Resistance of clinical isolates of Haemophilus influenzae in United Kingdom 1986.

Between 1 January and 31 March 1986, 2434 strains of Haemophilus influenzae collected from 23 laboratories in the United Kingdom were examined. With the same criteria as previous studies in 1977 and 1981 the prevalence of resistance was: ampicillin 7.8% (6.2% beta-lactamase producers and 1.6% non-producers), tetracycline 2.7%, chloramphenicol 1.7%, trimethoprim 4.2%, and sulphamethoxazole 3.5%. of the 87 capsulated strains, 15 produced beta-lactamase, nine were resistant to ampicillin but did not produce beta-lactamase, and two strains, one of which produced beta-lactamase, were resistant to chloramphenicol and tetracycline. Since 1977 the prevalence of resistance to ampicillin, chloramphenicol, and trimethoprim has increased significantly. During 1981-6 strains resistant to ampicillin but not producing beta-lactamase and strains resistant to trimethoprim have significantly increased.     

Mononucleotide markers of microsatellite instability in carcinomas of the urinary bladder.

AIMS: To determine the presence of microsatellite instability (MSI) and to assess the expression of the human mismatch repair (MMR) gene products hMLH1 and hMSH2 in primary transitional cell carcinomas (TCCs) of the urinary bladder in relation to clinico-pathological parameters. METHODS: Seventy-two cases of primary TCC were screened for the presence of alterations in MSI markers by molecular techniques and evaluated immunohistochemically for the expression of hMLH1 and hMSH2 proteins. Clinical data were available in 70 cases. The percentage of MSI rose to 16.6%. RESULTS: Reduced (<20%) hMLH1 expression was closely related to the presence of MSI (p=0.0004). Neither MMR proteins nor MSI was associated with grade, stage, papillary status. Clinical outcome analysed as a function of MSI did not show significant differences in terms of both disease-free and overall survival. Reduced hMLH1 expression was a significant predictor of shorter disease-free survival in univariate and multivariate analysis. CONCLUSIONS: The presence of MSI is not related to classical clinico-pathological parameters in TCCs, nor does it appear to be of prognostic significance. hMLH1 was an important indicator for recurrence.     

Pembrolizumab with R-CHOP in previously untreated diffuse large B-cell lymphoma: potential for biomarker driven therapy

Tumor programmed death-ligand 1 (PD-L1) expression in diffuse large B-cell lymphoma (DLBCL) is associated with inferior outcomes. The first-line immunologically-replete setting may be an opportune time for PD-1 inhibition. We evaluated pembrolizumab in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in untreated patients with DLBCL. Eligible patients were age 18 or older, had adequate organ function, and had DLBCL requiring full-course therapy. Patients received pembrolizumab 200 mg/cycle with R-CHOP, primarily to assess toxicity. Response assessment utilized standard criteria, and PD-L1 staining was performed at a validated central laboratory. Among 30 patients, toxicity was comparable to standard R-CHOP but with two grade ≥3 immune related adverse events (rash, pneumonitis). The overall and complete response rate was 90% and 77%. With 25·5 months of median follow-up, 2-year progression-free survival (PFS) is 83%. PD-L1 expression was associated with non-GCB subtype, and improved PFS and survival. Pembrolizumab can safely be added to R-CHOP, and is associated with a high CR rate and 2-year PFS. Improved PFS with PR-CHOP in PD-L1 expressing tumors contradicts historical data in R-CHOP treated patients, supporting evaluation of PD-L1 as a biomarker to identify DLBCL patients who may benefit from this first-line strategy.     

Fas signaling in thyroid carcinomas is diverted from apoptosis to proliferation.

