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BackgroundImmune-checkpoint inhibitors (ICIs) have significantly improved metastatic renal cell carcinoma (mRCC) prognosis, although their efficacy in patients with bone metastases (BMs) remains poorly understood. We investigated the prognostic role of natremia in pretreated RCC patients with BMs receiving immunotherapy.Materials and methodsThis retrospective multicenter study included RCC patients with BMs receiving nivolumab as second-line therapy or beyond. Inclusion criteria involved baseline sodium levels (pre-ICI) and sodium levels after 4 weeks of nivolumab initiation (post-ICI). The population was divided into two groups based on the median value, and response rates, progression-free survival (PFS), and overall survival (OS) were assessed.ResultsAmong 120 eligible patients, those with pre-treatment sodium levels ≥140 mEq/L showed longer OS (18.7 vs. 12.0 months, p=0.04). Pre-treatment sodium levels ≥140 mEq/L were associated with better OS compared to levels

The treatment landscape for metastatic renal cell carcinoma (mRCC) has undergone significant transformations in recent years. The introduction of novel combination therapies involving tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors has resulted in improved oncological outcomes compared to traditional TKI monotherapy. In this evolving paradigm, the pivotal role of the multidisciplinary tumor board is underscored, particularly in shaping the therapeutic trajectory for patients eligible for locoregional interventions like cytoreductive nephrectomy and metastasectomy. In cases where systemic treatment is deemed appropriate, the absence of direct comparisons among the various combination therapies complicates the selection of a first-line approach. The clinician is faced with the challenge of making decisions based on patient-specific factors such as performance status, risk classification according to the International Metastatic Renal Cell Carcinoma Database Consortium, comorbidities, and disease characteristics, including the number and location of metastases and tumor histology. Considering these concerns, we propose, as a member of a Tuscany Interdisciplinary Uro-Oncologic Group, an algorithm to streamline the decision-making process for mRCC patients, offering guidance to clinicians in their day-to-day clinical practice.

BackgroundImmunotherapies exhibit peculiar cancer response patterns in contrast to chemotherapy and targeted therapy. Some patients experience disease response after initial progression or durable responses after treatment interruption. In clinical practice, immune checkpoint inhibitors may be continued after radiological progression if clinical benefit is observed. As a result, estimating progression-free survival (PFS) based on the first disease progression may not accurately reflect the actual benefit of immunotherapy.MethodsThe Meet-URO 15 study was a multicenter retrospective analysis of 571 pretreated metastatic renal cell carcinoma (mRCC) patients receiving nivolumab. Time to strategy failure (TSF) was defined as the interval from the start of immunotherapy to definitive disease progression or death. This post-hoc analysis compared TSF to PFS and assess the response and survival outcomes between patients treatated beyond progression (TBP) and non-TBP. Moreover, we evaluated the prognostic accuracy of the Meet-URO score versus the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score based on TSF and PFS.ResultsOverall, 571 mRCC patients were included in the analysis. Median TSF was 8.6 months (95% CI: 7.0 – 10.1), while mPFS was 7.0 months (95% CI: 5.7 – 8.5). TBP patients (N = 93) had significantly longer TSF (16.3 vs 5.5 months; p < 0.001) and overall survival (OS) (34.8 vs 17.9 months; p < 0.001) but similar PFS compared to non-TBP patients. In TBP patients, a median delay of 9.6 months (range: 6.7-16.3) from the first to the definitive disease progression was observed, whereas non-TBP patients had overlapped median TSF and PFS (5.5 months). Moreover, TBP patients had a trend toward a higher overall response rate (33.3% vs 24.3%; p = 0.075) and disease control rate (61.3% vs 55.5%; p = 0.31). Finally, in the whole population the Meet-URO score outperformed the IMDC score in predicting both TSF (c-index: 0.63 vs 0.59) and PFS (0.62 vs 0.59).ConclusionWe found a 2-month difference between mTSF and mPFS in mRCC patients receiving nivolumab. However, TBP patients had better outcomes, including significantly longer TSF and OS than non-TBP patients. The Meet-URO score is a reliable predictor of TSF and PFS.

