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Abstract Background Immune checkpoint inhibitors (ICIs), administered alone or combined with chemotherapy, are the standard of care in advanced non-oncogene addicted Non-Small Cell Lung Cancer (NSCLC). Despite these treatments' success, most long-term survival benefit is restricted to approximately 20% of patients, highlighting the need to identify novel biomarkers to optimize treatment strategies. In several solid tumors, immune soluble factors, the activatory CD137+ Tcells, and the immunosuppressive cell subsets Tregs and MDSCs (PMN(Lox1+)-MDSC and M-MDSCs) correlated with responses to ICIs and clinical outcomes thus becoming appealing predictive and prognostic factors. This study investigated the role of distinct CD137+ Tcell subsets, Tregs, MDSCs, and immune-soluble factors in NSCLC patients as possible biomarkers. Methods The levels of T cells, MDSCs and soluble factors were evaluated in 89 metastatic NSCLC patients who underwent ICIs as first- or second-line treatment. T cell analysis was performed by cytoflurimetry evaluating Tregs and different CD137+ Tcell subsets also combined with CD3+, CD8+, PD1+, and Ki67+ markers. Circulating cytokines and immune checkpoints were also evaluated by Luminex analysis. All these parameters were correlated with several clinical factors (age, sex, smoking status, PS and TPS), response to therapy, PFS , and OS . The analyses were conducted in the overall population and in patients treated with ICIs as first-line (naïve patients). Results In both groups of patients, high levels of circulating CD137+ and CD137+PD1+ T cells (total, CD4 and CD8) and the soluble factor LAG3 positively correlated with response to therapy. In naïve patients, PMN(Lox1+)-MDSCs negatively correlated with clinical response, and a high percentage of Tregs was associated with favorable survival. Moreover, the balance between Treg/CD137+ Tcells or PMN(Lox1+)-MDSC/CD137+ Tcells was higher in non-responding patients and was associated with poor survival. CD137+ Tcells and Tregs resulted as two positive independent prognostic factors. Conclusion High levels of CD137+, CD137+PD1+ Tcells and sLAG3 could predict the response to ICIs in NSCLC patients independently by previous therapy. Combining the evaluation of CD137+ Tcells and Tregs also as Treg/CD137+ T cells ratio it is possible to identify naive patients with longer survival.

Abstract Objective This systematic review aimed at assessing the effect of the repositioned bone lid on bone augmentation in lateral sinus lift in pre-clinical in vivo and clinical studies. Secondary aims were to report on the healing of the bone window and to assess the implant survival rate. Material and methods Animal and human studies comparing lateral maxillary sinus floor elevation in combination or not with the repositioned bone lid were retrieved from MEDLINE (PubMed), Web of Science and Cochrane online library. Studies published in English up to April 2022 and reporting on histological and/or radiographic outcomes were considered. Case reports, case series and reviews were excluded. A hand search was also conducted. Risk of bias was assessed and meta-analysis performed to investigate the effect of the bone lid on new bone formation. Results After screening, 5 animal studies (4 in rabbits, 1 in sheep) and 2 clinical studies (1 RCT, 1 case–control) were included. Meta-analysis confirmed a higher new bone formation in rabbits at 2 and 8 weeks using the bone lid. The two clinical studies investigated lateral sinus lift with concomitant implant placement and reported similar results and high short-term implant success rate in both test and control groups. Conclusions The meta-analysis provided moderate evidence that the repositioned bone lid favored the formation of new bone to a higher extent as compared to resorbable membranes in animal studies. Implant success seems not to be influenced by the technique in the short term.

Abstract Objective First-line therapy for metastatic squamous cell carcinoma of the head and neck (R/M HNSCC) has been revolutionized by the introduction of anti-checkpoint monoclonal antibodies, which have shown a significant improvement in overall survival (OS) gaining approval in a first line setting. Efficacy and safety of first-line weekly chemotherapy, compared to 3-weeks treatment, was retrospectively evaluated in a frail patient population with R/M HNSCC with the aim to evaluate its role as part of a personalized first-line approach. Methods A total of 124 patients with locally incurable R/M HNSCC receiving weekly (21) or three-weekly (103) chemotherapy plus cetuximab in a first line setting from December 2010 to September 2020 were retrospectively reviewed. Treatment outcomes in terms of objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicities were analysed. Results Patients in the three-week subgroup were ECOG PS 0 (39) and 1 (64) while patients in weekly group (21) were all PS 2. No significant differences were reported in terms of age, sex, smoking and previous alcohol abuse considering the two distinct subgroups. Moreover, no statistically significant difference was found in PFS and OS between the two treatment subgroups. The response rate was 35% (36 patients) and 34% (7 patients) in three-week and weekly treatment group, respectively. Seventy patients (68%) in the three-week group experienced chemotherapy-related toxicities, predominantly G3. In the weekly group a predominantly low-grade toxicity was found in a lower number of patients (52%). Conclusion The weekly schedule appears to be an active and safe strategy in frail patients with R/M HNSCC. Based on these data, a weekly schedule could be considered as a first line treatment in all frail patients excluded from pembrolizumab treatment and a study on the combination of weekly chemotherapy and immunotherapy should be performed.

