Gender oncology: recommendations and consensus of the Italian Association of Medical Oncology (AIOM).

BACKGROUND: Following the development of gender medicine in the past 20 years, more recently in the field of oncology an increasing amount of evidence suggests gender differences in the epidemiology of cancers, as well as in the response and toxicity associated with therapies. In a gender approach, critical issues related to sexual and gender minority (SGM) populations must also be considered. MATERIALS AND METHODS: A working group of opinion leaders approved by the Italian Association of Medical Oncology (AIOM) has been set up with the aim of drafting a shared document on gender oncology. Through the 'consensus conference' method of the RAND/University of California Los Angeles (UCLA) variant, the members of the group evaluated statements partly from the scientific literature and partly produced by the experts themselves [good practice points (GPPs)], on the following topics: (i) Healthcare organisation, (ii) Therapy, (iii) Host factors, (iv) Cancer biology, and (v) Communication and social interventions. Finally, in support of each specific topic, they considered it appropriate to present some successful case studies. RESULTS: A total of 42 articles met the inclusion criteria, from which 50 recommendations were extracted. Panel participants were given the opportunity to propose additional evidence from studies not included in the research results, from which 32 statements were extracted, and to make recommendations not derived from literature such as GPPs, four of which have been developed. After an evaluation of relevance by the panel, it was found that 81 recommendations scored >7, while 3 scored between 4 and 6.9, and 2 scored below 4. CONCLUSIONS: This consensus and the document compiled thereafter represent an attempt to evaluate the available scientific evidence on the theme of gender oncology and to suggest standard criteria both for scientific research and for the care of patients in clinical practice that should take gender into account.

Future trends in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection: An in-depth review of newer antibiotics active against an enduring pathogen.

Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a major public health problem. Vancomycin and teicoplanin have been in clinical use for several decades but their drawbacks are well described. In the last 10 years, several antibiotics have been made available for clinical use. Daptomycin and linezolid have been extensively used during this period. Other agents such as ceftaroline, ceftobiprole, dalbavancin, oritavancin, tedizolid and telavancin have been approved by regulatory agencies since 2009. Many others, such as the newer tetracyclines, fluoroquinolones, oxazolidinones and pleuromutilins, are in various stages of development. In addition, an ongoing multicentre trial is investigating the role of combination of vancomycin or daptomycin with ß-lactam antibiotics. This review discusses the role of the newer antibiotics, reflecting the views of the 6th MRSA Consensus Conference meeting of the International Society of Chemotherapy MRSA Working Group that took place in 2016.

Methicillin-resistant Staphylococcus aureus infections: A review of the currently available treatment options.

This review is the result of discussions that took place at the 5th MRSA Working Group Consensus Meeting and explores the possible treatment options available for different types of infections due to methicillin-resistant Staphylococcus aureus (MRSA), focusing on those antibiotics that could represent a valid alternative to vancomycin. In fact, whilst vancomycin remains a viable option, its therapy is moving towards individualised dosing. Other drugs, such as the new lipoglycopeptides (oritavancin, dalbavancin and telavancin) and fifth-generation cephalosporins (ceftaroline and ceftobiprole), are showing good in vitro potency and in vivo efficacy, especially for patients infected with micro-organisms with higher vancomycin minimum inhibitory concentrations (MICs). Tedizolid is an attractive agent for use both in hospital and community settings, but the post-marketing data will better clarify its potential. Daptomycin and linezolid have shown non-inferiority to vancomycin in the treatment of MRSA bacteraemia and non-inferiority/superiority to vancomycin in the treatment of hospital-acquired pneumonia. Thus, several options are available, but more data from clinical practice, especially for invasive infections, are needed to assign specific roles to each antibiotic and to definitely include them in the new antibacterial armamentarium.

MTHFR-1298 A>C (rs1801131) is a predictor of survival in two cohorts of stage II/III colorectal cancer patients treated with adjuvant fluoropyrimidine chemotherapy with or without oxaliplatin.

Adjuvant treatment based on fluoropyrimidines (FL) improves the prognosis of stage II/III colorectal cancer (CRC). Validated predictive/prognostic biomarkers would spare therapy-related morbidity in patients with a good prognosis. We compared the impact of a set of 22 FL-related polymorphisms with the prognosis of two cohorts of CRC patients treated with adjuvant FL with or without OXA, including a total of 262 cases. 5,10-Methylentetrahydrofolate reductase (MTHFR) MTHFR-1298 A>C (rs1801131) polymorphism had a concordant effect: MTHFR-rs1801131-1298CC genotype carriers had a worse disease free survival (DFS) in both the cohorts. In the pooled population MTHFR-rs1801131-1298CC carriers had also a worse overall survival. We computed a clinical score related to DFS including MTHFR-rs1801131, tumor stage, sex and tumor location, where rs1801131 is the most detrimental factor (hazard ratio=5.3, 95% confidence interval=2.2-12.9; P-value=0.0006). MTHFR-rs1801131 is a prognostic factor that could be used as an additional criteria for the choice of the proper adjuvant regimen in stage II/III colorectal cancer patients.

