Identifying the significant parameters for early progression toward worse prognosis is fundamental for the management of COVID-19 patients. In this Journal, Zhi Lin and colleagues1Lin Z. Long F. Yang Y. Serum ferritin as an independent risk factor for severity in COVID-19 patients.J Infect. 2020 Jun 24; (Epub ahead of print)https://doi.org/10.1016/j.jinf.2020.06.053Abstract Full Text Full Text PDF Scopus (99) Google Scholar recently reported that Chinese patients with severe Sars-CoV2 disease showed higher levels of serum ferritin than patients with not severe one, confirming data from other authors on Chinese2Wu C. Chen X. Cai Y. Xia J. Zhou X. Xu S. et al.Risk Factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 Pneumonia in Wuhan, China.JAMA Intern Med. 2020; Crossref Scopus (5713) Google Scholar,3Henry B.M. de Oliveira M. Benoit S. Plebani M. Lippi G Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis.Clin Chem Lab Med. 2020; Crossref Scopus (1258) Google Scholar and Caucasian populations.4Bhatraju P.K. Ghassemieh B.J. Nichols M. Kim R. Jerome K.R. Nalla A.K. Covid-19 in critically ill patients in the Seattle region - case series.N Engl J Med. 2020; https://doi.org/10.1056/NEJMoa2004500Crossref PubMed Scopus (1796) Google Scholar,5Xu X.W. Wu X.X. Jiang X.G. Xu K.J. Ying L.J. Ma C.L. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series.BMJ. 2020; 368: m606https://doi.org/10.1136/bmj.m606Crossref PubMed Scopus (1437) Google Scholar Here we aimed to establish the most suitable panel for routine prognostic serum laboratory testing in COVID-19 patients upon first admission to the Emergency Department. We thus enrolled 141 patients (59 females and 82 males, aging 64,48 ± 16,58 years) diagnosed as COVID-19 by means of real-time polymerase chain reaction testing and admitted to the isolation ward of Emergency Department at Policlinico Umberto I Hospital in Rome, Italy, between March 2020 and June 2020. Serum samples were collected from patients upon admission before starting any treatment and tested by Laboratory Department. Of all patients included, 81 patients (57%) showed mild disease (control group) and 60 (43%) showed acute respiratory distress syndrome (ARDS) and systemic inflammation (severe group). Fig. 1A shows the differences in the baseline characteristics between severe and non-severe COVID-19 patients. The severe patients were older and more frequently males and showed significant higher levels of C Reactive Protein (CRP), d-Dimer (D-D), Lactate Dehydrogenase (LDH), Neutrophil to Lymphocyte ratio (NLR) and Ferritin. Serum ferritin levels were positively correlated with severity of COVID-19 (Fig. 1B) and hyperferritinemia (ferritin level > 500 µg/L), was observed in all patients with severe disease on admission. Moreover, ROC curve analysis confirmed the excellent prognostic accuracies of serum Ferritin in discriminate patients with severe clinical conditions. (AUC 0.939, CI: 0,894 to 0,985 p < 0.001) (Fig. 1C). The triaging of COVID-19 patients is based on a combination of clinical, laboratory and instrumental parameters, mainly represented by Computed Tomography (CT). Thus, based on the severity of pulmonary impairment in CT scan and respiratory failure in need of mechanical ventilation, patients were further divided in 4 groups according to the WHO guidelines updated in May 20206Clinical management of COVID-19 - interim guidance (May 2020)-WHO - https://reliefweb.int/sites/reliefweb.int/files/resources/2005_clinical_management_of_covid-19-v7.pdfGoogle Scholar: 29 patients with no CT alterations (Group 0-mild); 32 patients with changes in CT scan no oxygen (Group 1-moderate); 38 patients with CT scan plus oxygen (Group 2-severe) and 42 patients with CT abnormalities plus intensive care unit (ICU) admission (critical-Group 3). Our data strongly confirm that increased levels of ferritin were directly related with the disease severity (Fig 2A). Particularly, not only severe group showed 2.6 times higher ferritin levels than the mild group, but patients who needed admission to the ICU showed 5.8 times higher ferritin compared to patients with mild COVID-19. Among all parameters considered, we also noted that the NLR was statistically correlated with the severity of disease. (Fig. 2B). Conversely, D-D, LDH and CRP increased only in the group of critical patients (group 3), being substantially stable in the other groups characterized by mild, moderate and severe disease (Fig. 2, panel C, D, E). Multivariate logistic regression model adjusted for several disease-related risk factors at admission, including age, sex, NLR, D-D, LDH, ferritin and CRP, demonstrated that serum ferritin resulted as an independent predictor of disease severity in COVID-19 patients (OR = 1,0048, 95% CI, 1,0029 to 1,0083, p < 0,001.). If patients were grouped according to the serum ferritin level with a cut off of 500 µg/ml derived from the HLH-20047Henter J.I. Horne A. Aricó M. et al.HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis.Pediatr Blood Cancer. 2007; 48: 124-131https://doi.org/10.1002/pbc.21039Crossref PubMed Scopus (3632) Google Scholar criterion, hyperferritinemia accounted for 48,22% (68/141) of patients and the hyperferritinemia group had a higher proportion of severe cases (77,94% vs 10,30%, p < 0,001) than patients without hyperferritinemia. This is the first Italian report about the prognostic value of laboratory biomarkers considering 4 groups of mild, moderate, severe and critical patients with COVID-19. We clearly demonstrated that serum levels of ferritin progressively increased with the severity of disease and correlate with poor prognosis in COVID-19 patients. Increased ferritin levels could be indicative of a strong inflammatory reaction in COVID-19 and recent studies suggest that increased levels of circulating ferritin levels play a critical role by contributing to the development of a cytokine storm8Kernan K.F. Carcillo JA Hyperferritinemia and inflammation.Int Immunol. 2017; 29: 401-409Crossref PubMed Scopus (328) Google Scholar,9Wessling-Resnick M. Crossing the iron gate: why and how transferrin receptors mediate viral entry.Annu Rev Nutr. 2018; 38: 431-458Crossref PubMed Scopus (90) Google Scholar resembling macrophage activating syndrome.10Shoenfeld Y. Corona (COVID-19) time musings: our involvement in COVID-19 pathogenesis, diagnosis, treatment and vaccine planning.Autoimmun Rev. 2020; 102538Crossref PubMed Scopus (165) Google Scholar Timely control of the cytokine storm in its early stage through immunomodulators and cytokine antagonists, as well as the reduction of lung inflammatory cell infiltration, is the key to improving the treatment success rate and reducing the mortality rate of patients with COVID-19. In this regard, ferritin evaluation could be an early, available and easy to use screening tool to assess the disease severity at the first admission in the emergency department. This test might be of crucial importance for the timely identification of patients at higher risk of an adverse outcome.

