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BACKGROUND: The Rome Trial is a randomized phase II trial (NCT04591431). The aim is to evaluate efficacy and safety of a tailored treatment (TT) compared to standard of care (SoC) in patients with solid tumors. Here we report the preliminary results of the molecular alterations, microsatellite status (MS) and tumor mutational burden (TMB) in metastatic breast cancer (mBC) cohort. METHODS: MBC patients who received at least 1 and no more than 2 systemic treatments were enrolled. Tissue samples were collected within 6 months from the screening. Centralized Next Generation Sequencing (NGS) was performed on both tissue and liquid biopsy. Molecular alterations were evaluated by the Molecular Tumor Board (MTB) using COSMIC, ClinVar, OncoKB and VarSome datasets. Genes with at least 10% frequency of mutation, MS and TMB are reported. RESULTS: From Oct 2020 to June 2022, 980 pts with solid tumors were enrolled. Complete screening mutational data are available for sixty-two pts from the mBC cohort (63% HR+/HER2-, 35% triple negative, 2% HR-/HER2+). NGS was available both on tissue and liquid biopsy in 48 (77%) pts, 14 had only liquid biopsy available due to tissue test failure. 328 genes resulted altered with a median of 7 alteration per pts (0-31). Some pathways were frequently altered: PIK3CA/AKT/MTOR (60%), TP53 (60%), Cell cycle/cycline (35%), FGF/FGFR (26%), BRCA1/2 (17%). The most frequent altered genes were: TP53 (61%), PIK3CA (50%), ESR1 (27%), CCND1 (27%), FGF19 (24%), FGF3 (24%), FGF4 (22%), MYC (22%), FGFR1 (21%), PTEN (21%), EMSY (16%), RB1 (14%), RAD21 (14%), TET2 (13%), BRCA2 (11%), GATA3 (11%), KRAS (10%). No pts with MSI status were reported. Eight (13%) had a high TMB (>10) and the overall median TMB was 5.5 (0-24). Median TMB was similar in tissue and liquid samples (5 and 5.3 mut/mb, p= 0.8). Actionable mutations were detected in 34 pts (54%). Twenty-eight (45%) pts were assigned to a specific TT after the MTB discussion: ipatasertib (16), pemigatinib (5), ipilimumab plus nivolumab (4), lapatinib plus trastuzumab, TDM1 and everolimus (1). MTB requested a germline test for 6 pts: 4 were confirmed (66%; 2 BRCA, 1 PALB2, 1 BRIP1). CONCLUSIONS: The extensive NGS analysis performed in the ROME trial shown that several pathways are commonly mutated in mBC, with target drug potentially available. About 15% of pts had a high TMB but MSI is confirmed as a rare event in breast cancer. Germline mutations have been identified in patients with no prior indication for germline testing. Citation Format: Andrea Botticelli, Simone Scagnoli, Pierfranco Conte, Chiara Cremolini, Paolo Antonio Ascierto, Federico Cappuzzo, Massimo Aglietta, Federica Mazzuca, Ettore Capoluongo, Giovanni Blandino, Umberto Malapelle, Marianna Nuti, Giulia D’Amati, Bruna Cerbelli, Giancarlo Pruneri, Mauro Biffoni, Giuseppe Giannini, Francesco Cognetti, Giuseppe Curigliano, Paolo Marchetti. Mutational landscape of breast cancer patients in ROME trial: preliminary results [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-09.

Background: A previous study on 22 metastatic breast cancer (mBC) patients (Allegretti et al. Mol Cancer 2021) has associated drug resistance to Ado-trastuzumab emtansine (T-DM1) with two sets of genomic events: a) reversal of HER2 amplification, b) ‘oncogenic replacement’ of HER2 by alternative cancer drivers. To expand on this, we designed GIM21 (Gruppo Italiano Mammella) study. Materials and Methods: GIM21 is a multicentre, prospective study; tumor and circulating total nucleic acids (tTNA and ctTNA) were obtained from primary and metastatic lesions (n=36 altogether), as well as plasma samples (n=501), the latter serially collected coincident with medical imaging re-evaluations. tCNAs/ctTNAs were sequenced by ultra-deep, largely overlapping 50-gene panels on Ion Torrent Gene Studio S5. Ortogonal dPCR validation was by dPCR (Quant Studio 3D). ctTNAs were correlated with clinical readouts and patient outcomes. Results: from September 2018 to January 2022, 50 HER2+ mBC patients receiving T-DM1 as second-line treatment. Median time to progression was 6.5 months (range 2.0-27.2). As previously shown, only a minority of patients (9/50 – 18%) retained residual HER2 amplification in blood at baseline, likely due to HER2 counterselection during previous therapy lines; all of them (9/9) underwent further neutralization during T-DM1 treatment, but an HER2-neutral blood status was reached in only 5 patients. In contrast, 2 HER2-neutral patients acquired HER2 amplification, suggesting either insufficient T-DM1 pressure or an unprecedented clonal escape mechanism. Overall, the circulating HER2 status did not correlate with progression free survival (PFS), further highlighting a loss of clinically relevant HER2 oncogenic dependence. At baseline, 24 circulating mutations were detected in 29/50 (58%) patients, 9 of which did not overlap with tissue mutations. Of note, carrying a given aberration in either blood or tissue resulted in outcome trends (p=0.16), but no clear association with therapeutic response. Rather, it was serial monitoring (appearance of any aberration in the blood) that predicted a dismal clinical outcome in 16/41 (39%) patients, with a median time to progression of 2.8 months (2.2-3.9). Unfortunately, liquid biopsy (LB) was confirmed to miss most patients developing brain (3/3 patients) or skin (2/3 patients) metastases. Most circulating alterations present at progression (40/60) were actionable (OncoKB level < 3B) in 34/41 (82.9%) patients, suggesting that LB may guide therapeutic strategies in post-T-DM1 settings. Conclusions: GIM21 trial showed that LB accurately predicts clinical outcome and reveals actionable drivers of T-DM1 escape. The final analysis are ongoing. Citation Format: Alessandra Fabi, Matteo Allegretti, Elena Giordani, Gianluigi Ferretti, Grazia Arpino, Alberto Zambelli, Claudia Omarini, Ida Paris, Andrea Botticelli, Emilio Bria, Antonella Palazzo, Stefania Gori, Francesco Cognetti, Patrizio Giacomini. Liquid biopsy and Ado-trastuzumab emtansine (T-DM1): drug-resistance traits in the blood of HER2-positive metastatic breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-22-01.

