Can harmful lifestyle, obesity and weight changes increase the risk of breast cancer in BRCA 1 and BRCA 2 mutation carriers? A Mini review.

BACKGROUND AND AIM: The BRCA 1 and BRCA 2 genes are associated with an inherited susceptibility to breast cancer with a cumulative risk of 60% in BRCA 1 mutation carriers and of 30% in BRCA 2 mutation carriers. Several lifestyle factors could play a role in determining an individual's risk of breast cancer. Obesity, changes in body size or unhealthy lifestyle habits such as smoking, alcohol consumption and physical inactivity have been evaluated as possible determinants of breast cancer risk. The aim of this study was to explore the current understanding of the role of harmful lifestyle and obesity or weight change in the development of breast cancer in female carriers of BRCA 1/2 mutations. METHODS: Articles were identified from MEDLINE in October 2020 utilizing related keywords; they were then read and notes, study participants, measures, data analysis and results were used to write this review. RESULTS: Studies with very large case series have been carried out but only few of them have shown consistent results. Additional research would be beneficial to better determine the actual role and impact of such factors.

u-PAR expression in cancer associated fibroblast: new acquisitions in multiple myeloma progression.

BACKGROUND: Multiple Myeloma (MM) is a B-cell malignancy in which clonal plasma cells progressively expand within the bone marrow (BM) as effect of complex interactions with extracellular matrix and a number of microenvironmental cells. Among these, cancer-associated fibroblasts (CAF) mediate crucial reciprocal signals with MM cells and are associated to aggressive disease and poor prognosis. A large body of evidence emphasizes the role of the urokinase plasminogen activator (u-PA) and its receptor u-PAR in potentiating the invasion capacity of tumor plasma cells, but little is known about their role in the biology of MM CAF. In this study, we investigated the u-PA/u-PAR axis in MM-associated fibroblasts and explore additional mechanisms of tumor/stroma interplay in MM progression. METHODS: CAF were purified from total BM stromal fraction of 64 patients including monoclonal gammopathy of undetermined significance, asymptomatic and symptomatic MM, as well as MM in post-treatment remission. Flow cytometry, Real Time PCR and immunofluorescence were performed to investigate the u-PA/u-PAR system in relation to the level of activation of CAF at different stages of the disease. Moreover, proliferation and invasion assays coupled with silencing experiments were used to prove, at functional level, the function of u-PAR in CAF. RESULTS: We found higher activation level, along with increased expression of pro-invasive molecules, including u-PA, u-PAR and metalloproteinases, in CAF from patients with symptomatic MM compared to the others stages of the disease. Consistently, CAF from active MM as well as U266 cell line under the influence of medium conditioned by active MM CAF, display higher proliferative rate and invasion potential, which were significantly restrained by u-PAR gene expression inhibition. CONCLUSIONS: Our data suggest that the stimulation of u-PA/u-PAR system contributes to the activated phenotype and function of CAF during MM progression, providing a biological rationale for future targeted therapies against MM.

Role of bone marrow biopsy in staging of patients with classical Hodgkin's lymphoma undergoing positron emission tomography/computed tomography.

Several studies suggested that staging bone marrow biopsy (BMB) could be omitted in patients with classical Hodgkin's lymphoma (cHL) when a positron emission tomography/computed tomography (PET/CT) is performed at baseline.To address the concordance between BMB and PET/CT in the detection of bone marrow involvement (BMI) and the BMB role in determining the Ann Arbor stage, we retrospectively collected data on 1244 consecutive patients with cHL diagnosed from January 2007 to December 2013. One thousand eighty-five patients who had undergone both BMB and PET/CT were analyzed, comparing the Ann Arbor stage assessed with PET/CT only to that resulting from PET/CT combined with BMB.One hundred sixty-nine patients (16%) showed at least one focal skeletal lesion (FSL) at PET/CT evaluation. Only 55 patients had a positive BMB (5.1%); 34 of them presented at least one FSL at PET/CT. To the contrary, 895 out of 1030 patients with a negative BMB did not show any FSL (86.9%). Positive and negative predictive values of PET/CT for BMI were 20 and 98%, respectively; sensitivity and specificity were 62 and 87%, respectively. Fifty-four out of 55 patients with a positive BMB could have been evaluated as an advanced stage just after PET/CT; only one patient (0.1%) would have been differently treated without BMB.Our data showed a very high negative predictive value of PET/CT for BMI and a negligible influence of BMB on treatment planning, strengthening the recent indications that BMB could be safely omitted in cHL patients staged with PET/CT.