Background: Prostate cancer has a multifaceted treatment pattern. Evidence is lacking for optimal treatment sequences for metastatic castration-resistant prostate cancer (mCRPC). Objective: To increase the understanding of real-world treatment pathways and outcomes in patients with mCRPC. Design, setting, and participants: A prospective, noninterventional, real-world analysis of 3003 patients with mCRPC in the Prostate Cancer Registry (PCR; NCT02236637) from June 14, 2013 to July 9, 2018 was conducted. Intervention: Patients received first- and second-line hormonal treatment and chemotherapy as follows: abiraterone acetate plus prednisone (abiraterone)-docetaxel (ABI-DOCE), abiraterone-enzalutamide (ABI-ENZA), abiraterone–radium-223 (ABI-RAD), docetaxel-abiraterone (DOCE-ABI), docetaxel-cabazitaxel (DOCE-CABA), docetaxel-enzalutamide (DOCE-ENZA), and enzalutamide-docetaxel (ENZA-DOCE). Outcome measurements and statistical analysis: Baseline patient characteristics, quality of life, mCRPC treatments, and efficacy outcomes (progression and survival) were presented descriptively. Results and limitations: Data from 727 patients were eligible for the analysis (ABI-DOCE n = 178, ABI-ENZA n = 99, ABI-RAD n = 27, DOCE-ABI n = 191, DOCE-CABA n = 74, DOCE-ENZA n = 116, and ENZA-DOCE n = 42). Demographics and disease characteristics among patients between different sequences varied greatly. Most patients who started on abiraterone or enzalutamide stopped therapy because of disease progression. No randomisation to allow treatment/sequence comparisons limited this observational study. Conclusions: The real-world PCR data complement clinical trial data, reflecting more highly selected patient populations than seen in routine clinical practice. Baseline characteristics play a role in mCRPC first-line treatment selection, but other factors, such as treatment availability, have an impact. Efficacy observations are limited and should be interpreted with caution. Patient summary: Baseline characteristics appear to have a role in the first-line treatment selection of metastatic castration-resistant prostate cancer in the real-world setting. First-line abiraterone acetate plus prednisone seems to be the preferred treatment option for older patients and those with lower Gleason scores, first-line docetaxel for younger patients and those with more advanced disease, and first-line enzalutamide for patients with fewer metastases and more favourable performance status. The benefit to patients from these observations remains unknown.

Abstract Background Nephrectomy is considered the backbone of managing patients with localized and selected metastatic renal cell carcinoma (mRCC). The prognostic role of nephrectomy has been widely investigated with cytokines and targeted therapy, but it is still unclear in the immunotherapy era. Methods We investigated the Meet-URO-15 study dataset of 571 pretreated mRCC patients receiving nivolumab as second or further lines about the prognostic role of the previous nephrectomy (received in either the localized or metastatic setting) in the overall population and according to the Meet-URO score groups. Results Patients who underwent nephrectomy showed a significantly reduced risk of death (HR 0.44, 95% CI 0.32–0.60, p

Abstract Background Nivolumab and cabozantinib are currently approved agents in metastatic renal cell carcinoma (mRCC) but there are no data available for patients progressing to both treatments. The aim of this study was to compare active therapeutic options and best supportive care (BSC) after progression to nivolumab and cabozantinib in mRCC. Methods In this retrospective study, we selected 50 patients from eight Italian centers. The primary endpoint of the study was the overall survival (OS) of patients on active treatment versus BSC. Secondary endpoints were the progression‐free survival (PFS) and objective response rate (ORR). The efficacy of active therapy was also investigated. Results After progression to both nivolumab and cabozantinib, 57.1% of patients were given active treatment (mainly everolimus and sorafenib) while 42.9% received BSC. The median OS was 13 months (95% CI: 4‐NR) in actively treated patients and 3 months (95% CI: 2–4) in BSC patients (p = 0.001). Patients treated with sorafenib had better disease control than those treated with everolimus (stable disease: 71.4% vs. 16.7%, progression disease: 14.3% vs. 58.3%; p = 0.03), with no significant differences in PFS (5 and 3 months, 95% CI: 1–6 vs. 2–5; p = 0.6) and OS (12 and 4 months, 95% CI: 3‐NR vs. 2‐NR; p = 0.2). Conclusion After treatment with both nivolumab and cabozantinib, the choice of a safe active systemic therapy offered better outcomes than BSC.

Abstract Background Despite the increasing number of treatment options, reliable prognostic/predictive biomarkers are still missing for patients affected by metastatic clear cell renal cell carcinoma (mccRCC). Methods Patients with mccRCC undergoing standard first line treatment were enrolled. Blood (12 ml) was drawn at treatment baseline and circulating free DNA (cfDNA) was extracted from plasma. Next-generation sequencing (NGS) was performed on cfDNA using the Oncomine Pan-Cancer Cell-Free Assay and clinical outcomes were correlated with liquid biopsy findings. Results A total of 48 patients were enrolled, 12 received immunotherapy and 36 received a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI). A cfDNA cut-off of 0.883 ng/μl stratified patients based on progression-free survival (PFS) and overall survival (OS) (p = 0.001 and p = 0.008, respectively). cfDNA amount was also correlated with best response (p = 0.006). Additional cfDNA cut-points divided patients into short, intermediate and long responders, with PFS of 4.87 vs 9.13 vs 23.1 months, respectively (p

