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G. RAVAGLIA, P. FORTI, L. PRATELLI, F. MAIOLI, C. R. SCALI, A. M. BONINI, S. TEDIOLI, N. MARASTI, A. PIZZOFERRATO, G. GASBARRINI We measured calcium regulating hormones and bone mineral [...]

OBJECTIVE: To examine the association between depressive symptoms and prevalent and incident mild cognitive impairment (MCI) in elderly individuals; to verify whether it is affected by MCI subtype. DESIGN: Prospective, population-based, longitudinal cohort study. SETTING: Adults >or=65 years resident in an Italian municipality. PARTICIPANTS: Baseline data are for 595 subjects with no cognitive impairment (NCI) and 72 subjects with prevalent MCI. NCI subjects underwent a 4-year follow-up for incident MCI. MEASUREMENTS: MCI was diagnosed according to international criteria and classified as with (m + MCI) or without memory impairment (m - MCI). Baseline depressive symptoms were measured using the 30-item Geriatric Depression Scale (GDS). Baseline use of antidepressants was also recorded. RESULTS: Baseline depressive symptoms (GDS >or=10) were more frequent in prevalent MCI cases (44.4%) than in NCI participants (18.3%). The association was independent of MCI subtype, antidepressant use, and sociodemographic and vascular risk factors. In NCI subjects, baseline depressive symptoms were also associated with increased risk of MCI at follow-up, but only for subjects on antidepressant drugs at baseline (incident cases = 72.7%) compared with those without depressive symptoms and not on antidepressant therapy (incident cases = 24.0%). The association was independent of other confounders and stronger for m - MCI (incident cases = 45.4%) with respect to m + MCI (incident cases = 27.3%). CONCLUSIONS: Depressive symptoms are highly prevalent among elderly MCI subjects and, in cognitively normal elderly individuals, are associated with an increased risk of developing MCI. The association is stronger for the MCI subtype without memory impairment. [ABSTRACT FROM AUTHOR]

Abstract: Among the age-related diseases, the development of cognitive impairments, in particular dementia, is the most devastating for the individual and has great social and healthcare costs. Accurate information is needed about the prevalence and incidence of cognitive disorders and the physiology of the aging brain. In particular, only scarce data are available about the relationship between aging, cognitive status and nutritional factors. In order to address these issues, we planned the Conselice Study, a longitudinal study of physiological and pathological brain aging. The center involved in the study was the municipality of Conselice, (Province of Ravenna), in the Northern-Italian Region Emilia-Romagna. A total of 1,016 subjects aged 65 years and over was enrolled at baseline. Information about cognitive status at 4-years of follow-up was collected from 940 of them. These data have been used to estimate prevalence and incidence of dementia in the elderly Italian population and to investigate the possible role of homocysteine as a predictor of dementia. [Copyright &y& Elsevier]

OBJECTIVE: Little is known about the prevalence of the metabolic syndrome among elderly people in Italy, its association with all-cause mortality, and whether measurement of serum C-reactive protein (CRP) and interleukin (IL)-6 affects this association. RESEARCH DESIGN AND METHODS: The baseline prevalence of metabolic syndrome, diagnosed according to the National Cholesterol Education Program (NCEP) criteria, and all-cause mortality at 4 years were recorded in an Italian population-based cohort (981 subjects, 55% women, aged 65-97 years). A Cox model adjusted for sociodemographic, lifestyle, and medical variables was used to investigate 1) whether metabolic syndrome was a predictor of mortality and 2) how the association was affected by baseline high CRP (>3 mg/l) and IL-6 (>1.33 pg/ml). RESULTS: Overall, metabolic syndrome prevalence was 27.2% [95% CI 24.0-30.5] and higher in women (33.3% [28.7-38.0]) than in men (19.6% [15.5-24.2]). During follow-up, 137 deaths occurred. Using the no metabolic syndrome/no high IL-6 group as the reference, mortality was not associated with the metabolic syndrome alone (multivariable-adjusted hazard ratio 1.24 [0.60-2.59]), only weakly associated with high IL-6 alone (1.66 [1.04-2.63]), but strongly associated with the concurrent presence of metabolic syndrome and high IL-6 (3.26 [2.00-5.33]). High CRP was not a mortality predictor (0.83 [0.58-1.20]) nor did it affect the association of the other variables with mortality. CONCLUSIONS: Metabolic syndrome by NCEP criteria is highly prevalent in the Italian elderly population. It is not itself associated with mortality but may improve the usefulness of IL-6 as a mortality predictor in older age. [ABSTRACT FROM AUTHOR]