[Determination of persistent organic compounds in serum by using gas chromatography coupled with triple quadrupole mass spectrometry]. / Determinazione di composti organoclorurati persistenti in siero mediante gascromatografia abbinata a spettrometria di massa con triple quadrupolo.

Polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCs) are lipophilic and persistent compounds that were widely used in industrial and consumer products for decades until the late 70s. Due to their persistence and bioaccumulation, they are globally spread in the environment and may still be found in all environmental and biological media. Some have been classified as xenoestrogens or endocrine disruptors. Some others are known to have adverse effects for human health, including cancer. With the objective of establishing reference values, a fast and reliable method, previously developed and validated using single quadrupole mass spectrometry, was properly modified in order to simultaneously detect 10 organochlorine pesticides and 15 PCBs by using triple quadrupole. Use of triple quadrupole mass spectrometry has further increased the reliability of the method, so that it is now possible to collect more significant data concerning general population, which is the first step before the assessment of occupational exposure levels.

[Reference values for 42 trace elements in biological fluids (database RE-VA)]. / Valori di riferimento di 42 elementi in traccia in fluidi biologici della popolazione generale (database RE-VA).

The increasing use of multi-elementary techniques such as inductively coupled plasma mass spectrometer (ICP-MS), possibly in combination with dynamic reaction cell or other device, has greatly simplified the determination of trace elements in serum or plasma, whole blood and urine, even resorting to a phase of mineralization of the sample with microwave and teflon pressurized containers. This has made it necessary, however, an accurate control of interference, particularly polyatomic, using when possible, high-resolution ICP-MS, ICP-OES and ETA-AAS with electrothermal atomization. RE-VA study involved 162 subjects and has made available the reference values or background values for 42 elements in the matrix above. Physiological variables, life habits and food were also investigated. The aim is to implement the series through the sampling and analysis of similar types of samples in other Italian regions and countries in Europe and beyond. The data obtained allow to focus any inconsistencies for specific analytes and matrices, in order to identify critical variable attributable to both analytical and pre-analytical factors. For elements such as W, Ba, Cs, Pt, RE-VA study has revealed significant differences compared to other studies, and this is most likely to report high analytical sensitivity of DRC-ICP-MS as confirmed by comparative studies with Sector Field ICP-MS which provided matching values. It is also discussed the limitation of the use of VR for studies aimed at population groups living in industrial areas or where there are landfills, coal power plants and thermo incinerators.

[Antineoplastic profile assessment for the evaluation of occupational exposure in hospital personnel involved in handling cytotoxic agents]. / Definizione del profile di chemioterapici antiblastici nella valutazione dell'esposizione professionale in ambito sanitario.

Environmental and biological monitoring performed in health care settings during a 14-year period allowed numerous data to be obtained by using the HPLC coupled with tandem mass spectrometry (HPLC-MS/MS). Data was stored in a specific data-base for the assessment of risk exposure to antineoplastic agents (CA). The strategy of analysis was based on the simultaneous determination of different active substances with a lower limit of quantification (LOQ) optimized in the range of sub-units of microg/L. In the present study, the MRM-ESI-MS/MS profiles of seven antineoplastic agents in both environmental and biological matrices are reported. These methods validated according to FDA guidelines allowed our lab to define a profile of antineoplastic agents that was representative of the four IARC classes, such as cyclophosphamide (group 1), cisplatin and doxorubicin (group 2A), daunorubicin (group 2B), 5-fluorouracil, ifosfamide (group 3), taxol, and gemcitabine (group 4). Moreover, contamination levels on a number of work surfaces and trends over a 14-year period are presented. The evaluation of occupational exposure to CA has been based on ALARA principle for most of the past decades but this principle is nowadays overwhelmed by the fast development of technology. The assessment of a possible in-take of CA in hospital personnel, when the sources of environmental contamination are identified, has become possible by the defining of a limit of exposure close to the limit of detection of the analytical method.

