Normative data beyond the total scores: a process score analysis of the Rey's 15 word test in healthy aging and Alzheimer's Disease.

BACKGROUND: The Rey's 15 words test is currently the most frequently used task in Italy to detect memory deficits in AD. The current standardised version is however quite outdated and lacks some cognitive indexes which may highlight problems in recall or encoding processes. The aim of the study was to update the normative data of the test and to consider some variables which were not accounted for in the original study, that is, recognition, learning rate and forgetfulness. We also adopted the process scores approach to ascertain the effects of serial position (primacy and recency). METHODS: Three hundred ninety-six healthy participants were recruited. To detect any variables useful for intercepting the early stages of dementia, a group of 208 patients in the very early stage of AD was also recruited. Linear models were used to calculate the corrections scores for age, education, and gender, and ROCs were used to calculate cut-offs based on the maximum sum of sensitivity and specificity and the positive and negative predictive values. RESULTS: All main indexes showed excellent Area Under the Curve (0.90-1), strong sensitivity and PPVs for distinguishing between the HCs and AD participants. However, the Intrusions index performed poorly in all parameters. CONCLUSION: The study provides updated, normative data which may be reliably used as a cognitive marker to detect early AD. The strength of the study is the large sample size and the number of indexes which make it possible to explore the utility of memory test process scores.

5-Fluorouracil-associated severe hypertriglyceridaemia with positive rechallenge.

Chemotherapy-induced hypertriglyceridaemia (HTG) is a potential serious adverse event. Severe HTG with triglycerides (TG) >11.3 mmol/L (1000 mg/dL) can cause acute pancreatitis in addition to cardiovascular diseases such as coronary artery disease. While the association of capecitabine (5-fluorouracil (5-FU) prodrug) with clinically relevant HTG is a well-known adverse reaction, 5-FU is not typically associated with HTG. We here report the case of a patient who developed 5-FU-associated grade 4 HTG with TG level raising up to 37.1 mmol/L (3286 mg/dL) occurring after the ninth cycle of adjuvant FOLFOX (Fluorouracil and Oxaliplatin) chemotherapy. Fenofibrate treatment and diet were started. Chemotherapy was postponed and then resumed for two additional cycles. However, severe HTG recurred shortly after. Chemotherapy was therefore permanently stopped. Approximately 8 weeks after chemotherapy discontinuation, TG fell back to range at 2.1 mmol/L (189 mg/dL) allowing interruption of fenofibrate without HTG recurrence at 3 months.

Sundowning in Patients with Dementia: Identification, Prevalence, and Clinical Correlates.

BACKGROUND: The term sundowning is used to describe the emergence or worsening of neuropsychiatric symptoms in late afternoon or early evening in people with dementia. OBJECTIVE: Our aim was to evaluate sundowning's prevalence and clinical manifestations among patients attending a tertiary memory clinic and to investigate its clinical and neuropsychological correlates. METHODS: Patients with dementia attending our memory clinic were enrolled in the study. Sundowning was identified through a specifically designed questionnaire. Sociodemographic and clinical features of sundowners and non-sundowners were compared, and a logistic regression was performed to identify the variables associated with the phenomenon. A subgroup of patients underwent a complete neuropsychological assessment. RESULTS: Among 184 recruited patients, 39 (21.2%) exhibited sundowning, mostly expressed as agitation (56.4%), irritability (53.8%), and anxiety (46.2%). Sundowners were significantly older, had a later dementia onset, exhibited more severe cognitive and functional impairment, more frequent nocturnal awakenings, and hearing loss relative to non-sundowners. They were also more likely to use anticholinergic medications and antipsychotics, and less likely to use memantine. In a multi-adjusted model, the factors significantly associated with sundowning were the Clinical Dementia Rating score (OR 3.88; 95% CI 1.39-10.90) and the use of memantine (OR 0.20; 95% CI 0.05-0.74). Participants with and without sundowning obtained similar results in single domain neuropsychological tests. CONCLUSION: Sundowning is commonly experienced by patients with dementia and appears as a multiply determined condition. Its presence should always be evaluated in clinical practice and a multidimensional approach should be adopted to identify its predictors.