Metastatic hormone-sensitive prostate cancer (mHSPC) is usually categorized as high- or low-volume disease. This is relevant because low- and high-volume metastatic disease are associated with different outcomes, and thus management of the two forms should differ. Although some definitions have been reported, the concept of oligometastatic disease is not so clearly defined, giving rise to further variability in the choice of treatment, mainly between systemic agents and radiotherapy, especially in the era of metastasis-directed therapy. With the aim of providing clinicians with guidance on best practice, a group of medical and radiation oncologists, experts in prostate cancer, used the round robin method to generate a series of consensus statements on management of low-volume mHSPC. Consensus was obtained on three major areas of controversy: (1) with regard to clinical definitions of mHSPC, it was held that oligometastatic and low-volume disease refer to different concepts and should not be used interchangeably; (2) regarding therapy of de novo low-volume metastatic disease, androgen deprivation therapy alone can be considered undertreatment, and all patients should be evaluated for systemic treatment combinations; local therapy should not be denied in patients with mHSPC, regardless of the intensity of systemic therapy, and metastasis-directed therapy can be proposed in selected cases; (3) with regard to treatment of metachronous metastatic disease, patients should be evaluated for systemic treatment combinations. Metastasis-directed therapy can be proposed to delay systemic treatment in selected cases, especially if prostate-specific membrane antigen positron emission tomography staging has been performed and when indolent disease occurs. It is hoped that clinicians treating patients with mHSPC in daily practice will find this expert opinion of value.

Abstract Background The role of image-derived biomarkers in recurrent oligometastatic Prostate Cancer (PCa) is unexplored. This paper aimed to evaluate [18F]FMCH PET/CT radiomic analysis in patients with recurrent PCa after primary radical therapy. Specifically, we tested intra-patient lesions similarity in oligometastatic and plurimetastatic PCa, comparing the two most used definitions of oligometastatic disease. Methods PCa patients eligible for [18F]FMCH PET/CT presenting biochemical failure after first-line curative treatments were invited to participate in this prospective observational trial. PET/CT images of 92 patients were visually and quantitatively analyzed. Each patient was classified as oligometastatic or plurimetastatic according to the total number of detected lesions (up to 3 and up to 5 or > 3 and > 5, respectively). Univariate and intra-patient lesions' similarity analysis were performed. Results [18F]FMCH PET/CT identified 370 lesions, anatomically classified as regional lymph nodes and distant metastases. Thirty-eight and 54 patients were designed oligometastatic and plurimetastatic, respectively, using a 3-lesion threshold. The number of oligometastic scaled up to 60 patients (thus 32 plurimetastatic patients) with a 5-lesion threshold. Similarity analysis showed high lesions' heterogeneity. Grouping patients according to the number of metastases, patients with oligometastatic PCa defined with a 5-lesion threshold presented lesions heterogeneity comparable to plurimetastic patients. Lesions within patients having a limited tumor burden as defined by three lesions were characterized by less heterogeneity. Conclusions We found a comparable heterogeneity between patients with up to five lesions and plurimetastic patients, while patients with up to three lesions were less heterogeneous than plurimetastatic patients, featuring different cells phenotypes in the two groups. Our results supported the use of a 3-lesion threshold to define oligometastatic PCa.

BackgroundTreatment choice for metastatic renal cell carcinoma (mRCC) patients is still based on baseline clinical and laboratory factors.MethodsBy a pre-specified analysis of the Meet-URO 15 multicentric retrospective study enrolling 571 pretreated mRCC patients receiving nivolumab, baseline and early dynamic variations (Δ) of neutrophil, lymphocyte, and platelet absolute cell counts (ACC) and their inflammatory ratios (IR) were evaluated alongside their association with the best disease response and overall (OS) and progression-free survival (PFS). Multivariable analyses on OS and PFS between baseline and Δ ACC and IR values were investigated with receiving operating curves-based cut-offs.ResultsThe analysis included 422 mRCC patients. Neutrophil-to-lymphocyte ratio (NLR) increased over time due to consistent neutrophil increase (p < 0.001). Higher baseline platelets (p = 0.044) and lower lymphocytes (p = 0.018), increasing neutrophil Δ (p for time-group interaction

