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Purpose The prognostic significance of lactate dehydrogenase (LDH) in patients with metastatic seminoma is not defined. We investigated the prognostic impact of LDH levels prior to first-line systemic treatment and other clinical characteristics in this subset of patients. Methods Files from two registry studies and one single-institution database were analyzed retrospectively. Uni- and multivariate analyses were conducted to identify patient characteristics associated with recurrence free survival (RFS), overall survival (OS), and complete response rate (CRR). Results The dataset included 351 metastatic seminoma patients with a median follow-up of 5.36 years. Five-year RFS, OS and CRR were 82%, 89% and 52%, respectively. Explorative analysis revealed a cut-off LDH level of n = 228) vs. ≥ 2.5 ULN (n = 123) to be associated with a significant difference concerning OS associated with 5-years OS rates of 93% vs. 83% (p = 0.001) which was confirmed in multivariate analysis (HR 2.87; p = 0.004). Furthermore, the cut-off LDH p = 0.012) and 32% vs. 59% (p ≤ 0.001), respectively. Conclusions LDH levels correlate with treatment response and survival in metastatic seminoma patients and should be considered for their prognostic stratification.

Background Severe immune-related Adverse Events (irAEs) develop in 10–27% of patients treated with Immune-Oncology (IO) [Powles (Lancet 391:748–757, 2018); Galsky (Lancet 395:1547–1557, 2020); Haanen (Ann Oncol 28:119–142, 2017)]. The aim of our study was to evaluate efficacy and clinical outcome of metastatic renal cell carcinoma (mRCC) patients who stopped Immune Checkpoint Inhibitors (ICIs) due to early Grade (G) 3-G4 irAEs. Methods We retrospectively collected data from 204 mRCC patients treated with ICIs in 6 Italian referral centers adhering to the Meet-Uro group, between February 2017 and January 2020. To properly weight the results, patients who did not report early G3–G4 toxicities have been included as control group. Primary endpoint was to evaluate 6 months Progression Free Survival (PFS) after early treatment interruption for Grade (G) 3–4 toxicities compared to the control group. Secondary endpoints were to evaluate Time to treatment failure (TTF) and overall survival (OS) in both groups. All statistical analyses were performed using SPSS software (version 19.00, SPSS, Chicago). Results 18/204 (8.8%) patients had early treatment interruption for serious (G3-G4) irAEs. Early was defined as interruption of IO after only one or two administrations. Immune related nephritis and pancreatitis were the most common irAE that lead to treatment interruption. 6/18 patients received IO-IO combination whereas 12/18 patients antiPD1. In the study group, 12/18 (66.6%) were free from progression at 6 months since IO interruption, TTF was 1.6 months (95% CI 1.6–2.1), mPFS was 7.4 months (95% CI 3.16–11.6) and mOS was 15.5 months (5.1–25.8). In the control group 111/184 (60.3%) patients were free from progression at 6 months, TTF was 4.6 months (95% CI 3.5–5.6), mPFS was 4.6 months (95% CI 3.5–5.6) and mOS was 19.6 months (95% CI 15.1–24.0). In the overall population, mPFS was 5.0 months (95% CI 4.0–5.9) and mOS was 19.6 months (95% CI 15.1–24.0). Conclusions ICIs seem to maintain efficacy even after early interruption due to severe irAE.

In a Phase 2 clinical trial, we aimed to determine the lutetium-177 [177Lu]-PSMA-617 activity and the clinical utility of levels of plasma androgen receptor (AR) gene in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). We determined AR copy number in pretreatment plasma samples. We used logistic regression to estimate the odds ratio (OR) and 95% confidence intervals (95% CIs) in order to evaluate the independent relevance of AR status and to evaluate patients with early progressive disease (PD) defined as treatment interruption occurring within 4 months after the start of 177Lu-PSMA-617. Twelve of the 15 (80%) with AR gene gain and 5 of the 25 (20%) patients with no gain of AR had early PD (p = 0.0002). The OR for patients without PSA response having AR gain was 3.69 (95% CI 0.83–16.36, p = 0.085). The OR for patients with early PD having AR gain was 16.00, (95% CI 3.23–79.27, p = 0.0007). Overall, median PFS and OS were 7.5 and 12.4 months, respectively. AR-gained had a significant shorter OS compared to AR-normal patients (7.4 vs 19.1 months, p = 0.020). No treatment interruptions due to adverse effects were reported. Plasma AR status helped to indicate mCRPC with early resistance to 177Lu-PSMA-617. NCT03454750.

