Biological quality control for extracorporeal photochemotherapy: Assessing mononuclear cell apoptosis levels in ECP bags of chronic GvHD patients.

Extracorporeal photochemotherapy (ECP) is a treatment approved by the FDA for cutaneous T-cell lymphoma, and it is currently used off-label for graft-versus-host disease (GvHD) and other conditions. In agreement with good practices for the therapeutic use of human cells, quality control has to be performed to validate the ECP procedure with the off-line technique. Since no gold-standard biological test is available, we assessed the apoptosis generated in the ECP bag using a flow cytometric analysis. Thirty-one ECP procedures performed on 13 patients with chronic GvHD were studied by monitoring the induction of mononuclear cell (MNC) apoptosis using annexin V/propidium iodide double staining; residual lymphocyte proliferation to standard mitogens was also measured in 17 of the procedures. The kinetics of apoptosis was analyzed at different times in MNCs untreated or treated with 8-methoxy-psoralen plus ultraviolet A; the variation (ΔAPOPTOSIS ) after 24 h revealed the efficacy of the treatment. In 88.6% of the 31 ECP procedures, ΔAPOPTOSIS was >15% (the "alerting" threshold for ΔAPOPTOSIS was set at 15% on the basis of our data); in the remainder (19.4%), the increment in apoptosis was lower. In four procedures, the proliferation assay was useful for assessing the effect of ECP on the apheretic bag. In conclusion, both flow cytometric assays enabled a biologically significant result to be obtained. In our opinion, the apoptosis test-being faster and easier than the proliferation test-could be a reliable way to validate ECP procedures.

Metabolic and cardiovascular outcomes of fatherhood: results from a cohort of study in subjects with sexual dysfunction.

INTRODUCTION: Previous cross-sectional and longitudinal studies reported a negative correlation between fatherhood and testosterone (T) levels, likely due to a centrally mediated downregulation of the hypothalamic-pituitary-gonadal axis. Moreover, epidemiological data indicate that fatherhood might affect metabolic and cardiovascular outcomes, although different results have been reported. Up to now, no studies have evaluated these associations in a population of men seeking treatment for sexual dysfunction (SD). AIM: To explore biological and clinical correlates of number of children (NoC) and its possible associations with forthcoming major cardiovascular events (MACE) in a sample of men with SD. METHODS: A consecutive series of 4,045 subjects (mean age 52 ± 13.1 years old) attending the Outpatient Clinic for SD was retrospectively studied. A subset of the previous sample (N = 1,687) was enrolled in a longitudinal study. MAIN OUTCOME MEASURES: Information on MACE was obtained through the City of Florence Registry Office. RESULTS: Among patients studied, 31.6% had no children, while 26.3% reported having one child, 33.4% two, and 8.8% three or more children. Although fatherhood was negatively related with follicle-stimulating hormone levels and positively with testis volume, we found a NoC-dependent, stepwise decrease in T plasma levels, not compensated by a concomitant increase in luteinizing hormone. NoC was associated with a worse metabolic and cardiovascular profile, as well as worse penile blood flows and a higher prevalence of metabolic syndrome (MetS). In the longitudinal study, after adjusting for confounders, NoC was independently associated with a higher incidence of MACE. However, when the presence of MetS was introduced as a further covariate, the association was no longer significant. CONCLUSIONS: This study supports the hypothesis that bond maintenance contexts and fatherhood are associated with an adaptive downregulation of the gonadotropin-gonadal axis, even in a sample of men with SD. Moreover, our data suggest that NoC predicts MACE, most likely because of an unfavorable, lifestyle-dependent, parenthood-associated behavior.

COVID-19 Vaccination in Health Care Workers in Italy: A Literature Review and a Report from a Comprehensive Cancer Center.