To evaluate the influence on peri-implant soft and hard tissues of one-piece implants with a convergent hyperbolic profile collar placed at different depths with respect to the bone crest.Six dogs were included in the experiment. Three months after mandibular tooth extractions, two one-piece implants carrying a 2.8-mm-high convergent hyperbolic profile collar were placed in the alveolar crest with the coronal margin of the rough surface either 0.8 mm (test-1) or 1.8 mm (test-2) deeper with respect to the bone crest (Ct0). Two similar implants were instead placed flush to Ct0 as controls (control-1 and control-2, respectively). Healing screws were connected, and nonsubmerged healing was allowed. After 4 months, block sections were harvested, and histologic slides were prepared in a buccolingual plane.In the histologic analyses, both the buccal crest and coronal level of osseointegration were located more coronally at the test compared to the control implants concerning the implant. However, the buccal bone crest with respect to Ct0 presented a loss of 0.8 ± 0.4 mm at the test-1 and 0.5 ± 0.4 mm at the control-1 implants (P = .028), and a loss of 2.0 ± 1.0 mm and 0.7 ± 0.4 mm at the test-2 and control-2 implants (P = .028), respectively. At the control implants, the collars were exposed above the peri-implant mucosa, while those of the test implants were not. However, the coronal level of the peri-implant mucosa with respect to Ct0 was located more apically at the test compared to the control implants.The placement of implants with a hyperbolic convergent profile collar in the subcrestal position resulted in higher buccal bone resorption and more soft tissue recession compared to the crestal implants with respect to the level of the bone crest at placement.

Purpose: To monitor the early bone reaction in a canine model to a conventional sandblasted and dual acid-etched implant surface (ABT), a nanostructured hydrophilic surface (Nano), a dry salt–bioactivated ultra-hydrophilic surface (Hydro), and a bioactivated nanosurface obtained from the addition of dry salts to the Nano surface (Nano-Active). Materials and Methods: ABT, Nano, Hydro, and Nano-Active implants were placed in 12 dogs. A randomized split-mouth design was adopted. One implant of each type was placed in the mandible 3 months after tooth extraction in healed sites at the first molar region bilaterally. In the same session, the third and fourth premolars were extracted bilaterally and one implant of each type was immediately placed into the extraction socket. The dogs were euthanized at 14 and 28 days following surgery, and the peri-implant bone reaction was assessed histologically using Stevenel’s blue and alizarin red in nondecalcified sections. Results: The postoperative healing was uneventful. The 14-day histologic analysis reported nonsignificant results in terms of difference between the groups, while significant results were found 28 days after surgery. In fact, a significantly higher rate of new bone around the implant was reported in the Nano-Active compared to the Nano groups (51.0% ± 10.2% vs 36.0% ± 10.2%) and Hydro compared to the Nano groups (47.3% ± 10.7% vs 36.0% ± 10.2%). Conclusion: The results obtained indicate that new bone formed after 4 weeks demonstrated a tendency for dry salt–treated bioactivated surfaces to improve bone deposition in the interface in the early stages of healing; however, due to the limited number of dogs, the results failed to show a statistical significance. A study with a significantly larger group of animals should be performed in order to challenge the assumption that ultra-hydrophilic–surface implants might show higher bone-implant contact in immediate postextraction replacement.

Imaging spectroscopy has been developed in the last two decades in the visible and infrared spectral range for detecting pigments and binders on paintings. The near-infrared (NIR) region has been proved effective for the discrimination of lipids and proteinaceous binders. More recently, the mid-infrared (MIR) range has also been tested on paintings. Reflection imaging prototypes already developed could be further optimized for cultural heritage analysis, for example by: enhancing the instrument configuration and performance; adopting compressive strategies to increase data processing speeds; using data validation to confirm that the processed image reflects the composition of a painted surface; and lowering price to enable more cost-effective analysis of large surface areas. Here, we demonstrate a novel hyperspectral Fourier transform spectrometer (HS FTS), which enables an imaging strategy that provides a significant improvement in acquisition rate compared to other state-of-the-art techniques. We demonstrate hyperspectral imaging across the 1400–700 cm−1 region in reflection mode with test samples and the painting ‘Uplands in Lorne’ (Acc. No.: GLAHA43427) by D.Y. Cameron (1865–1945). A post-processing analysis of the resulting hyperspectral images, after validation of reference samples by conventional Fourier transform infrared spectroscopy, shows the potential of the method for efficient non-destructive classification of different materials found on painted cultural heritage. This research demonstrates that the HS FTS is a convenient and compact tool for non-invasive analysis of painted cultural heritage objects at spatio-spectral acquisition rates potentially higher than current FTS imaging techniques. Ultimately, when combined with fast graphics processing unit-based reconstruction, the HS FTS may enable fast, large area imaging. Graphical abstract