Background: Plasma AR status has been identified as a potential biomarker of response in metastatic castration-resistant prostate cancer (mCRPC) patients receiving docetaxel or AR-targeted therapies. However, the relevance of plasma AR in the overall management of CRPC patients receiving different docetaxel doses is unknown. Patients and methods: This was a multi-institution study of associations between baseline plasma AR copy number status, assessed by droplet digital PCR, and outcome in 325 mCRPC patients receiving docetaxel at standard or adapted regimen at the discretion of the treating physician. Upon analysis, patients were assigned randomly to either a training (n = 217) or validation (n = 108) cohort. Results: In the training cohort, AR-gained patients treated with adapted docetaxel regimen had a significantly worse median progression-free survival (PFS) (3.8 vs 6.3 months, hazard ratio [HR] 2.58, 95% confidence interval [CI] 1.34–4.95, p < 0.0001), median overall survival (10.8 vs 20.6 months, HR 1.98, 95% CI 1.09–3.62, p = 0.0064) and PSA response (PSA > −50%: odds ratio 4.88 95%CI 1.55–14.32, p = 0.013) as compared to plasma AR normal patients. These findings were all confirmed in the validation cohort. However, in patients treated with standard docetaxel regimen, these differences were not seen. The interaction between AR CN status and dose reduction of docetaxel was considered as independent factor for PFS in both the training and validation cohort (HR 2.84, 95% CI 1.41–5.73, p = 0.003, and HR 4.79, 95% CI 1.79–12.82, p = 0.002). Conclusion: Despite the retrospective non-randomised design of this study, our hypothesis-generating findings could suggest plasma AR as a potential biomarker for optimal docetaxel timing and dose in mCRPC patients. Prospective trials are warranted.

The treatment landscape for metastatic castration-resistant prostate cancer has evolved extremely in recent years and several drug classes are now available. Nonetheless, the lack of validated predictive biomarkers makes therapeutic choice and the best sequential approach difficult. The location of the metastatic site could be a valid criterion for choosing among the treatment options available. Although bone remains the most frequent metastatic site and a possible target for many drugs, recent data suggest a profound shift in the disease spectrum with visceral metastases increasing incidence. This review describes the presently available and ongoing therapies for patients with CRPC and bone metastases, focusing on the role of bone metastases as a possible driver for selecting therapies in these patients.

Introduction: Important changes in the treatment of prostate cancer have taken place in recent years. Non-metastatic castration-resistant prostate cancer (nmCRPC) has been clinically delineated. In this setting, three drugs have been approved in high-risk disease: apalutamide, enzalutamide and darolutamide.Areas covered:This manuscript aims to profile darolutamide, its clinical development, pharmacologic properties, efficacy and safety. We presented the results of published clinical studies, but we also investigated ongoing ones.Expert opinion: An indirect comparison with the other two aforementioned drugs emerged. While the clinical efficacy is comparable, the toxicity profile is different for darolutamide, resulting in greater tolerance. We must wait for the results of the trials that study darolutamide in hormone-sensitive disease, both in the metastatic phase and in the localized phase. Clinical experience will also be important to determine ever more personalized treatments for patients.

Breast cancer represents one of the most common tumor histologies. To date, based on the specific histotype, different therapeutic strategies, including immunotherapies, capable of prolonging survival are used. More recently, the astonishing results that were obtained from CAR-T cell therapy in haematological neoplasms led to the application of this new therapeutic strategy in solid tumors as well. Our article will deal with chimeric antigen receptor-based immunotherapy (CAR-T cell and CAR-M therapy) in breast cancer.

Background Androgen receptor (AR) signaling inhibitors represent the standard treatment in metastatic castration resistance prostate cancer (mCRPC) patients. However, some patients display a primary resistance, and several studies investigated the role of the AR as a predictive biomarker of response to treatment. This study is aimed to evaluate the role of AR in liquid biopsy to predict clinical outcome to AR signaling inhibitors in mCRPC patients. Methods Six milliliters of plasma samples were collected before first-line treatment with abiraterone or enzalutamide. Circulating free DNA (cfDNA) and exosome-RNA were isolated for analysis of AR gain and AR splice variant 7 (AR-V7), respectively, by digital droplet PCR. Results Eighty-four mCRPC patients received abiraterone (n = 40) or enzalutamide (n = 44) as first-line therapy. Twelve patients (14.3%) presented AR gain and 30 (35.7%) AR-V7+ at baseline. Median progression-free survival (PFS) and overall survival (OS) were significantly longer in AR-V7− vs AR-V7+ patients (24.3 vs 5.4 months, p p = 0.0001, respectively). Patients carrying the AR gain had a median PFS of 4.8 vs 24.3 months for AR normal patients (p AR normal vs patients with AR gain (not reached vs 8.17 months, p AR gain was observed (r = 0.28; p = 0.01). The AR gain/AR-V7 combined analysis confirmed a strong predictive effect for biomarkers combination vs patients without any AR aberration (PFS 3.8 vs 28 month, respectively; OS 6.1 vs not reached, respectively; p Conclusions The present study demonstrates that cfDNA and exosome-RNA are both a reliable source of AR variants and their combined detection in liquid biopsy predicts resistance to AR signaling inhibitors.

