Breakthrough Cancer Pain Clinical Features and Differential Opioids Response: A Machine Learning Approach in Patients With Cancer From the IOPS-MS Study.

PURPOSE: A large proportion of patients with cancer suffer from breakthrough cancer pain (BTcP). Several unmet clinical needs concerning BTcP treatment, such as optimal opioid dosages, are being investigated. In this analysis the hypothesis, we explore with an unsupervised learning algorithm whether distinct subtypes of BTcP exist and whether they can provide new insights into clinical practice. METHODS: Partitioning around a k-medoids algorithm on a large data set of patients with BTcP, previously collected by the Italian Oncologic Pain Survey group, was used to identify possible subgroups of BTcP. Resulting clusters were analyzed in terms of BTcP therapy satisfaction, clinical features, and use of basal pain and rapid-onset opioids. Opioid dosages were converted to a unique scale and the BTcP opioids-to-basal pain opioids ratio was calculated for each patient. We used polynomial logistic regression to catch nonlinear relationships between therapy satisfaction and opioid use. RESULTS: Our algorithm identified 12 distinct BTcP clusters. Optimal BTcP opioids-to-basal pain opioids ratios differed across the clusters, ranging from 15% to 50%. The majority of clusters were linked to a peculiar association of certain drugs with therapy satisfaction or dissatisfaction. A free online tool was created for new patients' cluster computation to validate these clusters in future studies and provide handy indications for personalized BTcP therapy. CONCLUSION: This work proposes a classification for BTcP and identifies subgroups of patients with unique efficacy of different pain medications. This work supports the theory that the optimal dose of BTcP opioids depends on the dose of basal opioids and identifies novel values that are possibly useful for future trials. These results will allow us to target BTcP therapy on the basis of patient characteristics and to define a precision medicine strategy also for supportive care.

RNA sequencing reveals PNN and KCNQ1OT1 as predictive biomarkers of clinical outcome in stage III colorectal cancer patients treated with adjuvant chemotherapy.

Five-year overall survival of stage III colorectal cancer (CRC) patients treated with standard adjuvant chemotherapy (ACHT) is highly variable. Genomic biomarkers and/or transcriptomic profiles identified lack of adequate validation. Aim of our study was to identify and validate molecular biomarkers predictive of ACHT response in stage III CRC patients by a transcriptomic approach. From a series of CRC patients who received ACHT, two stage III extreme cohorts (unfavorable vs. favorable prognosis) were selected. RNA-sequencing was performed from fresh frozen explants. Tumors were characterized for somatic mutations. Validation was performed in stage III CRC patients extracted from two GEO datasets. According to disease-free survival (DFS), 108 differentially expressed genes (104/4 up/downregulated in the unfavorable prognosis group) were identified. Among 104 upregulated genes, 42 belonged to olfactory signaling pathways, 62 were classified as pseudogenes (n = 17), uncharacterized noncoding RNA (n = 10), immune response genes (n = 4), microRNA (n = 1), cancer-related genes (n = 14) and cancer-unrelated genes (n = 16). Three out of four down-regulated genes were cancer-related. Mutational status (i.e., RAS, BRAF, PIK3CA) did not differ among the cohorts. In the validation cohort, multivariate analysis showed high PNN and KCNQ1OT1 expression predictive of shorter DFS in ACHT treated patients (p = 0.018 and p = 0.014, respectively); no difference was observed in untreated patients. This is the first study that identifies by a transcriptomic approach and validates PNN and KCNQ1OT1 as molecular biomarkers predictive of chemotherapy response in stage III CRC patients. After a further validation in an independent cohort, PNN and KCNQ1OT1 evaluation could be proposed to prospectively identify stage III CRC patients benefiting from ACHT.

Trabectedin in combination with pegylated liposomal doxorubicin in patients with ovarian tumors.

