New treatment strategies for HIV-positive cancer patients undergoing anticancer medical treatment: update of the literature.

The introduction of highly active antiretroviral therapy (ART) has deeply modified the outcome of HIV patients by improving their overall survival and ameliorating their quality of life (QoL). The prolongation of these patients' survival has led to an increased risk of highly diffused non-infectious diseases, e.g., cardiovascular diseases, endocrine disease, neurological diseases, and cancer. The management of antiretroviral therapy and anticancer agents (AC) can be challenging, due to the possible drug-drug interactions (DDI) between AC and ART. For this reason, a multidisciplinary approach is always preferred as demonstrated by the GICAT (Italian Cooperation Group on AIDS and Tumors). This review aims to analyze the current scientific data regarding the possible effects of ART on the management of HIV-positive cancer patients and to evaluate the possible DDIs that must be taken into consideration when co-administrating ART and AC. A collaboration between all the involved professional figures, particularly infectious disease specialists and oncologists, represents the key to the correct managing of these patients in order to guarantee the best oncological outcome possible.

Assessment of pharmacogenomic SLCO1B1 assay for prediction of neuromuscular pain in type 2 diabetes mellitus and cardiovascular patients: preliminary results.

OBJECTIVE: At present, several strategies for preventing neuromuscular pain in Type 2 Diabetes Mellitus (T2DM) have been investigated. Recently, findings on genetic variants associated with adverse events to statin-based therapy have been reported. The study aimed at measuring whether Pharmacogenomics (PGx) profile can affect neuromuscular pain in patients carrying T2DM and cardiovascular diseases. An extensive panel of 5 polymorphisms on 4 candidate genes, previously validated as significant markers related to Sulphonylureas and Glitinides (SU-G) plus Simvastatin neuromuscular toxicity, is herein analyzed and discussed. PATIENTS AND METHODS: We genotyped 76 T2DM patients carrying cardiovascular dyscrasia undergone anti-diabetic and anti-cholesterolemic polypharmacy. 35 subjects out of the total received concurrent SU-G and Statin-based therapy. Candidate variants consisted of drug transporters, such as Solute Carrier Organic 1B1 (SLCO1B1) Val174Ala ATP-binding cassette subfamily B member (ABCB1), subfamily C member 8 (ABCC8), and drug biotransformers of Cytochrome P450 Family (CYP) including CYP2C9*2 CYP2C9*3 CYP2C8*3, and CYP3A4*22. Moreover, we also focused on an early outline evaluation of the genotyping costs and benefits. RESULTS: 6 out of 35 patients treated with SU-G plus statins (17.1% experienced adverse neuropathy events). Pharmacogenomics analysis showed a lack of any correlation between candidate gene polymorphisms and toxicity, except for the SLCO1B1 T521C allele; 14.3% of patients had a high risk for grade >2 neuromuscular pain (Odds Ratio [OR] 2.61.95% CI 0.90-7.61, p=0.03). CONCLUSIONS: The clinical polymorphism effectiveness outlined therein will be assured by diagnostic improvements suitable for driving treatment decisions. In light of our experimental results and literature data, the analysis of the SLCO1B1 T521C variant will allow clinicians to take advantage from a better treatment planned for their patients in order to minimize neuromuscular pain and maximize benefits.

Features of microvessel density (MVD) and angiogenesis inhibitors in therapeutic approach of hepatocellular carcinoma (HCC).

OBJECTIVE: The curative hepatocellular carcinoma (HCC) therapy was traditionally based on surgical or loco-regional ablation approach. However, HCC is a solid tumor characterized by a highest level of vascularization; therefore, angiogenesis inhibitor could play a pivotal role in the pharmacological therapeutic approach. Despite the low number of approved drugs, a wide range of multi-kinase and MET inhibitor is currently being evaluated in phase II and III study. In this review, we described all the drugs that have shown efficacy in recently and ongoing trials. Moreover, the immunotherapy represents a recent challenge in the HCC treatment. The strategy based on the production of multi-epitope, multi-HLA peptide vaccine naturally processed and presented on primary tumor tissues of HCC patients. A further upgrade of cancer vaccine could be represented by the combination of metronomic chemotherapy and checkpoint inhibitors.