Purpose: No evidence exists as to whether type 2 diabetes (T2DM) impairs clinical outcome from Immune Checkpoint Inhibitors (ICI) in patients with solid tumors. Experimental Design: In a large cohort of ICI recipients treated at 21 institutions from June 2014 to June 2020, we studied whether patients on glucose lowering medications (GLM) for T2DM had shorter OS and PFS. We used targeted transcriptomics in a subset of patients to explore differences in the tumor microenvironment of patients with/without diabetes. Results: A total of 1395 patients were included. Primary tumors included NSCLC (54.7%), melanoma (24.7%), renal cell (15.0%) and other carcinomas (5.6%). Following multivariable analysis, patients on GLM (n=226, 16.2%) displayed an increased risk of death (HR 1.29, 95%CI:1.07-1.56) and disease progression/death (HR 1.21, 95%CI:1.03-1.43) independent of number of GLM received. We matched 92 metformin exposed with 363 controls and 78 patients on other oral GLM or insulin with 299 control patients. Exposure to metformin, but not other GLM was associated with an increased risk of death (HR 1.53, 95%CI:1.16-2.03) and disease progression/death (HR 1.34, 95%CI:1.04-1.72). T2DM patients with higher pre-treatment glycaemia had higher neutrophil-to-lymphocyte ratio (p=0.04), while exploratory tumoral transcriptomic profiling in a subset of patients (n=22) revealed differential regulation of innate and adaptive immune pathways in T2DM patients. Conclusions: In this study patients on GLM experienced worse outcomes from immunotherapy, independent of baseline features. Prospective studies are warranted to clarify the relative impact of metformin over a pre-existing diagnosis of T2DM in influencing poorer outcomes in this population.

A)VEGFR-1 expression on untreated DCs and DCs differentiated with sunitinib and pazopanib B) Fold-increase of the amount of IL- 12/IL-10 and CXCL-10/IL-10 released by untreated DCs and DCs differenziated with sunitinib and pazopanib

Tyrosine kinase inhibitors (TKIs) target angiogenesis by affecting, for example, the VEGF receptors in tumors and have improved outcomes for patients with metastatic renal cell carcinoma (mRCC). Immune checkpoint inhibitors (ICIs) have also been proposed for treatment of mRCC with encouraging results. A better understanding of the activity of immune cells in mRCC, the immunomodulatory effects of TKIs, and the characteristics defining patients most likely to benefit from various therapies will help optimize immunotherapeutic approaches. In this study, we investigated the influence of the TKI pazopanib on dendritic cell (DC) performance and immune priming. Pazopanib improved DC differentiation and performance by promoting upregulation of the maturation markers HLA-DR, CD40, and CCR7; decreasing IL10 production and endocytosis; and increasing T-cell proliferation. PD-L1 expression was also downregulated. Our results demonstrate that pazopanib inhibits the Erk/β-catenin pathway, suggesting this pathway might be involved in increased DC activation. Similar results were confirmed in DCs differentiated from mRCC patients during pazopanib treatment. In treated patients pazopanib appeared to enhance a circulating CD4+ T-cell population that expresses CD137 (4-1BB). These results suggest that a potentially exploitable immunomodulatory effect induced by pazopanib could improve responses of patients with mRCC in customized protocols combining TKIs with ICI immunotherapy. Cancer Immunol Res; 6(6); 711–22. ©2018 AACR.

A) T cell analysis cultured up to 24 hours with pazopanib and sunitinib. B)VEGF-R1 expression on T cells

Modulation of DCs phenotype during Pazopanib treatment (T0, T1, T2). HLA-DR, CD40 and PD-L1expression is shown for iDCs. mDCs have a strong down-regulation of PD-L1 during pazopanib treatment. Results are representative of Patient 1

Supplementary Table from Circulating CD137+ T Cells Correlate with Improved Response to Anti-PD1 Immunotherapy in Patients with Cancer

Supplementary Figure from Circulating CD137+ T Cells Correlate with Improved Response to Anti-PD1 Immunotherapy in Patients with Cancer

Purpose:CD137 molecule is expressed by activated lymphocytes, and in patients with cancer identifies the tumor-reactive T cells. In solid tumors, high levels of circulating CD137+ T cells are associated with the clinical response and the disease-free status. Here, we examined the role of the CD137+ T cells in the improvement of patients' selection for immunotherapy treatment.Experimental Design:Peripheral blood mononuclear cells derived from 109 patients with metastatic cancer (66 patients for the identification cohort and 43 for the validation cohort) were analyzed for the expression of CD3, CD4, CD8, CD137, and PD1 molecules before the beginning of anti-PD1 therapy. Twenty healthy donors were used as control. The soluble form of CD137 (sCD137) was also analyzed. The CD137+ T cell subsets and the sCD137 were correlated with the clinicopathologic characteristics. The distribution of CD137+ T cells was also examined in different tumor settings.Results:The percentage of CD137+ T cells was higher in healthy donors and in those patients with a better clinical status (performance status = 0–1, n°metastasis≤2) and these high levels were ascribed to the CD8+CD137+ T cell population. The high frequency of CD137+ and CD8+CD137+ T cells resulted as a prognostic factor of overall survival (OS) and progression-free survival (PFS), respectively, and were confirmed in the validation cohort. High levels of CD3+CD137+PD1+ lymphocytes were associated with a low number of metastasis and longer survival. Instead, the high concentration of the immunosuppressive sCD137 in the serum is associated with a lower PFS and OS. In tumor bed, patients with a complete response showed a high percentage of CD137+ and CD8+ T cells.Conclusions:We propose the CD137+ T subset as an immune biomarker to define the wellness status of the immune system for successful anticancer immunotherapy.