The majority of patients with ovarian cancer will experience relapse and thus require second-line therapy. While platinum-based therapies are the primary treatments for refractory disease other options are required, particularly for those with partially platinum-sensitive disease as their response rates are lower. Agents that can resensitize relapsed ovarian cancers to platinum, including trabectedin, are therefore of increasing interest. Trabectedin is a multitarget agent that has a complex, novel mechanism of action and has exhibited promising results in platinum-sensitive ovarian cancer when in combination with pegylated liposomal doxorubicin (PLD). The present study conducted retrospective analysis involving 11 cases (median age 60 years; range 45-75 years) of recurrent ovarian tumors and partial platinum sensitivity undergoing treatment with trabectedin + PLD. The cohort consisted of 7 serous carcinomas, 1 endometrial carcinoma, 2 undifferentiated carcinomas, and 1 mucinous carcinoma. Of the 11 patients, 4 exhibited a complete response, 3 achieved stable disease, and 4 had progression of disease. Mean overall survival was 32.42 months and median progression-free survival was 5.9 months. Trabectedin in combination with PLD was well tolerated in terms of gastrointestinal and hematological toxicity; Grade 3 cutaneous toxicity and grade 3 neutropenia were each observed in 18.2% of patients. There were no grade 4 events. Thus, the present study supports the use of trabectedin + PLD in patients with relapsed ovarian cancer and partial platinum sensitivity, with predictable and manageable toxicity.

Factors Influencing the Clinical Presentation of Breakthrough Pain in Cancer Patients.

Background: The aim of this study was to identify potential variables influencing the clinical presentation of breakthrough cancer pain (BTP). Methods: Cancer patients with a diagnosis of BTP were enrolled. Demographic and clinical characteristics, as well as background pain and BTP characteristics were collected. Multivariate analyses were conducted to assess the correlation between BTP characteristics and the variables examined. Results: Data of 4016 patients were analysed. Average daily number of BTP episodes was 2.4, mean intensity was 7.5, and a mean duration was 43.3 min. A short onset BTP was observed in 68.9% of patients. In 30.5% of patients BTP was predictable. There were 86.0% of participants who reported a marked interference of BTP with their daily activities. Furthermore, 86.8% of patients were receiving opioids for the management of BTP. The average time to meaningful pain relief was 16.5 min and 70.9% of patients were satisfied with their BTP medications. Age, head and neck cancer, Karnofsky, background pain intensity, predictable and fast onset BTP were independently associated with the number of BTP episodes. BTP pain intensity was independently associated with background pain intensity, fast onset BTP, and Karnofsky. Neuropathic pain mechanism was independently associated with unpredictable BTP. Variables independently associated with a longer duration of BTP were age, place of visit, cancer diagnosis, disease-oriented therapy, background pain intensity and mechanism, and unpredictable BTP. Age, Karnofsky, background pain intensity, fast onset, and long duration of BTP were independently associated with interference with daily activity. Conclusions: BTP has a variable presentation depending on interdependent relationships among its different characteristics.

The most appropriate therapeutic strategy for acute lower respiratory tract infections: a Delphi-based approach.

Lower respiratory tract infections (LRTIs) cause high morbidity and mortality worldwide. Empiric therapy often base the choice of antibiotic treatment on antibacterial spectrum of the agent rather than on its pharmacological properties or the pathogen resistance profile. Inappropriate prescribing leads to therapeutic failure and antibiotic resistance, with increasing direct and indirect health costs. A consensus on appropriate prescribing in LRTI therapy was appraised by this Delphi exercise, based on a panel of 70 pulmonologists, coordinated by a Scientific Committee of nine experts in respiratory medical care. Full or very high consensus was reached on several issues, including the role of oral cephalosporins in first-line treatments of LRTIs and the appropriateness of cefditoren, with balanced spectrum and high intrinsic activity, in LRTI treatment. Evidence-based medicine approach and a comprehensive process of disease management, from diagnosis to therapy and follow-up, should guide antibiotic prescribing.

