Comprehensive geriatric assessment in older adults with cancer: Recommendations by the Italian Society of Geriatrics and Gerontology (SIGG).

INTRODUCTION: Optimizing the approach to older adults with cancer is now a priority given the increasing frequency of new cancer diagnoses that are made in the older population. The comprehensive geriatric assessment (CGA) represents the gold-standard for (1) defining prognosis and ability to withstand cancer treatments, (2) exploring the multiple aspects that define the complexity of frail older persons, and (3) designing person-tailored interventions. MATERIALS AND METHODS: In this document, based on a comprehensive revision of the literature, the Italian Society for Geriatrics and Gerontology proposes a CGA model (ONCOGER CGA) to be adopted by oncology centers for their routine approach to older patients with cancer. RESULTS AND DISCUSSION: A widespread use of this standardized CGA format will facilitate comparisons across institutions, promote studies based on a multidimensional patient assessment, and foster the inclusion of geriatric endpoints in oncological clinical trials. Furthermore, we predict that the use of a standardized CGA approach will increase the integration of geriatricians into oncology care teams with the final result of improving therapeutic choices and clinical outcomes.

Fasting-mimicking diet and hormone therapy induce breast cancer regression.

Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.

Development of a predictor of one-year mortality in older patients with cancer by geriatric and oncologic parameters.

OBJECTIVES: More than 60% of the new cancer diagnoses are currently made in older adults, a highly heterogeneous population. Reliable and time-saving tools to define older adults' prognosis are needed to inform the oncologist's decisions in routine clinical practice. We sought to define a multi-domain classification tool for the prediction of all-cause one-year mortality in a cohort of older adults with solid tumors. MATERIALS AND METHODS: We conducted a single-centre, prospective study of patients with solid cancer aged 65 or older and with G8 score ≤ 14. All patients underwent a comprehensive geriatric assessment (CGA) before starting their surgical or medical treatment. One-year mortality was recorded. A CGA-based prediction tool of one-year mortality was developed and subsequently validated in two independent training and testing cohorts with a 70/30 split, respectively. RESULTS: 162 patients were enrolled. Mean patient age was 78 ±â€¯5.5 years. Forty-three percent of the patients were men. Colorectal and breast cancer were the most common diagnoses. The clinical variables selected for the development of the new classifier (MetaGENUA®) were: mini-nutritional assessment (MNA), instrumental day life activities (IADL), Cumulative Illness Rating Scale (CIRS), geriatric depression scale (GDS), age, and cancer stage. In our independent validation cohort, MetaGENUA® showed high specificity (0.86) and AUC = 0.71 (95% CI = 0.55-0.87). CONCLUSIONS: MetaGENUA® predicts one-year mortality in older patients with cancer with high specificity. As such, MetaGENUA® is predicted to reveal as a useful tool to guide the oncologist's decisions in clinical practice.

Frailty assessment in elective gastrointestinal oncogeriatric surgery: Predictors of one-year mortality and functional status.

OBJECTIVES: Perioperative frailty assessment is still a challenge, especially in oncogeriatrics. We aimed at assessing the diagnostic accuracy of the 40 items Frailty Index (FI) as compared to the comprehensive geriatric assessment (CGA) for the prediction of one-year mortality and functional status after colorectal surgery in old-age subjects. MATERIAL AND METHODS: Ninety-nine consecutive patients aged 65 years or older who were candidate for elective gastrointestinal cancer surgery, with G8 score ≤ 14 were enrolled and subjected to CGA and to frailty stratification according to the 40-items FI. Long-term outcomes including one-year mortality and functional decline were collected. RESULTS: Mean patient age was 80.3 ±â€¯5.6 years. Colorectal cancer was the most common diagnosis. The most prevalent clinical phenotype was pre-frail. CGA and FI showed similar predictive accuracy in identifying one-year mortality after surgery and patient functional status. Our multivariate analysis indicated the pre-morbid functional status (IADL) and cancer stage as the most significant predictors of one-year mortality. CONCLUSIONS: This is the first study to investigate the prognostic accuracy of the 40-items FI as compared to CGA in a vulnerable octogenarian cancer population. Its results are consistent with patient functional status being a mediator of frailty and with both serving as intertwined markers of clinical vulnerability. In addition, according to our results, cancer and specific environmental stressors, such as surgery, are likely to affect the frailty trajectory.