The coronavirus disease 2019 pandemic still represents a global public health emergency, despite the availability of different types of vaccines that reduced the number of severe cases, the hospitalization rate and mortality. The Italian Vaccine Distribution Plan identified healthcare workers (HCWs) as the top-priority category to receive access to a vaccine and different studies on HCWs have been implemented to clarify the duration and kinetics of antibody response. The aim of this paper is to perform a literature review across a total of 44 studies of the serologic response to COVID-19 vaccines in HCWs in Italy and to report the results obtained in a prospective longitudinal study implemented at the Fondazione IRCCS Istituto Nazionale Tumori (INT) of Milan on 1565 HCWs. At INT we found that 99.81% of the HCWs developed an antibody response one month after the second dose. About six months after the first serology evaluation, 100% of the HCWs were still positive to the antibody, although we observed a significant decrease in its levels. Overall, our literature review results highlight a robust antibody response in most of the HCWs after the second vaccination dose. These figures are also confirmed in our institutional setting seven months after the completion of the cycle of second doses of vaccination.

Is metabolic syndrome a useless category in subjects with high cardiovascular risk? Results from a cohort study in men with erectile dysfunction.

INTRODUCTION: Although several studies have demonstrated that MetS is associated with a two-fold increase in the risk of cardiovascular (CV) diseases, this risk does not appear to be greater than the sum of risks associated with each of its individual components. AIM: To determine the association of men with ED and individual components of MetS and their subsequent relationship to CV risk, and, more specifically whether the sum of the MetS components is greater than the individual components in predicting CV risk. METHODS: We longitudinally studied a consecutive series of 1,687 (mean age 52.9±12.8; range 17-88 years) patients attending our clinic for ED and evaluated different clinical and biochemical parameters. MAIN OUTCOME MEASURES: Information on major adverse CV event (MACE) was obtained through the City of Florence Registry Office. RESULTS: One hundred thirty-nine MACE, 15 of which were fatal, occurred during a mean follow-up of 4.3±2.6 years. Subjects with MetS at baseline showed a higher incidence of MACE (hazard ratio [HR]=1.77), after adjusting for age, however, the association disappeared in an alternative Cox model, adjusting both for age and for individual MetS components (HR=1,525 [0,564-4,123]; P=0.408). The two most predictive MetS components of CV risk were low high-density lipoprotein (HDL) cholesterol and high triglycerides. Exploring possible interactions between individual components of MetS and their effect on CV risk using two alternative approaches indicates that the effect of MetS components on CV risk is additive, but not synergistic. Among subjects with hypertension, after adjusting for age, elevated glycemia, and low HDL cholesterol confer relevant additional risk, while in subjects with high triglycerides, hyperglycemia increased the risk of incident MACE. CONCLUSIONS: With regards to CV risk, the MetS construct seems to add little or nothing to the careful assessment of its components. Thus, there is no reason to recommend the use of MetS as a diagnostic category in patients with ED.

Pulse pressure independently predicts major cardiovascular events in younger but not in older subjects with erectile dysfunction.

INTRODUCTION: Pulse pressure (PP; i.e., the arithmetic difference between systolic and diastolic blood pressure) has been suggested to be an independent cardiovascular risk (CV) factor in the general population. We previously also reported a negative association between PP and arteriogenic erectile dysfunction (ED). This finding has recently been questioned. AIM: To verify the association of PP with ED severity and to evaluate its role in predicting forthcoming CV events. METHODS: This is an observational prospective cohort study evaluating a consecutive series of 1,687 patients attending our Andrological Unit for ED. MAIN OUTCOME MEASURES: Several hormonal and biochemical parameters were studied, along with SIEDY structured interviews and penile Doppler ultrasound. RESULTS: Subjects with PP in the lowest quartile (I: 20-45; II: 46-55; III: 56-62; IV: 63-115 mm Hg) had a significant reduction in the risk of severe ED (RR = 0.60[0.47-0.76]; P < 0.0001). When the same analysis was repeated as a function of age quartile (I = 17-44, II = 45-55, III = 56-62, and IV = 63-88 years old), after adjusting for testosterone levels, mean blood pressure, Chronic Disease Score, and body mass index, PP was inversely related to ED only in the youngest age group. During a mean follow up of 4.4 ± 2.6 years, 147 major cardiovascular events (MACE) were observed. In a Cox regression model, after adjusting for possible confounding factors, a lower PP was associated with a lower risk of MACE in the whole sample and in younger subjects, but not in the older ones. CONCLUSIONS: Checking for blood pressure in ED subjects and calculating PP should become a routine practice in sexual medicine. In younger individuals, low PP reflects not only sexual health (better erection) but also cardiovascular health (less prevalence of MACE).