Abstract In metastatic breast cancer (mBC), the change of human epidermal growth factor receptor 2 (HER2) status between primary and metastatic lesions is widely recognized, however clinical implications are unknown. Our study address the question if relevant differences exist between subjects who preserve the HER2 status and those who gain the HER2 positivity when relapsed. Data of patients affected by HER2-positive mBC, treated with pertuzumab and/or trastuzumab-emtansine (T-DM1) in a real-world setting at 45 Italian cancer centers were retrospectively collected and analyzed. From 2003 to 2017, 491 HER2‐positive mBC patients were included. Of these, 102 (20.7%) had been initially diagnosed as HER2-negative early BC. Estrogen and/or progesterone receptor were more expressed in patients with HER2-discordance compared to patients with HER2-concordant status (p

Abstract Background The favourable safety profile and the increasing confidence with immune checkpoint inhibitors (ICIs) might have boosted their prescription in frail patients with short life expectancies, who usually are not treated with standard chemotherapy. Methods The present analysis aims to describe clinicians’ attitudes towards ICIs administration during late stages of life within a multicenter cohort of advanced cancer patients treated with single agent PD-1/PD-L1 checkpoint inhibitors in Italy. Results Overall, 1149 patients with advanced cancer who received single agent PD-1/PD-L1 checkpoint inhibitors were screened. The final study population consisted of 567 deceased patients. 166 patients (29.3%) had received ICIs within 30 days of death; among them there was a significantly higher proportion of patients with ECOG-PS ≥ 2 (28.3% vs 11.5%, p

Abstract Background The response to immunotherapy can be impaired by several factors including external intervention such as drug interactions with immune system. We aimed to examine the immunomodulatory action of opioids, since immune cells express opioid receptors able to negatively influence their activities. Methods This observational, multicenter, retrospective study, recruited patients with different metastatic solid tumors, who have received immunotherapy between September 2014 and September 2019. Immunotherapy was administered according to the standard schedule approved for each primary tumor and line of treatment. The concomitant intake of antibiotics, antifungals, corticosteroids and opioids were evaluated in all included patients. The relationship between tumor response to immunotherapy and the oncological outcomes were evaluated. A multivariate Cox-proportional hazard model was used to identify independent prognostic factors for survival. Results One hundred ninety-three patients were recruited. Overall, progression-free survival (PFS) and overall survival (OS) were significantly shorter in those patients taking opioids than in those who didn’t (median PFS, 3 months vs. 19 months, HR 1.70, 95% CI 1.37–2.09, p

Summary: Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are innovative small target molecules that, in combination with endocrine therapy, have recently been employed in the treatment of patients with HR+/HER2− metastatic breast cancer (mBC). In this prospective study, we investigate the impact of CDK4/6i on the immune profile of patients with HR+/HER2− mBC. Methods: Immune cell subsets were analysed using flow cytometry of peripheral blood mononuclear cells (PBMCs) isolated from patients with HR+/HER2− mBC, both before and during treatment. Regulatory T cells (Tregs) were identified using the markers CD4, CD25, CTLA4, CD45RA, and intracellular FOXP3. Monocytic and polymorphonuclear myeloid-derived suppressor cells (M-MDSCs and PMN-MDSCs) and other immune populations were analysed using CD45, CD14, CD66b, CD11c, HLA-DR, CD3, CD8, CD28, CD137, PD1, CD45RA, CCR7, and Ki67. Findings: The percentage of circulating Tregs and M/PMN-MDSCs was significantly downregulated from baseline during CDK4/6i-treatment (p