Cachexia and advanced dementia.

Cachexia is a complex metabolic process that is associated with several end-stage organ diseases. It is known to be also associated with advanced dementia, although the pathophysiologic mechanisms are still largely unknown. The present narrative review is aimed at presenting recent insights concerning the pathophysiology of weight loss and wasting syndrome in dementia, the putative mechanisms involved in the dysregulation of energy balance, and the interplay among the chronic clinical conditions of sarcopenia, malnutrition, and frailty in the elderly. We discuss the clinical implications of these new insights, with particular attention to the challenging question of nutritional needs in advanced dementia and the utility of tube feeding in order to optimize the management of end-stage dementia.

Investigation of hallmarks of carbonyl stress and formation of end products in feline chronic kidney disease as markers of uraemic toxins.

OBJECTIVES: Cats are commonly affected by chronic kidney disease (CKD). Many reactive carbonyl intermediates and end products originating from the oxidative stress pathways are recognised as uraemic toxins and may play a role in CKD progression. The aim of the present study is to confirm whether carbonyl end-product formation is higher in cats affected by CKD and to assess whether an angiotensin-converting enzyme inhibitor (ACEi) might affect these hallmarks. METHODS: Twenty-two cats were divided into three groups: a control group (CG), cats with CKD and cats with CKD treated with an ACEi. Serum levels of pentosidine, carboxymethyllysine, advanced oxidation protein products, malondialdehyde, methylglyoxal and hexanoyl-lysine were measured. In addition, biochemical parameters and systolic blood pressure were evaluated. After checking for normality, comparisons between groups were performed followed by multiple comparison tests. P values ⩽0.05 were considered significant. Correlations between concentrations of the considered biomarkers and of the other metabolic parameters were investigated. RESULTS: Advanced oxidation protein products, malondialdehyde and hexanoyl-lysine concentrations were significantly higher in CKD and ACEi-treated groups compared with the CG ( P <0.05). Carboxymethyllysine increased in the ACEi-treated group when compared with the CG, whereas intermediate values of these biomarkers were found in the CKD group ( P <0.05). The ACEi-treated group showed the highest values of carboxymethyllysine, advanced oxidation protein products and hexanoyl-lysine. By contrast, the CKD group had the highest concentration of malondialdehyde. No statistically significant difference was found in the levels of pentosidine or methylglyoxal. End products correlated with creatinine and urea and with each other. CONCLUSIONS AND RELEVANCE: Significantly high concentrations of both intermediate and end products of carbonyl/oxidative stress were detected in CKD cats. This is the first study to have concurrently taken into account several uraemic toxins and biochemical parameters in cats affected by CKD.

Predictive values of two frailty screening tools in older patients with solid cancer: a comparison of SAOP2 and G8.

OBJECTIVES: Comprehensive Geriatric Assessment (CGA), the gold standard for detecting frailty in elderly cancer patients, is time-consuming and hard to apply in routine clinical practice. Here we compared the performance of two screening tools for frailty, G8 and SAOP2 for their accuracy in identifying vulnerable patients. MATERIAL AND METHODS: We tested G8 and SAOP2 in 282 patients aged 65 or older with a diagnosis of solid cancer and candidate to undergo surgical, medical and/or radiotherapy treatment. CGA, including functional and cognitive status, depression, nutrition, comorbidity, social status and quality of life was used as reference. ROC curves were used to compare two screening tools. RESULTS: Mean patient age was 79 years and 54% were female. Colorectal and breast cancer were the most common types cancer (49% and 24%). Impaired CGA, G8, and SAOP2 were found in 62%, 89%, and 94% of the patients, respectively. SAOP2 had a better sensitivity (AUC 0.85, p<0.032) than G8 (AUC 0.79), with higher performance in breast cancer patients (AUC 0.93) and in patients aged 70-80 years (AUC 0.87). CONCLUSIONS: G8 and SAOP2 both showed good screening capacity for frailty in the cancer patient population we examined with SAOP2 showing a slightly better performance than G8.

The In-Hospital Length of Stay after Hip Fracture in Octogenarians: Do Delirium and Dementia Shape a New Care Process?