Body mass index regulates hypogonadism-associated CV risk: results from a cohort of subjects with erectile dysfunction.

INTRODUCTION: Obesity is an independent cardiovascular (CV) risk factor. Testosterone (T) is inversely related to body mass index (BMI) in males. There is substantial evidence suggesting that low T could play a role as a moderator of CV mortality in men. AIM: This study is designed to assess the possible interaction between T and obesity in predicting major CV events (MACE) in a sample of subjects with erectile dysfunction. METHODS: A consecutive series of 1,687 patients were studied. Different clinical, biochemical, and instrumental parameters were evaluated. According to BMI, subjects were divided into normal weight (BMI = 18.5-24.9 kg/m(2) ), overweight (BMI = 25.0-29.9 kg/m(2) ), and obese (BMI ≥ 30.0 kg/m(2) ). Hypogonadism was defined as total T below 10.4 nmol/L. Information on MACE was obtained through the City of Florence Registry Office. MAIN OUTCOME MEASURES: Information on MACE was obtained through the City of Florence Registry Office. RESULTS: Among the patients studied, 39.8% had normal weight, whereas 44.1% and 16.1% were overweight and obese, respectively. Unadjusted analysis in the whole sample showed that while hypogonadism and obesity were significantly associated with an increased risk of MACE, their interaction term was associated with a protective effect. In a Cox regression model, adjusting for confounders, hypogonadism showed a significant increased risk of MACE in normal weight subjects, whereas it was associated with a reduced risk in obese patients. CONCLUSIONS: Hypogonadism-associated CV risk depends on the characteristics of subjects, being more evident in normal weight than in obese patients. Further studies are advisable to clarify if low T in obese patients is a (positive) consequence of a comorbid condition (i.e., to save energy) or if it represents a pathogenetic issue of the same illness. Hence, possible misuse/abuse of T treatment in obese subjects must be avoided.

Poor response to alprostadil ICI test is associated with arteriogenic erectile dysfunction and higher risk of major adverse cardiovascular events.

INTRODUCTION: Intracavernous alprostadil injection (ICI) test has been considered useless in assessing the vascular status of subjects with erectile dysfunction (ED). AIM: To analyze the clinical correlates of ICI test in patients with ED and to verify the value of this test in predicting major adverse cardiovascular events (MACE). METHODS: A consecutive series of 2,396 men (mean age 55.9 ± 11.9 years) attending our outpatient clinic for sexual dysfunction was retrospectively studied. A subset of this sample (N = 1,687) was enrolled in a longitudinal study. MAIN OUTCOME MEASURES: Several clinical, biochemical, and instrumental (penile color Doppler ultrasound; PCDU) factors were evaluated. All patients underwent an ICI test, and responses were recorded on a four-point scale ranging from 1 = no response to 4 = full erection. RESULTS: Among the patients studied, 16.4%, 41.2%, 40.2% and 2.2% showed grade 4, 3, 2, and 1 ICI test response, respectively. After adjusting for confounders, subjects with grade 1 ICI test response showed reduced perceived sleep-related, masturbation-related, and sexual-related erections when compared with the rest of the sample. In addition, a worse response to ICI test was associated with a higher prevalence of hypogonadism-related symptoms and signs along with lower testosterone levels. The prevalence of both diabetes mellitus and metabolic syndrome was inversely related to ICI test response. Accordingly, dynamic and basal peak systolic velocity (PSV), as well as acceleration at PCDU, decreased as a function of ICI test response. In the longitudinal study, after adjusting for confounders, grade 1 response was independently associated with a higher incidence of MACE (hazard ratio = 2.745 [1.200-6.277]; P < 0.05). These data were confirmed even when only subjects with normal PSV (>25 cm/s) were considered. CONCLUSIONS: Our results demonstrate that poor ICI test response is associated with several metabolic disturbances and higher incidence of MACE. We strongly recommend performing ICI test with alprostadil in all ED subjects.