Stable disease in a patient with metastatic leiomyosarcoma treated with trabectedin.

Leiomyosarcomas represent the most common variant of uterine sarcomas, and are also considered to be the least chemosensitive. To date, adriamycin and ifosfamide are believed to be the most effective drugs for its treatment, in addition to docetaxel and gemcitabine. Recently, the introduction of trabectedin has provided clinicians with another treatment option, and the drug may have some benefits for patients as it may allow for long-term treatment. We present the case of a patient who previously failed multiple cycles of chemotherapy and who was subsequently treated with 30 cycles of trabectedin as third-line therapy for multiple metastases of uterine leiomyosarcoma. During the treatment period, the dosage and dose interval of trabectedin were optimized because of the appearance of grade 4 hematological and gastrointestinal toxicity. Dose adjustments led to acceptable tolerability. Trabectedin was associated with a very good partial response, especially at the pulmonary and pancreatic levels, and stable disease was achieved at all metastatic sites. The patient is currently continuing treatment with trabectedin and has clinically stable disease after 2 years of therapy. This case report provides further evidence that trabectedin is a valid and well-tolerated therapeutic option that can be used in the long term in uterine leiomyosarcoma.

Breakthrough Cancer Pain: Preliminary Data of The Italian Oncologic Pain Multisetting Multicentric Survey (IOPS-MS).

INTRODUCTION: An ongoing national multicenter survey [Italian Oncologic Pain multiSetting Multicentric Survey (IOPS-MS)] is evaluating the characteristics of breakthrough cancer pain (BTP) in different clinical settings. Preliminary data from the first 1500 cancer patients with BTP enrolled in this study are presented here. METHODS: Thirty-two clinical centers are involved in the survey. A diagnosis of BTP was performed by a standard algorithm. Epidemiological data, Karnofsky index, stage of disease, presence and sites of metastases, ongoing oncologic treatment, and characteristics of background pain and BTP and their treatments were recorded. Background pain and BTP intensity were measured. Patients were also questioned about BTP predictability, BTP onset (≤10 or >10 min), BTP duration, background and BTP medications and their doses, time to meaningful pain relief after BTP medication, and satisfaction with BTP medication. The occurrence of adverse reactions was also assessed, as well as mucosal toxicity. RESULTS: Background pain was well controlled with opioid treatment (numerical rating scale 3.0 ± 1.1). Patients reported 2.5 ± 1.6 BTP episodes/day with a mean intensity of 7.5 ± 1.4 and duration of 43 ± 40 min; 977 patients (65.1%) reported non-predictable BTP, and 1076 patients (71.7%) reported a rapid onset of BTP (≤10 min). Higher patient satisfaction was reported by patients treated with fast onset opioids. CONCLUSIONS: These preliminary data underline that the standard algorithm used is a valid tool for a proper diagnosis of BTP in cancer patients. Moreover, rapid relief of pain is crucial for patients' satisfaction. The final IOPS-MS data are necessary to understand relationships between BTP characteristics and other clinical variables in oncologic patients. FUNDING: Molteni Farmaceutici, Italy.

Urological infections due to multidrug-resistant bacteria: what we need to know?