Objectives: Mild cognitive impairment (MCI) is regarded as a precursor to dementia, but not all patients with MCI actually develop dementia. As Alzheimer and vascular dementia are thought to share many common etiopathogenetic mechanisms, we investigated whether the vascular risk factor atrial fibrillation affects the risk of conversion to dementia for different MCI subtypes diagnosed according to international criteria. Methods: One hundred and eighty elderly outpatients with MCI and 431 elderly outpatients with a normal cognition were followed up for a mean of 3 and 4 years, respectively. The risk of conversion to dementia associated with atrial fibrillation was studied in both samples using a Cox proportional hazards model adjusted for socio-demographic and medical variables. Results: Overall conversion rate to dementia was 10.5 (8.0–13.8 per 100 person-years) in the MCI group and 2.2 (1.5–3.1 per 100 person-years) in the normal cognition group. Atrial fibrillation was significantly associated with conversion to dementia [hazard ratio (HR): 4.63; 95% confidence interval: 1.72–12.46] in the MCI group but not in the cognitively normal group (HR: 1.10; 95% confidence interval: 0.40–3.03). Discussion: Current diagnostic criteria for MCI subtypes define heterogeneous populations, but atrial fibrillation can be useful in identifying people with increased risk of conversion to dementia. [ABSTRACT FROM AUTHOR]

BACKGROUND: In cross-sectional studies, elevated plasma total homocysteine (tHcy) concentrations have been associated with cognitive impairment and dementia. Incidence studies of this issue are few and have produced conflicting results. OBJECTIVE: We investigated the relation between high plasma tHcy concentrations and risk of dementia and Alzheimer disease (AD) in an elderly population. DESIGN: A dementia-free cohort of 816 subjects (434 women and 382 men; mean age: 74 y) from an Italian population-based study constituted our study sample. The relation of baseline plasma tHcy to the risk of newly diagnosed dementia and AD on follow-up was examined. A proportional hazards regression model was used to adjust for age, sex, education, apolipoprotein E genotype, vascular risk factors, and serum concentrations of folate and vitamin B-12. RESULTS: Over an average follow-up of 4 y, dementia developed in 112 subjects, including 70 who received a diagnosis of AD. In the subjects with hyperhomocysteinemia (plasma tHcy > 15 mumol/L), the hazard ratio for dementia was 2.08 (95% CI: 1.31, 3.30; P = 0.002). The corresponding hazard ratio for AD was 2.11 (95% CI: 1.19, 3.76; P = 0.011). Independently of hyperhomocysteinemia and other confounders, low folate concentrations (

Background: Bone loss in elderly men is associated with changes in body composition and reduced secretion of endogenous anabolizing hormones. The independent influences of body composition and endocrine factors on male bone metabolism, however, are unclear.Methods: Bone mass density (BMD) (bone mass content [BMC, g]/projected bone area [BA, cm2]) at different skeletal sites, skeletal muscle, and body fat mass were measured by dual-energy X-ray absorptiometry in 129 men aged 20 to 95 years. Free testosterone, 17-beta-estradiol, dehydroepiandrosterone-sulfate, and insulin-like growth factor 1 (IGF-1) serum concentrations were measured. Because BMD may fail to control for differences in skeletal size, the associations of bone mass with body composition and hormones were studied by comparing BMD regression models incorporating age and knee height only with BMC regression models also incorporating BA.Results: Skeletal muscle had close associations (p at least < .01) with BMD and BMC at almost all skeletal sites, but the strength of these associations was generally reduced in BMC with respect to BMD models. Weak associations (p < .05) were found in both models for fatness with femoral bone and for 17-beta-estradiol with total body and femoral bone. The association of 17-beta-estradiol with spinal bone was significant (p < .05) in the BMD but not in the BMC model. No association of BMC or BMD with androgens and IGF-1 reached significancy.Conclusions: Skeletal muscle may be more important than fatness and anabolizing hormones in preserving bone mass in elderly men. In contrast to traditional belief, estrogens may be more important than androgens and IGF-1 in male bone metabolism. [ABSTRACT FROM AUTHOR]

