Primary malignant mediastinal germ cell tumours: a literature review and a study of 18 cases

From 1957 to 1992, 18 cases of primary mediastinal germ cell tumours were referred to the Peter MacCallum Cancer Institute (PMCI). Six were seminomas, six were mixed germ cell tumours, two were embryonal cell carcinomas, three were teratocarcinomas and one was labelled an 'anaplastic germ cell tumour'. Two of the 18 patients were female. For seminomas, surgical (and in one case chemotherapeutic) debulking, followed by radiotherapy produced the best results. Mediastinal doses ranged from 30 to 40 Gy. Local control was achieved in those patients receiving mediastinal radiotherapy. Four patients currently survive disease-free. The non-seminomatous germ cell tumours showed a significantly poorer survival, and only two of 12 patients remain alive in remission at 110 and 130 months after diagnosis. Survival has been updated as of November 1997. Attention is focused on the anterior position of the primary germ cell tumours in the mediastinum. A review of the literature up to and including 1997 is presented.     

Metastatic basal cell carcinoma: rapid symptomatic response to cisplatin and paclitaxel

BACKGROUND: Basal cell carcinoma (BCC) is the most common cancer in the community, although it rarely metastasizes. The literature reports less than 100 patients who have received chemotherapy for metastatic BCC. A further case of this rare disease is reported here. The pattern of disease in the reported patient was similar to that described in the literature, but the patient experienced a long period with untreated metastatic disease compared with that in the literature. METHOD: The patient was treated with cisplatin in combination with paclitaxel. Literature review suggests this to be the first report of this combination. RESULTS: Rapid symptomatic response was achieved though late neurotoxicity occurred. CONCLUSION: This regimen is an active combination for the rare patient with metastatic BCC. The combination of carboplatin and paclitaxel causes less neurotoxicity and may therefore be a superior regimen.     

Pharmacodynamic comparisons of antimicrobials against nosocomial isolates of escherichia coli, klebsiella pneumoniae, acinetobacter baumannii and pseudomonas aeruginosa from the MYSTIC surveillance program: the OPTAMA Program, South America 2002

The OPTAMA (Optimizing Pharmacodynamic Target Attainment using the MYSTIC [Meropenem Yearly Susceptibility Test Information Collection] Antibiogram) Program provides insight into the appropriate antibiotic options for empiric therapy for common nosocomial pathogens. In this report, South America is represented by Brazil, Colombia, Peru, and Venezuela. A 5000-subject Monte Carlo Simulation estimated pharmacodynamic target attainment for meropenem, imipenem, ceftazidime, cefepime, piperacillin/tazobactam, and ciprofloxacin against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Pharmacokinetic parameter variability was derived from existing healthy volunteer data, and minimum inhibitory concentration (MIC) data came from the 2002 MYSTIC program. Piperacillin/tazobactam and ciprofloxacin displayed the lowest target attainment against all bacterial species (14% to 24% for A. baumannii, 26% to 37% for P. aeruginosa, and 48% to 66% for the Enterobacteriaceae). Overall, the carbapenems had the highest probabilities of attainment against the Enterobacteriaceae (98% to 100%) and A. baumannii (73% to 74%), whereas cefepime obtained the greatest target attainment against P. aeruginosa (65%). Because no single regimen had high target attainment against A. baumannii and P. aeruginosa, the use of combination therapy to treat these pathogens in South America may be justified. Because of the lack of agreement with percent susceptibility for certain antimicrobial regimens, the use of pharmacodynamic target attainment may be a more accurate predictor of microbiologic success.     