[Possible use of microRNAs as biomarkers for monitoring of workers exposed to asbestos]. / Possibile impiego di microRNA come biomarcatori nel monitoraggio dei lavoratori professionalmente esposti ad amianto.

Exposure to asbestos is the predominant cause of pleural mesothelioma (PM). The PM is a tumor difficult to diagnose, chemoresistant, and with rising Incidence. The long latency periods and the lack of preventive and therapeutic strategies for the MP, suggest that asbestos will be a social and health issue in the near future. Therefore, this overview focuses on current knowledge of epigenetic alterations and on the key role of microRNAs, small RNAs that negatively regulate gene expression, as biomarkers in PM development. Dysregulated microRNA expression pattern is specific for different cancers, including MP. MicroRNA expression analysis is a promising tool for diagnosis, typing of MP than normal tissue and other lung tumors and monitoring of new therapies. However, a better knowledge of miRNA signatures in PM is still necessary to verify the contribution of specific miRNAs as diagnostic biomarkers, also compared to different asbestos forms, exposure and subject work history.

Prevalence and clinical impact of incidental findings on the unenhanced CT images of PET/CT scan in patients with multiple myeloma: the value of radiological reporting in the multimodal hybrid imaging.

OBJECTIVE: In the hybrid Positron Emission Tomography/Computed Tomography (PET/CT) method, the functional evaluation is integrated with the morphological information provided by co-registered CT, still performed for attenuation correction and lesion localization. However, co-registered CT images could provide additional diagnostic information that PET alone could underestimate. To optimize the diagnostic potential of this hybrid examination, we evaluated the prevalence and the clinical significance of incidental findings detected on co-registered CT images in a cohort of multiple myeloma (MM) patients. PATIENTS AND METHODS: We evaluated 112 MM patients (mean age 65.8 y), who underwent [18F]FDG-PET/CT during their regular workup. All co-registered CT images were retrospectively reviewed by two expert radiologists and each non-myelomatous incidental finding (nM-IF) was collected and clinically graded according to a nM-IF Reporting and Data System (nM-RADS). In addition, nM-IFs were classified according to anatomic localization (skull, lung, mediastinum, abdomen, breast, gastrointestinal, genitourinary and cardiovascular system and muscle/soft tissue). RESULTS: 163 nM-IFs were detected in 94/112 patients (83.9%) (mean value: 1.5 IFs per patient). The most interested anatomic districts were the lung (n=33; 20.2%), genitourinary (n=33; 20.2%) and gastrointestinal (n=30; 18.4%) systems. Focusing on the clinically significant findings (nM3+nM4), 92/163 (56.4%) IFs could have been required further investigations, of which 38/163 (23.3%) were potentially important and detected in 33/112 (29.5%) patients. CONCLUSIONS: The high percentage of potentially clinically significant IFs detected in MM patients emphasizes that co-registered CT images hold precious information often missed. Giving more relevance to co-registered CT with tailored acquisition and reconstruction protocols and dedicated reporting could optimize the potentiality of this multimodality imaging method with impact on clinical management.

Heavy metals in human amniotic fluid: a pilot study.

OBJECTIVE: Many heavy metals are essential nutrients for a healthy life. However, significant evidence supports prolonged prenatal exposure as a risk factor for several adverse health effects. The aim of this study is to evaluate the presence of heavy metals in human amniotic fluid (AF) to demonstrate that there is an early fetal in utero exposure. METHODS: The concentrations of a variety of heavy metals, including Be, Ag, Ba, Pb, U, Hg, Sr, Cu, Mn, V, Pd, Sn, Sb, Te, Pt, Sc, Tl, Ni, As, Co, Zn and Se, were measured in 25 AF samples obtained from amniocentesis between 15 and 18 weeks of gestational, after informed consent. RESULTS: Be, Ag, Ba, Pb, U, Cu, Sr, Mn, V, Sn, Te, Pt, As, Tl, Sb, Co, Se and Zn concentrations were detected in measurable amounts in second trimester AF. Mg levels are elevated in all samples. Pd, Ni, Sc and Hg concentrations are below the detection limits in all samples. CONCLUSION: This study demonstrates that heavy metals pass into and accumulate in AF from a very early stage of gestation. Other studies are needed to evaluate the long-term health effects of this early exposure.

