Dopamine DRD2 and DRD3 Polymorphisms Involvement in Nicotine Dependence in Patients with Treatment-Resistant Mental Disorders.

Patients affected by mental disorders smoke more than the general population. The reasons behind this habit are genetic, environmental, etc. This study aims to investigate the correlations between some polymorphisms and the smoking habits and nicotine dependence in patients with psychiatric disorders. We recruited 88 patients with treatment-resistant mental disorders, including 35 with major depressive disorder, 43 with bipolar spectrum disorder, and 10 with schizophrenia spectrum disorder. We carried out a clinical and psychometric assessment on current smoking habits, years of smoking, number of daily cigarettes, and level of nicotine addiction. The patients performed a peripheral blood sample for DNA analyses of different polymorphisms. We searched for correlations between the measures of nicotine addiction and analysed genotypes. The expression of the T allele of the DRD2 rs1800497 and DRD3 rs6280 polymorphisms significantly correlated with a lower level of nicotine dependence and lower use of cigarettes. We did not find significant correlations between nicotine dependence and OPRM1 rs1799971, COMT rs4680 and rs4633 polymorphisms, CYP2A6 rs1801272 and rs28399433, or 5-HTTLPR genotype. Concluding, DRD2 rs1800497 and DRD3 rs6280 polymorphisms are involved in nicotine dependence and cigarette smoking habits in patients with treatment-resistant mental disorders.

Pharmacogenomics-Guided Pharmacotherapy in Patients with Major Depressive Disorder or Bipolar Disorder Affected by Treatment-Resistant Depressive Episodes: A Long-Term Follow-Up Study.

Treatment-resistant depression (TRD) reduces affected patients' quality of life and leads to important social health care costs. Pharmacogenomics-guided treatment (PGT) may be effective in the cure of TRD. The main aim of this study was to evaluate the clinical changes after PGT in patients with TRD (two or more recent failed psychopharmacological trials) affected by bipolar disorder (BD) or major depressive disorder (MDD) compared to a control group with treatment as usual (TAU). We based the PGT on assessing different gene polymorphisms involved in the pharmacodynamics and pharmacokinetics of drugs. We analyzed, with a repeated-measure ANOVA, the changes between the baseline and a 6 month follow-up of the efficacy index assessed through the Clinical Global Impression (CGI) scale, and depressive symptoms through the Hamilton Depression Rating Scale (HDRS). The PGT sample included 53 patients (26 BD and 27 MDD), and the TAU group included 52 patients (31 BD and 21 MDD). We found a significant within-subject effect of treatment time on symptoms and efficacy index for the whole sample, with significant improvements in the efficacy index (F = 8.544; partial η² = 0.077, p < 0.004) and clinical global impression of severity of illness (F = 6.818; partial η² = 0.062, p < 0.01) in the PGT vs. the TAU group. We also found a significantly better follow-up response (χ² = 5.479; p = 0.019) and remission (χ² = 10.351; p = 0.001) rates in the PGT vs. the TAU group. PGT may be an important option for the long-term treatment of patients with TRD affected by mood disorders, providing information that can better define drug treatment strategies and increase therapeutic improvement.

Individualized Drugs' Selection by Evaluation of Drug Properties, Pharmacogenomics and Clinical Parameters: Performance of a Bioinformatic Tool Compared to a Clinically Established Counselling Process.