BACKGROUND: Hip fracture is a major health problem and a patient's biological age, comorbidity, and cognitive vulnerability have an impact on its related outcomes. Length of stay (LOS) for these highly vulnerable patients is rather long and the possible causes have not been clearly identified yet. OBJECTIVE: We aimed to assess the main clinical factors associated with protracted LOS, focusing on delirium with or without dementia in older age hip fractured patients. METHODS: 218 subjects (mean age 86.70±6.18 years), admitted to the Orthogeriatric Unit of the Ospedale Policlinico San Martino (Italy), were recruited. All patients received physical and comprehensive geriatric assessment. Days to surgery, days from surgery to rehabilitation, and LOS were recorded. In-hospital and three months' mortality were reported. RESULTS: Prevalent delirium at hospital admission was of 3.1%. 35% of patients developed incident delirium. 56.4% were affected by dementia of Alzheimer-type. In addition, 52% of patients developed delirium superimposed to dementia. Mean LOS was 13.5±4.99 days. Namely, delirium, time to surgery, and complication rate disproportionally affected LOS. The analysis with 3 months mortality, based on cognitive vulnerability profiles, showed how delirium mainly affect short-term mortality in patients with dementia. CONCLUSION: Our exploratory study originally pointed out the high incidence of delirium superimposed to dementia in orthogeriatric wards and how delirium turns to be a moderator of LOS. The results meet the need for additional research by virtue of a deeper understanding of the impact of delirium and dementia on orthogeriatric clinical management and outcomes.

Delirium, Frailty, and Fast-Track Surgery in Oncogeriatrics: Is There a Link?

BACKGROUND/AIMS: Postoperative delirium (POD) is more frequent in elderly patients undergoing major cancer surgery. The interplay between individual clinical vulnerability and a series of perioperative factors seems to play a relevant role. Surgery is the first-line treatment option for cancer, and fast-track surgery (FTS) has been documented to decrease postoperative complications. The study sought to assess, after comprehensive geriatric assessment (CGA) and frailty stratification (Rockwood 40 items index), which perioperative parameters were predictive of POD development in elderly patients undergoing FTS for colorectal cancer. METHODS: A total of 107 consecutive subjects admitted for elective colorectal FTS were enrolled. All patients underwent CGA, frailly stratification, Timed up & go (TUG) test, 4AT test for delirium screening, anesthesiologists physical status classification, and Dindo-Clavien classification. RESULTS: The incidence of POD was 12.3%. Patients' prevalent clinical phenotype was pre-frail. The multivariate analysis indicated physical performance (TUG in seconds) as the most significant predictor of POD for each second of increase. CONCLUSIONS: Only few procedure-specific studies have examined the impact of FTS for colorectal cancer on POD. This is the first study to investigate the risk factors for POD, in a vulnerable octogenarian oncogeriatric population submitted to FTS surgery and frailty stratification.

Pectin-honey hydrogel: Characterization, antimicrobial activity and biocompatibility.

BACKGROUND: Novel pectin-honey hydrogels have been developed and characterized as medical device. Ideally, a wound dressing should maintain optimal fluid affinity, permit moisture evaporation, protect the wound from microbes, and have shape-conformability, biocompatibility, and antibacterial activity. OBJECTIVE: A novel, simple and fast method to produce pectin-honey wound dressings is described. METHODS: The properties of these pectin-honey hydrogels were investigated, including swelling ability, water vapour transmission rate, hydrogen peroxide production, methylglyoxal content and antibacterial activity. Biocompatibility was assessed by proliferation assays using cultured fibroblast cells and by in vivo study with subcutaneous and intraperitoneal implantation in rats. RESULTS: Hydrogel showed a good water vapour transmission rate, fluid uptake and were not cytotoxic for fibroblasts. The hydrogel demonstrated good antibacterial activity toward clinically relevant pathogens, including S. aureus and E. coli. Biocompatibility was confirmed by the measurement of plasma levels of interleukin (IL)1 beta, IL-6, tumour necrosis factor (TNF) alpha, and prostaglandin (PG)E2. No histological changes were observed. CONCLUSIONS: The presence of a natural active component, conformability, and complete resorbability are the main characteristics of this new biocompatible biomaterial that is well tolerated by the body, possibly improves healing, may be used for surgical complications prevention, with a simple and inexpensive production process.

Nicotinic Acid Phosphoribosyltransferase Regulates Cancer Cell Metabolism, Susceptibility to NAMPT Inhibitors, and DNA Repair.