PURPOSE: Recent epidemiological data have confirmed the increasing problem of antimicrobial resistance not only for hospitalized, healthcare-associated patients, but also for outpatients. In particular, the progressive increase in resistance to broad-spectrum antibiotics, such as third-generation cephalosporins, fluoroquinolones or carbapenems in Enterobacteriaceae, is an alarming situation for all urologists and general practitioners. Here, we aimed to review the epidemiological data of multidrug-resistant bacteria in the urological setting, in order to summarize all diagnostic and therapeutic recommendations to use in everyday clinical practice. METHODS: We collected all recent publications from Medline and Cochrane Library from January 2000 to December 2013. Moreover, data from the abstracts presented at the EAU and AUA Congresses during the last 5 years have also been analyzed. All papers were evaluated by an expert panel on urological infections on behalf of the Italian Urological Association (SIU). RESULTS: Fluoroquinolone and other antibiotic-resistant bacteria prevalence is normally very high in the lower urinary tract infection patients. In particular, multidrug-resistant bacteria prevalence in urological practice contributes to infectious morbidity increasing the financial costs to healthcare system. The expert panel on urological infections on behalf of the Italian Urological Association formulated new diagnostic pathway and therapeutic protocol in patients affected by urological tract infections due to multidrug-resistant bacteria. CONCLUSIONS: The recent emergence of multidrug-resistant pathogens is an alarming public health issue also in urological practice with socioeconomic importance. Our practice should be revised on the basis of these new acquisitions.

Pharmacological aspects of the antibiotics used for urological diagnostic procedures.

Surgical antimicrobial prophylaxis is the use of an antibiotic before, during, or shortly after a urological procedure to prevent postoperative infections such as urinary tract or wound infection. The optimal antimicrobial drug must be microbiologically active against the most frequent potential pathogens and have good pharmacological properties. Correct timing of antimicrobial prophylaxis is the first critical issue in determining treatment efficacy. The antibiotic must be administered before the start of the surgical procedure in order to ensure a high tissue level at the time of microbial contamination. If using an oral antibiotic, this must be administered 1-3 hours before the operation and a parenteral antibiotic should be administered at the induction of anaesthesia. The antibiotics potentially useful for antimicrobial prophylaxis are the beta-lactams, cotrimoxazole, fluoroquinolones, and fosfomycin trometamol. The criteria for choosing the optimal antibiotic include an appropriate antimicrobial spectrum, favourable pharmacokinetic parameters (especially good tissue penetration), and elevated safety or tolerability. The use of cotrimoxazole must be restricted due to increasing chemoresistance. Unfortunately fluoroquinolone-based regimens, once the mainstay of prophylaxis guidelines, are increasingly ineffective due to a constant increase in multidrug-resistant (MDR) Gram-negative bacteria. The same concerns apply with regard to the second and third generation cephalosporins that have problems of resistance and, if administered orally, do not sufficiently penetrate prostatic tissue. An appropriate beta-lactam could be an aminopenicillin combined with a beta-lactamase inhibitor. Fosfomycin trometamol can also be a good potential choice due to its elevated activity against MDR Gram-negative bacteria and its favourable pharmacokinetic parameters, including an elevated penetration into prostatic tissue.

Treatment of extensively drug-resistant Gram-negative infections in critically ill patients: Outcome of a consensus meeting at the 13th Asia-Pacific Congress of Clinical Microbiology and Infection, October 2012.

Infections caused by multidrug-resistant and extensively drug-resistant Gram-negative bacilli are increasingly challenging to manage in hospitals and long term-care facilities worldwide. As the therapeutic options are limited, the International Society of Chemotherapy in collaboration with the Asia-Pacific Society of Clinical Microbiology and Immunology organised a consensus conference as part of the 13th Asia-Pacific Congress of Clinical Microbiology and Infection. A panel of international experts from Europe, the Americas and Asia were convened to discuss the issues of therapeutic options for the management of these difficult-to-treat pathogens.

A survey on infection management practices in Italian ICUs.