Background: Baseline high circulating tumor DNA (ctDNA) fraction in plasma and androgen receptor (AR) copy number (CN) gain identify mCRPC patients with worse outcomes. This study aimed to assess if ctDNA associates with PSA kinetics. Methods: In this prospective biomarker study, we evaluate ctDNA fraction and AR CN from plasma samples. We divided patients into high and low ctDNA level and in AR gain and AR normal. Results: 220 baseline samples were collected from mCRPC treated with abiraterone (n = 140) or enzalutamide (n = 80). A lower rate of PSA decline ≥ 50% was observed in patients with high ctDNA (p = 0.017) and AR gain (p = 0.0003). Combining ctDNA fraction and AR CN, we found a different median PSA progression-free survival (PFS) among four groups: (1) low ctDNA/AR normal, (2) high ctDNA/AR normal, (3) low ctDNA/AR gain, and (4) high ctDNA/AR gain (11.4 vs. 5.0 vs. 4.8 vs. 3.7 months, p < 0.0001). In a multivariable analysis, high ctDNA, AR gain, PSA DT, PSA DT velocity remained independent predictors of PSA PFS. Conclusions: Elevated ctDNA levels and AR gain are negatively and independently correlated with PSA kinetics in mCRPC men treated with abiraterone or enzalutamide.

Introduction: Enzalutamide is the first characterized second-generation nonsteroidal androgen receptor inhibitor (ARi). Its efficacy has been established in several clinical trials evaluating its role in different settings of prostate cancer. Recently, enzalutamide has been approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC). Areas covered: In this paper, the authors describe the chemical structure and pharmacologic characteristics of enzalutamide, providing a summary of clinical trials evaluating its efficacy and safety in prostate cancer patients. Expert opinion: Enzalutamide adds to the growing arsenal of ARi used in nmCRPC. An improvement in metastasis-free survival was observed with the use of these new treatment options; recently released preliminary data report also an OS benefit. These novel agents are generally well tolerated, but their safety profiles differ slightly. Since head-to-head comparisons between ARi in nmCRPC are lacking, the adverse events profile, as well as drug availability, costs, and considerations on treatment-sequencing, would most likely influence the selection of the individual agent in this setting. Further research is needed to improve treatment selection and clarify many unsolved issues. Abbreviations: ARi: nonsteroidal androgen receptor inhibitor; nmCRPC: nonmetastatic castration resistant prostate cancer; ADT: androgen deprivation therapy; OS: overall survival; PSA: prostate specific antigen; FDA: Food and Drug Administration; AR: Androgen Receptor; MFS: metastasis free survival; PSA-DT: PSA doubling time; HR: hazard ratio; CI: confidence interval; AEs: adverse events; mCRPC: metastatic castration resistant prostate cancer; mHSPC: metastatic hormone-sensitive prostate cancer; rPFS: radiographic progression-free survival; OR: odds ratio.

BACKGROUND Cabozantinib improves survival in metastatic renal cell carcinoma (mRCC) after prior antiangiogenics. The best treatment at disease progression (PD) is unknown. Being also a AXL/MET inhibitor, involved in acquired resistance, we hypothesized a prolonged tumor growth control in patients continuing cabozantinib despite PD. RESEARCH DESIGN AND METHODS This retrospective multicenter study enrolled patients receiving cabozantinib after the first line between 2014 and 2020. We compared patients maintaining cabozantinib after first PD due to clinical benefit and good tolerability with those who changed therapy. The postprogression survival (PPS) of both was our primary endpoint. RESULTS We analyzed 89 patients: 45 received cabozantinib beyond PD and 44 switched therapy. 40.4%, 31.5%, and 28.1% of patients received 1, 2, or >2 prior treatment, respectively. 84.3% were intermediate-poor International Metastatic Renal Cell Carcinoma Database risk. Patients continuing cabozantinib showed a higher response rate to cabozantinib before PD (46.7% vs 25%, p = 0.03) and were more heavily pretreated. Continuing cabozantinib showed a significantly longer PPS compared with switching therapy (median PPS 16.9 vs 13.2 months, HR 0.66, 95%CI 0.48-0.92, p = 0.011). CONCLUSIONS We observed longer PPS in patients continuing cabozantinib beyond PD, suggesting that this could be an effective option.