Treatment options for methicillin-resistant Staphylococcus aureus (MRSA) infection: Where are we now?

Methicillin-resistant Staphylococcus aureus (MRSA) infection continues to be a substantial global problem with significant associated morbidity and mortality. This review summarises the discussions that took place at the 4th MRSA Consensus Conference in relation to the current treatment options for serious MRSA infections and how to optimise whichever therapy is embarked upon. It highlights the many challenges faced by both the laboratory and clinicians in the diagnosis and treatment of MRSA infections.

Vancomycin in the treatment of meticillin-resistant Staphylococcus aureus (MRSA) infection: End of an era?

Infection with meticillin-resistant Staphylococcus aureus (MRSA) continues to have significant morbidity and mortality. Vancomycin, which has been the mainstay of treatment of invasive MRSA infections, has several drawbacks related to its pharmacological properties as well as varying degrees of emerging resistance. These resistant subpopulations are difficult to detect, making therapy with vancomycin less reliable. The newer agents such as linezolid, daptomycin, ceftaroline, and the newer glycopeptides telavancin and oritavancin are useful alternatives that could potentially replace vancomycin in the treatment of certain conditions. By summarising the discussions that took place at the III MRSA Consensus Conference in relation to the current place of vancomycin in therapy and the potential of the newer agents to replace vancomycin, this review focuses on the challenges faced by the laboratory and by clinicians in the diagnosis and treatment of MRSA infections.

Do different susceptibility breakpoints affect the selection of antimicrobials for treatment of uncomplicated cystitis?

Because of increasing antibiotic resistance in Escherichia coli, the main uropathogen of uncomplicated urinary tract infections (UTIs), updated susceptibility data are vital in guiding the selection of first-line treatment agents. interpretation of these data depends on the breakpoints adopted, that may vary among different guidelines.In this study we report the minimum inhibitory concentrations (MICs) of eight antibiotics and compare antimicrobial susceptibility results obtained in 2315 E. coli strains recently collected during the ARESC survey using EUCAST and CLSI breakpoints. We have also evaluated the clinical impact of breakpoint discrepancies on the overall susceptibility patterns.Fosfomycin, nitrofurantoin and mecillinam showed the highest susceptibility rates in all countries (>92%) according to both CLSI and EUCAST criteria. Minor category shifts were observed for ciprofloxacin, amoxicillin-clavulanic acid, ampicillin and trimethoprim/sulfamethoxazole. A large number of strains classified as intermediate resistant to cefuroxime according to CLSI are included by the EUCAST in the susceptible category.In conclusion, fosfomycin, mecillinam, and nitrofurantoin have preserved their in vitro activity in all countries investigated, regardless of the criteria adopted. They continue to represent effective options for the empiric therapy of female patients with uncomplicated cystitis. The use of different interpretative criteria for E. coli responsible for UTIs therefore has no influence on the decision to be taken by the physicians managing the patients.

The pharmacokinetics and pharmacodynamics of the carbapanemes: focus on doripenem.

Carbapenems are the most potent group of beta-lactam agents, having a broad spectrum of bactericidal activity against both Gram-negative and Gram-positive bacteria including anaerobes. Doripenem is a new carbapenem endowed with excellent bactericidal activity, a wide spectrum of antibacterial activity against difficult nosocomial pathogens, including extended-spectrum beta-lactamase producers. Its high stability in solution render it extremely flexible for dosing and infusion time. It is the only carbapenem which has been registered officially for administration as an extended infusion of more than 4 hours, which can thus enhance its potential clinical efficacy against difficult bacterial pathogens with MICs of 4-8 mg/L.

The Charta of Milan: basic criteria for the appropriate and accurate use of antibiotics: recommendations of the Italian Society of Chemotherapy.

This article summarizes the recommendations drawn up by the Italian Society of Chemotherapy regarding the proper use of antimicrobial agents for infectious diseases.

Pharmacological rationale for antibiotic treatment of intra-abdominal infections.

The pharmacodynamic and pharmacokinetic (PK/PD) characteristics of antimicrobial agents are the two fundamental pharmacological components which provide a rationale for choosing therapy for intra-abdominal infections, especially when they are serious. It is well known which of the important PK/PD parameters can potentiate therapeutic efficacy. Antimicrobial agents can be subdivided into categories based on whether their activity depends on concentration or exposure time. Therefore, a correct dosing regimen for the time-dependent molecules (i.e. beta-lactams, linezolid, tigecycline) should prolong the maximum exposure time to maintain serum levels over the minimum inhibitory concentration (MIC). The concentration-dependent molecules, on the other hand, which include aminoglycosides and fluoroquinolones, should be administered to reach maximum concentrations, since they are bactericidal in direct proportion to their concentrations and possess a prolonged post-antibiotic effect.