Body Composition Change, Unhealthy Lifestyles and Steroid Treatment as Predictor of Metabolic Risk in Non-Hodgkin's Lymphoma Survivors.

Unhealthy lifestyle, as sedentary, unbalanced diet, smoking, and body composition change are often observed in non-Hodgkin's lymphoma (NHL) survivors, and could be determinant for the onset of cancer treatment-induced metabolic syndrome (CTIMetS), including abdominal obesity, sarcopenia, and insulin resistance. The aim of this study was to assess whether changes in body composition, unhealthy lifestyles and types of anti-cancer treatment could increase the risk of metabolic syndrome (MetSyn) and sarcopenia in long-term NHL survivors. We enrolled 60 consecutive NHL patients in continuous remission for at least 3 years. Nutritional status was assessed by anthropometry-plicometry, and a questionnaire concerning lifestyles and eating habits was administered. More than 60% of survivors exhibited weight gain and a change in body composition, with an increased risk of MetSyn. Univariate analysis showed a significantly higher risk of metabolic disorder in patients treated with steroids, and in patients with unhealthy lifestyles. These data suggest that a nutritional intervention, associated with adequate physical activity and a healthier lifestyle, should be indicated early during the follow-up of lymphoma patients, in order to decrease the risk of MetSyn's onset and correlated diseases in the long term.

[Epigenetics and environmental exposure to xenobiotics]. / Epigenetica ed esposizione ambientale a xenobiotici.

Environmental pollution, together with predisposing genetic factors, plays a key role in determining short and long-term adverse effects on human health. In the industrialized countries the identification of etiology related to diseases of environmental origin has then become a research of priority interest. With regard to this, it has been widely demonstrated that different chemical compounds, such as endocrine disruptors, are able to modify the epigenetic characteristics of a human being. According to recent studies, the paradigm "genotype is strongly correlated with a phenotype" is changing in favor of the concept that a phenotype is defined by a "genotype and by an epigenome". Thus, there is a genotype identical for all cells associated to the epigenome that causes changes in gene expression without modifying the nucleotide sequence of the genome, through alterations in DNA methylation, histone modifications and the pathway of small non-coding RNAs. The epigenome is easily affected by different factors, such as aberrations of normal epigenetic processes that can be caused by environmental factors as exposure to xenobiotics, social behavior and nutritional deficiencies. Epigenetic changes are thus a biological response to environmental stress factors and may be transmitted to the offspring. As the elimination of the environmental factor determines the possible reversion of epigenetic modifications, it seems not to play a role in the natural selection process. However, epigenetic aberrations affect gene expression by interfering with the stability and survival of cells and with the inactivation of onco-suppressor genes. Thus, it is of considerable interest to investigate about the possible elements of induction of epigenetic processes in order to implement prevention protocols. Moreover, the gene expression screening through high through-put techniques like microarray, represent a new tool for the identification of new epigenetic indicators in order to monitor the early biological effects on the population exposed to xenobiotics.

[Gene expression and environmental exposure to xenobiotics: overview and applications]. / Espressione genica ed esposizione ambientale a xenobiotici: overview e applicazioni.

Industrial chemicals, pesticides, pharmaceuticals, foods, heavy metals, air pollutants, and naturally occurring substances, are an integral part of our daily lives. Environmental exposure can induce changes in gene regulation associated with human diseases. A new discipline of toxicology is "predictive toxicology" that defines the relationship between the structure and activity of the genome and the adverse biological effects of exogenous agents. Toxicogenomic technologies allow complete assessment of the functional activity of biochemical pathways, and of the structural genetic (sequence) differences among individuals (polymorphisms), that were previously unattainable. Microarray technology provides the means to study multiple pathways and mechanisms at concurrent times. Gene expression is a sensitive indicator of toxicant exposure, disease state, and cellular metabolism and thus represents a way of characterising how cells and organisms adapt to changes in the external environment. The application of these technologies to toxicology can lead us into a new era when genotypes and toxicant-induced genome expression, proteins, and metabolite patterns can be used to screen compounds for hazard identification, to monitor individual exposure to toxicants, to track cellular responses to different doses, to assess mechanisms of action, and to predict individual variability in sensitivity to toxicants and potential ways to improve risk assessment.