48 Background: 68Ga prostate specific membrane antigen positron emission tomography/computed tomography (68Ga-PSMA PET/CT) is a highly sensitive diagnostic tool to detect prostate metastatic sites even at low levels of Prostate Specific Antigen (PSA). We evaluated the impact of 68Ga-PSMA PET/CT in patients treated with enzalutamide as first-line therapy for mCRPC. Methods: In an observational prospective study, 67 consecutive mCRPC patients were treated with enzalutamide 160 mg once daily in first-line for mCRPC. 68Ga-PSMA PET/CT was performed at baseline, after 3 months, during follow-up and at PSA/clinical progression. Patients were evaluated on a monthly basis for serological PSA response and safety. We measured at baseline the sum of metabolic total volume (SMTV), mean standardized uptake volume (SSUVmean), maximum standardized uptake volume (SSUVmax) and total lesion activity (STLA), which is the product of SMTV and SSUVmean, for a maximum of 20 lesions. These parameters together with baseline PSA level, Eastern Cooperative Oncology Group performance status (ECOG PS), Gleason Score (GS) and age were analyzed by univariate and multivariate Cox regression models as potential predictors of progression-free survival (PFS) and overall survival (OS). Results: At the moment of the present analysis, 58 mCRPC patients were considered fully evaluable. The median age was 75 years (range, 47-91), ECOG PS was 0 in 47 cases (81%), 1-2 in 11 (19%), GS was 3, median SSUVmax of 44.85, median SSUVmean of 25.80 and median STLA of 59.66. At the median follow-up of 52 months, median PFS was 28.9 months (95% CI 16.3-43.6), median OS was not reached (95% CI 36.8-not reached). In univariate analysis, SSUVmax and STLA were significant for PFS (p=0.015 and p=0.001, respectively) and OS (p=0.026 and p=0.019, respectively), while SSUVmean was significant only for OS (p=0.028). On multivariate analysis, STLA only remained significant for PFS (p68Ga-PSMA PET/CT before starting enzalutamide was associated with longer median PFS and OS compared to prior studies using standard imaging only. STLA, expression of both volume and intensity of 68Ga-PSMA uptake, appeared the strongest parameter able to predict PFS and OS.

223 Background: The need for genetic prognostic and predictive markers is urgent in order to identify potential target therapies or personalized therapeutic sequences for men with metastatic prostate cancer (mPC). The prevalence of pathogenic germline mutations in DNA damage repair (gDDR) such as germline mutations in BRCA2 (gBRCA) is well established: in the Anglo-American population with mPC was 5.3%, while in the Chinese population was 4.3% and in Spanish population 3.3%. This prospective multicenter cohort study evaluated the prevalence of gDDR alterations in the Italian population affected by mPC. Methods: In an observational prospective trial, 300 consecutive Italian patients affected by mPC were recruited between 2015 and 2019 and were screened for gDDR mutations in 107 genes. The primary aim was to assess the frequency of ATM/BRCA1/BRCA2/PALB2 germline mutations in the Italian population of patients with mPC. Secondary aims included the association of gDDR subgroups with metastatic onset, Gleason Score ≥8, and time to castration resistance. Results: We analyzed 300 patients and we identified 297 valuable patients. 46 patients had a pathogenic/likely pathogenic variants (15.4%): the more frequent is gBRCA2 in ten cases, gATM in five (1.7%), gMUTYH in four cases (1.3%), gCHEK2 in three cases (1%) and one case in PALB2 (0.3%). No mutations in BRCA1 were identified. We also highlighted six patients (2%) with clonal hematopoiesis of indeterminate potential (CHIP) interference in ATR (n=2), ATM (n=2), CHEK1 (n=1) and BRIP1 (n=1). Finally, we identified 117 alterations of variants of unknown significance (VUS) in 98 patients. In a univariate analysis, the median time to castration resistance in gBRCA2 patients was 11.6 months versus 22.3 months in patients with other mutation versus 23.4 months in no mutated patients. There were no associations of gDDR subgroups with metastatic onset and Gleason Score ≥8. Conclusions: The prevalence of gBRCA2 in the Italian population is 3%, which is similar to those of Spanish population, identifying interesting similarities between people of the Western Mediterranean area. The presence of gBRCA2 mutations correlates with lower time to the onset of castration resistant disease, according to a more aggressive phenotype.