Abstract Background After sinus floor augmentation, a thickening of the sinus mucosa has been described. The aim of the present study was to evaluate the involvement of the maxillary sinus ostium in the edematous processes after a sinus floor augmentation procedure. Methods Seventy-two cone-beam computerized tomographies (CBSTs) were taken before sinus floor augmentation and after 1 week and 9 months from surgery and analyses. Sinus mucosa thickness and area, ostium diameter and patency, and extension of the post-surgical transient mucosal thickening in relation to the ostium were evaluated on the CBCTs for all three periods. The term “virtual” when referring to sinus mucosa thickness and area was introduced because of the edema and bleeding that both contributed to a transient thickening and additional elevation of the sinus mucosa. Results The mean virtual thickness of the sinus mucosa was 2.7 ± 4.0 mm, 7.7 ± 7.1 mm, 1.7 ± 2.0 mm before surgery, and after 1 week and 9 months. The virtual mucosa area was 37.2 ± 52.5 mm2, 184.5 ± 153.8 mm2, and 34.0 ± 50.7 mm2. The ostium diameter at the three periods evaluated was 1.8 ± 0.5 mm, 1.1 ± 0.6 mm, 1.5 ± 0.8 mm, respectively. Three infundibula (4.2%) were found out of patency before surgery while this number increased to 14 (19.4%) after 1 week. Nine months after surgery, only one infundibulum (1.4%) was out of patency, however, without presenting signs of sinus pathologies. The extension of the mucosal edema on the palatal sinus was reduced after 9 months of healing. Conclusions One week after sinus floor augmentation, the maxillary sinus mucosa increased in dimensions and in several cases involved the ostium, reducing its diameter and producing a transient loss of patency. After 9 months of healing, the initial conditions were recovered.

Abstract Background In a previous experimental study, new bone was found growing within granules of HA/β-TCP. In vitro and experimental studies have shown increased protein adsorption and cell adhesion graft material bioactivated with Argon plasma. The aims of the present experiment were to study new bone ingrowth into β-TCP/HA granules used as filler material for sinus lifting and the influence on the healing of the bioactivation of the graft with argon plasma. Methods Sinus lifting was carried out in 20 rabbits using 60% HA and 40% β-TCP as filler material either bio-activated with argon plasma (plasma group) or left untreated (control group). The antrostomies were closed with collagen membranes. Biopsies representing the healing after 2 and 10 weeks were collected, and ground sections were prepared for histomorphometric analyses. Various regions of the elevated space were analyzed both around (outer bone; OB) and inside (interpenetrating bone network, IBN) the graft particles. Results After 2 weeks of healing, 8.2% and 9.3% (n = 10; p = 0.635) of total new bone (OB + IBN) was found in the plasma and control groups, respectively. Small fractions of IBN were found, spreading from the periphery inward of the graft particles. After 10 weeks of healing, the total new bone was 34.0% in the plasma and 31.3% in Control groups (n = 9; p = 0.594). The respective fractions of IBN were 18.0% and 16.0%. New bone was penetrating from the peripheral regions inside the remnants of graft particles, where it was forming a network of bridges in continuity to the remnants of biomaterial through its porosities. The biomaterial decreased in proportion between 2 and 10 weeks from 52.1 to 28.3% in the plasma group, and from 52.5% to 31.9% in the control group. Conclusion The bio-activation with argon plasma on a synthetic graft composed of 60% HA and 40% β-TCP used as filler material for sinus lifting showed a tendency to improve bone formation; however, the difference with the control group was neither statistically significant nor clinically relevant.

Abstract The objective of this study was to compare the healing of the augmented sinus at which the antrostomy was covered with a membrane or the repositioned bone plate. Eight sheep underwent bilateral maxillary sinus floor augmentation. The control site was covered with a resorbable membrane, while at the experimental site the bone plate was repositioned, and both were secured with cyanoacrylate. Animals were euthanised after 4 months and histomorphometric analysis was performed. A large amount of the graft appeared to be partially interpenetrated by the newly formed bone. Statistical analysis demonstrated different percentages of the new bone and bone interpenetrated to the graft between test and control site in the close-to-window area respectively 22.1 ± 12.6 vs 7.5 ± 4.5 (P = 0.028) and 66.1 ± 14.7 vs 44.2 ± 15.1 (P = 0.046). Other areas showed no difference in the bone and graft amount. More bone was found at the edges of the antrostomy in the experimental site, without statistical significance. In the centre of the antrostomy, the replaced bony window appeared bonded to the newly formed bone. No remnants and no biological response to cyanoacrylate were observed. The repositioning of the bony window after sinus floor elevation in sheep led to a larger amount of newly formed bone in the close-to-window zone of the grafted area. The bony window appeared partially bonded to the new bone. Newly formed bone was found interpenetrating the graft granules.