SARS-CoV-2 Serology Monitoring of a Cancer Center Staff in the Pandemic Most Infected Italian Region.

Since the beginning of the COVID-19 outbreak, Cancer Centers adopted specific procedures both to protect patients and to monitor the possible spread of SARS-CoV-2 among healthcare personnel (HCP). In April 2020 at Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, one of the three oncologic hubs in Lombardy where the Health Regional Authorities referred all the cancer patients of the region, we implemented a prospective longitudinal study aimed at monitoring the serological response to SARS-Cov-2 in HCP. One hundred and ten HCP answered a questionnaire and were screened by nasopharyngeal swabs as well as for IgM/IgG levels; seropositive HCPs were further screened every 40-45 days using SARS-CoV-2-specific serology. We identified a fraction of HCP with long-term anti-SARS-CoV-2 antibody responses, though negative for viral RNA, and thus probably able to safely approach fragile cancer patients. Monitoring asymptomatic HCP might provide useful information to organize the healthcare service in a Cancer Center, while waiting for the effectiveness of the active immunization by SARS-CoV-2 vaccines, which will provide protection from infection.

Low testosterone is associated with an increased risk of MACE lethality in subjects with erectile dysfunction.

INTRODUCTION: Although testosterone (T) has been suggested to play a protective role against the development of atherosclerosis, studies demonstrating an association between low T and incident major adverse cardiovascular events (MACE) are scanty in the general population and absent in subjects with erectile dysfunction (ED). AIM: To investigate whether low T in subjects with ED predict incident fatal or nonfatal MACE. METHODS: This is an observational prospective cohort study evaluating a consecutive series of 1687 patients attending our andrological unit for ED. Patients were interviewed using the structured interview on erectile dysfunction (SIEDY) and ANDROTEST structured interviews measuring components relative to ED and hypogonadal-related symptoms, respectively. MAIN OUTCOME MEASURES: Total T was evaluated at baseline. Information on MACE was obtained through the City of Florence Registry Office. RESULTS: Among the patients studied, 5.2, 13.8, and 22.4% were hypogonadal according to different thresholds (T < 8, 10.4 and 12 nmol/L or 230, 300 and 350 ng/dL, respectively). During a mean follow-up of 4.3 + or - 2.6 years, 139 MACE, 15 of which were fatal, were observed. Unadjusted incidence of MACE was not associated with T levels. Conversely, the proportion of lethal events among MACE was significantly higher in hypogonadal patients, using either 10.4 nmol/L (300 ng/dL) or 8 nmol/L (230 ng/dL) thresholds. However, after adjustment for age and Chronic Diseases Score in a Cox regression model, only the association between incident fatal MACE and T < 8 nmol/L (230 ng/dL) was confirmed (HR = 7.1 [1.8-28.6]; P < 0.001). Interestingly, measuring hypogonadal-related symptoms and signs through ANDROTEST, only fatal MACE were also associated with a higher score (HR = 1.2 [1.0-1.5] for each ANDROTEST score increment; P = 0.05 after adjustment for age and Chronic Diseases Score). CONCLUSIONS: T levels are associated with a higher mortality of MACE. The identification of low T levels should alert the clinician thus identifying subjects with an increased cardiovascular risk.

Male sexuality and cardiovascular risk. A cohort study in patients with erectile dysfunction.