INTRODUCTION: An online survey was conducted to characterize current infection management practices in Italian intensive care units (ICUs), including the antibacterial and antifungal drug regimens prescribed for various types of infections. METHODS: During February and March 2011, all 450 ICUs in public hospitals in Italy were invited to take part in an online survey. The questionnaire focused on ICU characteristics, methods used to prevent, diagnose, and treat infections, and antimicrobials prescribing policies. The frequency of each reported practice was calculated as a percentage of the total number of units answering the question. The overall response rate to the questionnaire was 38.8% (175 of the 450 ICUs contacted) with homogeneous distribution across the country and in terms of unit type. RESULTS: Eighty-eight percent of the responding facilities performed periodical surveillance cultures on all patients. In 71% of patients, cultures were also collected on admission. Endotracheal/bronchial aspirates were the most frequently cultured specimens at both time points. Two-thirds of the responding units had never performed screening cultures for methicillin-resistant Staphylococcus aureus. Around 67% of the ICUs reported the use of antimicrobial de-escalation strategies during the treatment phase. In general, the use of empirical antimicrobial drug regimens was appropriate. Although the rationale for the choice was not always clearly documented, the use of a combination therapy was preferred over antibiotic monotherapy. The preferred first-line agents for invasive candidiasis were fluconazole and an echinocandin (64% and 25%, respectively). Two-thirds of the ICUs monitored vancomycin serum levels and administered it by continuous infusion in 86% of cases. For certain antibiotics, reported doses were too low to ensure effective treatment of severe infections in critically ill patients; conversely, inappropriately high doses were administered for certain antifungal drugs. CONCLUSIONS: Although infection control policies and management practices are generally appropriate in Italian ICUs, certain aspects, such as the extensive use of multidrug empirical regimens and the inappropriate antimicrobial dosing, deserve careful management and closer investigation.

Overcoming tumor multidrug resistance using drugs able to evade P-glycoprotein or to exploit its expression.

Multidrug resistance (MDR) is a major obstacle to the effective treatment of cancer. Cellular overproduction of P-glycoprotein (P-gp), which acts as an efflux pump for various anticancer drugs (e.g. anthracyclines, Vinca alkaloids, taxanes, epipodophyllotoxins, and some of the newer antitumor drugs) is one of the more relevant mechanisms underlying MDR. P-gp belongs to the superfamily of ATP-binding cassette transporters and is encoded by the ABCB1 gene. Its overexpression in cancer cells has become a therapeutic target for circumventing MDR. As an alternative to the classical pharmacological strategy of the coadministration of pump inhibitors and cytotoxic substrates of P-gp and to other approaches applied in experimental tumor models (e.g. P-gp-targeting antibodies, ABCB1 gene silencing strategies, and transcriptional modulators) and in the clinical setting (e.g. incapsulation of P-gp substrate anticancer drugs into liposomes or nanoparticles), a more intriguing strategy for circumventing MDR is represented by the development of new anticancer drugs which are not substrates of P-gp (e.g. epothilones, second- and third-generation taxanes and other microtubule modulators, topoisomerase inhibitors). Some of these drugs have already been tested in clinical trials and, in most of cases, show relevant activity in patients previously treated with anticancer agents which are substrates of P-gp. Of these drugs, ixabepilone, an epothilone, was approved in the United States for the treatment of breast cancer patients pretreated with an anthracycline and a taxane. Another innovative approach is the use of molecules whose activity takes advantage of the overexpression of P-gp. The possibility of overcoming MDR using the latter two approaches is reviewed herein.

New insights into meticillin-resistant Staphylococcus aureus (MRSA) pathogenesis, treatment and resistance.

Meticillin-resistant Staphylococcus aureus (MRSA) remains one of the principal multiply resistant bacterial pathogens causing serious healthcare-associated and community-onset infections. This paper reviews recent studies that have elucidated the virulence strategies employed by MRSA, key clinical trials of agents used to treat serious MRSA infections, and accumulating data regarding the implications of antibacterial resistance in MRSA for clinical success during therapy. Recent pre-clinical data support a species-specific role for Panton-Valentine leukocidin in the development of acute severe S. aureus infections and have elucidated other virulence mechanisms, including novel modes of internalisation, varying post-invasion strategies (featuring both upregulation and downregulation of virulence factors) and phenotypic switching. Recent double-blind, randomised, phase III/IV clinical trials have demonstrated the efficacy of linezolid and telavancin in hospital-acquired pneumonia (HAP) and complicated skin and skin-structure infections (cSSSIs) caused by MRSA. Tigecycline was non-inferior to imipenem/cilastatin in non-ventilator-associated HAP but was inferior in ventilator-associated pneumonia and has shown a higher rate of death than comparators on meta-analysis. Ceftaroline was clinically and microbiologically non-inferior to vancomycin/aztreonam in the treatment of MRSA cSSSI. Key resistance issues include a rise in vancomycin minimum inhibitory concentrations in MRSA, reports of clonal isolates with linezolid resistance mediated by acquisition of the chloramphenicol/florfenicol resistance gene, and case reports of daptomycin resistance resulting in clinical failure. Novel antimicrobial targets must be identified with some regularity or we will face the risk of untreatable S. aureus infections.