Involvement of pmrAB and phoPQ in Polymyxin B Adaptation and Inducible Resistance in Non-Cystic Fibrosis Clinical Isolates of Pseudomonas aeruginosa

During investigation of susceptibility testing methods for polymyxins, 24 multidrug-resistant clinical isolates of Pseudomonas aeruginosa were observed to have a distinct, reproducible phenotype in which skipped wells were observed during broth microdilution testing for polymyxin B. Possible mechanisms underlying this phenotype were investigated. The effects of various concentrations of polymyxin B on growth, the expression of resistance genes, and outer-membrane permeability were observed. Real-time PCR was performed to compare the expression, in response to selected concentrations of polymyxin B, of genes related to the PhoP-PhoQ and PmrA-PmrB two-component regulatory systems in polymyxin B-susceptible isolate PAO1, polymyxin B-resistant isolate 9BR, and two isolates (19BR and 213BR) exhibiting the skipped-well phenotype. 19BR and 213BR appeared to have similar basal levels of expression compared to that of PAO1 for phoQ, arnB, and PA4773 (from the pmrAB operon), and in contrast, 9BR had 52- and 280-fold higher expression of arnB and PA4773, respectively. The expression of arnB and PA4773 increased in response to polymyxin B in a concentration-dependent manner for 9BR but not for 19BR and 213BR. For these isolates, expression was significantly increased for arnB and PA4773, as well as phoQ, only upon exposure to 2 μg/ml polymyxin B but not at a lower concentration of 0.125 μg/ml. The sequencing of the pmrAB and phoPQ operons for all three isolates revealed a number of unique mutations compared to that for PAO1. 1-N-phenylnaphthylamine (NPN) was used to study the effect of preincubation with polymyxin B on the self-promoted uptake of polymyxin B across the outer membrane. The preincubation of cells with 2 μg/ml polymyxin B affected baseline membrane permeability in 19BR and 213BR and also resulted in a reduced rate of NPN uptake in these isolates and in PAO1 but not in 9BR. The results presented here suggest that the skipped-well isolates have the ability to adapt to specific concentrations of polymyxin B, inducing known polymyxin B resistance genes involved in generating alterations in the outer membrane.The emergence of multidrug-resistant gram-negative organisms and the simultaneous lack of new clinically available antimicrobial agents have led to a resurgence of older compounds such as the polymyxins (6). These agents, including polymyxin B and colistin, have highly potent activity against gram-negative organisms, including Pseudomonas aeruginosa, but were previously abandoned due to a reported high incidence of nephrotoxicity and neurotoxicity (12).Resistance to polymyxin B is predominantly associated with decreased uptake into the bacterial cell resulting from a reduced capacity for initial binding (23). Polymyxin B and other polycationic compounds enter the cell via a process known as self-promoted uptake (10, 11). Polymyxin B binds to outer-membrane lipopolysaccharide (LPS) displacing Mg²⁺ and disrupting the Mg²⁺ cross bridges between anionic LPS molecules in the outer membrane, thus leading to membrane destabilization. This leads to an increased permeability of the outer membrane, allowing further uptake of the antibiotic. In P. aeruginosa, the ability of polymyxin to permeabilize outer membranes reflects its ability to bind to LPS with higher affinity than the native cross-bridging cation Mg²⁺ (20, 22).A polymyxin B adaptive resistance phenotype was first reported by Gilleland and Murray in 1976 (9) when the wild-type PAO1 strain was passaged in minimal medium containing low Mg²⁺ and exposed to increasing concentrations of polymyxin B. Since this time, many studies have focused on the structural basis of adaptive resistance (7, 8). Under various environmental conditions, P. aeruginosa has been found to synthesize different forms of the lipid A component of LPS (5). In particular, under Mg²⁺-limiting conditions, P. aeruginosa exhibits lipid A modifications, including the addition of aminoarabinose and palmitate. These modifications have been associated with polymyxin B resistance (17, 18).It is well established that two distinct two-component regulators, PhoP-PhoQ and PmrA-PmrB, respond to limiting Mg²⁺ conditions, resulting in polymyxin B resistance in P. aeruginosa (14-16). Under Mg²⁺-limiting conditions, PhoP-PhoQ autoregulates the oprH-phoP-phoQ operon (15), and similarly, PmrA-PmrB autoregulates the PA4773-5-pmrAB-PA4778 operon (17). Furthermore, the arnBCADTEF-PA3559 operon (PA3552-PA3559), which is responsible for the addition of aminoarabinose to lipid A (18), is separately regulated by each of these two-component regulatory systems and is upregulated under Mg²⁺-limiting conditions (17). Both the PA4773-PA4778 and the PA3552-PA3559 operons have shown independent upregulation in response to various cationic antimicrobial peptides in laboratory mutants (18). Mutations in PmrB and the presence of aminoarabinose have been directly associated with polymyxin B resistance (18).During a comparative study of MIC methods for testing polymyxin B and colistin susceptibility, it was observed that 24 of 243 multidrug-resistant clinical isolates of P. aeruginosa demonstrated skipped wells in the broth microdilution method for either polymyxin B, colistin, or both (a “skipped well” is an isolated well showing no growth of bacteria despite the fact that a well with a higher concentration demonstrates growth). According to Clinical and Laboratory Standards Institute (CLSI) guidelines, one skipped well is acceptable and MIC readings should be taken based on the well with the highest antibiotic concentration exhibiting growth (3). The assumption is that a technical error has occurred. The multidrug-resistant isolates described here skipped one to five wells, and bacteria recovered from wells at the higher polymyxin concentrations (i.e., after the skipped wells) also exhibited a polymyxin MIC profile containing skipped wells. The phenomenon of skipped wells has previously been described and was termed cocarde growth (1, 2, 23). In this study, we set out to determine the potential causes for this type of resistance profile in the identified P. aeruginosa clinical isolates.     