PurposeAnticancer treatment-related toxicities can impact morbidity and mortality, hamper the administration of treatment, worsen the quality of life and increase the burden on the healthcare system. Therefore, their prompt identification is crucial. NICSO (Italian Network for Supportive Care in Cancer) conducted a nationwide randomized trial to evaluate the role of a planned, weekly phone-based nurse monitoring intervention to prevent and treat chemotherapy, targeted therapy- and immunotherapy-related toxicities. Here, we report the results from the chemotherapy arm.MethodsThis was a nationwide, randomized, open-label trial conducted among 29 Italian centers (NCT04726020) involving adult patients with breast, colon, or lung cancer and a life expectancy ≥6 months receiving adjuvant chemotherapy. Patients received either a weekly nurse monitoring phone call and an educational leaflet reporting practical advice about prevention and treatment of toxicities (experimental group) or the educational leaflet only (control group).ResultsThe addition of a nurse monitoring intervention may help reduce time spent with severe toxicities (grade ≥3), particularly those less frequently reported in clinical practice, such as fatigue. When considering grade 1–2 AEs, times with mild/moderate diarrhea, mucositis, fatigue and pain were shorter in the experimental arm. Time spent without AEs was significantly longer in the experimental arms for all the toxicities. The requirement for special medical attention was comparable between groups.ConclusionThis study suggests the need for implementing a better system of toxicity assessment and management for patients treated with adjuvant chemotherapy to promote effective preventive and/or therapeutic intervention against these events.

BackgroundAlthough serum sodium concentration, particularly hyponatremia, has been shown to be a prognostic marker of survival in metastatic renal cell carcinoma (mRCC), the impact of normal sodium levels has not been investigated. Herein, we investigate the influence of normonatremia in mRCC patients treated with tyrosine kinase inhibitors (TKIs).Materials and methodsFor this retrospective study, the clinical and biochemical data of patients treated with first-line TKIs for mRCC were available from seven Italian cancer centers. We collected natremia levels at baseline and first evaluation after treatment excluding patients with sodium levels outside the normal range (145 mEq/L). The remaining patients were subdivided into two groups according to the median sodium value: natremia patients with

Abstract Background The incidence of Merkel cell carcinoma (MCC), a rare form of skin cancer with a poor prognosis, has increased in Italy in recent decades. Avelumab, an anti-programmed death ligand 1 monoclonal antibody, is approved for the treatment of metastatic MCC (mMCC) based on the results of the phase 2 JAVELIN Merkel 200 trial. The global avelumab expanded access program (EAP) was designed to provide compassionate use of avelumab prior to approval for patients with mMCC who had limited treatment options. We report findings from a subgroup of Italian patients enrolled in the avelumab EAP. Methods Eligible patients had mMCC and progressive disease following ≥ 1 prior line of chemotherapy or were ineligible for chemotherapy or clinical trial participation. Patients received avelumab 10 mg/kg intravenously every 2 weeks. Treating physicians were provided with an initial 3-month supply of avelumab; resupply was permitted if the patient achieved a complete response, partial response, stable disease, or other clinical benefit per physician assessment. Safety and efficacy data for the EAP were reported at the treating physician’s discretion. Results Between April 1, 2016, and September 14, 2018, 109 requests for avelumab were received from Italy, and 102 were approved. All but 1 of the approved patients had received ≥ 1 prior line of therapy. At data cutoff (March 22, 2019), 95 patients had been supplied with avelumab and response data were available for 55 patients. The objective response rate in response-evaluable patients was 29.1%, including 6 patients (10.9%) who achieved a complete response and 10 patients (18.2%) who achieved a partial response; in the total population supplied with avelumab (n = 95), the proportion who had an objective response was 16.8%. The median duration of treatment in responding patients was 9.7 months (range, 3.5–41.7 months). The most frequently reported treatment-related adverse events were infusion-related reaction (single preferred term; n = 3 [3.2%]) and pyrexia (n = 2 [2.1%]). Conclusions Results from Italian patients enrolled in the avelumab EAP are consistent with the findings of the JAVELIN Merkel 200 trial and confirm the efficacy and safety of avelumab treatment in this population.

This work presents a tectonic geomorphology analysis of a river bend in the middle Tavo River valley, in the piedmont area of the NE Apennines (Abruzzo Region), between the eastern slope of the chain (Gran Sasso Massif) and the Adriatic coast. The main map (1:15,000 scale) was obtained through a morphometric, geological, and geomorphological analysis, and was composed of four sections including orography and hydrography at basin scale, main map at local scale, geomorphological cross-section and longitudinal profiles, and morphoneotectonic analysis. This study provides a basis for the recognition of morphostructural and morphotectonic features that control the drainage evolution of the Tavo River. Specifically, the study is focused on the Tavo-Saline basin characterized by possible capture processes, and the evolution of the watershed with the Pescara basin. The results from this study can contribute to the understanding of the evolution of the NE Apennines piedmont area since the Middle Pleistocene.