BACKGROUND: Natural killer (NK) cells play a role in natural immunity against tumor and infected cells. Advanced aging is associated with functional impairment of NK cells and increased susceptibility to nutritional deficiencies. OBJECTIVE: Our objective was to test whether micronutrient status affects NK cell activity in an older population. DESIGN: The relations between NK cell variables (percentage of leukocytes and cytotoxicity) and blood concentrations of selected micronutrients were studied in 62 healthy, free-living northern Italian subjects (25 men, 37 women) aged 90-106 y. Anthropometric measurements were also made. RESULTS: All subjects were well nourished according to age-specific anthropometric norms but many of them had micronutrient deficiencies. The prevalence of micronutrient deficiency was highest for selenium (in approximately 50% of both sexes), zinc (in 52% of men and 41% of women), and vitamin B-6 (in 40% of men and 59% of women), followed by vitamin A (in 16% of men and 27% of women) and vitamin E, vitamin B-12, and folate (each in <10% of both sexes). Ubiquinone-10 status was inadequate in 40% of women and 24% of men (P = 0.02). The percentage of NK cells was associated with serum zinc (men: r = 0.573, P = 0. 007; women: r = 0.373, P = 0.031) and selenium (women: r = 0.409, P = 0.018) concentrations. In women only, NK cell cytotoxicity at different effector-target cell ratios was positively associated with plasma vitamin E and ubiquinone-10 concentrations (P < 0.05). No significant associations with NK cell variables were found for the other measured nutrients. CONCLUSIONS: The results of this study strengthen the hypothesis that individual micronutrients may affect the number and function of NK cells in old age. The study also confirms the high prevalence of micronutrient deficiencies in healthy and apparently well-nourished persons aged >/=90 y. Copyright © 2000 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Background: Nutritional evaluation of elderly people is of great importance. Two-component methods for body composition assessment, such as anthropometry and bioelectrical impedance (BIA), are widely used in clinical practice, but their fundamental assumptions may be invalid in older people. Dual-energy X-ray absorptiometry (DXA) is a relatively new method for reliable and direct measurements of body mass in its three basic components: total body bone mineral content (TBBMC), mineral free lean tissue mass (LTM), and fat. In this study, percent body fat (%BF) estimates from anthropometry and BIA in men of various ages were compared with corresponding measurements by DXA.Methods: Body fat percentage was estimated in 67 men aged 20-95 by anthropometric measurements (skinfold thickness, body mass index, or BMI), BIA, and DXA. Age-specific equations were used for anthropometry and BIA. Limits of agreement were calculated between DXA and the other methods.Results: The equations based on BMI and BIA systematically overestimated %BF with respect to %BF measured by DXA in people of all ages. Intermethod difference between DXA and skinfold thicknesses was less marked, but in over-80-year-olds %BF predicted by skinfold measurements underestimated %BF measured by DXA. Interindividual and age-related variation in TBBMC and in fat-free mass mineralization could partly explain the intermethod differences found between DXA and the other methods.Conclusions: Because of practical constraints, anthropometry and BIA are often the only available options for body composition assessment in clinical routine; therefore, further research on the validity and improvement of these methods in older people is indicated. [ABSTRACT FROM AUTHOR]