214 Background: Up to 80% of mCRPC have bone metastases and about 25% of metastatic prostate cancer harbor mutations in DNA damage repair defects (DDR). DDR gene mutations are a negative prognostic factor, being associated with short metastasis-free survival and cancer-specific survival. We analyzed the impact of somatic mutations in DDR genes on bone-related efficacy endpoints in mCRPC. Methods: We retrospectively analyzed the mutational status of mCRPC patients per FoundationOne analysis in tissue biopsy or, when it was not possible, in liquid biopsy (performed at the onset of mCRPC). We evaluated the impact of DDR gene mutations on bone-related efficacy endpoints at the time of mCRPC diagnoses, by dividing patients in two main groups (mutated DDR, specifically, mutations in at least one of BRCA1/2, ATM, FANCA, ATR, CHEK2, RAD51, PALB2, and CDK12 genes: group A; wild-type DDR: group B). We investigated differences between the two groups in terms of time from bone metastases onset to death, skeletal metastatic tumor burden (sites and number of lesions), skeletal-related events (SRE) incidence, and time to first on-study SRE. Results: Of the 131 patients with mCRPC enrolled, 115 had bone metastases. Clinical data distribution, according to molecular profile, is presented. There is no difference in terms of sites of metastases and time from bone metastases onset to death between the 2 groups. Mutated DDR status was associated with bone metastases volume (p = 0.0325), but did not affect SRE incidence and time to SRE onset. Conclusions: In our analysis, mutated DDR status was associated with higher bone metastases volume, although a not detrimental effect on the other bone-related efficacy endpoints was observed. [Table: see text]

The phosphoinositide 3 kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of the rapamycin (mTOR) axis is a key signal transduction system that links oncogenes and multiple receptor classes which are involved in many essential cellular functions. Aberrant PI3K signalling is one of the most commonly mutated pathways in cancer. Consequently, more than 40 compounds targeting key components of this signalling network have been tested in clinical trials among various types of cancer. As the oncogenic activation of the PI3K/AKT/mTOR pathway often occurs alongside mutations in other signalling networks, combination therapy should be considered. In this review, we highlight recent advances in the knowledge of the PI3K pathway and discuss the current state and future challenges of targeting this pathway in clinical practice.

The research on non-invasive circulating biomarkers to guide clinical decision is in wide expansion, including the earliest disease settings. Several new intensification/de-intensification strategies are approaching clinical practice, personalizing the treatment for each patient. Moreover, liquid biopsy is revealing its potential with multiple techniques and studies available on circulating biomarkers in the preoperative phase. Inflammatory circulating cells, circulating tumor cells (CTCs), cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), and other biological biomarkers are improving the armamentarium for treatment selection. Defining the escalation and de-escalation of treatments is a mainstay of personalized medicine in early breast cancer. In this review, we delineate the studies investigating the possible application of these non-invasive tools to give a more enlightened approach to escalating/de-escalating strategies in early breast cancer.

Outcomes of castration-sensitive prostate cancer (CSPC) have improved owing to new therapies and early treatment, previously reserved for castration-resistant disease (CRPC). Prostatic-specific antigen (PSA) remains the most used marker to follow-up patients under treatment, but only limited data are available about the prognostic role of its changes over time and the impact of response to subsequent therapies. This analysis aims to assess the prognostic role of the magnitude and velocity of PSA response in CSPC and describe how this may affect the outcome to subsequent treatment outcomes in CRPC.A retrospective analysis was performed on patients with de novo CSPC referring to six oncology centers in Italy. Clinical and pathological features were recorded. PSA response (PSA50), defined as a decrease50% compared to baseline, PSA velocity (PSAv), defined as any decrease in PSA levels over time and the deep and fast PSA response (4mPSA50), defined as the PSA response reached within the threshold of 4 months from the beginning of androgen deprivation therapy (ADT) have been evaluated for their impact on survival. Survivals were estimated using the Kaplan-Meier method and compared across groups using the log-rank test. Cox proportional-hazard models, stratified according to baseline characteristics, were used to estimate hazard ratios for overall survival (OS).A totals of 94.4% of patients had PSA50, which was correlated to longer OS compared to patients without PSA50 (56.0 vs. 14.8 months; p0.001). The median PSAv was 6.9 (ng/dl)/month, which was predictive for longer OS: Each decrease of 1 (ng/dl)/month was able to improve OS by 0.2% (HR=0.998, 95%CI=0.997-1.000; p=0.008). A total of 47.9% of patients reached 4mPSA50, with a median OS and progression-free survival (PFS) to ADT-based therapy of 101.0 and 23.4 months compared to 41.9 and 11.0 months for those who did not (p0.001), respectively. The independent prognostic role of 4mPSA50 was retained even when evaluated in multivariable analysis adjusted for other baseline characteristics and early docetaxel for CSPC. In CRPC, 4mPSA50 evaluated during CSPC retains its prognostic role even if it does not predict a different outcome between patients treated with abiraterone/enzalutamide or taxanes.Achieving a deep and fast PSA response correlates with a better outcome in patients with de novo mCSPC, also positively influencing the prognosis of the subsequent first-line therapy for CRPC disease.