Pharmacogenomics as a tool to prevent drug-related hospitalization of elderly cardiology-oncology patients receiving chemotherapeutic agents and multiple symptomatic treatments: a pilot study planned for the Italian health system.

OBJECTIVE: Current precision medicine approaches offer powerful tools to optimize medication regimens; however, the potential impact of these tools in cancer patients with multiple drug treatments has not fully appreciated yet. Here we describe a planning project scheduled to start in the next six months. PATIENTS AND METHODS: The overall endpoint of this project is to explore the potential association between the presence of individual genetic profile and severe toxicity rates in so-called "frail" cancer patients, using a nested case-control study design. The pilot study includes the detection of the individual pharmacogenetic profile of 150 (cases), prospect enrolled cancer "frail" patients, and 150 (control) retrospectively paired enrolled individuals. Methods for addressing the primary endpoint include: (a) Evaluation of cost-effectiveness analysis by recording QALY criteria; (b) Data recording by a brief self-administered questionnaire used to evaluate the adherence of a patient's tests and the impact of this genotyping on the patient's adverse drug reactions (ADR); (c) A sample size of paired (for age, gender, education, social status, geriatric syndromes, number of medications and comorbidities) 150 (cases) and 150 (controls); (d) Genotyping method choice by current widely diffuse platforms. RESULTS: The investigators believe that genotype screening and the management of the overall cost of health care personalized therapy has the potential to reduce the health care costs of the Italian national health system (SSN). CONCLUSIONS: Finally, the innovative issue of this project is to advocate the creation of a new model of the co-operative team (Physicians, pharmacist, geneticist and lab manager) that join for planning the most appropriated personalized therapy for their patient.

High incidence of MTHFR, CBS, and MTRR polymorphisms in vitiligo patients. Preliminary report in a retrospective study.

OBJECTIVE: Vitiligo is a multifactorial polygenic disorder with a complex pathogenesis. It is related to both genetic and no genetic factors. The role of genetics is currently studied with several analytical approaches, such as genetic linkage, candidate gene association studies, genome-wide association studies (GWAS), deep DNA re-sequencing and gene expression studies. To date, there are no genetic traits directly related to vitiligo pathogenesis. PATIENTS AND METHODS: 43 cases of vitiligo patients and 30 healthy donors recruited as control, were screened by assaying the biochemical molecules involved in the self-cells cytotoxicity (haptoglobin and homocysteine) and candidate genes involved in the regulatory process of the re-methylation cycles and transsulfuration. Candidate genes and their polymorphisms screened are methylene-tetrahydrofolate-reductase (MTHFR) C677T and A1298C; cystathionine-beta-synthase enzyme (CBS) I278T and Ins68bp; and methionine-synthase-reductase (MTRR) A66G. RESULTS: A peculiar genetic profile in vitiligo patients are defined: 11.6% of vitiligo patients shown polymorphic variant MTHFR 677TT vs. 3.3% of healthy donor MTHFR 677CC profile (p=0.0017); 14.0% of vitiligo patients shown CBS polymorphic variant 278TT vs. 3.3% of healthy donor 278II profile (p=0.0012); and 11.6% of vitiligo patients shown MTRR 66GG vs. 3.3% of healthy donor MTRR 677AA profile (p>0.0001). CONCLUSIONS: This is the first study reporting the correlation between the polymorphic status of MTHFR C677T, CBS I278T, and MTRR A66G and vitiligo. The genetic screening of these polymorphisms could be useful for early detection of the inheritance risk factor in a subject carrying relatives with vitiligo. Although these data could suggest a kind of dysregulation, genetically based, of thiols production mechanisms. Based on these results, we have not been able to get hypothesis about the putative pathogenesis of vitiligo, and the precise cause remains unclear.

Correlation between individual inflammation genetic profile and platelet rich plasma efficacy in hair follicle regeneration: a pilot study reveals prognostic value of IL-1a polymorphism.