OBJECTIVES:: To investigate whether alexithymia is linked to the disease process or to psychopathology, particularly depression, in Parkinson disease (PD) patients.DESIGN:: Cross-sectional study.SETTING:: Neuropsychiatry outpatient clinic.PARTICIPANTS:: One hundred PD patients and 100 comparison subjects (CS).MEASUREMENTS:: PD patients and CS underwent a clinical and neuropsychiatric evaluation. Alexithymia was assessed with the 20-item Toronto Alexithymia Scale (TAS-20). Severity of depressive symptoms was measured with the Beck Depression Inventory. A structured psychiatric interview was used to diagnose major and minor depression. Logistic regression analyses with 95% confidence intervals (CI) were used to assess the association between alexithymia and PD.RESULTS:: Alexithymia occurred twice as often in PD patients (22%) as in CS (11%) and major depressive disorder occurred twice as often in CS (30%) than in PD (16%). The frequency of minor depression was almost identical (about 40%) in the 2 groups. Alexithymia was also associated with PD independently from depression. Indeed, after adjustment for sociodemographic factors, antidepressant use and depression severity, PD patients had an almost fourfold higher risk of having alexithymia (OR: 3.9, 95% CI: 1.5-10.0) and 24 times increased odds of having high scores on the TAS-20 items assessing difficulty in identifying emotions than CS (OR: 23.7, 95% CI: 10.1-55.6).CONCLUSIONS:: Our findings suggest that alexithymia is a depression-independent phenomenon in PD patients and may be associated with the disease process. Alexithymia is an important nonmotor symptom of PD and should be considered in patient assessment and management.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline with loss of memory. In the last years there has been a great interest on the early phases of AD, trying to identify the pathogenic mechanisms of AD and define early treatment modalities. In particular, Mild Cognitive Impairment (MCI) is attractive because it represents a transitional state between normal aging and dementia, although not all MCI patients automatically convert to AD. The neurotrophin brain-derived neurotrophic factor (BDNF) is critical for survival and function of neurons that degenerate in AD and represents a potential neuroprotective agent. However, opposite data on serum levels of BDNF have been reported in AD patients, probably reflecting differences in patient recruitment and stage of the disease. Thus, in this study we measured BDNF serum levels in AD patients (with different degree of severity), MCI patients and healthy subjects. We found that serum BNDF levels were significantly increased in MCI and AD patients when compared to healthy subjects and this increase in AD patients was neither dependent on illness severity, nor on treatment with Acetylcholinesterase inhibitors and/or antidepressant medications.Our findings indicate that BDNF serum levels increase in MCI and AD patients, supporting the hypothesis of an upregulation of BDNF in both preclinical phase of dementia (MCI) and clinical stages of AD. Other studies are necessary to establish a direct link between BDNF peripheral levels and AD longitudinal course, as well as the role of other factors, such as blood cell activation, in determining these events.