Hyposplenism has been reported in elderly people. However, from previous studies, it was not clear whether the observed alterations in splenic function were a physiologic effect of advanced age itself or a consequence of age-related diseases. As hyposplenism is believed to predispose to infections, autoimmune phenomena and thrombosis, this question is of great clinical concern. In the present study splenic function was assessed by counting the pitted red cells in 65 healthy subjects aged 50-108 years. At variance from previous studies, our study population consisted of free-living individuals carefully selected in order to exclude any underlying disease. The percentage of pitted red cells in 37 subjects over 70 years was significantly higher than in 28 younger subjects, although only 1 subject had a pitted red cell count indicating splenic hypofunction. A positive, but weak, correlation between the percentage of pitted red cells and age was also found when considering the whole population (rs = 0.273, p = 0.029). In conclusion, although slightly reduced with advancing age, splenic function seems basically to be maintained in elderly people. [ABSTRACT FROM AUTHOR]

Background: Age is considered one of the important contraindications to surgery for hepatocellular carcinoma (HCC) in cirrhosis patients. We therefore evaluated the safety and prevalence of side effects in endoarterial therapy (EAT) in subjects aged over 65 years compared with younger treated patients.Methods: Thirty-eight patients with HCC aged 65 years and over underwent transcatheter arterial chemoembolization (TACE) (n = 28) or intraarterial chemotherapy (IAC) (n = 10). The survival rate was calculated using Kaplan-Meier's method with respect to a control group consisting of younger treated subjects (44 TACE; 21 IAC) comparable for stage of HCC and severity of the underlying cirrhosis.Results: The comparison between the two groups regarding side effects, procedure-related death, and survival did not show any difference considering the whole EAT procedure. TACE in elderly subjects reached a statistically lower outcome with respect to younger patients (p < .025) but remained statistically superior in survival versus both older and younger patients treated with IAC (p < .05, respectively). Stratifying the patients following the degree of Lipiodol uptake of tumor mass in the three groups (Group I, > 75%; Group II, 50-75%; Group III, < 50%), in the young subjects a higher probability of survival was strictly correlated to a degree of uptake over 75%, while in the elderly patients an impregnation over 50% was sufficient to obtain a satisfactory survival curve.Conclusions: EAT is a reliable and safe therapeutic option for the geriatric patient with HCC, with TACE showing a better efficacy than IAC, requiring a lesser degree of Lipiodol uptake to achieve an improvement of outcome. [ABSTRACT FROM AUTHOR]

Abstract: Depression, often accompanied by suicidal behavior or recurring thoughts about suicide, is one of the most common psychic impairments in old age. Statistics in Austria tell us clearly: Suicidal candidates among the elderly are likely to succeed. Especially in men, suicide has become a significant cause of death. In an age where traditional family structures are beginning to fall apart, and where the elderly increasingly feel to be a “burden” to society, unable to find their place, we tend to look at suicide more and more as a voluntary and autonomous decision, thus rationalizing it as in: “This life I would not want to live either”. But is it permissible for physicians to consider a patient, who has acted suicidal, to be “not ill,” or to have acted “with good reason”? The present paper shall critically revisit the concept of “rational suicide.” What I hope to illuminate is the tension between medical care for, and autonomy of the patient that physicians have to negotiate in their work. [Copyright &y& Elsevier]

Abstract: MCI is regarded as a precursor of dementia, but not all patients with MCI actually develop dementia. As Alzheimer and vascular dementia (AD and VD, respectively) are thought to share many common etiopathogenetic mechanisms, we investigated whether the vascular risk factor atrial fibrillation affect the risk of conversion to dementia for different MCI subtypes diagnosed according to international criteria. One-hundred-eigthy elderly outpatients with MCI and 431 elderly outpatients with a normal cognition were followed-up for a mean of 3 and 4 years, respectively. The risk of conversion to dementia associated with atrial fibrillation was studied in both samples using a Cox proportional-hazards model adjusted for sociodemographic and medical variables. Overall conversion rate to dementia was 10.5 (8.0–13.8) per 100 person-years in the MCI group and 2.2 (1.5–3.1) per 100 person-years in the normal cognition group. Atrial fibrillation was significantly associated with conversion to dementia (hazard ratio=HR=4.63, 95% confidence interval=Cl=1.72–12.46) in the MCI group, but not in the cognitively normal group (HR=1.10, 95% Cl=0.40–3.03). Current diagnostic criteria for MCI subtypes define heterogeneous populations, but atrial fibrillation can be useful in identifying people with increased risk of conversion to dementia. [Copyright &y& Elsevier]