PURPOSE: Inefficacy and safety concerns are main medications' problems, especially in the case of poly-therapies, when drug-drug interactions may alter the expected drug disposition. Ongoing efforts are aimed to establish drug selection processes aimed to preemptive evaluation of a plethora of factors affecting patient's specific drug response, including pharmacogenomic markers, in order to minimize prescription of improper medications. In previous years, we established at the University Hospital Sant'Andrea of Rome, Italy, a Precision Medicine Service based on a multi-disciplinary experts' team. The team is in charge to produce a drug therapy counselling report, including pharmacogenomic, pharmacokinetic and pharmacodynamic considerations. In this study, we aimed to evaluate the performance of this established "manual" process of therapy selection with a novel bioinformatic tool, the Drug-PIN system. PATIENTS AND METHODS: A total of 200 patients diagnosed with Major Depressive Disorders or a depressive episode in Bipolar Disorder, with at least three previous failed treatments, who underwent pharmacogenomic profiling and therapy counselling in the Sant'Andrea Hospital from 2017 to 2020. The baseline poly-therapy of these patients was re-evaluated and optimized by Drug-PIN. Results of the Drug-PIN poly-therapy evaluation/optimization were compared with the results of the original poly-therapy evaluation/optimization by therapy counselling. To compare the results between the two processes, the risk associated with each poly-therapy was classified as low, moderate, or high. RESULTS: The number of baseline poly-therapies classified in low-, moderate- or high-risk did not change significantly between manual system or Drug-PIN system. As the counselling process, also the Drug-PIN system produces a significant decrease in the predicted treatment-associated risk. CONCLUSION: Drug-PIN substantially replicates the output of the counselling process, allowing a substantial reduction in the time needed for therapy evaluation. Availability of an effective bioinformatic tool for proper drug selection is expected to exponentially increase the actuation of targeted therapy strategies.

PON1 polymorphisms can predict generalized anxiety and depressed mood in patients with multiple chemical sensitivity.

Background: Multiple chemical sensitivity (MCS) is a chronic condition with somatic, cognitive and affective symptoms that follow contact with chemical agents at usually non toxic concentrations. We aimed to assess the role of genetic polymorphisms involved in oxidative stress on anxiety and depression in MCS. Materials & methods: Our study investigated the CAT rs1001179, MPO rs2333227, PON1 rs662 and PON1 rs705379 polymorphisms in MCS. Results: The AG genotype of the PON1 rs662 and the TT and CT genotypes of the PON1 rs705379 were involved in anxiety and depression. Discussion: These results are in line with existing evidence of PON1 involvement in MCS and suggest a further role of this gene in the exhibition of anxiety and depression in this disease.

Drug-Drug Interactions and Pharmacogenomic Evaluation in Colorectal Cancer Patients: The New Drug-PIN® System Comprehensive Approach.

Drug-drug interactions (DDIs) can affect both treatment efficacy and toxicity. We used Drug-PIN® (Personalized Interactions Network) software in colorectal cancer (CRC) patients to evaluate drug-drug-gene interactions (DDGIs), defined as the combination of DDIs and individual genetic polymorphisms. Inclusion criteria were: (i) stage II-IV CRC; (ii) ECOG PS (Performance status sec. Eastern coperative oncology group) ≤2; (iii) ≥5 concomitant drugs; and (iv) adequate renal, hepatic, and bone marrow function. The Drug-PIN® system analyzes interactions between active and/or pro-drug forms by integrating biochemical, demographic, and genomic data from 110 SNPs. We selected DDI, DrugPin1, and DrugPin2 scores, resulting from concomitant medication interactions, concomitant medications, and SNP profiles, and DrugPin1 added to chemotherapy drugs, respectively. Thirty-four patients, taking a median of seven concomitant medications, were included. The median DrugPin1 and DrugPin2 scores were 42.6 and 77.7, respectively. In 13 patients, the DrugPin2 score was two-fold higher than the DrugPin1 score, with 7 (54%) of these patients experiencing severe toxicity that required hospitalization. On chi-squared testing for any toxicity, a doubled DrugPin2 score (p = 0.001) was significantly related to G3-G4 toxicity. Drug-PIN® software may prevent severe adverse events, decrease hospitalizations, and improve survival in cancer patients.

Increased kynurenine-to-tryptophan ratio in the serum of patients infected with SARS-CoV2: An observational cohort study.