BackgroundImmune-Oncology (IO) improves Overall Survival (OS) in metastatic Renal Cell Carcinoma (mRCC). The prognostic impact of previous Cytoreductive Nephrectomy (CN) and radical nephrectomy (RN), with curative intent, in patients treated with IO is not well defined. The aim of our paper is to evaluate the impact of previous nephrectomy on outcome of mRCC patients treated with IO.Methods287 eligible patients were retrospectively collected from 16 Italian referral centers adhering to the MeetUro association. Patients treated with IO as second and third line were included, whereas patients treated with IO as first line were excluded. Kaplan–Meier method and log-rank test were performed to compare Progression Free Survival (PFS) and OS between groups. In our analysis, both CN and RN were included. The association between nephrectomy and other variables was analyzed in univariate and multivariate setting using the Cox proportional hazard model.Results246/287 (85.7%) patients had nephrectomy before IO treatment. Median PFS in patients who underwent nephrectomy (246/287) was 4.8 months (95%CI 3.9–5.7) vs 3.7 months (95%CI 1.9–5.5) in patients who did not it (HR log rank 0.78; 95%CI 0.53 to 1.15; p = 0.186). Median OS in patients who had previous nephrectomy (246/287) was 20.9 months (95%CI 17.6–24.1) vs 13 months (95%CI 7.7–18.2) in patients who did not it (HR log rank 0.504; 95%CI 0.337 to 0.755; p = 0.001). In the multivariate model, nephrectomy showed a significant association with OS (HR log rank 0.638; 95%CI 0.416 to 0.980), whereas gland metastases were still associated with better outcome in terms of both OS (HR log rank 0.487; 95%CI 0.279 to 0.852) and PFS (HR log rank 0.646; 95%CI 0.435 to 0.958).ConclusionsIO treatment, in patients who had previously undergone nephrectomy, was associated with a better outcome in terms of OS. Further prospective trials would assess this issue in order to guide clinicians in real word practice.

BACKGROUND Aeromonas species are uncommon pathogens in biliary sepsis and cause substantial mortality in patients with impaired hepatobiliary function. Asia has the highest incidence of infection from Aeromonas, whereas cases in the west are rare. CASE SUMMARY We report the case of a 64-year-old woman with advanced pancreatic cancer and jaundice who manifested fever, abdominal pain, severe thrombocytopenia, anemia and kidney failure following the insertion of a percutaneous transhepatic biliary drainage. Blood culture results revealed the presence of Aeromonas veronii biovar veronii (A. veronii biovar veronii). After antibiotic therapy and transfusions, the life-threatening clinical conditions of the patient improved and she was discharged. CONCLUSION This was a rare case of infection, probably the first to be reported in West countries, caused by A. veronii biovar veronii following biliary drainage. A finding of Aeromonas must alert clinician to the possibility of severe sepsis.