Abstract Aim To study the influence on the healing of the placement of particulate autogenous bone in the antrostomy and in the subjacent region after maxillary sinus elevation. Material and methods Sixteen New Zealand rabbits were undergone to bilateral maxillary sinus floor augmentation with 4 × 4 mm antrostomy dimension. The sinus mucosa was elevated, and the space obtained was filled with xenograft. In the test site (treated sites), autogenous bone was harvested from the tibia and was placed either in the antrostomy and the subjacent region while the control site was left untreated. Antrostomy was covered bilaterally with collagen membranes. Animals were euthanized after 1 and 8 weeks of healing, with 8 rabbits in each group. Histomorphometric evaluations were done. The Wilcoxon test is used for statistical analysis, for a 5% statistical significance. Results After 1 week of healing, the new bone proportion in the antrostomy was 7.7 ± 11.2% and 6.1 ± 6.4% in the treated and untreated sites, respectively. In the subjacent region (close-to-window region), hardly any new bone was assessed. In the elevated region, 2.7–2.8% of total new bone was found in both sites. In the antrostomy region, after 8 weeks of healing, 35.5 ± 20.9% of new bone in the treated sites, and 28.6 ± 24.1% in the untreated sites was observed (p = 0.499). In the close-to-window region, the respective proportions were 25.8 ± 16.1% and 17.6 ± 16.3% (p = 0.018). In the elevated region, the total new bone reached fractions of 27.9 ± 12.9% and 23.6 ± 15.2% in the treated and untreated sites, respectively (p = 0.128). Conclusions The placement of autogenous bone in the antrostomy and the subjacent region after maxillary sinus elevation, slightly enhanced bone formation compared with sites only grafted with xenograft. Though, only the subjacent close-to-window region showed a statistical significance at 8 weeks of healing. Despite the limitations of the present study, due to its preclinical nature, findings should be extrapolated to humans with caution.

Abstract Background Despite the efficacy of immune checkpoint inhibitors (ICIs) only the 20–30% of treated patients present long term benefits. The metabolic changes occurring in the gut microbiota metabolome are herein proposed as a factor potentially influencing the response to immunotherapy. Methods The metabolomic profiling of gut microbiota was characterized in 11 patients affected by non-small cell lung cancer (NSCLC) treated with nivolumab in second-line treatment with anti-PD-1 nivolumab. The metabolomics analyses were performed by GC–MS/SPME and 1H-NMR in order to detect volatile and non-volatile metabolites. Metabolomic data were processed by statistical profiling and chemometric analyses. Results Four out of 11 patients (36%) presented early progression, while the remaining 7 out of 11 (64%) presented disease progression after 12 months. 2-Pentanone (ketone) and tridecane (alkane) were significantly associated with early progression, and on the contrary short chain fatty acids (SCFAs) (i.e., propionate, butyrate), lysine and nicotinic acid were significantly associated with long-term beneficial effects. Conclusions Our preliminary data suggest a significant role of gut microbiota metabolic pathways in affecting response to immunotherapy. The metabolic approach could be a promising strategy to contribute to the personalized management of cancer patients by the identification of microbiota-linked “indicators” of early progressor and long responder patients.

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.

Abstract Objectives To evaluate histomorphometrically the healing at implants installed with standard or very low insertion torque values Material and methods Twelve volunteer patients were recruited, and two screw-shaped titanium devices were installed in the distal segments of the mandible using insertion torque values of either < 10 Ncm or ~ 30 Ncm. The implants were left to heal in a non-submerged fashion. After 8 weeks, biopsies were retrieved, and ground sections were prepared for histological evaluation. Results Histological slides from 11 patients were available for (n = 11). The new bone in contact with the implant surface was 39.3 ± 18.5% and 49.4 ± 9.4% at the < 10 and ~ 30 Ncm sites, respectively. Considering the pre-existing old bone, the total mineralized bone was 46.8 ± 22.1% at the < 10 Ncm sites and 57.0 ± 14.1% at the ~ 30 Ncm. No statistically significant differences were found. New bone density and total mineralized bone density were 36.6 ± 8.1% and 53.0 ± 13.5% at the < 10 Ncm sites and 35.9 ± 10.0% and 52.2 ± 16.0% at the ~ 30 Ncm sites, respectively. No statistically significant differences were disclosed. Conclusion From the data of the present study, it can be concluded that a trend of higher osseointegration was observed at the ~ 30 Ncm compared to the < 10 Ncm torque group. Nevertheless, it can be concluded that an implant installed with a very low torque may achieve a good integration. Trial registration ClinicalTrials.gov NCT04017156; trial retrospectively registered on 12 July 2019.