Immune dysregulation is a hallmark of patients infected by SARS-CoV2 and the balance between immune reactivity and tolerance is a key determinant of all stages of infection, including the excessive inflammatory state causing the acute respiratory distress syndrome. The kynurenine pathway (KP) of tryptophan (Trp) metabolism is activated by pro-inflammatory cytokines and drives mechanisms of immune tolerance. We examined the state of activation of the KP by measuring the Kyn:Trp ratio in the serum of healthy subjects (n = 239), and SARS-CoV2-negative (n = 305) and -positive patients (n = 89). Patients were recruited at the Emergency Room of St. Andrea Hospital (Rome, Italy). Kyn and Trp serum levels were assessed by HPLC/MS-MS. Compared to healthy controls, both SARS-CoV2-negative and -positive patients showed an increase in the Kyn:Trp ratio. The increase was larger in SARS-CoV2-positive patients, with a significant difference between SARS-CoV2-positive and -negative patients. In addition, the increase was more prominent in males, and positively correlated with age and severity of SARS-CoV2 infection, categorized as follows: 1 = no need for intensive care unit (ICU); 2 ≤ 3 weeks spent in ICU; 3 ≥ 3 weeks spent in ICU; and 4 = death. The highest Kyn:Trp values were found in SARS-CoV2-positive patients with severe lymphopenia. These findings suggest that the Kyn:Trp ratio reflects the level of inflammation associated with SARS-CoV2 infection, and, therefore, might represent a valuable biomarker for therapeutic intervention.

Multiple Chemical Sensitivity Syndrome: A Principal Component Analysis of Symptoms.

Multiple Chemical Sensitivity (MCS) is a chronic and/or recurrent condition with somatic, cognitive, and affective symptoms following a contact with chemical agents whose concentrations do not correlate with toxicity in the general population. Its prevalence is not well defined; it mainly affects women between 40 and 50 years, without variations in ethnicity, education and economic status. We aimed to assess the core symptoms of this illness in a sample of Italian patients. Two physicians investigated different symptoms with a checklist compilation in 129 patients with MCS (117 women). We conducted a categorical Principal Component Analysis (CATPCA) with Varimax rotation on the checklist dataset. A typical triad was documented: hyperosmia, asthenia, and dyspnoea were the most common symptoms. Patients also frequently showed cough and headache. The CATPCA showed seven main factors: 1, neurocognitive symptoms; 2, physical (objective) symptoms; 3, gastrointestinal symptoms; 4, dermatological symptoms; 5, anxiety-depressive symptoms; 6, respiratory symptoms; 7, hyperosmia and asthenia. Patients showed higher mean prevalence of factors 7 (89.9%), 6 (71.7%), and 1 (62.13%). In conclusion, MCS patients frequently manifest hyperosmia, asthenia, and dyspnoea, which are often concomitant with other respiratory and neurocognitive symptoms. Considering the clinical association that is often made with anxiety, more studies are necessary on the psychosomatic aspects of this syndrome. Further analytical epidemiological studies are needed to support the formulation of aetiological hypotheses of MCS.

Persistent Post-Traumatic Headache and Migraine: Pre-Clinical Comparisons.

Background: Oftentimes, persistent post traumatic headache (PPTH) and migraine are phenotypically similar and the only clinical feature that differentiate them is the presence of a mild or moderate traumatic brain injury (mTBI). The aim of this study is to describe the differences in brain area and in biochemical cascade after concussion and to define the efficacy and safety of treatments in use. Methods: Sources were chosen in according to the International Classification of Headache Disorder (ICHD) criteria. Results: The articles demonstrated a significant difference between PPTH and migraine regarding static functional connectivity (sFC) and dynamic functional connectivity (dFC) in brain structure that could be used for exploring the pathophysiological mechanisms in PPTH. Many studies described a cascade of neuro-metabolic changes that occur after traumatic brain injury. These variations are associated to the mechanism occurring when developing a PPTH. Conclusions: The state of art of this important topic show how although the mechanisms underlying the development of the two different diseases are different, the treatment of common migraine is efficacious in patients that have developed a post traumatic form.

Optimising migraine treatment: from drug-drug interactions to personalized medicine.