In the last decade, substantial efforts have been made to identify NAD+ biosynthesis inhibitors, specifically against nicotinamide phosphoribosyltransferase (NAMPT), as preclinical studies indicate their potential efficacy as cancer drugs. However, the clinical activity of NAMPT inhibitors has proven limited, suggesting that alternative NAD+ production routes exploited by tumors confer resistance. Here, we show the gene encoding nicotinic acid phosphoribosyltransferase (NAPRT), a second NAD+-producing enzyme, is amplified and overexpressed in a subset of common types of cancer, including ovarian cancer, where NAPRT expression correlates with a BRCAness gene expression signature. Both NAPRT and NAMPT increased intracellular NAD+ levels. NAPRT silencing reduced energy status, protein synthesis, and cell size in ovarian and pancreatic cancer cells. NAPRT silencing sensitized cells to NAMPT inhibitors both in vitro and in vivo; similar results were obtained with the NAPRT inhibitor 2-hydroxynicotinic acid. Reducing NAPRT levels in a BRCA2-deficient cancer cell line exacerbated DNA damage in response to chemotherapeutics. In conclusion, NAPRT-dependent NAD+ biosynthesis contributes to cell metabolism and to the DNA repair process in a subset of tumors. This knowledge could be used to increase the efficacy of NAMPT inhibitors and chemotherapy. Cancer Res; 77(14); 3857-69. ©2017 AACR.

Evaluation of prognostic indices in elderly hospitalized patients.

AIM: Prognosis informs the physician's decision-making process, especially for frail older adults. So far, any non-disease-specific index has proven full evidence for routine use in clinical practice. Here, we aimed at assessing, prospectively, the calibration and discriminating accuracy of validated prognostic indices in a cohort of elderly hospitalized patients. METHODS: This was a prospective observational study that enrolled elderly patients (n = 100). The patients' assessment included clinical variables, as well as the following five prognostic indices of mortality: (i) Levine index (2007); (ii) Walter index (2001); (iii) CARING (C, primary diagnosis of cancer; A, ≥ 2 admissions to the hospital for a chronic illness within the last year; R, resident in a nursing home; I, intensive care unit admission with multiorgan failure, NG, noncancer hospice guidelines [meeting ≥ 2 of the National Hospice and Palliative Care Organization's guidelines]) criteria of Fischer (2006-2011); (iv) Silver Code of Di Bari (2010); and (v) Burden of Illness Score for Elderly Persons of Inouye (2003). RESULTS: Patients' clinical characteristics: 70% women (age 86.20 ± 0.69 years), 30% men (age 85.40 ± 1.07 years), Comorbidity Illness rating scale (CIRS) 4.3 ± 0.61 and Barthel Index 28 ± 0.54. Walter and Burden of Illness Score for Elderly Persons scores showed similar prediction rates when compared with the expected validated values (ancova: F = 14.00, P < 0.008). Burden of Illness Score for Elderly Persons was the most calibrated and accurate index (receiver operating characteristic curve 0.72; P < 0.02). CONCLUSIONS: None of the assessed prognostic indices, in a "real world" scenario, afforded the optimal predictive accuracy (receiver operating characteristic curve 0.90); all these indices are still far from a robust answer to the prognosis in older age, reflecting a poor ability to encompass the spectrum of frailty. Effort should be made to tailor the prognostication in geriatrics, moving from a disease-centered model to a precision model, tailored to the frail phenotype. Geriatr Gerontol Int 2017; 17: 1015-1021.

Do Cancer Drugs Counteract Neurodegeneration? Repurposing for Alzheimer's Disease.

In spite of in depth investigations in the field of the amyloid cascade hypothesis, so far, no disease modifying therapy has been developed for Alzheimer's disease (AD). The pathophysiology provides some evidence of the inverse correlation between cancer and AD. Both AD and cancer are characterized by abnormal cellular behaviors; trigger factors along with a meta synchronously action is expected to drive cancer or neurodegeneration, supporting, respectively, progressive neuronal loss or uncontrolled cell proliferation in cancer cells. So far, cancer and AD are seemingly two opposite ends of the same biological spectrum. Basic science increasingly indicates shared molecular mechanisms between cancer and AD and gives weight to key relevant biological theories; according to them, the inverse tuning of clustered gene expression, the sharing of mutual independent pathway or the deregulated unfolded proteins system (UPR) may count for this inverse association. Additionally, the common biological background gave credibility to the recent discovery of a repurposing role for cancer drugs in AD. It refers to the development of new uses for existing pharmaceuticals having the same role as the original mechanism or to the discovery of a new drug action with disease modifying effects. The present review summarizes the most important biological theories that link neurodegeneration and cancer and provides an up-to-date revision of the repurposing cancer agents for AD. The review also addresses the gap of knowledge, since drug cancer repositioning holds an important promise but further investigations are warranted to ascertain the clinical relevance of such attractive clinical candidate compounds for AD.