Prevalence and Safety of COVID-19 Vaccination in Community-Dwelling People with Dementia: Findings from a Tertiary Memory Clinic in Italy.

This study aimed to explore the prevalence and safety of SARS-CoV-2 vaccination in individuals with dementia. Patients with mild cognitive impairment or dementia were recruited at a tertiary memory clinic, from March 15 to September 15, 2021. Information on COVID-19 vaccination and adverse events experienced after vaccine administration were collected from caregivers. Two-hundred-seventy subjects were finally recruited. Among them, 253 (93.7%) had received the vaccine and only 69 (27.3%) experienced adverse events. Cognitive and behavioral changes following immunization were only rarely reported. COVID-19 vaccination is safe and well-tolerated in patients with cognitive impairment who should be prioritized in the vaccination campaign.

Multiple primary malignancies: synchronous lymphoma, pancreatic neuroendocrine tumour and colorectal cancer.

A 67-year-old woman underwent a medical check-up by her general practitioner after complaining of atypical pain in the shoulder girdle. Due to the important inflammatory syndrome noticed on blood testing, a polymyalgia rheumatica was suspected and she was started on corticosteroid treatment with good clinical response, but no impact on inflammation. She underwent extensive imaging with a thoraco-abdominal CT scanner that demonstrated a pancreatic mass, then later a PET-CT showed 3 different hyperactive lesions. Biopsies then revealed simultaneous diffuse large B-cell lymphoma (DLBCL), colorectal adenocarcinoma and pancreatic neuroendocrine tumour. She benefited from low rectal endoscopic excision of the colorectal tumour, R-CHOP chemotherapy for DLBCL and laparoscopic left pancreatectomy. Successful treatment required a good multidisciplinary collaboration between the different specialists. The patient made a good recovery and achieved complete remission at 1 year. This an unusual presentation of multiple primary malignancies.

Role of frailty in the assessment of cognitive functioning.

Neuropsychological tests, besides reflecting the cognitive reserves and deficits of the tested individual, might also be differently affected by his/her underlying biological asset. In this context, the construct of frailty may offer an opportunity for better weighting the results of traditional tests. We evaluated the relationships between a set neuropsychological measures and a 35-item Frailty Index (FI). The role played by the FI in the relationship between neuropsychological tests and global cognition was also explored. Data from the first neurological and neuropsychological assessments of 79 subjects attending our university memory clinic because complaining cognitive disturbances were considered for the present analysis. A statistically significant correlation between FI and Trail Making Test-B was observed (Spearman's rho 0.33; p = 0.02). The relationship between the performance at the Rey Complex Figure and global cognition (as measured by the Mini Mental State Examination) was influenced by the FI. In fact, participants with higher FI levels had a weakened association linking constructional/visual memory abilities and general cognitive functioning. The interpretation of the neuropsychological assessment can be biased by the frailty status of the tested individual. It can be hypothesized the need of developing new models of correction, that may better reflect the person's biology and complexity.

Solid cancer development in solid organ transplant recipients within the Swiss Transplant Cohort Study.

In solid organ transplant recipients (sOTRs), 5 years after transplantation cancer is a relevant cause of death. We aimed to report cancer incidence in the Swiss Transplant Cohort Study (STCS) between 2008 and 2014 and conducted a prospective cohort study of kidney, heart, lung, pancreas and liver transplant recipients enrolled into the STCS by retrospective analysis of collected data. The STCS provided data on 2758 solid organ transplants. In total, 134 cases of cancer were observed (30 liver, 21 prostate, 18 lung, 13 kidney, 52 other cancers). Standardised incidence ratios (SIRs) were highest for liver cancer, kidney cancer, thyroid cancer, gastric cancer, bladder cancer, cancer of the oral cavity and the pharynx and for lung cancer. Cancer occurrence differed according to the transplanted organ. Cancers were mainly diagnosed at World Health Organisation (WHO) stages I and IV. Treatment received was mainly surgery and, in some cases, included also radiation and/or chemotherapy. Bladder, kidney, liver, lung and prostate cancer were detected at a younger age compared with the general population. Cumulative hazards for death were increased for transplant recipients with cancer. Solid organ transplant recipients show an organ specific increase of cancer compared with the general Swiss population. Clinical trial registration number: NCT02333279.