The difficulties of polytherapy: examples from antimicrobial chemotherapy.

Medical therapy in patients with more than one pathology means using more pharmaceuticals, which results in a higher risk of drug interactions which are modifications in the action of one drug when it is administered in the presence of another. The consequences can be diminished therapeutic effect or increased adverse reactions. The pharmacological interactions can be either physico-chemical, pharmacokinetic or pharmacodynamic, on the basis of their mechanisms. Pharmacokinetic interactions are the most important and can emerge during various phases of absorption, distribution, metabolism and drug elimination. The absorption of many antimicrobial agents can be modified through various mechanisms. Some drugs (for example the anticholinergics and opiates) or food can slow gastric motility, slowing the absorption and reducing maximum concentrations of the antibiotic. Variations in gastric pH can alter the solubility or chemical stability of molecules such as the beta-lactams, the natural macrolides and some azoles. The bioavailability of these drugs can be reduced due to molecules used to raise gastric pH. Antibiotics such as tetracycline or the fluoroquinolones have reduced bioavailability due to chelation from bi- and trivalent cations. The primary number of clinically relevant pharmacological interactions is correlated with modifications of biotransformation of drugs due to Cytochrome P450 (CYP) hepatic enzymes which are involved in oxidative drug processes, including lipophilic antimicrobial drugs such as the macrolides, the fluoroquinolones (to be considered amphoteric) and the antifungal azole derivatives. CYP3A is probably one of the most important isoenzymes since it contributes to at least the partial transformation of 60% of drugs that undergo oxidation: erythromycin and clarithromycin are CYP3A4 substrates. Many isoenzymes can also be inhibited by antimicrobial drugs, including both antibacterials and antifungals (for example the macrolides, fluoroquinolones, metronidazole, sulfonamides and azole derivatives) with a consequent reduction in the metabolism of other drugs, thus increasing their blood concentrations and possible correlated adverse reactions. On the other hand, rifampicin, rifabutin and some anticonvulsants can induce enzymatic metabolism, causing reduced blood concentrations and lower AUC of itraconazole and voriconazole with possibly lower therapeutic efficacy. This brief review of pharmacological interactions among certain chemotherapeutic agents leads us to believe that this problem is destined to occur with more frequency in daily clinical practice. What is needed is basic knowledge of drug interactions on the part of all physicians who work in the fields of clinical therapeutics with the goal of reducing the high number of medical errors.

Thymidylate synthase expression and genotype have no major impact on the clinical outcome of colorectal cancer patients treated with 5-fluorouracil.