OBJECTIVE: Hair loss generates severe psychosocial implications. To date, exploring the prognostic factors of possible clinical benefit of autologous blood concentrate platelet rich plasma (PRP) was failed. The aim of our pilot study was to explore the correlation between the individual inflammation genetic profile and PRP efficacy in the treatment of hair follicle regeneration. PATIENTS AND METHODS: 41 volunteers (25 men, 16 women) took part in this retrospective study. All the patients were scheduled for 4 sessions of PRP application with intervals of 40-60 days. All the patients were checked up at 6 weekly intervals for 6 months and, then, at the end of the first year. A panel of 5 polymorphisms on 4 genes (IL-1a, IL-1b, IL-6, and IL-10) implicated in the individual genetic inflammation profile were performed. RESULTS: A significant increase rate in hair density was noticed after the third month of treatment in 32/41 (78%) of the subjects. We found an interesting association between the pro-inflammatory cytokine IL-1α polymorphism C>A (rs17561) and responders to PRP treatment. The cases carrying C/C genotype (coding for Ser114) were 21 (66%) in responders and only 2 (22%) in non-responders (p<0.05). In addition, about IL-1a, the frequency of G/G genotype in responder patients was over two times lower in responder (31%) than in non-responder patients (78%). CONCLUSIONS: Our pilot study demonstrated a correlation between the individual genetic inflammatory profile and the efficacy of the PRP treatment in males. On the contrary, in females, it showed a negative correlation. IL-1a could be used as a prognostic value for PRP efficacy. Also, these results provide preliminary evidence that may encourage the design of controlled clinical trials to properly test this modus operandi on a large number of subjects.

Multimodal approach of advanced gastric cancer: based therapeutic algorithm.

Gastric cancer (GC) is the third leading cause of cancer death in both sexes worldwide, with the highest estimated mortality rates in Eastern Asia and the lowest in Northern America. However, the availability of modern treatment has improved the survival and the prognosis is often poor due to biological characteristics of the disease. In oncology, we are living in the "Era" of target treatment and, to know biological aspects, prognostic factors and predictive response informations to therapy in GC is mandatory to apply the best strategy of treatment.The purpose of this review, according to the recently published English literature, is to summarize existing data on prognostic aspects and predictive factors to response to therapy in GC and to analyze also others therapeutic approaches (surgery and radiotherapy) in locally, locally advanced and advanced GC. Moreover, the multidisciplinary approach (chemotherapy, surgery and radiotherapy) can improve the prognosis of GC. The purpose of this review, according to the recently published English literature, is to summarize existing data on prognostic aspects and predictive factors to response to therapy in GC and to analyze also others therapeutic approaches (surgery and radiotherapy) in locally, locally advanced and advanced GC. Moreover, the multidisciplinary approach (chemotherapy, surgery and radiotherapy) can improve the prognosis of GC.

Antioxidant diet and genotyping as tools for the prevention of liver disease.

It is well-known that 75% of risk factors of chronic liver disease (CLD) are related to nutrition. These circumstances potentially progress towards liver steatosis, fibrosis and hepatocellular carcinoma (HCC). It still represents an enormous problem for the economy of public health worldwide. Furthermore, validated prevention programs could be the solution. Recent knowledge in understanding molecular determinants of energy liver metabolism and new genetic markers offers new insights into the pathogenesis of CLD and HCC. The main rationale of the present issue is to provide a summary of recent insights into the inherited variants regulating lipid metabolism (steatohepatitis) and acquired mutation for early diagnosis of HCC, specifically focusing on the significance of antioxidant agents and genotyping tests as a cost-effectiveness tool for the prevention of liver disease. Several national healthy programs worldwide promote the daily use of antioxidant nutrients either for the prevention and/or as complementary and alternative medicines (CAM). This review could be advising for the planning of a large-scale clinical trial including a combination strategy of antioxidant agents and genotyping tests in patients with high risk of CLD.