Abstract Background Fatigue was reported as the most common any-grade adverse event (18.3%), and the most common grade 3 or higher immune-related adverse event (irAE) (0.89%) in patients receiving PD-1/PD-L1 checkpoint inhibitors in clinical trial. Methods The aim of this retrospective multicenter study was to evaluate the correlations between “early ir-fatigue”, “delayed ir-fatigue”, and clinical outcomes in cancer patients receiving PD-1/PD-L1 inhibitors in clinical practice. Results 517 patients were evaluated. After the 12-weeks landmark selection, 386 (74.7%) patients were eligible for the clinical outcomes analysis. 40.4% were NSCLC, 42.2% were melanoma, 15.3% renal cell carcinoma and 2.1% other malignancies. 76 patients (19.7%) experienced early ir-fatigue (within 1 month from treatment commencement), while 150 patients (38.9%) experienced delayed ir-fatigue. Early ir-fatigue was significantly related to shortened PFS (HR = 2.29 [95% CI 1.62–3.22], p

Abstract Aim To study the influence of a collagen membrane placed subjacent to the sinus mucosa on the dimensional changes of augmented maxillary sinus floor. Methods Twenty patients were recruited in the study and randomly assigned to two groups. After the elevation of the maxillary sinus mucosa, a collagen membrane with standardized dimensions was placed at the test sites subjacent to the sinus mucosa and the elevated space was filled with a xenograft, both at test and control sites. A collagen membrane was then used to cover the antrostomy at both sites, and sutures were applied to close the wounds. Cone beam computed tomographies (CBCTs) were taken for all patients before surgery (T0), after 1 week from sinus floor augmentation (T1), and after 9 months of healing (T2). Dimensional changes over time of soft and hard tissues were evaluated on the CBCTs. Results After 1 week of healing, the sinus floor was elevated by 10.0 ± 2.8 mm and 10.6 ± 2.5 mm at the no-membrane and membrane groups, respectively. After 9 months of healing, a similar reduction of the height was observed in both groups, providing a total vertical augmentation of 8.6 ± 2.8 mm at the no-membrane sites and 9.1 ± 3.1 mm at the membrane sites. After 9 months of healing, the hard tissues subjacent to the sinus mucosa appeared to be partially corticalized in three patients in the no-membrane group and in six patients in the membrane group. Conclusions The use of collagen membranes subjacent to the sinus mucosa did not influence the dimensional variations of the augmented regions and the clinical outcomes after 9 months of healing also in absence of perforations.

Abstract Aim To evaluate the progression of an induced peri-implantitis at implants with different diameters and the outcome of a corrective surgical debridement. Methods Three months after the extraction of the mandibular premolars and first molars in six dogs, non-submerged narrow implants (3.3 mm in diameter) or standard implants (3.8 mm and 4.1 mm) were installed in the molar regions, bilaterally. After 3 months, peri-implantitis lesions were induced with ligatures and plaque accumulation for 3 months. Plaque accumulation was allowed for a further month after ligatures removal. A surgical mechanical decontamination of the surfaces was subsequently performed using gauzes soaked in saline and irrigation. Five months after, biopsies were retrieved and histological slides prepared. X-rays were taken at treatment and 5 months after. Results Fourth months after peri-implantitis induction, 2.2 ± 1.0 mm at the standard implants and 3.2 ± 0.4 mm at the narrow implants were observed. Five months after treatment, a mean gain of marginal bone of 0.5 ± 0.6 mm was obtained at the standard implants and of 0.9 ± 0.4 at the narrow implants (p = 0.249). The vertical and horizontal defects were found partially closed. At the histological analysis, the coronal level of osseointegration after 5 months of healing was at 2.1 ± 0.8 mm at the standard implants, and 2.8 ± 0.3 mm at narrow implants (p = 0.116). Conclusions In conclusion, the narrow implants showed a tendency of a faster progression of the induced peri-implantitis compared to standard implants. The implant diameter did not influence the outcome of a surgical treatment of an induced peri-implantitis.

Abstract Background The advent of immune checkpoint inhibitors (ICIs) has considerably expanded the armamentarium against non-small cell lung cancer (NSCLC) contributing to reshaping treatment paradigms in the advanced disease setting. While promising tissue- and plasma-based biomarkers are under investigation, no reliable predictive factor is currently available to aid in treatment selection. Methods Patients with stage IIIB–IV NSCLC receiving nivolumab at Sant’Andrea Hospital and Regina Elena National Cancer Institute from June 2016 to July 2017 were enrolled onto this study. Major clinicopathological parameters were retrieved and correlated with patients’ survival outcomes in order to assess their prognostic value and build a useful tool to assist in the decision making process. Results A total of 102 patients were included in this study. The median age was 69 years (range 44–85 years), 69 (68%) were male and 52% had ECOG PS 0. Loco-regional/distant lymph nodes were the most commonly involved site of metastasis (71%), followed by lung parenchyma (67%) and bone (26%). Overall survival (OS) in the whole patients’ population was 83.6%, 63.2% and 46.9% at 3, 6 and 12 months, respectively; while progression-free survival (PFS) was 66.5%, 44.4% and 26.4% at 3, 6 and 12 months, respectively. At univariate analysis, age ≥ 69 years (P = 0.057), ECOG PS (P