Purpose Single-agent immune checkpoint inhibitor (IO) therapy is the standard of care for non-oncogene addicted advanced non-small cell lung cancer (aNSCLC) with PD-L1 ≥ 50%. High tumor mutation burden (H-TMB) is a notable biomarker for IO response. Smoking-induced harm generates H-TMB in smoking aNSCLC patients (S-pts), whereas never-smoking patients (NS-pts) usually have low TMB and are IO-unresponsive. However, NS-pts with H-TMB have not been well molecularly characterized. Experimental design Clinical data of 142 aNSCLC patients with PD-L1 ≥ 50% treated with first-line pembrolizumab were retrospectively collected. Next-generation sequencing was performed using the FoundationOne®CDx assay to correlate genomic alterations with clinical characteristics and response outcomes. Detected mutations were classified into eleven main pathways: cell cycle, Hippo, Myc, Notch, oxidative stress/Nrf2, PI3K, RTK/RAS/MAP, TGF-b, p53, b-catenin/Wnt, and DDR. Enrichment analysis was performed on pathways with at least one mutation per patient to characterize patient subgroups based on mutated pathways. Moreover, to further investigate the molecular characterization of patients’ subgroups, we built and analyzed the patient similarity network exploiting the mutational profile to compute the pairwise similarity between patients. Results There were 111 S-pts and 31 NS-pts; S-pts had higher TMB (median TMB: 8 vs. 4 Mut/Mb). However, 11 NS-pts had high TMB (median TMB: 16.39 Mut/Mb) and were significantly enriched in b-catenin/Wnt and DDR pathway mutations (p-values=0.0027 and 0.0014, respectively) compared to others and H-TMB/S-pts. Using publicly available molecular characterization data (of 853 NSCLC patients from 2 randomized controlled trials), DDR pathway mutations were confirmed to be enriched in NS-pts with H-TMB. In the real world cohort the subgroup of H-TMB/NS-pts with DDR pathway mutation showed better IO response and survival. Moreover, the similarity network analysis of the NS-pts revealed the presence of one subgroup characterized by high TMB, improved OS and a prevalence of DDR pathway mutations. Conclusions DDR signature has a potential role as additional generator of H-TMB in NS-pts. This subgroup of IO-responsive NS-pts may have better prognosis.

In this paper, we provide evidence that Zn$$^{2+}$$ 2 + ions play a role in the SARS-CoV-2 virus strategy to escape the immune response mediated by the BST2-tetherin host protein. This conclusion is based on sequence analysis and molecular dynamics simulations as well as X-ray absorption experiments [1].

Samuel Cabanchik. La redención de la realidad. Borges, una peripecia filosófica. Buenos Aires: Eudeba, 2021, 142 páginas. Pablo Maurette. La carne viva. Buenos Aires: Mardulce, 2018, 240 páginas.

Ghrelin is an octanoylated peptide acting by the activation of the growth hormone secretagogue receptor, namely, GHS-R1a. The involvement of ghrelin in several physiological processes, including stimulation of food intake, gastric emptying, body energy balance, glucose homeostasis, reduction of insulin secretion, and lipogenesis validates the considerable interest in GHS-R1a as a promising target for the treatment of numerous disorders. Over the years, several GHS-R1a ligands have been identified and some of them have been extensively studied in clinical trials. The recently resolved structures of GHS-R1a bound to ghrelin or potent ligands have provided useful information for the design of new GHS-R1a drugs. This perspective is focused on the development of recent nonpeptide small molecules acting as GHS-R1a agonists, antagonists, and inverse agonists, bearing classical or new molecular scaffolds, as well as on radiolabeled GHS-R1a ligands developed for imaging. Moreover, the pharmacological effects of the most studied ligands have been discussed.

Purpose: CD137 molecule is expressed by activated lymphocytes, and in patients with cancer identifies the tumor-reactive T cells. In solid tumors, high levels of circulating CD137+ T cells are associated with the clinical response and the disease-free status. Here, we examined the role of the CD137+ T cells in the improvement of patients' selection for immunotherapy treatment. Experimental Design: Peripheral blood mononuclear cells derived from 109 patients with metastatic cancer (66 patients for the identification cohort and 43 for the validation cohort) were analyzed for the expression of CD3, CD4, CD8, CD137, and PD1 molecules before the beginning of anti-PD1 therapy. Twenty healthy donors were used as control. The soluble form of CD137 (sCD137) was also analyzed. The CD137+ T cell subsets and the sCD137 were correlated with the clinicopathologic characteristics. The distribution of CD137+ T cells was also examined in different tumor settings. Results: The percentage of CD137+ T cells was higher in healthy donors and in those patients with a better clinical status (performance status = 0–1, n°metastasis≤2) and these high levels were ascribed to the CD8+CD137+ T cell population. The high frequency of CD137+ and CD8+CD137+ T cells resulted as a prognostic factor of overall survival (OS) and progression-free survival (PFS), respectively, and were confirmed in the validation cohort. High levels of CD3+CD137+PD1+ lymphocytes were associated with a low number of metastasis and longer survival. Instead, the high concentration of the immunosuppressive sCD137 in the serum is associated with a lower PFS and OS. In tumor bed, patients with a complete response showed a high percentage of CD137+ and CD8+ T cells. Conclusions: We propose the CD137+ T subset as an immune biomarker to define the wellness status of the immune system for successful anticancer immunotherapy.