PURPOSE: The death receptor Fas is present in thyroid carcinomas, yet fails to trigger apoptosis. Interestingly, Fas has been reported to be actually overexpressed in papillary thyroid carcinomas, suggesting that it may confer a survival advantage. EXPERIMENTAL DESIGN: We investigated the expression and activation status of Fas pathway mediators in thyroid carcinoma cell lines and tumor specimens. RESULTS: All cell lines tested express Fas-associated death domain, procaspase-8, procaspase-9, and procaspase-3; resistance to Fas-mediated apoptosis could not be attributed to lack of any of these apoptosis mediators. Moreover, Fas death domain mutations were not found in our study. The proteasome inhibitors MG132 and PS-341 (bortezomib, Velcade), which lead to accumulation of the nuclear factor kappaB (NF-kappaB) inhibitor IkappaB, did not sensitize SW579 cells to Fas-mediated apoptosis, suggesting that resistance to Fas-mediated apoptosis is not due to proteasome or NF-kappaB activity. Cross-linking of Fas in vitro induced recruitment of Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein (FLIP) instead of procaspase-8. Inhibition of FLIP expression with a FLIP antisense oligonucleotide resulted in significant sensitization to Fas-mediated apoptosis. Fas cross-linking promoted BrdUrd incorporation; activated the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase, NF-kappaB, and activator protein-1 pathways in thyroid carcinoma cells in vitro; and protected cells from tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. We also found that good prognosis papillary thyroid carcinoma specimens exhibited higher immunoreactivity for cleaved (activated) caspase-8 than poor prognosis tumors. CONCLUSIONS: In thyroid carcinomas, the proteolytic cleavage and activation of caspase-8 depends on the balance between expression levels for procaspase-8 and FLIP and correlates with favorable clinical prognosis. Fas may actually stimulate proliferation and confer a survival advantage to thyroid cancer cells.     

The infrequency of malignant disease in diaphyseal aclasis and neurofibromatosis.

The association of diaphyseal aclasis and neurofibromatosis with malignant neoplasms has been variously reported as between 5 and 28% of all cases, but malignant disease invariably presents at hospital and the true frequency from an unselected group is unknown. The current survey reviews not only hospital patients but also their affected relatives, with particular reference to malignant disease and the cause of death in all family members. A survey of 36 index patients and 80 known affected relatives with diaphyseal aclasis and 37 index patients and 33 known affected relatives with neurofibromatosis has been carried out. The observed proportions with associated malignant disease were 0.9% of all cases of diaphyseal aclasis and 4.3% of neurofibromatosis. The authors consider this is still too high an estimate in view of the number of persons in the families only mildly affected by the inherited disease who cannot be identified, although their malignant disease will be known. A more likely figure for malignant change in diaphyseal aclasis is calculated at 0.5% (or 1.3% of those over 21 years) and in neurofibromatosis 2.0% (or 4.2% of those over 21 years).     

Preliminary evaluation of the school-smoking-prevention policy in Greece

Sirs, Cigarette smoking among adolescents is one of the leading healthindicators that reflect major health concerns at the EuropeanUnion. Greece's leading position on cigarette smoking amongits European partners forced the Hellenic Ministry of Healthand Welfare to assume tobacco-control programs, introducingsmoke-free zones, smoking-cessation centres, and an intensepromotional strategy against     

Bladder cancer mortality in the Epirus district population (Greece)

Objective: To describe the pattern of bladder cancer mortality in the Epirus district population (North-Western Greece) and to establish some relationships with cigarette smoking. Patients and methods: Mortality rates of bladder cancer in the Epirus district population were analysed according to the official data from the Department of Statistics of the University Hospital of Ioannina during the last decade (January 1990–January 2000). Age –standardization of death rates was done by the direct method, using the world population as a standard. Fisher's test was used as a significance test for linear regression coefficient in time trend analysis of mortality. Results: The average annual standardized mortality rates from bladder cancer during the study period were 5.23 per 100,000population (96% Confidence Interval – CI 4.02–5.63)in males and 1.63 per 100,000 population (96% Confidence Interval– CI 1.18–1.96) in females. Significantly increasing trends of the rates were observed in males (y = 2.421 + 0.231x; p < 0.01), but not in females (y = 1.263 +0.027x; p > 0.05). The greatest increase in age –specific rates in males was observed in the age group of 70 and more years (y = 25.602 + 3.673x; p < 0.01). In females,all age – specific rates except for the group 60–69 years showed significantly increasing tendency. The increasing tendency of bladder cancer mortality is followed by the rise of per capita cigarette consumption among the Epirus district population. Conclusion:Further studies are needed for the explanation of the irregularities in the age-specific rates. This revised version was published online in September 2006 with corrections to the Cover Date.     

Genetic evaluation based on family history and Her2 status correctly identifies TP53 mutations in very early onset breast cancer cases

Currently, hereditary breast cancer is being attributed to more than 20 genes of differing penetrance. Although BRCA1 and BRCA2 are still the genes of reference for breast cancer susceptibility, extreme breast cancer phenotypes may be the result of deleterious alleles of other genes. Here, we report three families with early‐onset breast cancer that were initially referred for BRCA1/BRCA2 genetic testing. They were diagnosed with breast cancer at an extraordinarily early age. On the basis of their extensive family history, which included multiple cancer types, and their Her2 status, they were suspected for Li–Fraumeni syndrome. Indeed, all three probands were found to harbor TP53 tumor suppressor gene mutations. These included p.C275X, described here for the first time, as well as p.R213X and p.Y220C, which have been described in the past. Our conclusion is that decisions on genetic analysis for inherited early onset breast cancer should always be based on detailed pedigree information, combined with Her2 status.     