Current knowledge on Leishmania infection after kidney transplantation (KT) is limited. In order to offer a comprehensive guide for the management of post-transplant Leishmaniasis, we performed a systematic review following the latest PRISMA Checklist and using PubMed, Scopus, and Embase as databases. No time restrictions were applied, including all English-edited articles on Leishmaniasis in KT recipients. Selected items were assessed for methodological quality using a modified Newcastle–Ottawa Scale. Given the nature and quality of the studies (case reports and retrospective uncontrolled case series), data could not be meta-analyzed. A descriptive summary was therefore provided. Eventually, we selected 70 studies, describing a total of 159 cases of Leishmaniasis. Most of the patients were adult, male, and Caucasian. Furthermore, they were frequently living or travelling to endemic regions. The onset of the disease was variable, but more often in the late transplant course. The clinical features were basically similar to those reported in the general population. However, a generalized delay in diagnosis and treatment could be detected. Bone marrow aspiration was the preferred diagnostic modality. The main treatment options included pentavalent antimonial and liposomal amphotericin B, both showing mixed results. Overall, the outcomes appeared as concerning, with several patients dying or losing their transplant.

Background: ICIs have strongly improved the outcome of NSCLC patients. However, primary and secondary resistance occur during treatment in most of the patients, with several of them developing fast progressions. Autoantibodies can be related with a dysfunctional immune system, although their association with immune-based anti-cancer therapies has never been investigated. Moreover, so far no reliable predictive factor is currently available to aid in treatment selection. CD137+T-cells are largely known to be the anti-tumor activated effector cells, but they have never been associated with the response to immunotherapies. Methods: Forty-two patients with metastatic NSCLC receiving anti-PD-1 ICIs at Sant'Andrea Hospital and Policlinico Umberto I, from June 2016 to September 2018 were enrolled. Circulating levels of IgM-Rheumatoid Factor were evaluated at baseline and correlated with patients clinical response following the anti-PD-1 treatment. IgM-RF interaction and effect on T-cells in vivo and in vitro were investigated. Findings: IgM-RF in NSCLC patient sera strongly predicted the development of early progression to ICIs. Also, a significant reduction of progression-free survival rate in anti-PD-1 treated patients could be identified when patients were stratified based on IgM-RF positivity and titers. IgM-RF bound preferentially circulating naïve and central memory T-cells and a significant reduction of CD137+ anti-tumor T effector cells was found in IgM-RF positive patients. In addition, a higher percentage of CD137+T-cells in peripheral blood of NSCLC patients at baseline resulted as a strong independent prognostic factor for a better outcome in terms of PFS and OS after the anti-PD-1 treatment. Furthermore, T-cells exposed to IgM-RF showed a robust defect in their migratory ability in response to CCL19 chemokine. Interpretation: In this study we showed that serum IgM-RF can be regarded as predictive factor for the development of early progression and prognostic factor of a reduced progression-free survival and overall-survival in anti-PD-1 treated NSCLC patients. The ability of IgM-RF to bind naïve and central memory T-cells and impair their migration could make account for the reduction of the tumor-reactive CD137+ T-cells population that may cause a non-effectiveness of these T-cells targeting drugs. Fundings: AIRC, MIUR and Sapienza University of Rome.

Immune checkpoint inhibitors (ICIs) and platinum-based chemotherapy (CT) are effective therapeutic agents for the palliative treatment of metastatic non-small-cell lung cancer (NSCLC); the aim of our study was to investigate the acute and chronic renal toxicities in this setting. We collected data on 292 patients who received cisplatin (35%), carboplatin-based regimens (25%), or ICI monotherapy (40%). The primary and secondary outcomes were compared to the acute kidney injury (AKI) rate and the mean estimated GFR (eGFR) decay between groups, respectively, over a mean follow-up duration of 15 weeks. We observed 26 AKI events (8.9%), mostly stage I AKI (80.7%); 15% were stage II AKI, 3.8% were stage III, and none required renal replacement therapy or ICU admission. The AKI rates were 10.9%, 6.8%, and 8.9% for the cisplatin, carboplatin, and ICI groups, respectively, and no significant differences were observed between the groups (p = 0.3). A global mean eGFR decay of 2.2 mL/min was observed, while for the cisplatin, carboplatin, and ICI groups, the eGFR decay values were 2.3 mL/min, 1.1 mL/min, and 3.5 mL/min, respectively. No significant differences were observed between the groups. Cisplatin/carboplatin-based CT and ICIs resulted in a similar incidence of AKI and eGFR decay, suggesting the safety of their cautious use, even in CKD patients.