AIM To describe the histological events that occur after maxillary sinus floor elevation when the elevated and undetached sinus mucosa are in close proximity or in contact with each other. MATERIALS AND METHODS From 76 rabbits, 152 elevated maxillary sinuses were analyzed histologically. Sites without adhesions were classified as "No proximity," whereas the adhesion stages were divided into "Proximity," "Fusion," and "Synechia stages." The width of the pseudostratified columnar epithelium and the distance between the two layers of the elevated and undetached sinus mucosae were measured at various standardized positions. RESULTS Thirty-one sites presenting with adhesions were found. Twelve sites were in the proximity stage," presenting cilia of the two epithelial layers that were shortened and interlinked within the mucous context. Hyperactivity of the goblet cells was also observed. In the other cases, the hyperplastic epithelium showed attempts to reach the contralateral mucosa. The 15 "fusion stage" sites presented regions with epithelial cells of the two mucosal layers that penetrated each other. Four sites presented "synechiae stages," represented by bridges of connective tissue connecting the two lamina propria. CONCLUSIONS Close proximity or tight contact between the elevated and undetached mucosa adhering to the bone walls might occur after maxillary sinus floor elevation. This induced hyperplasia of the epithelial cells and adhesion of the two layers until synechiae formation.

OBJECTIVES To assess upgrading rates in patients on active surveillance (AS) for prostate cancer (PCa) after serial multiparametric magnetic resonance imaging (mpMRI). METHODS We conducted a retrospective analysis of 558 patients. Five different criteria for mpMRI progression were used: 1) a Prostate Imaging Reporting and Data System (PI-RADS) score increase; 2) a lesion size increase; 3) an extraprostatic extension score increase; 4) overall mpMRI progression; and 5) the number of criteria met for mpMRI progression (0 vs 1 vs 2-3). In addition, two definitions of PCa upgrading were evaluated: 1) International Society of Urological Pathology Grade Group (ISUP GG) ≥2 with >10% of pattern 4 and 2) ISUP GG ≥ 3. Estimated annual percent changes methodology was used to show the temporal trends of mpMRI progression criteria. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of mpMRI progression criteria were also analysed. Multivariable logistic regression models tested PCa upgrading rates. RESULTS Lower rates over time for all mpMRI progression criteria were observed. The NPV of serial mpMRI scans ranged from 90.5% to 93.5% (ISUP GG≥2 with >10% of pattern 4 PCa upgrading) and from 98% to 99% (ISUP GG≥3 PCa upgrading), depending on the criteria used for mpMRI progression. A prostate-specific antigen density (PSAD) threshold of 0.15 ng/mL/mL was used to substratify those patients who would be able to skip a prostate biopsy. In multivariable logistic regression models assessing PCa upgrading rates, all five mpMRI progression criteria achieved independent predictor status. CONCLUSION During AS, approximately 27% of patients experience mpMRI progression at first repeat MRI. However, the rates of mpMRI progression decrease over time at subsequent mpMRI scans. Patients with stable mpMRI findings and with PSAD

BackgroundDespite the efficacy of immunotherapy, only a small percentage of patients achieves a long-term benefit in terms of overall survival. The aim of this study was to define an immune profile predicting the response to immune checkpoint inhibitors (ICIs).MethodsPatients with advanced solid tumors, who underwent ICI treatment were enrolled in this prospective study. Blood samples were collected at the baseline. Thirteen soluble immune checkpoints, 3 soluble adhesion molecules, 5 chemokines and 11 cytokines were analyzed. The results were associated with oncological outcomes.ResultsRegardless of tumor type, patients with values of sTIM3, IFNα, IFNγ, IL1β, IL1α, IL12p70, MIP1β, IL13, sCD28, sGITR, sPDL1, IL10 and TNFα below the median had longer overall survival (pConclusionThe combined evaluation of soluble molecules, rather than a single circulating factor, may be more suitable to represent the fitness of the immune system status in each patient and could allow to identify two different prognostic and predictive outcome profiles.

The Archival / Preservation Education SIG session explores curricular innovations for teaching preservation and archival studies. Session includes four presentations of 15 minutes each plus moderated Q&A. Presentations address provenance-based learning with archival collections, the expansion of preservation education and practice, community-engaged learning and archiving with public art, and the development of creative pedagogical tools to support archival advocacy

Spectrally-resolved imaging provides a spectrum for each pixel of an image that, in the mid-infrared, can enable its chemical composition to be mapped by exploiting the correlation between spectroscopic features and specific molecular groups. The compatibility of Fourier-transform interferometry with full-field imaging makes it the spectroscopic method of choice, but Nyquist-limited fringe sampling restricts the increments of the interferometer arm length to no more than a few microns, making the acquisition time-consuming. Here, we demonstrate a compressive hyperspectral imaging strategy that combines non-uniform sampling and a smoothness-promoting prior to acquire data at 15% of the Nyquist rate, providing a significant acquisition-rate improvement over state-of-the-art techniques. By illuminating test objects with a sequence of suitably designed light spectra, we demonstrate compressive hyperspectral imaging across the 700–1400 cm-1 region in transmission mode. A post-processing analysis of the resulting hyperspectral images shows the potential of the method for efficient non-destructive classification of different materials on painted cultural heritage.