Home traction in the management of congenital dislocation of the hip

Summary A retrospective review of sixty children with seventy-eight congenitally dislocated hips who had pre-reduction traction at home was undertaken to assess the effectiveness of the traction and the incidence of severe complications, with specific reference to the incidence and severity of avascular necrosis. Thirty other children with forty-two congenitally dislocated hips who had pre-reduction traction while in the hospital were used as controls. Traction failed to radiologically improve the position of the head in relation to the acetabulum in two hips in each group. The incidence of avascular necrosis was 17.9 percent in hips treated at home and 23.8 percent in hips treated in the hospital. The hospital control group demonstrated higher incidences of the more severe types of necrosis. Traction at home was found to be an advantageous alternative to traction in the hospital, in that it is safe, effective, and less costly; however, it must be stressed that proper patient selection and careful monitoring of the program are required.

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Zusammenfassung Eine retrospektive Studie wurde an 60 Kindern mit einer congenitalen Hüftluxation an 78 Hüftgelenken durchgeführt, bei denen die Extensions-Einrenkungsbehandlung zu Hause durchgeführt wurde. Die Wirksamkeit der Extension und die Häufigkeit schwerer Komplikationen sollte ermittelt werden, insbesondere die Häufigkeit und die Ausdehnung avaskulärer Nekrosen. 30 andere Kinder mit 42 congenital luxierten Hüftgelenken, bei denen die Extensions-Einrenkungsbehandlung im Krankenhaus durchgeführt wurde, dienten als Kontrollgruppe. Bei jeweils 2 Hüftgelenken in jeder Gruppe gelang es mit der Extension nicht, die Stellung des Hüftkopfes gegenüber dem Acetabulum zu verbessern. Die Häufigkeit der avasculären Nekrosen betrug bei den zu Hause behandelten Hüften 17,9% und bei den im Krankenhaus behandelten 23,8%. Bei der letztgenannten Gruppe waren auch die schweren Nekroseformen häufiger. Es hat sich herausgestellt, daß die Extensionsbehandlung zu Hause eine vorteilhafte Alternative zu der Behandlung im Krankenhaus darstellt, weil sie sicher, wirksam und kostensparend ist. Es muß jedoch betont werden, daß eine richtige Auswahl der Patienten und eine sorgfältige Überwachung des Behandlungsprogramms erforderlich sind.

     

Risk Factors and Outcomes Associated with Acquisition of Colistin-Resistant KPC-Producing Klebsiella pneumoniae: a Matched Case-Control Study

A matched 1:3 case-control study investigated factors predicting colistin-resistant versus colistin-susceptible KPC-producing Klebsiella pneumoniae acquisition and its impact on patient outcomes. Case patients were more often admitted from other institutions (P = 0.019) and had longer therapy with β-lactam/β-lactamase inhibitors (P = 0.002) and higher overall mortality (P = 0.05). All 52 study isolates were clonally related, suggesting horizontal dissemination. None of these parameters independently predicted colistin resistance, which probably occurred in a susceptible KPC-KP strain that was subsequently disseminated horizontally.Klebsiella pneumoniae isolates producing KPC carbapenemases (KPC-KP) have been widely disseminated in several regions worldwide (15). In Greek hospitals, carbapenem resistance among K. pneumoniae isolates, mediated by verona imipenemase (VIM) or, more recently, KPC enzymes is a major problem (16, 17). Colistin represents one of the few antimicrobials active against KPC producers (15) and is frequently used for the treatment of the respective infections. The emergence of colistin resistance among KPC-KP (1, 2, 5, 11) poses a new threat that necessitates detailed investigation.In our hospital, KPC-KP isolates are widespread, and since April 2008, colistin-resistant (CR) KPC-KP isolates have also emerged. Studies analyzing risk factors for CR KPC-KP acquisition have not been described in the literature. In this context, we conducted a case-control study to investigate the risk factors and epidemiological characteristics associated with the acquisition of CR KPC-KP and its impact on patient outcomes.