Abstract Background Immune checkpoint inhibitors have revolutionized the treatment paradigm of highly lethal malignancies like advanced non-small cell lung cancer (NSCLC), demonstrating long-term tumour control and extended patient survival. Unfortunately, only 25–30% of patients experience a durable benefit, while the vast majority demonstrate primary or acquired resistance. Recently, indoleamine 2,3-dioxygenase (IDO) activity has been proposed as a possible mechanism of resistance to anti-PD-1 treatment leading to an immunosuppressive microenvironment. Methods Pre-treatment serum concentrations of tryptophan (trp) and kynurenine (kyn) were measured by high-performance liquid chromatography tandem mass spectrometry in NSCLC patients treated with second-line nivolumab. The IDO activity was expressed with kyn/trp ratio. The associations between kyn/trp ratio and early progression, performance status (PS), age, sex, brain metastases, pleural effusion, progression free survival (PFS) and overall survival (OS) were analyzed using Spearman test and Mann–Whitney test. Results Twenty-six NSCLC patients were included in our study; 14 of them (54%) presented early progression (

Spastic equinovarus (SEV) foot deformity is commonly observed in patients with post-stroke spasticity. Tibialis posterior (TP) is a common target for botulinum toxin type-A (BoNT-A) injection, as a first-line treatment in non-fixed SEV deformity. For this deep muscle, ultrasonographic guidance is crucial to achieving maximum accuracy for the BoNT-A injection. In current clinical practice, there are three approaches to target the TP: an anterior, a posteromedial, and a posterior. To date, previous studies have failed to identify the best approach for needle insertion into TP. To explore the ultrasonographic characteristics of these approaches, we investigated affected and unaffected legs of 25 stroke patients with SEV treated with BoNT-A. We evaluated the qualitative (echo intensity) and quantitative (muscle depth, muscle thickness, overlying muscle, subcutaneous tissue, cross-sectional area) ultrasound characteristics of the three approaches for TP injection. In our sample, we observed significant differences among almost all the parameters of the three approaches, except for the safety window. Moreover, our analysis showed significant differences in cross-sectional area between treated and untreated. Advantages and disadvantages of each approach were investigated. Our findings can thus provide a suitable reference for clinical settings, especially for novice operators.

The Neuropeptide S (NPS), a 20 amino acids peptide, is recognized as the endogenous ligand of a previously orphan G protein-coupled receptor, now termed NPS receptor (NPSR). The limited distribution of the NPS-expressing neurons in few regions of the brainstem is in contrast with the extensive expression of NPSR in the rodent central nervous system, suggesting the involvement of this receptor in several brain functions. In particular, NPS promotes locomotor activity, behavioral arousal, wakefulness, and unexpectedly, at the same time, it exerts anxiolytic-like properties. Intriguingly, the NPS system is implicated in the rewarding properties of drugs of abuse and in the regulation of food intake. Here, we focus on the anorexigenic effect of NPS, centrally injected in different brain areas, in both sated and fasted animals, fed with standard or palatable food, and, in addition, on its influence in the gastrointestinal tract. Further investigations, regarding the role of the NPS/NPSR system and its potential interaction with other neurotransmitters could be useful to understand the mechanisms underlying its action and to develop novel pharmacological tools for the treatment of aberrant feeding patterns and obesity.

Background: Previous locoregional treatment could affect the response to nivolumab in platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). The aim of this study is to evaluate the impact of the clinicopathological characteristics and previous treatment in predicting early progression to nivolumab in a real-world population. Methods: This is an observational, multicenter retrospective/prospective study including patients (pts) with platinum refractory R/M HNSCC who received nivolumab 240 mg every 2 weeks from October 2018 to October 2019. We analyzed the association between previous treatment, clinicopathological characteristics, and early progression (within 3 months). Results: Data from 61 pts were reviewed. Median age was 67 years (30–82). Forty-two pts (69%) received previous locoregional treatment. Early progression to nivolumab occurred in 36 pts (59%), while clinical benefit (stable disease and partial response) was achieved in 25 pts (41%). Early progression to nivolumab was significantly associated to previous locoregional treatment both at univariate and multivariate analysis (p = 0.005 and p = 0.048, respectively). Conclusion: nivolumab in R/M HNSCC is burdened with a high early progression rate. Previous wide neck dissection and high dose radiotherapy may compromise the efficacy of nivolumab, distorting the anatomy of the local lymphatic system and hindering the priming of immune response.