BACKGROUND AND OBJECTIVES: Thymidylate synthase (TS) expression levels appear to be related to response to 5-fluorouracil-(5-FU)-based chemotherapy in colorectal cancer (CRC) patients. Three polymorphisms have been proposed as modulators of TS expression: a tandemly repeated sequence (2R/3R) in the 5' UTR, a SNP (G>C) within the 3R allele and a 6bp deletion in the 3' UTR. To evaluate the influence of TS expression and polymorphisms on clinical outcome of 5-FU-treated patients we performed a comprehensive genetic analysis on 63 CRC patients. METHODS: TS expression levels were analyzed in normal and tumor tissues. TS coding sequence and UTR polymorphisms were investigated on DNA from normal tissue. LOH analysis was performed to determine tumor genotype. RESULTS: A difference in disease-free survival (DFS), although not statistically significant, was observed between high and low mRNA expression levels: patients with low levels showed longer DFS. The 2R2R genotype showed significantly lower expression than the 3R3R and 2R3R genotypes in normal tissue. No other TS polymorphism was associated with mRNA expression or clinical outcome. CONCLUSIONS: The results obtained in this pilot study indicate that the number of 5' UTR repeats is the major genetic determinant of TS expression. The lack of association with other polymorphisms might be partially explained by the existence of linkage disequilibrium in the TS gene. Our data support the growing evidence that TS control may require multiple mechanisms acting in close coordination with one another and suggest that TS genotyping alone in tumor samples is not sufficient to accurately predict response to 5-FU.

Management of serious meticillin-resistant Staphylococcus aureus infections: what are the limits?

Severe (life-threatening) meticillin-resistant Staphylococcus aureus (MRSA) infection continues to be treated with vancomycin despite accumulating evidence of poor outcome, increasing resistance and unachievable pharmacokinetic/pharmacodynamic (PK/PD) targets. The minimum inhibitory concentration (MIC) susceptibility breakpoint for vancomycin was recently reduced to 2 mg/L. Whilst the great majority of clinical isolates are thus still classified as susceptible, the available clinical evidence argues for a method-dependent breakpoint of 0.5 mg/L (broth dilution) or 1.0 mg/L (Etest), which would classify many strains as resistant, or at best intermediate. However, automated susceptibility testing systems are not currently capable of performing accurately at this low level, and such low breakpoints are unsatisfactory because the poor reproducibility of tests (plus or minus one doubling dilution) results in a critical non-reproducibility around the modal MIC of 1 mg/L described in most published data. Therefore, vancomycin should be used with caution in severe (life-threatening) staphylococcal disease and the MIC should always be reported by method. Daptomycin is generally preferred for bacteraemia/endocarditis and linezolid for pneumonia. Better outcome data for vancomycin, based on achievable PK/PD targets and using robust MIC tests, are urgently required.

Identification of potential pharmacogenomic markers of clinical efficacy of 5-fluorouracil in colorectal cancer.

Although adjuvant chemotherapy has significantly increased overall survival in resected Stage III colorectal cancer, disease recurrence is still high (30-40%). 20-25% of Stage II patients also develop recurrent disease. Thus, high-risk patients may benefit from chemotherapy. As patient response to standard chemotherapy varies, the study of molecular differences in the expression of pharmacologically relevant genes may help clinicians to understand variability and tailor therapy. The expression of 5-fluorouracil (5-FU) pathway genes in tumors from 53 Stages II-III colorectal cancer patients who underwent 5-FU adjuvant chemotherapy was investigated by reverse transcription quantitative real-time polymerase chain reaction. Patients were dichotomized into high- and low-mRNA expression level groups using median values of gene mRNA levels. Then, a threshold analysis to identify a cut-off distinguishing recurrent- or nonrecurrent-disease was used. A high degree of interpatient variation in relative tumor expression of study genes was observed. Multiple gene correlations were found, which suggest possible coregulation mechanisms. No statistically significant relationship between experimental data and baseline clinical/pathological characteristics or clinical outcome was observed using gene expression median values. Threshold analysis indicated significant inverse relationships between deoxyuridine triphosphatase (DUT), ferrodoxin reductase (FDXR) or tumor protein p53 (TP53) and disease-free survival (DFS) in the entire case series and between DUT or NM23-H1 and DFS in Stage III patients: higher gene expression was associated with shorter DFS. This study provides data on relationships between expression of 5-FU pathway genes and clinical outcome of colorectal cancer patients undergoing 5-FU adjuvant chemotherapy and underscores the predictive role of specific genes. Validation in an independent case series is warranted.