BackgroundThyroid hormone impairment, represented as an alteration in levels of thyroid hormones and a lower fT3/fT4 ratio, has been correlated with a worse prognosis for both cancer and non-cancer patients. The role of baseline thyroid function in patients with metastatic renal cell carcinoma (mRCC) however, has not been studied yet.Materials and MethodsWe recorded clinical data, baseline biochemical results, and oncological outcomes from 10 Oncology Units in Italy. We stratified patients into three groups according to the fT3/fT4 ratio value and subsequently analyzed differences in progression-free survival (PFS) and overall survival (OS) in the three groups. We also performed univariate and multivariate analyses to find prognostic factors for PFS and OS.ResultsWe analyzed 134 patients treated with systemic treatment for mRCC. Median PFS in the low, intermediate, and high fT3/fT4 ratio group were 7.5, 12.1, and 21.7 months respectively (p

Background: Considering the growing genitourinary (GU) cancer population undergoing systemic treatment with immune checkpoint inhibitors (ICIs) in the context of the COVID-19 pandemic, we planned a clinical audit in 24 Italian institutions treating GU malignancies. Objective: The primary objective was investigating the clinical impact of COVID-19 in GU cancer patients undergoing ICI-based therapy during the first outbreak of SARS-CoV-2 contagion in Italy. Design, setting, and participants: The included centers were 24 Oncology Departments. Two online forms were completed by the responsible Oncology Consultants, respectively, for metastatic renal cell carcinoma (mRCC) and metastatic urothelial carcinoma (mUC) patients receiving at least one administration of ICIs between 31 January 2020 and 30 June 2020. Results and limitation: In total, 287 mRCC patients and 130 mUC patients were included. The COVID-19 incidence was, respectively, 3.5%, with mortality 1%, in mRCC patients and 7.7%, with mortality 3.1%, in mUC patients. In both groups, 40% of patients developing COVID-19 permanently discontinued anticancer treatment. The pre-test SARS-CoV-2 probability in the subgroup of patients who underwent nasal/pharyngeal swab ranged from 14% in mRCC to 26% in mUC. The main limitation of the work was its nature of audit: data were not recorded at the single-patient level. Conclusion: GU cancer patients undergoing active treatment with ICIs have meaningful risk factors for developing severe events from COVID-19 and permanent discontinuation of therapy after the infection. Treatment delays due to organizational issues during the pandemic were unlikely to affect the treatment outcome in this population.

Objective: To investigate and compare the effectiveness of active surveillance versus post-surgical active treatment, in patients with testicular germ cells tumor (TGCT). Materials and methods: We retrospectively analyzed 52 patients who underwent surgery for TGCT from January 2009 to December 2014. All the patients were divided into two age groups: the Group A included children-adolescents from 18 months to 21 years old, while the Group B comprised young adults from 22 to 39 years old. Clinical, histopathological, therapeutic and follow-up data were collected. Results: Overall, 22 patients (42,3%) were enrolled in the Group A and 30 patients (57.7%) were categorized in the Group B. Inguinal orchiectomy was performed in all patients. Retroperitoneal lymphadenectomy was performed in 4 patients (7.7%). Post-surgical management differed based on clinical stage, resulting in active surveillance or adjuvant therapy. After an average 7 years follow-up period (range: 3.5-9.0 years), the overall survival rate is 100%. The relapse risk is significantly higher for the patients in the Group B, displaying a recurrence free-survival rate of 72% versus 95% (Group A); 11 relapses (21.1%) were recorded 2 years after surgery. Of these, 3 recurrences (12.0%) occurred in patients undergoing an active surveillance approach, while 8 (29.6%) in patients subjected to an active treatment. Conclusions: The excellent prognosis in both age groups confirms the high curability of this neoplasia. The active surveillance could represent an optimal option for low recurrence risk tumors. However, post-surgical treatments should be taken into consideration for TGCT with high risk factors, including tumor size, lymphovascular and rete testis invasion.

Abstract Background This multi-institutional retrospective real life study was conducted in 22 Italian Oncology Centers and evaluated the role of Axitinib in second line treatment in not selected mRCC patients. Methods 148 mRCC patients were evaluated. According to Heng score 15.5%, 60.1% and 24.4% of patients were at poor risk, intermediate and favorable risk, respectively. Results PFS, OS, DCR and ORR were 7.14 months, 15.5 months, 70.6% and 16.6%, respectively. The duration of prior sunitinib treatment correlated with a longer significant mPFS, 8.8 vs 6.3 months, respectively. Axitinib therapy was safe, without grade 4 adverse events. The most frequent toxicities of all grades were: fatigue (50%), hypertension (26%), and hypothyroidism (18%). G3 blood pressure elevation significantly correlated with longer mPFS and mOS compared to G1-G2 or no toxicity. Dose titration (DT) to 7 mg and 10 mg bid was feasible in 24% with no statistically significant differences in mPFS and mOS. The sunitinib-axitinib sequence was safe and effective, the mOS was 41.15 months. At multivariate analysis, gender, DCR to axitinib and to previous sunitinib correlated significantly with PFS; whereas DCR to axitinib, nephrectomy and Heng score independently affected overall survival. Conclusions Axitinib was effective and safe in a not selected real life mRCC population. Trial registration INT – Napoli – 11/16 oss. Registered 20 April 2016. http://www.istitutotumori.na.it