Sirt6 regulates dendritic cell differentiation, maturation, and function.

Dendritic cells (DCs) are antigen-presenting cells that critically influence decisions about immune activation or tolerance. Impaired DC function is at the core of common chronic disorders and contributes to reduce immunocompetence during aging. Knowledge on the mechanisms regulating DC generation and function is necessary to understand the immune system and to prevent disease and immunosenescence. Here we show that the sirtuin Sirt6, which was previously linked to healthspan promotion, stimulates the development of myeloid, conventional DCs (cDCs). Sirt6-knockout (Sirt6KO) mice exhibit low frequencies of bone marrow cDC precursors and low yields of bone marrow-derived cDCs compared to wild-type (WT) animals. Sirt6KO cDCs express lower levels of class II MHC, of costimulatory molecules, and of the chemokine receptor CCR7, and are less immunostimulatory compared to WT cDCs. Similar effects in terms of differentiation and immunostimulatory capacity were observed in human monocyte-derived DCs in response to SIRT6 inhibition. Finally, while Sirt6KO cDCs show an overall reduction in their ability to produce IL-12, TNF-α and IL-6 secretion varies dependent on the stimulus, being reduced in response to CpG, but increased in response to other Toll-like receptor ligands. In conclusion, Sirt6 plays a crucial role in cDC differentiation and function and reduced Sirt6 activity may contribute to immunosenescence.

A calcified lipoma of the foot in a 100-year-old Italian woman.

Lipomas are the most common benign soft-tissue tumors found in the body. They tend to occur in areas of abundant adipose tissue, which explains why they are rarely found in the sole. Very few published cases of lipomas in the sole exist. When lipomas cannot be excised for histologic confirmation, ultrasonography has been shown to be a valuable assessment tool with high diagnostic capabilities. We present the case of 100-year-old patient with a long-standing plantar mass with late-stage clinical and sonographic features of a calcified lipoma.

A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan.

Prolonged fasting (PF) promotes stress resistance, but its effects on longevity are poorly understood. We show that alternating PF and nutrient-rich medium extended yeast lifespan independently of established pro-longevity genes. In mice, 4 days of a diet that mimics fasting (FMD), developed to minimize the burden of PF, decreased the size of multiple organs/systems, an effect followed upon re-feeding by an elevated number of progenitor and stem cells and regeneration. Bi-monthly FMD cycles started at middle age extended longevity, lowered visceral fat, reduced cancer incidence and skin lesions, rejuvenated the immune system, and retarded bone mineral density loss. In old mice, FMD cycles promoted hippocampal neurogenesis, lowered IGF-1 levels and PKA activity, elevated NeuroD1, and improved cognitive performance. In a pilot clinical trial, three FMD cycles decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease, and cancer without major adverse effects, providing support for the use of FMDs to promote healthspan.

Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition.

Tyrosine kinase inhibitors (TKIs) are now the mainstay of treatment in many types of cancer. However, their benefit is frequently short-lived, mandating the search for safe potentiation strategies. Cycles of fasting enhance the activity of chemo-radiotherapy in preclinical cancer models and dietary approaches based on fasting are currently explored in clinical trials. Whether combining fasting with TKIs is going to be potentially beneficial remains unknown. Here we report that starvation conditions increase the ability of commonly administered TKIs, including erlotinib, gefitinib, lapatinib, crizotinib and regorafenib, to block cancer cell growth, to inhibit the mitogen-activated protein kinase (MAPK) signaling pathway and to strengthen E2F-dependent transcription inhibition. In cancer xenografts models, both TKIs and cycles of fasting slowed tumor growth, but, when combined, these interventions were significantly more effective than either type of treatment alone. In conclusion, cycles of fasting or of specifically designed fasting-mimicking diets should be evaluated in clinical studies as a means to potentiate the activity of TKIs in clinical use.