Rational selection of predictive pharmacogenomics test for the Fluoropyrimidine/Oxaliplatin based therapy.

OBJECTIVE: Both Fluoropyrimidine and Oxaliplatin (FluOx) are the most common anticancer drugs used to treat colorectal, ovarian, and gastrointestinal cancers. Nevertheless, the efficacy of FluOx-based therapy is often compromised by the severe risk of neurotoxicity, cardiotoxicity, and gastrointestinal toxicity. Stratification of patients for their individual response to drugs is a promising approach for cancer treatment and cost-effectiveness. Here we evaluate the most recent findings on the most appropriate gene variants related to the toxicity in patients receiving FluOx chemotherapy. MATERIALS AND METHODS: A systematic literature search of the MEDLINE, EMBASE, and Cochrane databases was conducted to identify all clinical studies of any association between DPYD and 5-FU correlated to allelic status of 6 validated polymorphisms in five genes Dihydropyrimidine Dehydrogenase (DPYD), Thymidylate Synthase (TYMS), Glutathione S-Transferase (GSTP1), and DNA-repair genes (ERCC2 and XRCC1). RESULTS: The stratification of the patients into three genotype profiles group, who are most likely responders to FluOx treatments, provide informations about toxicity and/or resistance before starting therapy. Also, early evaluation cost of panel testing proposed is averaged about €100,00 per sample. The evaluation costs of genotyping before starting treatment could be a good cost-effectiveness strategy. CONCLUSIONS: Based on the individual genomic profile, the oncologists will have new possibilities, based on the individual genetic profile, to make treatment decisions for their patients and to redefine scheduling and dosage of FluOx-based therapy.

Clinical presentation and outcome of non-AIDS defining cancers, in HIV-infected patients in the ART-era: the Italian Cooperative Group on AIDS and tumors activity.

The advent of antiretroviral therapy (ART) has markedly extended the survival rates of patients with human immunodeficiency virus (HIV), leading to suppression even though not eradication of HIV. In HIV infected patients, cancer has become a growing problem, representing the first cause of death. A large number of worldwide studies have shown that HIV infection raises the risk of many non-AIDS defining cancers (NADCs), including squamous cell carcinoma of the anus (SCCA), testis cancer, lung cancer, cancer of the colon and rectum (CRC), skin (basal cell skin carcinoma and melanoma), Hodgkin disease (HD) and hepatocellular carcinoma (HCC). Generally in HIV positive patients NADCs are more aggressive and in advanced stage disease than in the general population. In the ART era, however, the outcome of HIV positive patients is more similar as in the general population. Only about lung cancer the outcome seems different between HIV positive and HIV negative patients. The aim of this article is to provide an up-date on NADCs within the activity of the Italian Cooperative Group on AIDS and Tumors (GICAT) to identify clinical prognostic and predicting factors in patients with HIV infection included in the GICAT.

Quantitative PCR detection of t(11;14) bcl-1/JH in mantle cell lymphoma patients: comparison of peripheral blood and bone marrow aspirate samples.

OBJECTIVE: Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma (NHL) featured by participation of the lymph nodes, spleen, blood and bone marrow with a short remission period to standard therapies and a median overall survival of 4-5 years. PATIENTS AND METHODS: In this study, we compare the levels of bcl-1/JH fusion products detected by q-PCR in the concurrent peripheral blood (PB) and bone marrow (BM) aspirate samples from 7 patients with MCL. RESULTS: In patients with moderate to high levels of bcl-1/JH copies, the results of q-PCR analysis of PB and BM aspirate samples correlate well. In patients with high levels of bcl-1/JH copies, instead, PB levels are a good indication of tumor burden. Finally, in patients with low levels of bcl-1/JH copies, the t(11;14) may be detected by identification of neoplastic cells. CONCLUSIONS: Our data suggest that PB can be reliably used in place of BM aspirate both for detection of translocation status during minimal residual disease monitoring and for a possible molecular relapse, especially in those patients who have moderate to high levels of bcl-1/JH copies. If these results will be confirmed on a wider number of MCL patients, future study will be required to address the issue.