Background: Tyrosine kinase inhibitors (TKIs) prolong progression-free survival (PFS) in patients with metastatic renal cell carcinoma (mRCC), some of which may achieve long-term responses. Herein, we report clinical and pathological characteristics of patients who achieved long-term responses during first-line TKI treatment. Methods: Patients receiving TKI as first-line therapy from January 2010 to December 2017 in seven Italian Oncology Centers were reviewed. Sixty-six patients were considered as long-term responders, as they remained progression-free for 36 months or more during TKI treatment. A logistic regression model was performed to evaluate the effect of each clinical-pathological variable on the probability of responding long-term. Results: A total of 335 patients with a median age of 66 years were included in the analysis. The median PFS and overall survival among the long-term responders was 70 and 106 months, respectively. At a landmark PFS analysis performed 36 months after the start of treatment, the median PFS was 34 months. Multivariate analysis from all patients identified previous nephrectomy, Eastern Cooperative Oncology Group Performance Status (ECOG PS) < 1, and lack of liver metastasis as favorable prognostic factors for long-term response. Female gender and lack of liver metastasis positively correlated with long-term responses in favorable-risk-score population, as well as ECOG PS < 1 in intermediate-poor risk score population. Patients Summary: Previous surgery, clinical condition, and lack of liver metastasis may predict long-term responses to tyrosine kinase inhibitors. Conclusions: TKIs can lead to a long-term response in a subset of patients with metastatic RCC. Previous nephrectomy, optimal performance status (ECOG PS = 0), and lack of liver metastasis may predict long-term responses.

The aim of the present study was to evaluate whether prostate cancer (PC) patients can be accurately classified on the bases of tissue expression of gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA). This retrospective study included 28 patients with PC. Formalin-fixed paraffin-embedded samples were used for diagnosis. Immunohistochemistry staining techniques were used to evaluate PSMA and GRPR expression (both number of cells expressed and % of area stained). To assess the independent associations among selected variables, a multi-dimensional scaling (MDS) analysis was used. It was found that the PSMA expression was inversely correlated with GRPR expression. Only the number of cells expressing GRPR was significantly related to the Gleason score. Both the percentage of area expressing GRPR and the number of cells expressing PSMA were close to reaching significance at the 0.05 level. MDS provided a map of the overall, independent association confirming that GRPR and PSMA represent inversely correlated measures of the same dimension. In conclusion, our data showed that GRPR expression should be evaluated in prostate biopsy specimens to improve our ability to detect PC with low grades at the earliest phases of development. Considering that GRPRs appear to be directly involved in the mechanisms of tumor proliferation, advancements in nuclear medicine radiotherapy can focus on this receptor to improve the therapeutic approach to PC. Further studies in our laboratory will investigate the molecular mechanisms of activation based on GRPR.

Introduction: Studies have shown that the Ki-67 index is a valuable biomarker for the diagnosis, and classification of gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). We re-evaluated the expression of Ki-67 based on the intensity of the stain, basing our hypothesis on the fact that the Ki-67 protein is continuously degraded. Background: The aim was to evaluate whether a new scoring method would be more effective in classifying NETs by reducing staining heterogeneity. Methods: Patients with GEP-NET (n = 87) were analyzed. The classification difference between the two methods was determined. Results: The classification changed significantly when the Ki-67 semiquantal index was used. The percentage of G1 patients increased from 18.4% to 60.9%, while the G2 patients decreased from 66.7% to 29.9% and the G3 patients also decreased from 14.9% to 9.2%. Moreover, it was found that the traditional Ki-67 was not significantly related to the overall survival (OS), whereas the semiquantal Ki-67 was significantly related to the OS. Conclusions: The new quantification was a better predictor of OS and of tumor classification. Therefore, it could be used both as a marker of proliferation and as a tool to map tumor dynamics that can influence the diagnosis and guide the choice of therapy.