To Rate or Not to Rate? Autonomic Response and Psychological Well-being of Employees During Performance Review.

Organizational research started including neurosciences exploring pivotal phenomena and promoting organizational well-being. Leadership was investigated by assessing psychophysiological responses during performance review characterized by narrative or quantitative assessments and their effects on employees' well-being. As is known, rating could be perceived as threatening for employees' ranking and status perception, leading to avoidant behaviors. DESIGN AND METHODOLOGY: Here, manager-employee dyads were assigned to 2 conditions: in the nonrate scenario, managers were asked to describe the employee's performance; in the rate one, they had to provide a quantitative rating. Skin conductance level and response and heart rate indices were continuously recorded. FINDINGS: Dyads in nonrate condition showed higher arousal-related responses (skin conductance level and skin conductance response), perhaps highlighting an increased engagement triggered by a rewarding exchange. Conversely, in rate condition, employees showed higher heart rate, usually related to negative and stressful conditions, and avoidant behaviors. ORIGINALITY/VALUE: Results are discussed for their possible applications to employees' well-being.

Early clinical experience of radiotherapy of prostate cancer with volumetric modulated arc therapy.

BACKGROUND: To report about initial clinical experience in radiation treatment of carcinoma of prostate with volumetric modulated arcs with the RapidArc (RA) technology. METHODS: Forty-five patients with a median age of 72 +/- 3, affected by prostate carcinoma (T1c: 22 patients, T2a-b: 17 patients, T3a-b: 6 patients. N0: 43 patients, N1-Nx: 2 patients, all M0), with initial PSA of 10.0 +/- 3.0 ng/mL, were treated with RapidArc in a feasibility study. All patients were treated with single arc using 6MV photons. Dose prescription ranged between 76 (7 patients) and 78 Gy (38 patients) in 2 Gy/fraction. Plan quality was assessed by means of Dose Volume Histogram (DVH) analysis. Technical parameters of arcs and pre-treatment quality assurance results (Gamma Agreement Index, GAI) are reported to describe delivery features. Early toxicity was scored (according to the Common Terminology Criteria of Adverse Effects scale, CTCAE, scale) at the end of treatment together with biochemical outcome (PSA). RESULTS: From DVH data, target coverage was fulfilling planning objectives: V95% was in average higher than 98% and V107% approximately 0.0% (D2% approximately 104.0% in average). Homogeneity D5%-D95% ranged between 6.2 +/- 1.0% to 6.7 +/- 1.3%. For rectum, all planning objectives were largely met (e.g. V70Gy = 10.7 +/- 5.5% against an objective of < 25%) similarly for bladder (e.g. D2% = 79.4 +/- 1.2 Gy against an objective of 80.0 Gy). Maximum dose to femurs was D2% = 36.7 +/- 5.4 Gy against an objective of 47 Gy. Monitor Units resulted: MU/Gy = 239 +/- 37. Average beam on time was 1.24 +/- 0.0 minutes. Pre-treatment GAI resulted in 98.1 +/- 1.1%. Clinical data were recorded as PSA at 6 weeks after RT, with median values of 0.4 +/- 0.4 ng/mL. Concerning acute toxicity, no patient showed grade 2-3 rectal toxicity; 5/42 (12%) patients experienced grade 2 dysuria; 18/41 (44%) patients preserved complete or partial erectile function. CONCLUSION: RapidArc proved to be a safe, qualitative and advantageous treatment modality for prostate cancer.

Neo-adjuvant chemo-radiation of rectal cancer with volumetric modulated arc therapy: summary of technical and dosimetric features and early clinical experience.