The cancer stem cell (CSC) hypothesis provides an attractive model of tumour development and progression, holding that solid tumours are hierarchically organized and sustained by a minority of the tumour cell population with stem cell properties, such as self-renewal, tumorigenicity and multilineage differentiation capacity. Therapeutic resistance, underlying tumour recurrence and the lack of curative treatments in metastatic disease, raise the question if conventional anticancer therapies target the right cells. Indeed, these treatments might miss CSCs, which represent a more chemoresistant and radioresistant subpopulation within cancer. Recently, a direct link between the epithelial-mesenchymal transition process and the gain of stem cell competence were demonstrated in cultured breast cells. In particular, it was shown that the induction of EMT program not only allow cancer cells to disseminate from the primary tumor, but also promotes their self-renewal capability. Furthermore, the expression of stemness and EMT markers in CTCs were associated with resistance to conventional anti-cancer therapies and treatment failure, highlighting the urgency of improving tools for detecting and eliminating minimal residual disease.

What clinical oncologists learned about metastatic process, is that it is the main cause of cancer-related deaths. What scientists learned about metastatic disease, is that it is due to a highly selective process, which involves a minority of tumor cells that are able to survive within the bloodstream, and to initiate a new growth in distant sites. These cells "in transit" are known as circulating tumor cells (CTCs). Although their nature is not fully understood, what is widely accepted, is that they are drug resistant, and that their presence may represent the main reason for treatment failure. Despite this body of evidence, the pharmacological approach against cancer, with both chemotherapic and biological drugs, is still targeted on the primary tumor, raising the question as to whether we are missing the target. Targeting circulating tumor cells, may represent a new promising approach to indivisualize anticancer therapy.

We are slightly concerned about the effects of the paper by Payne and colleagues on the Pope’s mental health.1 Hence we suggest:

BACKGROUND:Major depressive disorder (MDD) is a common condition in the elderly that is frequently associated with disability and cognitive impairment. Duloxetine is an antidepressant medication that inhibits both 5-HT and NE reuptake.OBJECTIVE:The objective of this review is to summarize the available know-how on the use of duloxetine in elderly population.METHODS:An extensive literature search was performed in Medline and Embase. Peer-reviewed articles only were included in this review.RESULTS:A total of four articles meeting search criteria were identified in the Medline and Embase databases. In the short-term controlled studies, treatment with duloxetine was associated with significantly greater improvement in cognitive function, depression and health state compared with placebo, as well as in rate of patients achieving response or remission. Overall pain and back pain also improved in patients receiving duloxetine. The long-term open-label data showed that the significant improvements of HAM-D-17 score and of both clinician-(CGI-S) and patient-(PGI-I) rated health state were rapid and sustained up to week 52. Observed case response and remission rates at end point were 89.4% and 72.3% respectively. Duloxetine was effective in patients who did not respond or tolerate previous treatment with escitalopram. Nausea and dry mouth were the most common events. The safety results in the long-term study, in which duloxetine was given at the upper dose limit, showed that most events occurred early in the study and that rates of events in patients aged >or= 65 years were not greater than those in the younger cohort.CONCLUSIONS:Duloxetine given in elderly patients with MDD provides rapid and sustained antidepressant efficacy and seems to be as safe as in younger patients.