Up to 80% of castration-resistant prostate cancer (CRPC) patients develop bone metastases during the natural history of disease and about 25% harbor mutations in DNA damage repair (DDR) genes. This retrospective observational study evaluated the prevalence of DDR alterations in CRPC patients and their effect on the clinical outcomes associated with bone metastases. The mutational status of CRPC patients was analyzed per FoundationOne ® analysis in tissue biopsy or, when it was not possible, in liquid biopsy performed at the onset of metastatic CRPC (mCRPC). The impact of DDR gene mutations on bone-related efficacy endpoints was evaluated at the time of mCRPC diagnoses. In total, 121 mCRPC patients with bone metastases were included: 38 patients had mutations in at least one DDR gene, the remaining 83 ones had a non-mutated DDR status. DDR mutated status was associated with bone metastases volume ( p = 0.006), but did not affect SRE (skeletal-related events) incidence and time to SRE onset. Liquid and tissue biopsies were both available for 61 patients with no statistically significant difference in terms of incidence and type of molecular DDR alterations. Mutated DDR status was associated with higher bone metastasic volume, although a not detrimental effect on the other bone-related efficacy endpoints was observed.

Abnormalities in the plasma amino acid and/or urinary organic acid profile have been reported in autism spectrum disorder (ASD). An imbalance between excitatory and inhibitory neuronal activity has been proposed as a mechanism to explain dysfunctional brain networks in ASD, as also suggested by the increased risk of epilepsy in this disorder. This study explored the possible association between presence of EEG paroxysmal abnormalities and the metabolic profile of plasma amino acids and urinary organic acids in children with ASD. In a sample of 55 children with ASD (81.8% male, mean age 53.67 months), EEGs were recorded, and 24 plasma amino acids and 56 urinary organic acids analyzed. EEG epileptiform discharges were found in 36 (65%) children. A LASSO regression, adjusted by age and sex, was applied to evaluate the association of plasma amino acids and urinary organic acids profiles with the presence of EEG epileptiform discharges. Plasma levels of threonine (THR) (coefficient = -0.02, p = 0.04) and urinary concentration of 3-Hydroxy-3-Methylglutaric acid (HMGA) (coefficient = 0.04, p = 0.02) were found to be associated with the presence of epileptiform discharges. These results suggest that altered redox mechanisms might be linked to epileptiform brain activity in ASD.