Increased levels of CA 125 and CA 19.9 serum tumour markers following cyclic combined hormone replacement therapy.

We report a case of increase in serum tumour markers CA 125 and CA 19.9 induced by cyclic combined hormone replacement therapy (HRT). A 52-year-old Caucasian post-menopausal woman presented with a slight enlargement of the right ovary and uterine fibromyomatosis. She was taking HRT for 4 years in a cyclic combined regimen of 2 mg oestradiol with 1 mg cyproterone acetate. The serum tumour markers occasionally measured were in normal range except CA 19.9 (997 U/mL; normal values 0.0-37) and CA 125 (85 U/mL; normal values 0.0-35). However, on one occasion, the CA 19.9 and CA 125 were high and then showed persistently high values (1005 and 81.3 U/mL, respectively). Radiodiagnostic investigations excluded any malignancies and a hysteroscopy showed endometrial thickening. After discontinuation of HRT, CA 125 levels returned to normal after 1 month, whereas CA 19.9 took 6 months to do so. Four months after the beginning subsequent therapy with over-the-counter phyto-oestrogens a new serum test showed an increase in CA 19.9 but CA 125 remained within the normal range. Phyto-oestrogen therapy was then interrupted and 1 month later CA 19.9 returned to normal. In this case, cyclic HRT was the probable cause of CA 19.9 and CA 125 increase. Positive dechallenge and subsequent CA 19.9 increase after phyto-oestrogen intake seem to confirm the role of oestrogens as the cause of the endometrial thickening through hormonal imbalance. Increased CA 19.9 and CA 125 levels in benign gynaecological conditions may be a source of misdiagnosis of malignant disease.

Bimonthly chemotherapy with oxaliplatin, irinotecan, infusional 5-fluorouracil/folinic acid in patients with metastatic colorectal cancer pretreated with irinotecan- or oxaliplatin-based chemotherapy.

This study was conducted to assess the tolerability and efficacy of a ternary bimonthly irinotecan (CPT-11) - oxaliplatin (OHP) - infusional 5-fluorouracil (5-FU)/folinic acid (FA) combination in advanced colorectal cancer patients who had received prior CPT-11 and/or OHP-based chemotherapy regimen. Colorectal cancer patients were given bimonthly CPT-11 as a 90-min infusion, followed by OHP (85 mg/m(2)), FA (200 mg/m(2)) 2-h infusions and 5-FU (48-h infusion). CPT-11 and 5-FU doses were escalated as reported below. 26 patients were recruited. Fourteen patients had received a prior CPT-11-, 6 patients a prior OHP-based chemotherapy regimen and 6 patients both regimens. Three dose levels were investigated: CPT-11 100, 120 and 140 mg/m(2) and 5-FU 1500, 1800 and 2100 mg/m(2) in 6, 12 and 8 patients, respectively. All patients were evaluable for toxicity, 24 for antitumor activity. At all dose levels toxicity was acceptable. Grade 4 toxicity occurred in two patients only (neutropenia in one case and stomatitis in another one, 3.8%). Grade 3 toxicities included nausea and vomiting (34.6%), asthenia (26.9%), neurosensory toxicity (15.4%), neutropenia (3.8%) and diarrhea (3.8%). Hematological toxicity was infrequent and generally mild. At the third dose level, a higher, although not significantly different incidence of hematological and neurosensory toxicity (both occurring in 62.5% of cases, all grades) was observed compared to the other two, while nausea and vomiting were significantly less frequent (37.5% vs 100%). Overall, we observed 2 complete responses, 9 partial responses (OR 45.8%), 8 stable disease (33.3%), and 5 disease progression (20.8%). Median overall survival was 18 months and median time-to-progression 5.5 months. This combination showed moderate toxicity and promising antitumor activity in CPT-11 and/or OHP pretreated colorectal cancer patients. The second dose level using CPT-11 at 120 mg/m(2) and 5-FU at 1800 mg/m(2) is recommended for further phase II studies in this patient population.

[Beta-lactam antibiotics: when and how in acute otitis media and pharyngotonsillitis]. / Antibiotici beta-lattamici: quando e come nell'otite media acuta e nella faringotonsillite.

Acute otitis media (AOM) and pharyngitis are very frequent diseases in pediatric parients. However, it is not always agreed which are the diagnostic criteria and empiric antibacterial treatment. It is often difficult to follow the different guidelines and not always can you choose between the different classes of antibiotics available. Furthermore, there's no unanimous agreement with respect to the most appropriate antibacterial agent to administer and the correct duration of the treatment. The aim of this article is to underline and discuss the emerging controversies in the empiric treatment of AOM and pharyngitis in pediatrics, with special attention to the use of beta-lactams in light of the most recent evidences regarding both clinical pharmacology and microbiology.