INTRODUCTION: Although penile blood flow (PBF) has been recommended as an additional diagnostic test in identifying erectile dysfunction (ED) patients at risk for latent cardiovascular disease, no study has ever assessed the possible association of PBF and the relational component of sexual function with incident major cardiovascular events (MACE). AIM: The aim of this study is to investigate whether severity of ED, PBF, and other factors related to a couple's relationship predict incident MACE. METHODS: A consecutive series of 1,687 patients was studied. Different clinical, biochemical, and instrumental (penile flow at color Doppler ultrasound) parameters were evaluated. MAIN OUTCOME MEASURES: Information on MACE was obtained through the City of Florence Registry Office. RESULTS: During a mean follow-up of 4.3 +/- 2.6 years, 139 MACE, 15 of which were fatal, were observed. Cox regression analysis, after adjustment for age and Chronic Disease Score, showed that severe ED predicted MACE (hazard ratio [HR] 1.75; 95% confidence interval 1.10-2.78; P < 0.05). In addition, lower PBF, evaluated both in flaccid (before) and dynamic (after prostaglandin-E1 stimulation) conditions, was associated with an increased risk of MACE (HR = 2.67 [1.42-5.04] and 1.57 [1.01-2.47], respectively, for flaccid [<13 cm/second] and dynamic [<25 cm/second] peak systolic velocity; both P < 0.05). Reported high sexual interest in the partner and low sexual interest in the patient proved to have a protective effect against MACE. CONCLUSIONS: The investigation of male sexuality, and in particular PBF, and sexual desire, could provide insights not only into present cardiovascular status but also into prospective risk.

Is obesity a further cardiovascular risk factor in patients with erectile dysfunction?

INTRODUCTION: Erectile dysfunction (ED) and, in particular, arteriogenic ED have been proposed as new markers of risk for incident major adverse cardiovascular events (MACE). Reduced penile blood flow is more common in obese people than in leaner ED subjects. AIM: To explore the interaction of overweight/obesity and penile blood flow in the prediction of incident MACE. METHODS: This is an observational prospective cohort study evaluating a consecutive series of 1,687 patients attending our andrological unit for ED. Different clinical, biochemical, and instrumental (penile flow at color Doppler ultrasound: PCDU) parameters were evaluated. MAIN OUTCOMES MEASURES: According to body mass index (BMI), subjects were divided into three groups: normal weight (BMI = 18.5-24.9 kg/m(2)), overweight (BMI = 25.0-29.9 kg/m(2)), and obese (BMI >or= 30.0 kg/m(2)). Information on MACE was obtained through the City of Florence Registry Office. RESULTS: Among patients studied, 39.8% were normal weight, while 44.1% and 16.1% showed BMI 25-29.9 and 30 kg/m(2) or higher, respectively. During a mean follow-up of 4.3 +/- 2.6 years, 139 MACE, 15 of which were fatal, were observed. Cox regression model, after adjusting for age and Chronic Diseases Score, showed that obesity classes along with the presence of arteriogenic ED (peak systolic velocity at PCDU <25 cm/second) were significantly and independently associated with incident MACE (hazard ratio = 1.47 [1.1-1.95], P < 0.05 and 2.58 [1.28-5.09], P < 0.001, respectively). When a separate analysis was performed for classes of obesity, reduced peak systolic velocity at PCDU (<25 cm/second) was significantly associated with incident MACE in obese (BMI >or= 30 kg/m(2)), but not in leaner, subjects. CONCLUSIONS: In obese subjects, more than in leaner ED subjects, impaired penile blood flow is associated with an increased risk of incident cardiovascular disease. The interaction with concomitant risk factors, such as obesity, should be taken into account when assessing the predictive value of penile blood flow for cardiovascular diseases.

Severe depressive symptoms and cardiovascular risk in subjects with erectile dysfunction.