Recent phase II randomised trials in colorectal cancer failed to demonstrate any advantage of celecoxib combined with standard chemotherapy; some authors even reported that the addition of celecoxib to irinotecan and oxaliplatin in colon cancer results in an inferior response rate. This observation leads to the hypothesis that there are pharmacokinetic interactions between celecoxib and chemotherapeutic drugs. The aim of the study was to investigate the induction by celecoxib of some multidrug resistance proteins, MRP1, MRP2, MRP4 and MRP5, involved in the transport of irinotecan and 5-FU. WiDr and COLO-205 cells were treated with celecoxib at a clinically relevant concentration. A viability assay was performed by treating cells with chemotherapy alone and chemotherapy plus celecoxib. The expression of MRP1, MRP2, MRP4 and MRP5 was analysed by RT-PCR and Western blot analysis. The sub cellular localization of MRP4 and MRP5 was investigated by cryoimmunoelectron microscopy. In both cell lines celecoxib induced MRP4 and MRP5 over-expression at RNA and protein levels. No induction of MRP1 and MRP2 was observed in treated cells compared to controls. Cryoimmunoelectron microscopy showed increased MRP4 and MRP5 immunolabeling in celecoxib treated cells both at cytoplasmic level and along the plasma membrane. Our findings suggest that the low response rate observed in clinical trials using celecoxib added to 5-fluorouracil and irinotecan may reflect celecoxib-mediated extrusion of chemotherapeutic drugs from cancer cells through the up regulation of ATP-binding cassette proteins. Our findings, together with the results of clinical trials, may suggest that the combined use of celecoxib and drugs that are substrate for MRP4/MRP5 should be avoided.

Raloxifene (RAL), a selective estrogen receptor modulator, is indicated for the prevention and treatment of postmenopausal osteoporosis. RAL, by decreasing bone turnover, prevents bone loss and microarchitecture damage, reducing the incidence of osteoporotic fractures. Our previous in vitro data demonstrated that RAL modulates osteoclast activity by, at least in part, an IL-6- and TNF-alpha-dependent mechanism. In this study we evaluated the effects of RAL treatment (60 mg/d) on circulating levels of these cytokines in 14 postmenopausal women with osteoporosis. Lumbar bone density (determined by dual energy x-ray absorptiometry) and IL-6 and TNF-alpha levels were measured before and after 6 and 24 months of therapy. After 24 months, RAL increased bone density. IL-6 and TNF-alpha expression, elevated before treatment, significantly decreased (50% and 30%, respectively) after 6 months. This effect was sustained up to the end of the treatment (75% and 35%, respectively). Thus, our data show that RAL can modulate circulating levels of cytokines involved in osteoclastogenesis and bone resorption, suggesting that modulation of soluble factors could play a pivotal role in the mechanisms of the osteoprotective effect of RAL.

Due to the ageing of the population and the sharp increase in life expectancy, cancer in the older person has become an increasingly common problem in the Western world. Although several authors have stressed that elderly cancer patients deserve special attention as a target group for research efforts, older aged patients are still less likely to be offered participation in clinical trials. The cellular and molecular mechanisms regulating the physiological process of ageing and senescence are far from understood, although inflammation is likely to play an important role, at least in some cancers. In addition, the relationship between ageing and cancer risk is also far from understood. One of the most intriguing aspects of ageing is how different the ageing process is from person to person; the basis for this variation is largely unknown. Population-based studies and longitudinal surveys have shown that comorbidity and physical and mental functioning are important risk factors; thus, a meaningful assessment of comorbidity and disability should be implemented in clinical practice. Modern geriatrics is targeted towards patients with multiple problems. Such patients are not simply old, but are geriatric patients because of interacting psychosocial and physical problems. As a consequence, the health status of old persons cannot be evaluated by merely describing the single disease, and/or by measuring the response, or survival after treatment. Conversely, it is necessary to conduct a more comprehensive investigation of the ‘functional status’ of the aged person. A geriatric consultation provides a variety of relevant information and enables the healthcare team to manage the complexity of health care in the elderly; this process is referred to as the Comprehensive Geriatric Assessment (CGA). The use of CGA is now being introduced into oncological practice. The definition of frailty is still controversial and represents a major issue of debate in clinical geriatrics. As the frail population increases, clinical trials in frail persons are needed. The usefulness of these trials requires a consensus as to the definition of frailty. Clearly, the management of older persons with cancer requires the acquisition of special skills in the evaluation of the older person and in the recognition and management of emergencies as well as experience in geriatric case management.