Safety profile of the fluoroquinolones: analysis of adverse drug reactions in relation to prescription data using four regional pharmacovigilance databases in Italy.

BACKGROUND: Fluoroquinolones are widely used both in primary care and in hospital settings. Since the last comparison performed in Italy on the safety profiles of different fluoroquinolones, a new molecule, prulifloxacin, has been introduced into the market and several warnings concerning this class of drugs have been released. The aim of this study was to reassess the safety profiles of fluoroquinolones using the database of the Italian Interregional Group of Pharmacovigilance (IGP) and the administrative data of fluoroquinolone prescriptions. METHODS: All adverse drug reactions (ADRs) reported in four Italian regions (Lombardy, Veneto, Emilia Romagna and Tuscany) were retrieved from the IGP database. Consumption data (defined daily dose [DDD]/1000 inhabitants/day) were used as denominators. Both single reports and all ADRs (classified by System Organ Classes and MedDRA Preferred Term [PT]) due to fluoroquinolones were considered as numerators of each analysis, comparing two periods (2005 vs 2006). All fluoroquinolones with at least ten reports per year were included in the analysis. RESULTS: On the basis of 272 reports (532 single ADRs or PTs), patients did not show any statistically significant differences between 2005 and 2006 in terms of sex, age and number of concurrent medications. After adjustment for drug consumption, moxifloxacin showed the highest reporting rate (84.6 reports/DDD/1000 inhabitants/day; 15.4 serious reports/DDD/1000 inhabitants/day) followed by prulifloxacin (72.2; 22.2 serious) and levofloxacin (55.3; 30.6 serious) in 2005. An increment of ADR/report rates was observed over the 2 years for all fluoroquinolones except prulifloxacin, which had the lowest ADR reporting rate in 2006 (25.0; 12.5 serious). In 2006, the rate of serious ADRs associated with prulifloxacin was lower than with ciprofloxacin, while in 2005 serious events were almost equal for both compounds (55.6 vs 47.6 serious ADRs/DDD/1000 inhabitants/day). Ciprofloxacin showed the highest proportion of cutaneous PTs (e.g. rash, exanthema). Tendinopathies were mainly due to levofloxacin. CONCLUSIONS: These data suggest that different fluoroquinolones are characterized by different rates and types of ADRs. Among them, prulifloxacin was associated with more ADRs than other fluoroquinolones in 2005 but with fewer ADRs in 2006, when its consumption increased. Although these findings may represent an encouraging perspective towards a more appropriate use of fluoroquinolones because of their individual safety profiles, further pharmacoepidemiological studies must be performed to substantiate these results.

Pharmacological properties of antifungal drugs with a focus on anidulafungin.

Drug classes for the treatment of invasive fungal infections include the polyenes, the triazoles and the echinocandins. Older agents such as the commonly used amphotericin B have a number of limitations, including toxicity and requirements for monitoring during treatment. These limitations led to the development of a number of new formulations of the agent, with the aim of reducing toxicity while maintaining or improving efficacy. Regarding other drug classes, some of the newer agents, such as the echinocandins, have more favourable pharmacokinetic/pharmacodynamic (PK/PD) profiles, with less toxicity and no need for monitoring. The newest echinocandin, anidulafungin, offers significant promise for antifungal infections, and has a number of favourable features, including a lack of known drug interactions and no need for dosage adjustment for any degree of renal or hepatic failure. From a pharmacological point of view, knowledge of both PK and PD characteristics of antifungal drugs is mandatory for evaluating the role of the different agents in the clinical setting. Overall, in the search for safer and more efficacious antifungal agents, PK/PD investigations have been valuable for defining optimal antifungal dosing regimens and developing in vitro susceptibility breakpoints. This article reviews the PK/PD properties of the polyenes, the triazoles and the echinocandins, with a focus on anidulafungin.