Pharmacodynamic profiling of imipenem, meropenem and ertapenem against clinical isolates of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp. from Brazil

The pharmacodynamic potency of imipenem, meropenem and ertapenem against extended-spectrum beta-lactamase (ESBL)-producing isolates was investigated. Minimal inhibitory concentration (MIC) determination, confirmation of ESBLs by Etest and the disk approximation test were performed for 133 ESBL-producing isolates of Escherichia coli and Klebsiella spp. Pharmacodynamic exposure, measured as percent of the dosing interval during which free drug was above the MIC (% fT>MIC), was modelled via a 5000-subject Monte Carlo simulation. Bactericidal cumulative fraction of response (CFR), defined as 40% fT>MIC, was calculated against each bacterial population. All agents achieved high bactericidal CFR against all ESBL isolates as a group, but ertapenem (96.26%) was slightly less effective than imipenem (99.96%) and meropenem (99.90%) (P<0.05). Similar results were observed against Klebsiella spp. only (P<0.05). Against E. coli, CFRs were close to 100%. Ertapenem is probably an effective agent against ESBL-producing bacteria, although its ability to achieve bactericidal pharmacodynamic exposures will depend on the bacterial susceptibility.     

Primary malignant mediastinal germ cell tumours: A literature review and a study of 18 cases

From 1957 to 1992, 18 cases of primary mediastinal germ cell tumours were referred to the Peter MacCallum Cancer Institute (PMCI). Six were seminomas, six were mixed germ cell tumours, two were embryonal cell carcinomas, three were teratocarcinomas and one was labelled an ‘anaplastic germ cell tumour’. Two of the 18 patients were female. For seminomas, surgical (and in one case chemotherapeutic) debulking, followed by radiotherapy produced the best results. Mediastinal doses ranged from 30 to 40 Gy. Local control was achieved in those patients receiving mediastinal radiotherapy. Four patients currently survive disease-free. The non-seminomatous germ cell tumours showed a significantly poorer survival, and only two of 12 patients remain alive in remission at 110 and 130 months after diagnosis. Survival has been updated as of November 1997. Attention is focused on the anterior position of the primary germ cell tumours in the mediastinum. A review of the literature up to and including 1997 is presented.