Cellular pharmacology of gemcitabine.

Gemcitabine (2',2'-difluoro 2'-deoxycytidine, dFdC) is the most important cytidine analogue developed since cytosine arabinoside (Ara-C). The evidence of its potent antitumor activity in a wide spectrum of in vitro and in vivo tumor models has been successfully confirmed in the clinical setting. Despite structural and pharmacological similarities to Ara-C, gemcitabine displays distinctive features of cellular pharmacology, metabolism and mechanism of action. Following influx through the cell membrane via nucleoside transporters, gemcitabine undergoes complex intracellular conversion to the nucleotides gemcitabine diphosphate (dFdCDP) and triphosphate (dFdCTP) responsible for its cytotoxic actions. The cytotoxic activity of gemcitabine may be the result of several actions on DNA synthesis. dFdCTP competes with deoxycytidine triphosphate (dCTP) as an inhibitor of DNA polymerase. dFdCDP is a potent inhibitor of ribonucleoside reductase, resulting in depletion of deoxyribonucleotide pools necessary for DNA synthesis and, thereby potentiating the effects of dFdCTP. dFdCTP is incorporated into DNA and after the incorporation of one more nucleotide leads to DNA strand termination. This extra nucleotide may be important in hiding the dFdCTP from DNA repair enzymes, as incorporation of dFdCTP into DNA appears to be resistant to the normal mechanisms of DNA repair. Gemcitabine can be effectively inactivated mainly by the action of deoxycytidine deaminase to 2,2'-difluorodeoxyuridine. Also, 5'-nucleotidase opposes the action of nucleoside kinases by catalysing the conversion of nucleotides back to nucleosides. Additional sites of action and self-potentiating effects have been described. Evidence that up- or down-regulation of the multiple membrane transporters, target enzymes, enzymes involved in the metabolism of gemcitabine and alterations in the apoptotic pathways may confer sensitivity/resistance to this drug, has been provided in experimental models and more recently also in the clinical setting. Synergism between gemcitabine and several other antineoplastic agents has been demonstrated in experimental models based on specific pharmacodynamic interactions. Knowledge of gemcitabine cellular pharmacology and its molecular mechanisms of resistance and drug interaction may thus be pivotal to a more rational clinical use of this drug in combination regimens and in tailored therapy.

Intraoperative positive fluid balance improves tissue diffusion of ceftizoxime.

AIM OF STUDY: To demonstrate that administration of fluids and the consequent improvement of fluid balance during a surgical procedure can modify the tissue diffusion of ceftizoxime. METHODS: Twenty-eight patients (30-79 years) undergoing major abdominal surgery of the colon were administered ceftizoxime 30 mg/kg i.v. at induction of anesthesia. A sample of arterial blood was taken before administration of the drug (t0) and then again at the time of vascular occlusion of the colon segment to be removed (t1). A sample of the segment of removed colon was taken. The patients were divided into two groups on the basis of the fluid balance between t0 and t1: group A (n = 17) with a fluid balance <1,000 ml and group B (n = 11) with a fluid balance >1,000 ml. The parameters evaluated in each group were: weight, height and age of the patients, serum and tissue antibiotic concentration, percent ratio of serum and tissue concentration, time elapsed between t0 and t1, volume of administered fluids between t0 and t1, diuresis and hourly diuresis between t0 and t1 and body fluid distribution, obtained using a bioelectrical impedance analyzer. The mean results obtained in the two groups were then compared using Student's t test. RESULTS: The balance of fluids calculated up to t1 was 675 +/- 308 ml for group A and 1,411 +/- 405 ml for group B (p < 0.01). The means of the recorded values that showed statistically significant differences were: mean percent concentration ratio (43.6 +/- 8.4 vs. 84 +/- 16%; p < 0.05), concentration in the colonic segment (16.3 +/- 7.9 vs. 37.2 +/- 25.9 mg/ml; p < 0.05), urinary volume gathered up to t1 (538 +/- 557 vs. 169 +/- 104 ml; p < 0.05), hourly urinary volume up to t1 (311.1 +/- 296 vs. 97.6 +/- 77.9 ml/h; p < 0.05), percent variation of resistance (95.1 +/- 5.1 vs. 89.7 +/- 8.6; p < 0.05). The other means did not show any significant statistical differences. CONCLUSIONS: A higher tissue water level seems to facilitate the penetration of the antibiotic into the tissue according to the pharmacokinetic characteristics of ceftizoxime: high amount of free drug (not bound to plasma proteins) and high hydrosolubility.