Migraine is the most disabling and expensive chronic disorders, the etiology of which is still not fully known. The neuronal systems, (glutammatergic, dopaminergic, serotoninergic and GABA-ergic) whose functionality is partly attributable to genetically determined factors, has been suggested to play an important role. The treatment of acute attacks and the prophylactic management of chronic forms include the use of different category of drugs, and it is demonstrated that not each subject has the same clinical answer to them. The reason of this is to be searched in different functional capacity and quantity of phase I enzymes (such as different isoforms of CYP P450), phase II enzymes (such as UDP-glucuronosyltransferases), receptors (such as OPRM1 for opioids) and transporters (such as ABCB1) involved in the metabolic destiny of each drug, all of these dictated by DNA and RNA variations. The general picture is further exacerbated by the need for polytherapies, often also to treat comorbidities, which may interfere with the pharmacological action of anti-migraine drugs. Personalized medicine has the objective of setting the optimal therapies in the light of the functional biochemical asset and of the comorbidities of the individual patient, in order to obtain the best clinical response. Novel therapeutic perspectives in migraine includes biotechnological drugs directed against molecules (such as CGRP and its receptor) that cause vasodilatation at the peripheral level of the meningeal blood vessels and reflex stimulation of the parasympathetic system. Drug-drug interactions and the possible competitive metabolic destiny should be studied by the application of pharmacogenomics in large scale. Drug-drug interactions and their possible competitive metabolic destiny should be studied by the application of pharmacogenomics in large scale.

Changing the Approach to Anticoagulant Therapy in Older Patients with Multimorbidity Using a Precision Medicine Approach.

The ageing of the world population has resulted in an increase in the number of older patients with multimorbid conditions receiving multiple therapies. This emerging clinical scenario poses new challenges, which are mostly related to the increased incidence of adverse effects. This translates into poor clinical care, reduced cost-effectiveness of drug therapies, and social isolation of multimorbid patients due to reduced autonomy. A strategy to address these emerging challenges could involve the personalization of therapies based on the clinical, molecular, and genetic characterization of multimorbid patients. Anticoagulation therapy is a feasible model to implement personalized medicine since it generally involves older multimorbid patients receiving multiple drugs. In this study, in patients with atrial fibrillation, the use of the new generation of anticoagulation therapy, i.e., direct oral anti-coagulants (DOACs), is based on a preliminary assessment of the molecular targets of DOACS and any possible drug⁻drug interactions. Then, the genetic polymorphism of enzymes metabolizing DOACs is studied. After DOAC prescription, its circulating levels are measured. Clinical data are being collected to assess whether this personalized approach improves the safety and efficacy profiles of anticoagulation therapy using DOACs, thereby reducing the costs of healthcare for ageing multimorbid patients.

CT-guided fine-needle ago-biopsy of pulmonary nodules: predictive factors for diagnosis and pneumothorax occurrence.

OBJECTIVE: To evaluate variables that could predict diagnosis during CT-guided fine-needle aspiration. METHODS: Data from 249 patients who underwent FNAB from January 2010 to December 2012 were analyzed in a retrospective observational study. RESULTS: Mean age was 66.7 ± 11.5 years, male/female ratio 158/91 (63 vs. 37 %). The nodules were in right lung in 123 patients (49 %), in left lung in 126 patients (51 %), the upper, lower and middle lobe localizations were, respectively in 122 (49 %), 100 (40 %) and 17 (6 %) patients. Mean nodule-chest wall distance was 63.89 ± 21.38 mm. The tumor location, the needle diameter, the presence of necrosis or cavitation, the node-chest wall distance and the number of passages were not related to the diagnostic outcome (p = NS). The nodule diameter was predictive of diagnosis. Odds ratio for a 10-30 mm tumor was 2.51 (95 % OR: 1.24-5.08, p value = 0.011), the odds ratio for a 30-50 mm tumor was 2.39 (95 % OR: 1.22-4.69, p value = 0.011), and the odds ratio for a tumor larger than 50 mm was 4.44 (95 % OR: 1.89-10.44, p value = 0.001). Post-procedure pneumothorax occurred in 62 cases (25 %). The determinant factors for pneumothorax occurrence were emphysema, odds ratio 6.87 (95 % CI 1.07-44.10, p value = 0.04), and the number of pleural passages, odds ratio of 5.47 (95 % OR: 1.92-15.58), 7.44 (95 % OR: 2.58-21.5), 6.13 (95 % OR: 2.07-18.11) p value = 0.001 for one, two, three or more of three passages, respectively. CONCLUSIONS: In our experience, nodule size is the most important diagnostic factor during fine-needle aspiration, while the number of passages and the presence of emphysema constitute risk factors for pneumothorax occurrence.