Hematological toxicity is the most common and the most frequent fatal complication of chemotherapy. It is observed with increased frequency with age, it is a significant independent predictor of the development of febrile neutropenia, and may contribute to a reluctance to administer chemotherapy in the elderly patient population. The authors analyze published data on effectiveness and results of the use of colony stimulating factors for preventing and treating elderly patients affected by tumors during chemotherapy.

PURPOSE:Despite the great number of studies performed to detect circulating markers of disease progression in colorectal cancer, few have shown a clinical use; among those, epidermal growth factor receptor (EGFR) and, more recently, interleukin (IL)-10. In this article, we sought to investigate how primary surgery could affect expression levels of EGFR, IL-6, and IL-10 in blood from colorectal cancer patients.EXPERIMENTAL DESIGN:We investigated by reverse transcriptase-PCR assay the expression at mRNA level of EGFR, IL-6, and IL-10 in blood samples taken from 56 colorectal cancer patients. Each gene expression was evaluated 1 day before and 20 days after primary surgery. Persistence of each gene in blood after surgery was then correlated to the relapse free time in a follow-up of 3 years.RESULTS:In blood samples taken before surgery, EGFR, IL-6, and IL-10 were found expressed in 62, 100, and 100% of patients, respectively. EGFR expression, but not IL-6 and IL-10, correlates with stage of disease. In the group of 41 patients who underwent follow-up studies, EGFR was found persistently high in 67%; 94% of them had relapse. Persistence of IL-10 after surgery also identifies relapses in 89% of cases. IL-6 persistence was not found to significantly correlate to progression of disease.CONCLUSIONS:Persistence of both EGFR and IL-10 in blood of colorectal cancer patients after surgery identifies patients with high propensity to relapse. These findings may suggest a clinical use of preoperative EGFR/IL-10 reverse transcriptase-PCR assay in the prediction of tumor recurrence.

PURPOSE: To appraise the performance of Comprehensive Geriatric Assessment (CGA) in elderly cancer patients (≥ 65 years) and to evaluate whether it could add further information with respect to the Eastern Cooperative Oncology Group performance status (PS). PATIENTS AND METHODS: We studied 363 elderly cancer patients (195 males, 168 females; median age, 72 years) with solid (n = 271) or hematologic (n = 92) tumors. In addition to PS, their physical function was assessed by means of the activity of daily living (ADL) and instrumental activities of daily living (IADL) scales. Comorbidities were categorized according to Satariano’s index. The association between PS, comorbidity, and the items of the CGA was assessed by means of logistic regression analysis. RESULTS: These 363 elderly cancer patients had a good functional and mental status: 74% had a good PS (ie, lower than 2), 86% were ADL-independent, and 52% were IADL-independent. Forty-one percent of patients had one or more comorbid conditions. Of the patients with a good PS, 13.0% had two or more comorbidities; 9.3% and 37.7% had ADL or IADL limitations, respectively. By multivariate analysis, elderly cancer patients who were ADL-dependent or IADL-dependent had a nearly two-fold higher probability of having an elevated Satariano’s index than independent patients. A strong association emerged between PS and CGA, with a nearly five-fold increased probability of having a poor PS (ie, ≥ 2) recorded in patients dependent for ADL or IADL. CONCLUSION: The CGA adds substantial information on the functional assessment of elderly cancer patients, including patients with a good PS. The role of PS as unique marker of functional status needs to be reappraised among elderly cancer patients.

In this paper the hypothesis that some features of immunosenescence might impact on the levelling off of cancer incidence and mortality in the oldest old will be considered. In fact, the term immunosenescence suggests that a progressive loss of immune system (IS) function occurs with aging. However, the age-related modifications of the IS can be more properly acknowledged as a 'remodeling' characterized by profound structural changes, which modify the functional properties of IS. We suggest that the expansion with age of natural killer cells (NK) and of T cells which progressively acquire phenotypes intermediate between T lymphocytes and NK cells, together with the age-related changes in the production of inflammatory/anti-inflammatory cytokines, such as INFgamma and IL-4, might create an environment unfavorable for neoplastic growth in the oldest old. In this perspective, studies on immunosenescence likely provide insights on mechanisms responsible for the individual capacity to escape from the life-threatening consequences of cancer outgrowth.