BACKGROUND: To report about initial technical and clinical experience in preoperative radiation treatment of rectal cancer with volumetric modulated arcs with the RapidArc (RA) technology. METHODS: Twenty-five consecutive patients (pts) were treated with RA. All showed locally advanced rectal adenocarcinoma with stage T2-T4, N0-1. Dose prescription was 44 Gy in 22 fractions (or 45 Gy in 25 fractions). Delivery was performed with single arc with a 6 MV photon beam. Twenty patients were treated preoperatively, five did not receive surgery. Twenty-three patients received concomitant chemotherapy with oral capecitabine. A comparison with a cohort of twenty patients with similar characteristics treated with conformal therapy (3DC) is presented as well. RESULTS: From a dosimetric point of view, RA improved conformality of doses (CI95% = 1.1 vs. 1.4 for RA and 3DC), presented similar target coverage with lower maximum doses, significant sparing of femurs and significant reduction of integral and mean dose to healthy tissue. From the clinical point of view, surgical reports resulted in a down-staging in 41% of cases. Acute toxicity was limited to Grade 1-2 diarrhoea in 40% and Grade 3 in 8% of RA pts, 45% and 5% of 3DC pts, compatible with known effects of concomitant chemotherapy. RA treatments were performed with an average of 2.0 vs. 3.4 min of 3DC. CONCLUSION: RA proved to be a safe, qualitatively advantageous treatment modality for rectal cancer, showing some improved results in dosimetric aspects.

Identification of a sperm protein 17 CTL epitope restricted by HLA-A1.

Sperm protein 17 (Sp17) is a novel cancer-testis antigen. We previously reported the successful generation of Sp17-specific HLA-A1-restricted cytotoxic T-lymphocytes (CTLs) from the peripheral blood of a healthy donor using a recombinant Sp17 protein. These CTLs were able to kill not only target cells pulsed with the recombinant protein but also fresh Sp17+ tumor cells. In the present study, we have identified a nonapeptide sequence within the Sp17 protein that is predicted to have a high binding affinity for the HLA-A1 molecules. We generated the synthetic nonapeptide and successfully propagated a peptide-specific CTL line. We confirmed that peptide Sp17(103-111) (ILDSSEEDK) contains an Sp17 CTL epitope restricted by HLA-A1 and identified amino acid residues 104, 107, 109 and 110 as crucial for the CTL lysis. Our findings therefore provide the tool for the characterization of CD8 T-cell function in vivo and generation of epitope-specific treatment strategies.

Gene expression and immunologic consequence of SPAN-Xb in myeloma and other hematologic malignancies.

Recent studies in tumor immunology indicate that malignant cells frequently express normal testicular-specific proteins. Because these proteins show restricted normal tissue distribution, they are usually highly immunogenic and may be potential targets for immunotherapy. In the present study, we have used a pair of sequence-specific primers in reverse transcription-polymerase chain reaction (RT-PCR) and sequence analysis to demonstrate that the X-linked gene encoding SPAN-Xb is expressed in multiple myeloma and other hematologic malignancies such as chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML). RT-PCR analysis demonstrates that SPAN-Xb is a cancer/testis antigen and shows a restricted normal tissue expression. It is not expressed in any normal tissue except testis. SPAN-Xb recombinant protein was produced and used in enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. High-titer immunoglobulin G (IgG) antibodies, of IgG3 or IgG2 subclass, against SPAN-Xb were detectable in the sera of these patients. In contrast, SPAN-Xb mRNA or antibodies could not be detected in any of the healthy donors. There was a good correlation between SPAN-Xb gene expression and B-cell immune responses. These results suggest the in vivo immunogenicity of the SPAN-Xb protein. The presence of high-titer IgG responses suggests that the B-cell responses are likely to have been generated with CD4 T-cell cognitive help. Based on these data, we conclude that SPAN-Xb is a novel member of the family of cancer/testis antigens aberrantly expressed by, and capable of inducing, immune responses in patients with multiple myeloma and other hematologic malignancies.

Sperm protein 17 (Sp17) is a suitable target for immunotherapy of multiple myeloma.