Background: Severe acute respiratory syndrome coronavirus 2 disease (COVID-19) has caused a worldwide challenging and threatening pandemic. Multinational, placebo-controlled, observer-blinded trials were conducted since the beginning of pandemic because safe and effective vaccines were needed urgently. In most trials of COVID-19 vaccines patients affected by malignancies or on treatment with immunosuppressive drugs were excluded. Patients and methods: A retrospective monocentric study was conducted at Medical Oncological Unit of Santa Chiara Hospital (Pisa, Italy) in this subset of population to investigate safety and tolerability of COVID-19 vaccines; 377 patients with solid tumor on treatment were enrolled. Vaccine-related adverse events were recorded using a face-to-face questionnaire including a toxicity grading scale. Most of the patients (94%) received mRNA vaccine as indicated by Italian health ministry guidelines. Mean age was 66 years (range 27–87), 62% of the patients were older than 65 years and 68% had at least one additional comorbidity. The majority (86%) of patients were in a metastatic setting and 29% received immunotherapy-based treatment. For statistical analysis, multivariate binary logistic regression models were performed and linear regression models were applied. Results: Adverse events were mild and transient and ended in a few days without any sequelae. No severe or uncommon adverse events were recorded. In multivariate analysis, we found that the female sex was associated with a greater risk of more severe and longer lasting adverse events, and a higher risk of adverse events was found for patients treated with immunotherapy. Conclusions: Our results demonstrate that COVID-19 vaccines were safe and well-tolerated in this population of patients being treated for solid tumors.

Cancer cachexia has been reported to be directly responsible for at least 20% of cancer deaths. Management of muscle wasting in cancer-associated cachexia appears to be of pivotal importance for survival of patients. In this regard, it would be interesting to identify before its patent appearance eventual functional markers of muscle damage, to plan specific exercise protocols to counteract cachexia. The muscle function of 13 oncologic patients and 15 controls was analyzed through: i) analysis of the oxidative metabolism, indirectly evaluated trough dosage of blood lactate levels before and after a submaximal incremental exercise on a treadmill; ii) analysis of strength and, iii) endurance, in both lower and upper limbs muscles, employing an isokinetic dynamometer. Statistical analyses were carried out to compare the muscle activities between groups. Analysis of oxidative metabolism during the incremental exercise on a treadmill showed that patients performed a shorter exercise than controls. Lactate levels were significantly higher in patients both at baseline and after the task. Muscle strength analysis in patients group showed a reduction of Maximum Voluntary Contraction during the isometric contraction and, a tendency to fatigue during endurance task. Data emerging from this study highlight an impairment of muscle oxidative metabolism in subjects affected by a pre-cachexia stage of cancer. A trend of precocious fatigability and an impairment of muscle strength production were also observed. This evidence underlines the relevance of assessing muscle function in order to develop novel rehabilitative approaches able to counteract motor impairment and eventually to prevent cachexia in these patients.

BACKGROUND:Results from phase III clinical trial CheckMate 025 have established nivolumab as the standard of care for treatment of metastatic renal-cell carcinoma (mRCC) after VEGF inhibitor failure; however, elderly patients are under-represented in the registration trial and little is known about the activity of nivolumab in this subgroup. The purpose of the Expanded Access Program was to provide nivolumab to patients with mRCC who had progressed despite treatment with other agents that were considered standard of care. METHODS:Nivolumab 3 mg/kg was administered intravenously every 2 weeks to a maximum of 24 months or until progression or unacceptable toxicity. The current analysis included all patients from the EAP Italian cohort who had received ≥1 dose of nivolumab. Adverse events (AEs) were monitored using Common Terminology Criteria for Adverse Events v4.0. RESULTS:A total of 389 patients with advanced RCC were enrolled in the Italian cohort of the EAP and treated with nivolumab. Of these patients, 125 (32%) were at least 70 years of age and 70 (18%) were at least 75 years of age. Efficacy with nivolumab in the elderly patients was similar to that observed in the overall EAP population and in the CheckMate 025 trial. Safety was comparable between the elderly patients and the overall EAP population, and was consistent with what previously reported. CONCLUSION:The final results suggest that elderly patients with pretreated metastatic RCC may benefit from therapy with nivolumab.

Axitinib is an oral angiogenesis inhibitor, currently approved for treatment of metastatic renal cell carcinoma (mRCC) after failure of prior treatment with Sunitinib or cytokine. The present study is an Italian Multi-Institutional Retrospective Analysis that evaluated the outcomes of Axitinib, in second-line treatment of mRCC. The medical records of 62 patients treated with Axitinib, were retrospectively reviewed. The Progression Free Survival (PFS), the Overall Survival (OS), the Objective Response Rate (ORR), the Disease Control Rate (DCR) and the safety profile of axitinib and sunitinib-axitinib sequence, were the primary endpoint. The mPFS was 5.83 months (95% CI 3.93-7.73 months). When patients was stratified by Heng score, mPFS was 5.73, 5.83, 10.03 months according to poor, intermediate and favourable risk group respectively. The mOS from the start of axitinib was 13.3 months (95% CI 8.6-17.9 months); the observed ORR and DCR were 25% and 71%, respectively. When stratified patients by subgroups defined by duration of prior therapy with Sunitinib (≤ vs >median duration), there was a statistically significant difference in mPFS with 8.9 ( 95% CI 4.39-13.40 months) vs 5.46 months (95% CI 4.04-6.88 months) for patients with a median duration of Sunitinib >13.2 months. DCR and ORR to previous Sunitinib treatment was associated with longer statistically mPFS, 7.23 (95% CI 3.95-10.51 mo, p=0.01) and 8.67 (95% CI 4.0-13.33 mo, p=0.008) vs 2.97 (95% CI 0.65-5.27 mo, p=0.01) and 2.97 months (95% CI 0.66-5.28 mo, p=0.01) respectively. Overall Axitinib at standard schedule of 5 mg bid, was well tolerated. The most common adverse events of all grades were fatigue (25.6%), hypertension (22.6%), gastro-intestinal disorders (25.9%) and hypothyroidism (16.1%). The sequence Sunitinib-Axitinib was well tollerated without worsening in side effects, with a median OS of 34.7 months (95% CI 18.4-51.0 months). Our results are consistent with the available literature; this retrospective analysis confirms that Axitinib is effective and safe in routine clinical practice.