Long-term results after resection of bronchial carcinoid tumour: evaluation of survival and prognostic factors.

OBJECTIVES: We retrospectively analysed morbidity, mortality and oncological results of patients who had undergone surgery for bronchial carcinoid tumours. METHODS: Between 2002 and 2012, 65 patients with bronchial carcinoids underwent lobectomy (n = 34), sublobar resection (segmentectomy/wedge) (n = 18), sleeve lobectomy (n = 5) (reconstruction of the pulmonary artery was associated in 1 case), sleeve resection of the main bronchus (n = 4) or pneumonectomy (n = 4) (reconstruction of the carina was associated in 1 case). RESULTS: Resection was radical with histologically negative margins in all patients (R0). Histology showed typical carcinoid (TC) in 55 (84.6%) patients and atypical carcinoid (AC) in 10 (15.4%) patients. Final pathological stages were Stage I in 42 (64.6%) patients, Stage II in 18 (27.7%) and Stage III in 5 (7.7%). No postoperative mortality was observed. The postoperative morbidity rate was 15.4% (no bronchial and/or vascular reconstructive-related complications occurred). The median follow-up was 58 (range 2-121) months. The overall recurrence rate was 12.3% (n = 8). The survival rate at 5 years was 100% for TC and 87% for AC. Disease-free survival rates at 3 and 5 years were 95 and 93% for TC and 78 and 44% for AC, respectively (P = 0.004). Pathological nodal involvement (pN1-N2) did not affect overall survival or recurrence. CONCLUSIONS: The surgical treatment of bronchial carcinoids provides high long-term survival rates. Low postoperative morbidity and mortality can be expected even after bronchial reconstruction. The AC appears to be the main factor that determines the risk of recurrence. Bronchial reconstructive lung sparing operations are not related to an increased recurrence rate.

Bilateral single-port sympathectomy: long-term results and quality of life.

OBJECT: Video-assisted thoracoscopic sympathectomy is a safe, effective, and minimally invasive procedure for primary hyperhidrosis. This study aims to evaluate long-term results and patients' quality of life and investigate potential variables responsible for compensatory sweating after one-stage bilateral single-port thoracoscopic sympathectomy. METHODS: Between 2005 and 2011, 260 consecutive bilateral thoracoscopic sympathectomies were performed in 130 patients for primary palmar and axillary hyperidrosis through one-port access. Residual pain, postoperative complications, recurrence of symptoms, heart rate adjustment, and quality of life were analyzed. Multivariate analysis was performed. RESULTS: No operative mortality and conversion to open surgery were recorded. Mean operative time was 38 ± 5 minutes. Mean hospital stay was 1.1 ± 0.6 days. Eight patients (6%) had unilateral pneumothorax. Twenty-five cases (19%) were complicated by compensatory sweating. Winter and fall were identified as protective factors for compensatory sweating occurrence. Decreased heart rate was observed 1 year after surgery and permanently over the time. No recurrence during the follow-up period (31.5 months) was observed and 90% of patients showed improved quality of life. CONCLUSIONS: One-stage bilateral miniuniportal thoracoscopic sympathectomy is a valid and safe treatment for primary hyperhidrosis, achieving definitive and esthetic results, with excellent patients' satisfaction. Compensatory sweating may potentially occur in a season-dependent manner.