re-excision to secure microscopic negative margins. Radiation therapy was given to 75% of patients, chemotherapy in 36%. At 5 years, OS was 75.3%; CCI of DSD, LR, and DM were 17.5%, 2.3%, and 32.5%. Larger tumor size was strongly associated with worse OS (p = 0.028) and DSD (p ≤ 0.001). A subgroup of patients (n = 10, 23%) with smaller, predominantly Grade 2 tumors underwent surgery alone without any LR or DM event at a median follow-up of 7.9 years. CONCLUSIONS: In PLPS, aggressive surgery and when appropriate, radiation therapy, results in excellent local control. Chemotherapy can be considered for larger tumors. Patients with smaller, Grade 2 tumors may be potentially cured with surgery alone.

Extent of macroscopic vascular invasion predicts distant metastasis in primary leiomyosarcoma of the inferior vena cava.

BACKGROUND: In retroperitoneal leiomyosarcoma (RP LMS), the predominant issue is distant metastasis (DM). We sought to determine variables associated with this outcome and disease-specific death (DSD). METHODS: Data were retrospectively collected on patients with primary RP LMS treated at a high-volume center from 2002 to 2023. For inferior vena cava (IVC)-origin tumors, the extent of macroscopic vascular invasion was re-assessed on each resection specimen and correlated with preoperative cross-sectional imaging. Crude cumulative incidences were estimated for DM and DSD and univariable and multivariable models were performed. RESULTS: Among 157 study patients, median tumor size was 11.0 cm and 96.2% of cases were intermediate or high grade. All patients underwent complete resection, 56.7% received chemotherapy (43.9% neoadjuvant) and 14.6% received radiation therapy. Only tumor size and grade and not site of tumor origin (e.g., IVC vs. other) were associated with DM and DSD (p < 0.05). Among 64 patients with IVC-origin tumors, a novel 3-tier classification was devised based on the level of intimal disruption, which was associated with both DM (p = 0.007) and DSD (0.002). CONCLUSION: In primary RP LMS, only tumor size and grade are predictive of DM and DSD. In IVC-origin tumors, the extent of macroscopic vascular invasion is also strongly predictive of these outcomes.

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.