INTRODUCTION: Erectile dysfunction (ED) and mood depression are often associated and both are correlated with an increased risk of cardiovascular morbidity and mortality. AIM: The aim of the present study is to explore biological and clinical correlates of depressive symptomatology in a sample of men consulting for sexual dysfunction and to verify possible associations between depressive symptoms and incidence of major cardiovascular events (MACE). METHODS: A consecutive series of 2,303 male patients attending the Outpatient Clinic for sexual dysfunction was retrospectively studied. A subset of the previous sample (N= 1,687) was enrolled in a longitudinal study. All patients were investigated using a Structured Interview on Erectile Dysfunction (SIEDY), composed of 3 scales which explore organic, relational and intra-psychic components of ED. MHQ-D scoring from Middlesex Hospital Questionnaire (MHQ) was used as a putative marker of depressive symptoms. MAIN OUTCOME MEASURES: Information on MACE was obtained through the City of Florence Registry Office. RESULTS: We found a positive relationship between MHQ-D score and a progressive impairment in obtaining an erection hard enough for penetration, even after adjusting for confounding factors. Moreover, we observed positive relationships between MHQ-D score and the three pathogenetic domains underlying ED. When the longitudinal subset was evaluated, during a mean follow-up of 4.3±2.6 years, 139 MACE, 15 of which were fatal, were observed. Unadjusted incidence of MACE was significantly associated with baseline depressive symptoms. When the presence of severe depressive symptoms were introduced in a Cox regression model, along with the arteriogenic ED and partner's hypoactive sexual desire, after adjusting for age, Chronic Diseases Score, and ΣMHQ (a broader index of psychopathology), severe depressive symptomatology was independently associated with a higher incidence of MACE. CONCLUSION: Depressive symptomatology constitutes an independent risk factor for cardiac morbidity and mortality in men with ED.

Priapus is happier with Venus than with Bacchus.

INTRODUCTION: The relationship between alcohol consumption and erectile function is still not completely clarified. AIM: Aims of the present study are to explore a number of biological and clinical correlates of alcohol consumption in a sample of men consulting for sexual dysfunction, and to verify possible associations with the incidence of major adverse cardiovascular events (MACEs). METHODS: A consecutive series of 1956 (mean age 55 ± 11.9 years old) attending our outpatient clinic for sexual dysfunction was retrospectively studied. A subset of the previous sample (N = 1687) was enrolled in a longitudinal study. MAIN OUTCOME MEASURES: Different clinical, biochemical, instrumental (penile Doppler ultrasound [PCDU]), and intrapsychic (Middlesex Hospital Questionnaire [MHQ]) were evaluated. We considered alcohol abuse more than three drinks per day. RESULTS: Among the patients studied 81% reported no or mild (<4 drinks/day) alcohol consumption whereas 14.3% and 3.9% declared a moderate (4-6 drinks/day) or severe (>6 drinks/day) alcohol abuse, respectively. After adjustment for confounders, both moderate or severe alcohol abuse was associated with low perceived partner's sexual desire, worse couple relationship, and smoking abuse. Furthermore, moderate and severe alcohol abuse was associated with low prolactin and thyroid-stimulating hormone levels, as well as an increase in triglycerides and total cholesterol levels. Penile blood flow was reduced in moderate and severe alcohol drinkers even after adjustment for confounders. In the longitudinal study, after adjusting for confounding factors, any kind of alcohol abuse was independently associated with a higher incidence of MACE (hazard ratio = 2.043 [1.059-3.943]; P < 0.0001). CONCLUSIONS: Our findings demonstrate that, in subjects consulting for erectile dysfunction, severe alcohol consumption is associated with a worse sexual function and a higher incidence of MACE.

Metabolic syndrome and cardiovascular mortality in older type 2 diabetic patients: a longitudinal study.

BACKGROUND: Although age does not seem to modify the association of the metabolic syndrome (MS) with cardiovascular risk in middle-aged individuals, no comparison of risks associated with MS between old and middle-aged persons has been reported so far. METHODS: An observational study was performed on a consecutive series of 1716 type 2 diabetic outpatients (age range: 28-96 years). The diagnosis of MS was made following either the National Cholesterol Education Program-Adult Treatment Panel (NCEP-ATPIII) or the International Diabetes Federation (IDF) criteria. RESULTS: The difference in cardiovascular mortality between patients with and without MS was significant up to the age of 70 years. After adjusting for age and sex, hazard ratios of MS for cardiovascular mortality were 3.03 (95% confidence interval, 1.45-6.29), 1.56 (0.91-2.68), and 1.17 (0.42-3.22) in patients < or =70, 71-80, and >80 years old, respectively. CONCLUSIONS: MS is associated with increased cardiovascular risk in middle-aged type 2 diabetic patients, and the clinical utility of this category in older diabetic individuals is questionable.