Immune checkpoint inhibitors have revolutionized treatment and outcome of melanoma and many other solid malignancies including non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Unfortunately, only a minority of patients have a long-term benefit, while the remaining demonstrate primary or acquired resistance. Recently, it has been demonstrated that the prevalence of programmed death-ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs) varies based on the anatomical site of metastases. In particular, liver seems to have more immunosuppressive microenvironment while both the presence of lymph nodal disease and lung metastases seem to have the highest prevalence of PD-L1 and TILs. The aim of the present study is to investigate the possible role of site of metastases as a predictive factor for response or resistance to immunotherapy in several types of cancer. In this multicenter retrospective study, we enrolled patients with metastatic NSCLC, melanoma, RCC, urothelial, merkel carcinoma, and colon cancer who received immunotherapy from April 2015 to August 2019. Major clinicopathological parameters were retrieved and correlated with patients’ survival outcomes in order to assess their prognostic value and build a useful tool to assist in the decision-making process. A total of 291 patients were included in this study. One hundred eighty-seven (64%) patients were male and 104 (36%) female. The tumor histology was squamous NSCLC in 56 (19%) patients, non-squamous NSCLC in 99 (34%) patients, melanoma in 101 (35%) patients, RCC in 28 (10%) patients, and other tumors in the remaining 7 (2%) patients. The number of metastatic sites was 1 in 103 patients (35%), 2 in 104 patients (36%) and 3 in 84 patients (29%). Out of 183 valuable patients, the entity of response was complete response (CR), partial response (PR), stable disease (SD), and progression disease (PD) in 15, 53, 31, and 79 patients, respectively. Using an univariate analysis (UVA), tumor burden (p = 0.0004), the presence of liver (p = 0.0009), bone (p = 0.0016), brain metastases (p < 0.0001), the other metastatic sites (p = 0.0375), the number of metastatic sites (p = 0.0039), the histology (p = 0.0034), the upfront use of immunotherapy (p = 0.0032), and Eastern Cooperative Oncology Group (ECOG) Perfomance status (PS) ≥ 1 (p < 0.0001) were significantly associated with poor overall survival (OS). Using a multivariate analysis (MVA) the presence of liver (p = 0.0105) and brain (p = 0.0026) metastases, the NSCLC diagnosis (p < 0.0001) and the ECOG PS (p < 0.0001) resulted as significant prognostic factors of survival. Regarding the progression free survival (PFS), using a UVA of the tumor burden (p = 0.0004), bone (p = 0.0098) and brain (p = 0.0038) metastases, the presence of other metastatic sites (p = 0.0063), the number of metastatic sites (p = 0.0007), the histology (p = 0.0007), the use of immunotherapy as first line (p = 0.0031), and the ECOG PS ≥ 1 (p ≤ 0.0001) were associated with a lower PFS rate. Using an MVA, the presence of brain (p = 0.0088) and liver metastases (p = 0.024) and the ECOG PS (p < 0.0001) resulted as predictors of poor PFS. Our study suggests that the site of metastases could have a role as prognostic and predictive factor in patients treated with immunotherapy. Indeed, regardless of the histology, the presence of liver and brain metastases was associated with a shorter PFS and OS, but these results must be confirmed in further studies. In this context, a deep characterization of microenvironment could be crucial to prepare patients through novel strategies with combination or sequential immunotherapy in order to improve treatment response.

The aim of the experiment was to study the healing at implants installed in site prepared in bone type 1 using different rotation speeds and cooling strategies. The tibiae of twelve sheep were used as experimental sites. Two implant sites were prepared in each tibia using drills either at a high or a mixed speed under irrigation. At the mixed-speed sites, 60 rpm without irrigation were applied for the last drill, the countersink and during implant installation. Biopsies representing the healing after 1, 2, and 6 weeks were obtained and ground sections were prepared. At the histological analyses, after 1 week of healing, no new bone was found at both high- and mixed-speed sites. After 2 weeks of healing, small amounts of newly formed bone were observed in the cortical layer, reaching percentages of 3.6±3.0% at the mixed-speed sites, and of 2.2±1.5% at the high-speed sites. An irrelevant quantity of new bone was seen in the marrow compartments of a few specimens. After 6 weeks of healing, new bone was found in higher quantity, reaching in the cortical compartment 66.9±6.8% and 67.3±17.7% at the mixed- and high-speed sites, respectively. The respective percentages in the marrow compartment were 23.2±13.0% and 30.6±29.2%. No statistically significant differences between high- and mixed-speed groups were found. It was concluded that the use of the last drill and the installation of the implant with or without irrigation yielded similar bone healing and osseointegration.