e17038 Background: Programmed death-ligand 1 (PD-L1) has been recently found in tumor-derived exosomes and associated with progressive disease (PD) ( Poggio, Cell 2019). In localized prostate cancer, PD-L1 tumor expression has been shown to be a biomarker for node-positive patients (pts) ( Petitprez, Eur Urol Focus 2019) but its role in mCRPC is largely unexplored. We aimed to determine the potential of PD-L1 exosomal expression to predict lymph nodal PD in mCRPC receiving abi or enza. Methods: In a biomarker prospective study (REC 2192/2013), exosomes were isolated from plasma samples collected before first-line therapy with abi/enza between December 2014 and October 2018. RNA was extracted for analysis of PD-L1 by digital droplet PCR ( Del Re, Prostate Cancer Prostatic Dis 2021). Results: In our cohort of 55 node-positive mCRPC pts (median age: 76 years, range 47-89), the amount of exosomal PD-L1 expression (pts dichotomized in “high” and “low” as below or above median PD-L1/ACTB ratio = 0.0052) was associated with radiographic response after the first 3 months abi/enza therapy [high PD-L1 vs low PD-L1: 8 (25.8%) vs 0 (0%) PD, 23 (74.2%) vs 18 (75%) stable disease, and 0 vs 6 (25%) partial/complete response] (p = 0.0009). We observed an overall median progression-free survival (PFS) of 14.3 months [95% confidence interval (CI) 8.6-not reached] shorter in high PD-L1 compared to low PD-L1 10.6 (6.5-23.4) vs not reached [hazard ratio (HR) 3.1 (95% CI 1.1-8.5), p = 0.023]. In multivariable analysis including exosomal PD-L1 and androgen receptor (AR) variant 7, AR copy number gain detected in plasma, neutrophil lymphocyte ratio (NLR), lactate dehydrogenase, exosomal PD-L1; AR-V7 and AR gain were independent predictors of nodal PFS (HR 5.8, 95% CI 1.4-24.2, p = 0.01, HR 3.2, 95% CI 1.1-9.2, p = 0.03 and HR 12.9, 95% CI 2.3-73.2, p = 0.004), whereas AR-V7, AR gain, NLR > 3 were independent predictors of OS (HR 4.9, 95% CI 1.8-13.1, p = 0.001, HR 4.4, 95% CI 1.1-17, p = 0.02, and HR 3.2 95% CI 1.1-9.4, p = 0.03, respectively). Moreover, a trend of a worse OS was reported in high PD-L1 compared to low PD-L1 pts (HR 2.6, 95% CI 0.9-7.5, p = 0.07). Conclusions: In mCRPC pts treated with ARSI, exosomal PD-L1 expression may be considered as a predictive biomarker of lymph nodal response, playing a potential role in individualized disease monitoring and treatment combining between ARSI and immunotherapy. Larger evaluation of treatment decisions based on exosomal PD-L1 expression is now required.

Testicular cancer (TC) is the most frequent tumor in young males. In the vast majority of cases, it is a curable disease; therefore, very often patients experience a long survival, also due to their young age at diagnosis. In the last decades, the role of the vitamin D deficiency related to orchiectomy has become an increasingly debated topic. Indeed, vitamin D is essential in bone metabolism and many other metabolic pathways, so its deficiency could lead to various metabolic disorders especially in long-term TC survivors. In our article, we report data from studies that evaluated the incidence of hypovitaminosis D in TC survivors compared with cohorts of healthy peers and we discuss molecular mechanisms and clinical implications.

Considerable numbers of patients with metastatic urothelial carcinoma (mUC) develop bone metastases (BoM). Their impact on the efficacy of immune-checkpoint inhibitors (ICIs) is not yet investigated.Between July 2014 and August 2020 data on pts treated with single-agent ICIs after failure of at least 1 previous line of chemotherapy for advanced disease, were retrospectively collected across 14 Italian centers. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method. Cox regression analysis was performed evaluating potential prognostic factors for OS and PFS. Each factor was evaluated in univariable (UVA) and multivariable analysis (MVA).A total of 208 evaluable patients treated with ICIs were identified, including 122 (59%) without BoM (BoM-) and 86 (41%) with bone metastases (BoM+). After a median follow-up of 22.3 months, BoM+ patients showed shorter OS (median 3.9 vs 7.8 months, HR 1.59 [95%CI, 1.15-2.20], P = .005) and shorter PFS (median 2.0 vs 2.6 months, HR 1.76 [95%CI, 1.31-2.37], P.001). Probability of being alive was 62% vs 40% after 6 months, 38% vs 23% after 1 year and 24% vs 13% after 2 years, in BoM- and BoM+ respectively. Within each Bellmunt score, OS and PFS of BoM+ patients were shorter. Both presence of BoM and higher Bellmunt risk score were significantly associated with shorter OS and PFS in UVA and MVA.Patients treated with single-agent ICIs for BoM+ mUC have a dismal prognosis compared to BoM-. Further research is needed to understand the mechanism behind these outcomes.