Chaperon and adjuvant activity of hsp70: different natural killer requirement for cross-priming of chaperoned and bystander antigens.

Heat shock proteins (HSP) convey both chaperoned propeptide and danger signal to dendritic cells (DC). However, few studies have compared the two activities. Using a murine inducible hsp70 secreted by cells distinct from those providing the tumor antigens, we showed that hsp70 exerts efficacious adjuvant effects toward DC cross-priming. Hsp70 induces DC maturation and phagocytosis of cellular debris both in vitro and in vivo, which are conducive to CTL response to chaperoned and nonchaperoned antigens. Whereas the ability of hsp70 to induce cross-presentation of chaperoned peptides is natural killer (NK) independent, the adjuvant activity requires NK cells at the site of DC-hsp70 interaction to induce CTL response and therapeutic effect against lung metastases. However, although bystander activity provides equal CTL induction, the best therapeutic efficacy rests on cell vaccine secreting hsp70 that combines chaperoned antigen and danger signal within the same cell.

Enhanced efficacy of tumor cell vaccines transfected with secretable hsp70.

Tumor immunotherapy has exploited the ability of heat shock proteins to chaperone precursors of antigenic peptides to antigen-presenting cells and to activate efficiently an immune response against tumor-associated antigens. The most common strategy is based on the purification of heat shock protein-peptide complexes from tumor cell lines or from tumor surgical samples for in vivo administration. In this article, we have modified the murine-inducible hsp70 into a secreted protein and engineered tumor cells to secrete constitutively their antigenic repertoire associated with the hsp70 protein. In vitro studies showed that the relocalization of hsp70 from the cytoplasm to the secretory pathway did not modify the ability of hsp70 to interact with peptides derived either from natural tumor-associated antigens or model antigens, and that antigen-presenting cells specifically took up the secreted hsp70 and presented the chaperoned epitopes to T cells. In vivo studies showed that tumors secreting hsp70 displayed increased immunogenicity, with induction of a strong and specific CTL response. Mice injected with hsp70-secreting tumors showed increased survival and impaired tumor take compared with mice bearing parental tumors. More than 70% of mice rejected tumor cells secreting hsp70 through mechanisms that involve T lymphocytes and natural killer cells, with the induction of a memory response in the case of T lymphocytes. Moreover, hsp70 secretion increased the immunogenic potential of tumor cell vaccines.

The OECI model: the experience of INT Milan with a focus on the integration of psycho-oncology support.

The procedure for Organisation of European Cancer Institutes (OECI) accreditation identified the formation of MDTs for the diagnosis and scheduling of primary treatment with integration of supportive care as a key strength at Istituto Nazionale Tumori (INT). The opportunities for improvement highlighted by the OECI peer review inspired a study on the evaluation of psychological distress, with a view to integrating this evaluation into global patient management and to defining standardized criteria for the provision of psychological services. This article describes the OECI accreditation experience at INT and the study conducted between January and May 2015 on the evaluation of patients' distress levels during cancer treatment, defining a score-based cutoff point that triggers the intervention of a psychologist. The Distress Thermometer was used as a tool for evaluating psychological distress, performed by nurses on admitting the patient. A total of 261 questionnaires were completed by patients admitted to the medical oncology and hematology departments, with an average distress value of 4.1, and 60% of patients experiencing clinically detectable emotional distress. Emotion-related problems had a significant association with a greater level of distress, while there were few reports of relationship issues as a cause of distress. As a result of the improvement initiative supported by the psychological distress evaluation study, we validated the screening questionnaire to be included at the initial patient evaluation stage with a cutoff point triggering the intervention by a psychologist at a score of ≥7.

Metformin and cancer occurrence in insulin-treated type 2 diabetic patients.