Sperm protein 17 (Sp17) is a protein recently identified as a novel cancer-testis (CT) antigen in multiple myeloma (MM). Because this tumor antigen demonstrates a very restricted normal tissue expression, Sp17 may be an excellent target for tumor vaccine of MM. In this study, we determined the ability to generate Sp17-specific HLA class I-restricted cytotoxic T lymphocytes (CTLs) from the peripheral blood of 4 patients with MM, 3 consecutive Sp17(+) patients, and 1 Sp17(-) patient. Dendritic cells were generated from monocytes of 4 patients with MM and used to present a recombinant Sp17 protein to autologous T cells. Following 4 rounds of antigen stimulation, the CTLs were tested for their ability to kill autologous targets in an Sp17-dependent and HLA-class I- restricted manner in standard cytotoxicity assays. Despite previous chemotherapy and the immunosuppression so often associated with MM, CTL generation was successful in all 4 patients, irrespective of the Sp17 status of their tumors. Most importantly, the CTLs were able to lyse autologous tumor cells that expressed Sp17. Tumor cell lysis in all cases appeared to be mainly mediated by perforin and could be blocked by concanamycin A. We conclude that Sp17 is a suitable target for immunotherapy of MM. Our findings provide the basis for a clinical study aimed at inducing a cellular immune response directed at Sp17(+) MM.

Tumor vaccine for ovarian carcinoma targeting sperm protein 17.

BACKGROUND: The authors previously identified sperm protein 17 (Sp17) as being expressed in patients with multiple myeloma. The restricted expression of Sp17 in normal tissue makes it an ideal target for tumor vaccine. In the current study, the authors extended their research to include ovarian carcinoma. METHODS: A pair of sequence specific primers was used in reverse transcriptase-polymerase chain reaction to determine the gene expression of Sp17. A recombinant Sp17 protein was used with monocyte-derived dendritic cells and autologous peripheral blood mononuclear cells to generate Sp17 specific cytotoxic T-lymphocytes (CTLs). The successful generation of Sp17 specific CTLs was confirmed using standard (51)chromium-release assays. RESULTS: Sp17 was found to be expressed in the primary tumor cells from 70% of the patients with ovarian carcinoma. Human leukocyte antigen (HLA) class I- restricted Sp17 specific CTLs were generated successfully from the peripheral blood of three patients with ovarian carcinoma at the time of disease presentation. These CTLs were able to lyse autologous Epstein-Barr virus-transformed lymphoblastoid cells in a Sp17-dependent manner. Target lysis was HLA class I-dependent and could be blocked by antibodies against monomorphic HLA class I but not HLA class II molecules. The CTLs also lysed Sp17-positive autologous tumor cells, suggesting that Sp17 is processed and presented in association with the HLA class I molecules in Sp17- positive tumor cells in a concentration and configuration that could be recognized by recombinant protein-primed CTLs. Tumor cell killing by the CTLs appeared to be mediated through the perforin pathway. Flow cytometric analysis of the CTLs indicated that they predominantly were CD8 in phenotype and produced interferon-gamma and scant amounts of interleukin-4. CONCLUSIONS: The results of the current study suggest the potential of Sp17 as a target for immunotherapy in patients with ovarian carcinoma.

Efficient generation of cytotoxic T lymphocytes against cervical cancer cells by adeno-associated virus/human papillomavirus type 16 E7 antigen gene transduction into dendritic cells.

Adeno-associated virus (AAV) is able to efficiently deliver a cytokine gene into dendritic cells (DC). Improvements in T cell priming by DC might be effected by the delivery of antigen genes into DC, resulting in continuous protein expression, as most proteins have short half-lives. In this study, a recombinant AAV vector containing the human papillomavirus (HPV)-16 E7 gene was used to pulse/infect DC and compared to the pulsing of DC by the lipofection of bacterially produced E7 protein. Pulsing of DC with AAV/antigen (Ag) gene was found to be superior to pulsing with protein in six different assay systems: (1) the level of antigen transfer into DC as determined by intracellular staining; (2) the level of MHC class I-restricted killing in cytotoxic T lymphocyte (CTL) assays; (3) the level of IFN-gamma expression; (4) the level of DC-T cell priming clusters generated; (5) the level of CD80 and CD83 expression on DC; and (6) in the resulting CD8:CD4 ratio. Finally, AAV/Ag gene pulsing resulted in strong CTL activity after only 7 days of priming. These data suggest that AAV vectors may offer advantages over the commonly used protein-pulsing technique and that AAV vectors may be useful for the stimulation of CTL activity and adoptive immunotherapy protocols.