Objectives The aim of our study was to collect data about of the outcome of metastatic renal cell carcinoma patients who progressed after immune checkpoint inhibitors in order to enhance data about efficacy and safety of treatment beyond immune-oncology (IO). Materials and methods A total of 162 eligible patients, progressing to IO, were enrolled from 16 Italian referral centers adhering to the Meet-Uro association. Baseline characteristics, outcome data and toxicities were retrospectively collected. Descriptive analysis was made using median values and ranges. Kaplan-Meier method and Mantel-Haenszel log-rank test were performed to compare differences between groups. Results A total of 111 patients (68.5%) were treated after IO progression. In all, 51 patients (31.5%) did not receive further treatment for clinical deterioration. Median IO progression free survival (PFS) was 4 months (95% confidence interval [CI]: 3.1-4.8). IO-PFS tends to be longer in patients reporting adverse events (AE) of any grade (5.03 [95% CI: 3.8-6.1] vs. 2.99 [95% CI: 2.4-3.5] months P=0.004). Subsequent therapies included cabozantinib (n=79, 48%), everolimus (n=11, 6.7%), and others (n=21, 12.9%).Median PFS post-IO was 6.5 months (95% CI: 5.1-7.8). Cabozantinib showed longer PFS compared with everolimus (7.6 mo [95% CI: 5.2-10.1] vs. 3.2 mo [95% CI: 1.8-4.5]) (hazard ratio: 0.2; 95% CI: 0.1026-0.7968) and other drugs (4.3 mo [95% CI: 1.3-7.4]) (hazard ratio: 0.6; 95% CI: 0.35-1.23). All grade AE were reported in 83 patients (74%) and G3 to G4 AE in 39 patients (35%). Target therapies post-IO showed median overall survival of 14.7 months (95% CI: 0.3-21.4). Conclusions In our real world experience after progression to IO, vascular endotelial groth factor-tyrosine kinase inhibitors, given to patients, proved to be active and safe choices. Cabozantinib was associated with a better outcome in terms of median PFS.

Testicular cancer (TC) is the most frequent solid tumor diagnosed in young adult males. Although it is a curable tumor, it is frequently associated with considerable short-term and long-term morbidity. Both biological and psychological stress experienced during cancer therapy may be responsible for stimulating molecular processes that induce premature aging and deterioration of immune system (immunosenescence) in TC survivors, leading to an increased susceptibility to infections, cancer, and autoimmune diseases. Immunosenescence is a remodeling of immune cell populations with inversion of the CD4:CD8 ratio, accumulation of highly differentiated memory cells, shrinkage of telomeres, shift of T-cell response to Th2 type, and release of pro-inflammatory signals. TC survivors exposed to chemotherapy show features of immunological aging, including an increase in memory T-cells (CD4+ and CD8+) and high expression of the senescence biomarker p16INK4a in CD3+ lymphocytes. However, the plethora of factors involved in the premature aging of TC survivors make the situation more complex if we also take into account the psychological stress and hormonal changes experienced by patients, as well as the high-dose chemotherapy and hematopoietic stem cell transplantation that some individuals may be required to undergo. The relatively young age and the long life expectancy of TC patients bear witness to the importance of improving quality of life and of alleviating long-term side-effects of cancer treatments. Within this context, the present review takes an in-depth look at the molecular mechanisms of immunosenescence, describing experimental evidence of cancer survivor aging and highlighting the interconnected relationship between the many factors modulating the aging of the immune system of TC survivors.

Background: Despite the survival advantage, not all metastatic renal cell carcinoma (mRCC) patients achieve a long-term benefit from immunotherapy. Moreover, the identification of prognostic biomarkers is still an unmet clinical need. Methods: This multicenter retrospective study investigated the prognostic role of peripheral-blood inflammatory indices and clinical factors to develop a novel prognostic score in mRCC patients receiving at least second-line nivolumab. The complete blood count before the first cycle of therapy was assessed by calculating neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), and systemic inflammation response index (SIRI). Clinical factors included pre-treatment International Metastatic RCC Database Consortium (IMDC) score, line of therapy, and metastatic sites. Results: From October 2015 to November 2019, 571 mRCC patients received nivolumab as second- and further-line treatment in 69% and 31% of cases. In univariable and multivariable analyses all inflammatory indices, IMDC score, and bone metastases significantly correlated with overall survival (OS). The multivariable model with NLR, IMDC score, and bone metastases had the highest c-index (0.697) and was chosen for the developing of the score (Schneeweiss scoring system). After internal validation (bootstrap re-sampling), the final index (Meet-URO score) composed by NLR, IMDC score, and bone metastases had a c-index of 0.691. It identified five categories with distinctive OSs: group 1 (median OS – mOS = not reached), group 2 (mOS = 43.9 months), group 3 (mOS = 22.4 months), group 4 (mOS = 10.3 months), and group 5 (mOS = 3.2 months). Moreover, the Meet-URO score allowed for a fine risk-stratification across all three IMDC groups. Conclusion: The Meet-URO score allowed for the accurate stratification of pretreated mRCC patients receiving nivolumab and is easily applicable for clinical practice at no additional cost. Future steps include its external validation, the assessment of its predictivity, and its application to first-line combinations.