Our understanding of the gut microbiota has significantly evolved over the last two decades. Advances in the analysis of the gut microbiome continues to reveal complex microbial communities and discoveries about their role in health and diseases, including cancer development, are continuously growing. In addition, research has demonstrated that the use of antibiotics can modulate the gut microbiota composition negatively and influence cancer treatment outcomes, suggesting that antibiotics should be avoided if possible. In this article, we review the role of the gut microbiota in the formation of GI cancers. We show that specific bacterial populations can positively or negatively affect cancer formation with specific attention given to gastric and colorectal cancer. We also review the role of microbial-targeted therapies on cancer treatment outcomes.

Background Metastasis is the main cause of breast cancer (BC) mortality. Increasing evidence points to a role of syndecan-1 (CD138) expression as a prognostic marker involved in BC tissue and leptomeningeal metastasis. Aim of this study was to investigate and compare syndecan-1 tissue expression and localization in primary and secondary BC, focusing on brain metastases. Methods Syndecan-1 expression was determined by immunohistochemistry. Focal vs diffuse ( 50% of cancer cells, respectively) pattern of expression, cellular localization (cytoplasm vs membrane) and intensity of immunostaining on neoplastic cells were evaluated. Moreover, the extent and pattern of expression of syndecan-1 were compared between primary tumors and paired metastases and correlated with the tumor intrinsic subtype. Results A total of 23 cases, 10 with paired primary and metastatic tumor and 13 brain metastases, were evaluated. Syndecan-1 was expressed in both primary and metastatic BC. A diffuse cytoplasmic expression was observed in most primary BCs; by contrast, all metastatic lesions showed a membrane pattern of expression, suggesting a shift in cellular localization of syndecan-1 during the metastatic process. Concerning the extent of expression, we observed in metastatic lesions, a trend of association between intrinsic subtypes and extent of positivity. In particular, both BC characterized by overexpression of HER2 and triple-negative tumors were correlated with a diffuse pattern of expression with a moderate to strong intensity. Conclusion A diffuse cytoplasmic expression was observed in most primary BCs; by contrast, all metastatic lesions showed a membrane pattern of expression, suggesting a shift in cellular localization of syndecan-1 during the metastatic process.

The melanocortinergic neural circuit, known for its influence on energy expenditure and feeding behavior, also plays a role in stress and stress-induced psychiatric disorders, including anxiety and depression. The major contribution is given by the melanocortin-4 receptor (MC4R) subtype, highly expressed in brain regions involved in the control of stress responses. Furthermore, the MC4R appears to profoundly affect the activity of the hypothalamic-pituitary-adrenal (HPA) axis, and it has been also highlighted a functional and anatomical interaction with the corticotropin-releasing factor (CRF), an important mediator of stress and stress-related behaviors. The MC4R agonists seem to exacerbate stress-inducing anxiety- and depressive-like behavior, while MC4R antagonists have been demonstrated to mitigate such disorders, as shown in several preclinical behavioral tests. The evidence collected in the present review suggests that the melanocortin system, through the MC4R, could possibly modulate behavioral responses to stress, suggesting the use of MC4R antagonists as a possible novel treatment for anxiety and depression induced by stress.

Current knowledge on

Purpose:This 3-year study aimed to evaluate hard and soft tissue modification around a two-piece implant characterized by a transmucosal hyperbolic neck in healthy consecutive patients with a need for single-tooth replacement. Materials and Methods: Two-piece implants (n = 66) were placed with a flapless technique in 56 patients (27 men; 29 women; mean age 55 ± 9 years): 16 immediately after root extraction (immediate group), 20 after 8 to 12 weeks (early group), and 30 after 10 or more months (delayed group). The transmucosal hyperbolic neck was exposed 1 to 1.5 mm above gingival level. Customized abutments were positioned 3 months later with the implant-abutment connection located approximately 1 to 1.5 mm above soft tissue level. Provisional cemented resin crowns were designed with the finishing line at the hyperbolic neck and then positioned to avoid excessive compression of soft tissue, to guide gingival contours. Twenty days later, a definitive metal-ceramic crown was cemented. In all patients, the gingival biotype (thin or thick) was also evaluated. The primary outcomes were as follows: 36-month implant survival rate, peri-implant marginal bone level (MBL, in mm) changes observed in single-blind on radiographs at 1, 3, 6, 12, 24, and 36 months (T1, T3, T6, T12, T24, and T36), and pink esthetic score (PES) at T6, T12, and T36 to analyze soft tissue adaptation after loading and crown application. The secondary outcomes were as follows: plaque score and bleeding on probing (BOP). Linear regression models and multilevel mixed logistic regression were used to detect any statistical difference of MBL according to operative parameters. Kruskal-Wallis one-way analysis of variance (ANOVA) on ranks was performed to assess statistical differences of PES at T6, T12, and T36. Results: The survival rate was 100%. The dropout rate was 1.79%. No infections, mucositis, or peri-implantitis were reported. Implants placed in thick-biotype tissues showed a statistically different lower bone loss at 36 months with respect to the thin biotype (P

The ‘Roman emperor’ Sponsian is known only from an assemblage of coins allegedly found in Transylvania (Romania) in 1713. They are very unlike regular Roman coins in style and manufacture, with various enigmatic features including bungled legends and historically mixed motifs, and have long been dismissed as poorly made forgeries. Here we present non-destructive imaging and spectroscopic results that show features indicative of authenticity. Deep micro-abrasion patterns suggest extensive circulation-wear. Superficial patches of soil minerals bound by authigenic cement and overlain by oxidation products indicate a history of prolonged burial then exhumation. These observations force a re-evaluation of Sponsian as a historical personage. Combining evidence from the coins with the historical record, we suggest he was most likely an army commander in the isolated Roman Province of Dacia during the military crisis of the 260s CE, and that his crudely manufactured coins supported a functioning monetary economy that persisted locally for an appreciable period.