In this paper, we describe an undergraduate foundational course on design methodology, in which strong emphasis is given on the philosophical questioning on method, methodology and, more generally, on designing itself. The course approach and structure are accounted in short steps, as a preliminary case presented for further discussions in the HCI educators community.

Pancreatic metastases from renal cell carcinoma are uncommon and their prognostic significance is not well defined. In this analysis we evaluated the outcome of patients with pancreatic metastases treated with either targeted therapies or local treatment to the pancreas. Patients with pancreatic metastases from renal cell carcinoma treated between 1993 and 2014 were identified from 11 European centers. Clinical records were retrospectively reviewed. Kaplan-Meier method and log-rank test were used to evaluate progression-free survival and overall survival. Cox's proportional hazard models were used for survival analysis. In total, 276 PM patients were evaluated, including 77 (28%) patients treated by either surgery or radiotherapy to the pancreas, and 256 (93%) who received systemic therapy. Median time from nephrectomy to diagnosis of pancreatic metastases was 91 months (IQR 54-142). Disease control rate after first-line TTs was 84%, with a median progression-free survival of 12 months (95% CI 10-14). Median overall survival was 73 months (95% CI 61-86) with a 5-year OS of 58%. Median OS of patients treated with local treatment was 106 months (95% CI 78-204) with a 5-year overall survival of 75%. On multivariable analysis, nephrectomy (HR 5.31; 95%CI 2.36-11.92; p

Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved for the treatment of metastatic renal cell carcinoma (mRCC). We aimed to assess the association between the baseline values and treatmentrelated modifications of total serum cholesterol (C), triglycerides (T), body mass index (BMI), fasting blood glucose level (FBG) and blood pressure (BP) levels and the outcome of patients treated with everolimus for mRCC.177 patients were included in this retrospective analysis. Time to progression (TTP), clinical benefit (CB) and overall survival (OS) were evaluated.Basal BMI was significantly higher in patients who experienced a CB (p=0,0145). C,T and C+T raises were significantly associated with baseline BMI (p=0.0412, 0.0283 and 0.0001). Median TTP was significantly longer in patients with T raise compared to patients without T (10 vs 6, p=0.030), C (8 vs 5, p=0.042) and C+T raise (10.9 vs 5.0, p=0.003). At the multivariate analysis, only C+T increase was associated with improved TTP (p=0.005). T raise (21.0 vs 14.0, p=0.002) and C+T increase (21.0 vs 14.0, p=0.006) were correlated with improved OS but were not significant at multivariate analysis.C+T raise is an early predictor for everolimus efficacy for patients with mRCC.

Toxoplasma gondii, a ubiquitous intracellular parasite, has a strong tropism for the brain tissue, where it forms intracellular cysts within the neurons and glial cells, establishing a chronic infection. Although latent toxoplasmosis is generally assumed to be asymptomatic in immunocompetent individuals, it is now clear that it can induce behavioral manipulations in mice and infected humans. Moreover, a strong relation has emerged in recent years between toxoplasmosis and psychiatric disorders. The link between T. gondii and schizophrenia has been the most widely documented; however, a significant association with bipolar disorder (BD) and suicidal/aggressive behaviors has also been detected. T. gondii may play a role in the etiopathogenesis of psychiatric disorders affecting neurotransmitters, especially dopamine, that are implicated in the emergence of psychosis and behavioral Toxoplasma-induced abnormalities, and inducing brain inflammation by the direct stimulation of inflammatory cytokines in the central nervous system. Besides this, there is increasing evidence for a prominent role of immune dysregulation in psychosis and BD. The aim of this review is to describe recent evidence suggesting a link between Toxoplasma gondii and BD, focusing on the interaction between immune responses and this infectious agent in the etiopathogenesis of psychiatric symptoms.