Trace element levels in adult patients with proteinuria.

AIM: Trace elements are involved in many metabolic processes. They circulate prevalently bound to protein. In literature few studies deal with metal metabolism in adult patients with proteinuria, so we decided to further investigate metal metabolism in proteinuric patients. METHODS: We studied 27 patients (14 male, 13 female), mean age 61.6+/-17 years with different degrees of renal function, serum albumin and proteinuria. Metal concentrations of copper (Cu), zinc (Zn) and aluminum (Al) were measured in serum and urine. No patient had environmental exposure to these metals. RESULTS: The serum Zn level was below the normal range in 11 patients. The serum Cu level was reduced in 5 patients. The Al serum level was elevated in 4 patients. Six patients had reduced and 6 patients had elevated Zn excretion. The urinary Cu excretion was elevated in 6 patients. The urinary Al excretion was elevated in 1 patient. Trace metal concentrations were related neither to renal function nor to total serum protein or albumin levels. Serum zinc was directly correlated with proteinuria and urinary zinc and negatively correlated with testosterone levels in both sexes. CONCLUSION: Adult patients with proteinuria have several modification of trace metal concentration in serum and urine. Serum concentration of metals did not depend on renal function or serum protein levels. Urinary Zn excretion was directly related to proteinuria and serum Zn levels. A negative correlation between serum Zn levels and testosterone was found in both sexes. Renal failure reduced urinary excretion of Cu and Al.

[Occupational and environmental exposure to anilide and dicarboximide pesticides]. / Esposizione ambientale e professionale a pesticidi propionanilidici e dicarbossimidici.

Dicarboximide fungicides (DF) such as vinclozolin, iprodione, procymidone are widely used on vines, fruit and vegetables, and anilide herbicides (AH) such as diuron, linuron, propanil are used to control weeds on hard surfaces, such as, roads, railway tracks, paths, and in crops, forestry. Italian reports on food safety found many samples contaminated by pesticides belonging to these categories, even though only few exceeding L.M.R. Since adverse effects on human health, such as endocrine disruption, have been reported, biological monitoring is essential for exposure assessment both of occupationally exposed subjects and of the general population. Common metabolites of DF and AH are dichloroanilinines such as 3,4-DCA and 3,5-DCA, urine samples from 153 subjects living in Novafeltria, central Italy, were collected for analysis of 3,4- and 3,5-DCAs, each participant was invited to complete a very detailed questionnaire. A total of 151 out of 153 samples were found to be positive for 3,5-DCA, and 81.7% were positive for 3,4-DCA. Also 33 workers, engaged in application of propanil on rice in northern Italy, were involved in the study and 3,4-DCA was determined as marker of exposure. 3,4 and 3,5 dichloroaniline are useful and promising biological indicators for monitoring occupational and environmental exposure to these classes of pesticides.

[Headache as "sentinel" symptom in personnel involved in the preparation and administration of antineoplastic drugs]. / La Cefalea sintomo "sentinella" nel personale addetto alla preparazione e somministrazione di Chemioterapici Antiblastici.

The increased prevalence of neoplastic diseases observed over the last years has resulted for in more frequent operations of preparation and administration of antiblastic drugs performed by the medical personnel. In this study, we examined a group of subjects involved in the preparation of ACNU, Methotrexate, Novantrone, Vincristine, Cyclophosphamide, Carboplatinum, Mythoxantrone, in order to elucidate whether headache may represent an early symptom of exposure to these products. At the same time, we measured the degree of pollution in the air surrounding the vertical laminar flow aspiration cabinet used for drug preparation. The 66.6% of the 12 subjects studied, 9 females and 3 males, complained of headache. However, the environmental detection using high performance liquid chromatography coupled with triple quadrupole mass spectrometry (HPLC/MS/MS) gave negative results with respect to a possible environmental damage. These findings suggest that headache is the onset symptom of the toxic effect of antiblastic chemiotherapics in the medical personnel involved in drug preparation and administration.