The rising demand for digital information resources and services in the LAM sector has sparked many innovations by educators in recent years, as we seek to prepare students for careers in an environment that has continued to witness rapid and hard-to-predict changes. Granting agencies such as IMLS have played an important role in driving innovation to meet the needs of new professionals, in part by funding curriculum development projects within LIS schools, but also by facilitating dialogues between educators and practitioners. This work traces a 10-year process whereby one LIS school has designed and tested new courses as well as a new Master’s concentration geared to the needs of LAM professionals who will be expected to work intensively with digital technologies, workflows, and collections. Through a succession of projects, some with grant funding, the school has been able to engage practitioners on an ongoing basis, enabling it to build a substantial and regularly updated body of case-study data on LAM practices, which has informed course development efforts and which has enabled the school to meet its key objectives of delivering authentic learning experiences for students and to maintain an up-to-date curriculum in an evolving area of study within the LAM disciplines. It is hoped that both the experience and the results to date will help justify continued support for innovations in LAM education.

Psoriatic arthritis (PsA) is an inflammatory chronic arthritis associated with psoriasis. Currently, data about gender differences in clinical manifestation and therapeutic outcomes of PsA are limited. Frequently, women manifest a peripheral disease while men have an axial localization. Moreover, women display higher disease activity and physical activity limitations, if compared to men. Although the involvement of the temporomandibular joint (TMJ) is quite rare, it can seriously impact the quality of life. The morpho-functional peculiarities of TMJ require a multidisciplinary approach to perform a correct diagnosis and a successful treatment. Here, we report a case of a woman affected by PsA involving TMJ treated by combining pharmacological therapy and an occlusal splint. The coordination between different specialties led to a complete remission of clinical symptoms and a regression of lesions.

Made available in DSpace on 2021-06-25T10:22:10Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-01-01 Aim: To evaluate the modifications and possible perforations of the sinus mucosa lining graft particles and implant surfaces after sinus lifting. Material and methods: Twelve New Zealand rabbits underwent a bilateral sinus lifting using either autogenous bone harvested from the tibia (AB; autogenous bone group) or deproteinized bovine bone mineral (DBBM group) as filler. Implants were simultaneously installed. Thinned sites (

Objective BRCA carriers are recommended to undergo prophylactic risk-reducing salpingo-oophorectomy (RRSO). Possible adverse health impacts of RRSO, particularly when done before natural menopause, can reduce the long-term satisfaction with this risk-reducing strategy. The aim of this study was to prospectively evaluate the level of satisfaction of women undergoing RRSO, also in relation to some specific characteristics at RRSO. Methods A prospective cohort study was performed in the Modena Family Cancer Clinic of the University Hospital of Modena (Italy). All BRCA1/2 confirmed mutation carriers who decided to undergo RRSO were recruited between 2016 and 2019. Results Fifty-five women (29 BRCA1 and 26 BRCA2) (mean age: 50.4 ± 7.7 years [range 35-79]) were included with a mean follow-up after RRSO of 660.9 days (1.8 years) (range 35-1,688 days) (median: 549 days). No intraepithelial (Serous Tubal Intraepithelial Carcinoma)/invasive cancers were found (0%) at RRSO. No vasomotor symptoms at 1 month after surgery were reported by 11/22 (50%) premenopausal women at RRSO. All women (100%) with new "RRSO-caused" vasomotor symptoms with no previous breast cancer initiated postmenopausal hormone therapy. At the final follow-up the satisfaction rate (0-100 visual analog scale points) of the participants was 96.4 ± 8.6 points (range 62-100). To the question "Would you undergo RRSO again if it was proposed today? (0-100 visual analog scale points)" the answer was 99.4 ± 3.2 points (range 79-100). These scores were in general very high and did not change in the different groups according to pre/postmenopausal status at RRSO, cancer survivors versus healthy women at RRSO, BRCA status, hormone therapy users/nonusers after RRSO, "RRSO-caused" symptoms versus not RRSO-caused (P > 0.05). Conclusions Findings from this prospective study suggest that satisfaction with RRSO is very high and little dependent on the participants' characteristics at surgery. Women at high risk for ovarian cancer are very satisfied with their choice of risk-reduction strategy.

Background: Anticoagulants (AC) are among the most often prescribed drugs in the world. Data regarding ACs’ effect on the osseointegration of dental implants is lacking. Purpose: The aim of the present retrospective cohort study was to evaluate the effect of anticoagulants (AC) on early implant failure (EIF). The null hypothesis was that the use of AC increases the incidence of EIF. Materials and Methods: The research included 687 patients who underwent 2971 dental implant placements in the department of oral and maxillofacial surgery in Rabin medical center, Beilinson hospital, by specialists in oral and maxillofacial surgery. The study group comprised 173 (25.2%) patients and 708 (23.8%) implants using AC. The rest of the cohort served as a control. A structured form was used to collect data at patient and implant level. EIF was defined as implant failure within a period of up to 12 months from loading. EIF was the primary outcome parameter. A logistic regression model was used to predict EIF. Results: Implants placed in individuals ≥ 80 (odds ratio (OR) = 0.34, p = 0.05), and ASA 2/3 vs. ASA 1 individuals (OR = 0.30, p = 0.02/OR = 0.33, p = 0.03, respectively) had decreased odds of EIF, and implants in those using anticoagulants (OR = 2.64, p = 0.01) had increased odds of EIF. At the patient level, the odds of EIF in ASA 3 (OR = 0.53, p = 0.02) and IHD (OR = 0.40, p = 0.02) individuals decreased. In AF/VF (OR = 2.95, p = 0.01) individuals, EIF odds increased. Conclusions: Within the limitations of the present study, the use of AC is significantly associated with an increased likelihood of EIF: the OR was 2.64. Future research is required to validate and examine the prospective impact of AC on the osseointegration phenomena.