Background: Cabazitaxel improves overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients progressing after docetaxel. In this prospective study, we evaluated the prognostic role of CTC gene expression on cabazitaxel-treated patients and its association with plasma androgen receptor (AR) copy number (CN)., Methods: Patients receiving cabazitaxel 20 or 25 mg/sqm for mCRPC were enrolled. Digital PCR was performed to assess plasma AR CN status. CTC enrichment was assessed using the AdnaTest EMT-2/StemCell kit. CTC expression analyses were performed for 17 genes. Data are expressed as hazard ratio (HR) or odds ratio (OR) and 95% CI., Results: Seventy-four patients were fully evaluable. CTC expression of AR-V7 (HR=2.52, 1.24-5.12, p=0.011), AKR1C3 (HR=2.01, 1.06-3.81, p=0.031), AR (HR=2.70, 1.46-5.01, p=0.002), EPCAM (HR=3.75, 2.10-6.71, p< 0.0001), PSMA (HR=2.09, 1.19-3.66, p=0.01), MDK (HR=3.35, 1.83-6.13, p< 0.0001), and HPRT1 (HR=2.46, 1.44-4.18, p=0.0009) was significantly associated with OS. ALDH1 (OR=5.50, 0.97-31.22, p=0.05), AR (OR=8.71, 2.32-32.25, p=0.001), EPCAM (OR=7.26, 1.47-35.73, p=0.015), PSMA (OR=3.86, 1.10-13.50, p=0.035), MDK (OR=6.84, 1.87-24.98, p=0.004), and HPRT1 (OR=7.41, 1.82-30.19, p=0.005) expression was associated with early PD. AR CN status was significantly correlated with AR-V7 (p=0.05), EPCAM (p=0.02), and MDK (p=0.002) expression. In multivariable model, EPCAM and HPRT1 CTC expression, plasma AR CN gain, ECOG PS=2, and liver metastases and PSA were independently associated with poorer OS. In patients treated with cabazitaxel 20 mg/sqm, median OS was shorter in AR-V7 positive than negative patients (6.6 versus 14 months, HR=3.46, 1.47-8.17], p=0.004)., Conclusions: Baseline CTC biomarkers may be prognosticators for cabazitaxel-treated mCRPC patients. Cabazitaxel at lower (20 mg/sqm) dose was associated with poorer outcomes in AR-V7 positive patients compared to AR-V7 negative patients in a post hoc subgroup analysis., Trial Registration: Clinicaltrials.gov NCT03381326 . Retrospectively registered on 18 December 2017., (© 2022. The Author(s).)

Gynecological tumors are malignancies with both high morbidity and mortality. To date, only a few chemotherapeutic agents have shown efficacy against these cancer types (only ovarian cancer responds to several agents, especially platinum-based combinations). Within this context, the discovery of immune checkpoint inhibitors has led to numerous clinical studies being carried out that have also demonstrated their activity in these cancer types. More recently, following the development of chimeric antigen receptor (CAR)-T cell therapy in hematological malignancies, this strategy was also tested in solid tumors, including gynecological cancers. In this article, we focus on the molecular basis of gynecological tumors that makes them potential candidates for immunotherapy. We also provide an overview of the main immunotherapy studies divided by tumor type and report on CAR technology and the studies currently underway in the area of gynecological malignancies.

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.

Purpose: Biomarkers for treatment personalization in metastatic castration-resistant prostate cancer (mCRPC) could help improve patient outcomes. Multiple tests on blood have reported associations with poorer outcome, including serum lactate dehydrogenase (LDH), chromogranin A (CGA), neutrophil:lymphocyte ratio (NLR), and, recently, copy number (CN) of androgen receptor (AR) in plasma DNA. Biologic data suggest an association between choline uptake and AR signaling. We aimed to integrate 18 F -fluorocholine (FCH) uptake on positron emission tomography/computed tomography (PET/CT) scanning with plasma AR CN and other routinely obtained circulating biomarkers to evaluate their association with outcome., Materials and Methods: We determined plasma AR CN by digital droplet polymerase chain reaction from 105 mCRPC samples collected before abiraterone (n = 65) or enzalutamide (n = 40) therapy in the before (n = 26) and after (n = 79) chemotherapy settings. Pretreatment serum LDH, CGA, and NLR were also measured. FCH-PET/CT scan was performed at baseline, and maximum standardized uptake value (SUV max ), total lesion activity (TLA), and metabolic tumor volume (MTV) were calculated. Main end points were the correlation of FCH-PET/CT parameters with circulating biomarkers and their impact on outcome., Results: Plasma AR CN gain was observed in 27 patients (25.7%), and it correlated significantly with higher median SUV max , TLA, and MTV values ( P < .001). Kaplan-Meier curves showed significantly worse progression-free survival and overall survival in patients with plasma AR gain and higher SUV max , TLA, and MTV values ( P < .001 in each prognostic group). Conversely, no association was reported for prostate-specific antigen response. On multivariable analysis of overall survival, we showed as independent factors AR gain (hazard ratio [HR], 1.92; 95% CI, 1.07 to 3.47; P = .029), presence of visceral metastasis (HR, 3.04; 95% CI, 1.66 to 5.58; P = < .001), LDH (HR, 2.95; 95% CI, 1.72 to 5.05; P < .001), NLR (HR, 3.51; 95% CI, 2.14 to 5.74; P < .001), serum CGA (HR, 3.36; 95% CI, 1.99 to 5.67; P < .001), and MTV (HR, 2.09; 95% CI, 1.25 to 3.50; P = .005)., Conclusion: Our results indicate the potential usefulness of integrating functional imaging with plasma DNA analysis and other noninvasive biomarkers as a tool to improve treatment selection for CRPC. A larger prospective evaluation is warranted.