"Real world" outcome of lenalidomide plus dexamethasone in the setting of recurrent and refractory multiple myeloma: extended follow-up of a retrospective multicenter study by the "rete ematologica pugliese".

This current retrospective multicenter analysis represents, to our knowledge, the first Italian study evaluating the efficacy and toxicity profile of "lenalidomide plus dexamethasone" as salvage therapy in patients with recurrent-refractory MM in the real life contest. Our study included patients who are usually excluded from clinical trials because of unfavorable baseline characteristics. Median OS was significantly longer in patients receiving "lenalidomide plus dexamethasone" for more than 12 months compared with those who had received "lenalidomide plus dexamethasone" for a shorter interval (P<0.0001). Median OS was not affected by best response achieved (P 0.4) and age (P 0.3). Quality of response did not correlate with number of previous lines of therapy (P 0.77) and age. Higher ORRs were recorded in the patients group with relapsed MM compared to those with refractory disease, but this difference was not statistically significant (P 0.38).

Seasonal effect on airborne pyrene, urinary 1-hydroxypyrene, and benzo(a)pyrene diol epoxide-hemoglobin adducts in the general population.

Exposure to airborne polycyclic aromatic hydrocarbons (PAHs) in 65 employees (40 sampled both in summer and winter, 15 sampled in summer only, and 10 sampled in winter only) with no occupational exposure to PAHs was assessed by measuring: personal exposure to pyrene, urinary excretion of 1-hydroxypyrene (1-OHP), and benzo(a)pyrene diol epoxide adducts to hemoglobin (BPDE-Hb). Overall, office employees were exposed to significantly higher levels of pyrene in winter (4.54 +/- 2.35 ng/m3, mean +/- SD) than in summer (1.67 +/- 1.92 ng/m3, mean +/- SD; P < 0.001), but no such seasonal variability was observed in 1-OHP excretion. Tobacco smoking was the major determinant of 1-OHP excretion. BPDE-Hb adducts were measured by gas chromatography-mass spectrometry as benzo(a)pyrene tetrols (BPT) released from adducted hemoglobin. In the 65 employees analyzed, mean BPT levels +/- SD were higher in winter (0.14 +/- 0.38 fmol/mg Hb) than summer (0.031 +/- 0.022 fmol/mg Hb). This difference was not statistically significant, probably because of the small proportion of subjects with detectable adducts (11% in summer and 16% in winter). BPDE-Hb adducts were not significantly associated with sex, age, diet, smoking habits, or with pyrene levels and 1-OHP excretion. This is the first report providing reference BPDE-Hb adduct values for the general population not occupationally exposed to environmental PAHs and shows a tendency to seasonal variability, with higher BPT levels in winter when environmental PAHs are also high.

Effects of different schedules of oxaliplatin treatment on the peripheral nervous system of the rat.

The aim of this study was to determine the influence of oxaliplatin scheduling on the onset of peripheral neurotoxicity and ototoxicity in a rat model. Animals were treated with four different schedules of oxaliplatin using two cumulative doses (36 and 48 mg/kg intraperitoneally (i.p.)). The neuropathological examination evidenced dorsal root ganglia (DRG) nucleolar, nuclear and somatic size reduction with nucleolar segregation in the treated rats. Sensory nerve conduction velocity (SNCV) was reduced after oxaliplatin treatment, while the auditory pathway was unaffected. After treatment, platinum was detected in the kidney, DRG and sciatic nerve. After a 5-week follow-up period, recovery of the pathological changes in the DRG and sciatic nerves occurred, although platinum was still detectable in these tissues. The following conclusions may be drawn: the main targets of oxaliplatin neurotoxicity were the DRG; the shorter the interval between the injections, the higher the severity of peripheral neuropathy and this was also related to the cumulative oxaliplatin dose; the peripheral neurotoxicity tended to be reversible; ototoxicity was absent even with high cumulative doses of oxaliplatin.