OBJECTIVE: Metformin is associated with reduced cancer-related morbidity and mortality. The aim of this study was to assess the effect of metformin on cancer incidence in a consecutive series of insulin-treated patients. RESEARCH DESIGN AND METHODS: A nested case-control study was performed in a cohort of 1,340 patients by sampling, for each case subject, age-, sex-, and BMI-matched control subjects from the same cohort. RESULTS: During a median follow-up of 75.9 months, 112 case patients who developed incident cancer and were compared with 370 control subjects. A significantly lower proportion of case subjects were exposed to metformin and sulfonylureas. After adjustment for comorbidity, glargine, and total insulin doses, exposure to metformin, but not to sulfonylureas, was associated with reduced incidence of cancer (odds ratio 0.46 [95% CI 0.25-0.85], P = 0.014 and 0.75 [0.39-1.45], P = 0.40, respectively). CONCLUSIONS: The reduction of cancer risk could be a further relevant reason for maintaining use of metformin in insulin-treated patients.

TLR9 agonists oppositely modulate DNA repair genes in tumor versus immune cells and enhance chemotherapy effects.

Synthetic oligodeoxynucleotides expressing CpG motifs (CpG-ODN) are a Toll-like receptor 9 (TLR9) agonist that can enhance the antitumor activity of DNA-damaging chemotherapy and radiation therapy in preclinical mouse models. We hypothesized that the success of these combinations is related to the ability of CpG-ODN to modulate genes involved in DNA repair. We conducted an in silico analysis of genes implicated in DNA repair in data sets obtained from murine colon carcinoma cells in mice injected intratumorally with CpG-ODN and from splenocytes in mice treated intraperitoneally with CpG-ODN. CpG-ODN treatment caused downregulation of DNA repair genes in tumors. Microarray analyses of human IGROV-1 ovarian carcinoma xenografts in mice treated intraperitoneally with CpG-ODN confirmed in silico findings. When combined with the DNA-damaging drug cisplatin, CpG-ODN significantly increased the life span of mice compared with individual treatments. In contrast, CpG-ODN led to an upregulation of genes involved in DNA repair in immune cells. Cisplatin-treated patients with ovarian carcinoma as well as anthracycline-treated patients with breast cancer who are classified as "CpG-like" for the level of expression of CpG-ODN modulated DNA repair genes have a better outcome than patients classified as "CpG-untreated-like," indicating the relevance of these genes in the tumor cell response to DNA-damaging drugs. Taken together, the findings provide evidence that the tumor microenvironment can sensitize cancer cells to DNA-damaging chemotherapy, thereby expanding the benefits of CpG-ODN therapy beyond induction of a strong immune response.

Doses of insulin and its analogues and cancer occurrence in insulin-treated type 2 diabetic patients.

OBJECTIVE: Recent epidemiological studies suggested that some insulin analogues could be associated with increased risk of cancer. The present study is aimed at assessing the long-term association of different insulin analogues with cancer incidence. RESEARCH DESIGN AND METHODS: A nested case-control study dataset was generated from the cohort study dataset (n = 1,340 insulin-treated diabetic outpatients) by sampling control subjects from the risk sets. For each case subject, the control subjects (up to five) were chosen randomly from those members of the cohort who are at risk for the same follow-up time of the case subject. Five-year age classes, sex, and BMI classes (<18.5, 18.5-24.9, 25-29.9, and >or=30 kg/m(2)) were considered as additional categorical matching variables. RESULTS: During a median follow-up of 75.9 months (interquartile range 27.4-133.7), 112 case subjects of incident cancer were compared with 370 matched control subjects. A significantly higher mean daily dose of glargine was observed in case subjects than in control subjects (0.24 IU/kg/day [0.10-0.39] versus 0.16 IU/kg/day [0.12-0.24], P = 0.036). Incident cancer was associated with a dose of glargine >or=0.3 IU/kg/day even after adjusting for Charlson comorbidity score, other types of insulin administration, and metformin exposure (odds ratio 5.43 [95% CI 2.18-13.53], P < 0.001). No association between incident cancer and insulin doses was found for human insulin or other analogues. CONCLUSIONS: The possibility of association between cancer and higher glargine doses suggests that dosages should always be considered when assessing the possible association of insulin and its analogues with cancer.