The introduction of the so-called immune checkpoint inhibitors (ICIs) substantially changed the history of cancer therapy. On the other hand, they can induce the development of rheumatic immune-related adverse events (Rh-irAEs). In the scenario of a joint oncology/rheumatology outpatient clinic, we conducted a single-centre descriptive study to define from a laboratory, clinical and therapeutic point of view, rheumatic conditions developed during anti-PD1 treatment. The study included 32 patients (M/F 16/16, median age 69, IQR 16.5). According to the international classification criteria, eight patients could be classified as affected by Rheumatoid Arthritis, one by Psoriatic Arthritis, six by Polymyalgia Rheumatica, five by systemic connective tissue diseases (two systemic lupus erythematosus, two Sjögren’s syndrome, one undifferentiated connective tissue disease). The remaining patients were diagnosed as having undifferentiated arthritis or inflammatory arthralgia. The median interval between ICIs starting and the onset of symptoms was 14 weeks (IQR 19.75). Moving to treatment, the longitudinal observation revealed that all RA, PsA and CTD patients required the introduction of treatment with DMARDs. In conclusion, the growing use of ICIs in a real-life setting confirmed the possible development of different rheumatological conditions, further emphasising the need for shared oncology/rheumatology management.

Precancerous lesions of the uterine cervix, due to HPV infections, are still today a great medical challenge. This clinical case highlighted the effectiveness of epigallocatechin gallate (EGCG), vitamin B12, folic acid, and hyaluronic acid (HA) in counteracting HPV lesions in a 39-year-old patient with a long history of viral persistence, cervical lesions of various degree, and several unsuccessful surgical approaches. After eight weeks of treatment, both the histological and cytological analyses revealed only a chronic cervicitis without any malignant lesions or cellular dysplasia, thus reducing the urgency of an invasive surgery, a total hysterectomy.

Background: One year of adjuvant trastuzumab with 12 cycles of weekly paclitaxel represents the standard of care for patients with pathological tumor size ≤2cm, node-negative, HER2-positive early breast cancer. Data supporting this indication derive from a single-arm, phase II trial that enrolled 410 patients in the United States only, where the 3 years invasive disease-free survival (DFS) rate was 98.7% (95% CI 97.6-99.8). Therefore, real-world data regarding the clinical outcomes of these patients are needed to confirm the efficacy and safety of this adjuvant anthracycline-free regimen in this population. Methods: We conducted a retrospective, observational, multicentric study to investigate survival outcomes of patients with stage I HER2-positive early breast cancer treated with adjuvant paclitaxel and trastuzumab in seven selected sites in two countries (Belgium and Italy). Eligible patients were men and women with early breast cancer of pathological tumor size between 5 and 20 mm, node-negative (N0 or N1mic), and treated with weekly adjuvant paclitaxel for 12 weeks and trastuzumab (6 mg/kg every 3 weeks administration for 1 year). Patients with a history of previous cancers were not included. The primary endpoint was disease-free survival (DFS) at 3 years from diagnosis. Thus, an optimal follow-up of 3 years from surgery was required. Baseline clinico-pathological characteristics, treatment data, disease recurrences and survival status were extracted from medical records. Survival analysis was performed using log-rank regression test. Results: Overall, 240 patients who received their adjuvant treatment between January 2014 and December 2018 were included in the analysis. The median age was 59.5 years (IQR 50.0-66.9), and 69.6% of patients were post-menopausal at the time of diagnosis. Seventy (31.8%) patients had hypertension and 20 (8.3%) had other cardiac comorbidities. Ductal carcinoma was the most represented histological type (86.3%). The median tumor size was 12mm (IQR 9-15), only seven (2.9%) patients had N1miC, and the majority of tumors (85.0%) were ER-positive. Breast-conserving surgery was performed in 80.8% of patients and 78.2% of patients had adjuvant radiotherapy. The median number of administrated cycles of weekly paclitaxel was 12 (range 1-12) and for trastuzumab 18 (range 1-19). Only one patient stopped trastuzumab prematurely because of safety reason. Aromatase inhibitors were the most frequently administered endocrine therapy (75.7% of patients with ER-positive disease). With a median follow-up of 4.7 (IQR 3.6-5.6) years, we observed a 3-year DFS rate of 98.8% (95% CI 96.2-99.6), with only three disease recurrences (one local and two distant) and four deaths (none of which was breast cancer related) during the duration of the follow-up. Conclusions: In this real-world clinical outcome of patients with stage I HER2-positive breast cancer treated with adjuvant trastuzumab and paclitaxel appeared excellent, with a 1.2% rate of recurrence at 3 years. Our data support the efficacy of an anthracycline-free regimen in this population. A longer follow-up will provide more mature data on overall survival and late relapses, especially in the ER-positive subgroup of patients. Citation Format: Veronique Debien, Elisa Agostinetto, Marianna Sirico, Flavia Jacobs, Chiara Molinelli, Michel Moreau, Marianne Paesmans, Ugo De Giorgi, Armando Santoro, Donatienne Taylor, François P. Duhoux, Andrea Botticelli, Giacomo Barchiesi, Matteo Lambertini, Evandro de Azambuja, Martine Piccart. Real-world clinical outcomes of patients with stage I HER2-positive breast cancer treated with adjuvant paclitaxel and trastuzumab [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-01-04.