The therapeutic landscape of prostate cancer has expanded rapidly over the past 10 years, and there is now an even greater need to understand the biological mechanisms of resistance and to develop noninvasive biomarkers to guide treatment. The androgen receptor (AR) is known to be involved in the pathogenesis and progression of prostate cancer. Recently, highly sensitive next-generation sequencing and PCR-based methods for analyzing androgen receptor gene (AR) copy numbers (CN) and mutations in plasma were established in cell-free DNA (cfDNA) of patients with castration-resistant prostate cancer (CRPC) treated with different drugs. The study of cfDNA holds great promise for improving treatment in CRPC, especially in the advanced stage of the disease. Recent findings showed the significant association of plasma AR aberrations with clinical outcome in CRPC patients treated with AR-directed therapies, whereas no association was observed in patients treated with taxanes. This suggests the potential for using plasma AR as a biomarker for selecting treatment, i.e., hormone therapy or chemotherapy, and the possibility of modulating taxane dose. In recent years, plasma AR status has also been investigated in association with novel agents, such as 177 Lu-PSMA radioligand therapy and PARP inhibitors. This review will focus on AR testing in plasma that may have clinical utility for treatment selection in advanced prostate cancer.

Immunotherapy represents the new era of cancer treatment because of its promising results in various cancer types. In urological tumors, the use of the immune-checkpoint inhibitors (ICIs) is increasingly spreading. Although not all patients and not all diseases respond equally well to immunotherapy, there is an increasing need to find predictive markers of response to ICIs. Patient- and tumor-related factors may be involved in primary and secondary resistance to immunotherapy: tumor-derived protein and cytokines, tumor mutational burden, and patient performance status and comorbidities can condition tumor response to ICIs. Recently, some of these factors have been evaluated as potential biomarkers of response, with conflicting results. To date, the expression of programmed death-ligand 1 (PD-L1) and the presence of deficient mismatch repair (dMMR) in tumor tissue are the only biomarkers capable of guiding the clinician's decision in urothelial cancer and prostate cancer, respectively. In this review, we performed a comprehensive search of the main publications on biomarkers that are predictive of response to ICIs in urological cancers. Our aim was to understand whether existing data have the potential to drive clinical decision-making in the near future., Competing Interests: Ugo De Giorgi has received personal fees for advisory board/consultancy from Astellas, Bayer, BMS, Ipsen, Janssen, Merck, Novartis, Pfizer, and Sanofi. Other authors declare no conflicts of interest., (Copyright © 2019 Giuseppe Schepisi et al.)

Purpose: Our study aims to investigate the association between copy number of the androgen receptor (AR) and testosterone levels in metastatic castration-resistant prostate cancer (mCRPC) treated with second-generation antiandrogen therapies., Materials and Methods: We retrospectively collected data from mCRPC treated with abiraterone acetate and enzalutamide. Serum testosterone levels were collected at baseline, at 3 months since the start of therapy and at disease progression. A cohort of cases treated with docetaxel was also used to evaluate the impact of testosterone levels., Results: Patients treated with abiraterone with AR copy number aberrations and basal testosterone levels below 0.09 nmol/L had worse progression-free survival (PFS) compared to patients with no AR copy number abnormalities (8.5 vs 2.9 months, P = 0.005). No relevant differences were observed in the enzalutamide group with a PFS of 3.9 months (no AR gain) vs 2.7 months ( AR gain, P = 0.004) for patients with below 0.09 nmol/L testosterone levels. Similar results are obtained for univariate analysis for overall survival (OS). The negative prognostic role of AR copy number gain in OS for both treatment groups (25.5 vs 10.6 months, P = 0.0002 for abiraterone and 14.1 vs 8.3 months, P = 0.031 for enzalutamide) was confirmed, and it was recognized the negative prognostic impact of testosteronemia below 0.09 only for patients treated with enzalutamide (8.8 vs 42.8 months, P = 0.016). On multivariate analysis for patients treated with abiraterone, low testosterone levels below 0.09 and plasma AR gain were significantly associated with worse PFS and OS. These data are confirmed in the enzalutamide group for PFS., Conclusions: Testosterone levels and the AR copy number alterations were considered as independent prognostic factors. The results of this study show that serum testosteronemia associated with changes in copy number of AR gene could represent a noninvasive biomarker useful to identify a subgroup of patients with worse prognosis that can benefit less from second-generation antiandrogen therapies in the mCRPC setting., (© 2019 Wiley Periodical, Inc.)

In the last few years, substantial progress has been made in the treatment of ovarian cancer, with increased knowledge about the biology of the disease. Ovarian cancer is a neoplasm strongly linked to defects in DNA repair mechanisms, where deficiency in the homologous recombination (HR) system results in a better response of ovarian cancers to therapy, whether platinum-based chemotherapy, anthracyclines, or poly (ADP-ribose) polymerase (PARP) inhibitors. More recently, it has been demonstrated that different ovarian cancer histotypes may have different immunogenicity. Interestingly, defects in HR systems are associated more frequently with higher tumor infiltrating lymphocytes, providing a rationale for developing combination therapy with immune-modulating agents and PARP inhibitors. Again, locoregional therapies combining heat shock and chemotherapy delivery have been shown to induce an anticancer immune response in vitro. Thus, the potential for locoregional therapeutic approaches that may impact the immune system, perhaps in combination with immune-modulating agents or PARP inhibitors, needs to be further explored. With this premise, we reviewed the main biological and clinical data demonstrating a strict interplay between the immune system, DNA repair mechanisms, and intraperitoneal therapies in ovarian cancer, with a focus on potential future therapeutic implications.

Testicular cancer is the most frequent tumor in young males aged 15-39 years. As cure rates are currently around 90%, the prevalence of survivors is increasing. However, a disease-free condition does not necessarily correspond to a life free of physical and psychosocial health problems. The aim of this review was to explore psychosocial morbidity among testicular cancer survivors. A literature search was conducted in three electronic databases (PubMed, Medline, and Embase). The results of the search on cancer survivors were then combined with those of the search on psychosocial concerns and work performance. Eighty-four publications met the inclusion criteria. Physical, psychological, work-related problems and changing perspectives about work and life in general influenced life and career decisions among testicular cancer survivors. Individual health, sexual relationships and work problems, affect several important aspects of survival and significantly influence the QoL of long-term survivors.

Background: The management of visceral leishmaniasis (VL) in HIV-infected patients is often complex with patients experiencing higher mortality rates, more toxic side effects and a higher possibility of treatment failure and relapse than HIV-negative individuals with VL., Case Presentation: We report on successful salvage therapy in two HIV-infected patients suffering with disseminated cutaneous and visceral leishmaniasis, recalcitrant to therapy with liposomal amphotericin B. After the employment of combination anti-leishmanial treatment, parasite genomes were not detectable up to the last follow up visit, 57 and 78 weeks after treatment onset, respectively. CD4+ lymphocyte counts fluctuated over time, but were generally higher than counts detected at treatment onset, which likely contributed to protection against VL relapse., Conclusions: Results achieved with the anti-leishmanial combination treatment were promising, but are based on only two patients. Future investigation is necessary to confirm the efficacy of this salvage therapy in sustaining the immunological response and control of VL.