Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study).

BACKGROUND: The efficacy and toxicity of olaparib as combination therapy in early breast cancer (BC) patients with homologous recombinant deficiency (HRD) [score high and/or germline (g) or tumour (t) BRCA1/2 mutation] is not well described. GeparOLA (ClinicalTrials.gov, NCT02789332) investigated olaparib in combination with paclitaxel in HER2-negative early BC with HRD. PATIENTS AND METHODS: Patients with untreated primary HER2-negative cT2-cT4a-d or cT1c with either cN+ or pNSLN+ or cT1c and triple-negative breast cancer (TNBC) or cT1c and Ki-67>20% BC with HRD were randomised either to paclitaxel (P) 80 mg/m2 weekly plus olaparib (O) 100 mg twice daily for 12 weeks or P plus carboplatinum (Cb) area under the curve 2 weekly for 12 weeks, both followed by epirubicin/cyclophosphamide (EC). Stratification factors were hormone receptor (HR) status (HR+ versus HR-) and age (<40 versus ≥40 years). The primary endpoint was pathological complete response (pCR; ypT0/is ypN0). A two-sided one-group χ2-test was planned to exclude a pCR rate of ≤55% in the PO-EC arm. Secondary end points were other pCR definitions, breast conservation rate, clinical/imaging response, tolerability and safety. RESULTS: A total of 107 patients were randomised between September 2016 and July 2018; 106 (PO N = 69; PCb N = 37) started treatment. Median age was 47.0 years (range 25.0-71.0); 36.2% had cT1, 61.0% cT2, 2.9% cT3, and 31.8% cN-positive tumours; grade 3 tumours: 86.8%; Ki-67>20%: 89.6%; TNBC: 72.6%; confirmed gBRCA1/2 mutation: 56.2%. The pCR rate with PO was 55.1% [90% confidence interval (CI) 44.5% to 65.3%] versus PCb 48.6% (90% CI 34.3% to 63.2%). Analysis for the stratified subgroups showed higher pCR rates with PO in the cohorts of patients <40 years and HR+ patients. CONCLUSION: GeparOLA could not exclude a pCR rate of ≤55% in the PO arm. PO was significantly better tolerated and the combination merits further evaluation.

Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto)†.

BACKGROUND: The GeparQuinto study showed that adding bevacizumab to 24 weeks of anthracycline-taxane-based neoadjuvant chemotherapy increases pathological complete response (pCR) rates overall and specifically in patients with triple-negative breast cancer (TNBC). No difference in pCR rate was observed for adding everolimus to paclitaxel in nonearly responding patients. Here, we present disease-free (DFS) and overall survival (OS) analyses. PATIENTS AND METHODS: Patients (n = 1948) with HER2-negative tumors of a median tumor size of 4 cm were randomly assigned to neoadjuvant treatment with epirubicin/cyclophosphamide followed by docetaxel (EC-T) with or without eight infusions of bevacizumab every 3 weeks before surgery. Patients without clinical response to EC ± Bevacizumab were randomized to 12 weekly cycles paclitaxel with or without everolimus 5 mg/day. To detect a hazard ratio (HR) of 0.75 (α = 0.05, ß = 0.8) 379 events had to be observed in the bevacizumab arms. RESULTS: With a median follow-up of 3.8 years, 3-year DFS was 80.8% and 3-year OS was 89.7%. Outcome was not different for patients receiving bevacizumab (HR 1.03; P = 0.784 for DFS and HR 0.974; P = 0.842 for OS) compared with patients receiving chemotherapy alone. Patients with TNBC similarly showed no improvement in DFS (HR = 0.99; P = 0.941) and OS (HR = 1.02; P = 0.891) when treated with bevacizumab. No other predefined subgroup (HR+/HER2-; locally advanced (cT4 or cN3) or not; cT1-3 or cT4; pCR or not) showed a significant benefit. No difference in DFS (HR 0.997; P = 0.987) and OS (HR 1.11; P = 0.658) was observed for nonearly responding patients receiving paclitaxel with or without everolimus overall as well as in subgroups. CONCLUSIONS: Long-term results, in opposite to the results of pCR, do not support the neoadjuvant use of bevacizumab in addition to an anthracycline-taxane-based chemotherapy or everolimus in addition to paclitaxel for nonearly responding patients. CLINICAL TRIAL NUMBER: NCT 00567554, www.clinicaltrials.gov.

Use of culture and molecular analysis to determine the effect of antibiotic treatment on microbial community diversity and abundance during exacerbation in patients with cystic fibrosis.

BACKGROUND: Anaerobic bacteria are increasingly regarded as important in cystic fibrosis (CF) pulmonary infection. The aim of this study was to determine the effect of antibiotic treatment on aerobic and anaerobic microbial community diversity and abundance during exacerbations in patients with CF. METHODS: Sputum was collected at the start and completion of antibiotic treatment of exacerbations and when clinically stable. Bacteria were quantified and identified following culture, and community composition was also examined using culture-independent methods. RESULTS: Pseudomonas aeruginosa or Burkholderia cepacia complex were detected by culture in 24/26 samples at the start of treatment, 22/26 samples at completion of treatment and 11/13 stable samples. Anaerobic bacteria were detected in all start of treatment and stable samples and in 23/26 completion of treatment samples. Molecular analysis showed greater bacterial diversity within sputum samples than was detected by culture; there was reasonably good agreement between the methods for the presence or absence of aerobic bacteria such as P aeruginosa (κ=0.74) and B cepacia complex (κ=0.92), but agreement was poorer for anaerobes. Both methods showed that the composition of the bacterial community varied between patients but remained relatively stable in most individuals despite treatment. Bacterial abundance decreased transiently following treatment, with this effect more evident for aerobes (median decrease in total viable count 2.3×10(7) cfu/g, p=0.005) than for anaerobes (median decrease in total viable count 3×10(6) cfu/g, p=0.046). CONCLUSION: Antibiotic treatment targeted against aerobes had a minimal effect on abundance of anaerobes and community composition, with both culture and molecular detection methods required for comprehensive characterisation of the microbial community in the CF lung. Further studies are required to determine the clinical significance of and optimal treatment for these newly identified bacteria.

Tobramycin once- vs thrice-daily for elective intravenous antipseudomonal therapy in pediatric cystic fibrosis patients.

PURPOSE: We hypothesized that a single intravenous (iv) tobramycine infusion (treatment B) would have equivalent anti-infectious efficacy in chronic Pseudomonas aeruginosa (PA) infection in cystic fibrosis (CF) as the commonly performed treatment of three doses (treatment A) . Toxicity and practicability may even be improved in the single-dose regimen. METHODS: This was a randomized crossover study comparing outcome after 14 and 35 days. The primary end-point was a decrease in the leukocyte count, and the secondary end-points were clinical and lung function parameters, Pseudomonas quantification in sputum, and inflammation markers (immunoglobulin G, C-reactive protein) in serum. 30 patients (20 female, mean age 11.2 years, mean age range 1.7-18.1 years) received elective 14-day courses of treatments A or B, followed by the alternative treatment after a mean interval of 37 (+/- 21) weeks. RESULTS: With the exception of PA density, there were no significant differences between both treatment strategies after 14 days of treatment. After 35 days of treatment, there were no significant changes in the leukocyte count and inflammation markers. Both treatment strategies reduced the bacterial load in the airways, as reflected by a decreased PA density in sputum. Nephrotoxicity was equal in both groups, with a transient slight elevation of urinary N-acetyl-beta-glucosaminidase concentrations. Standard audiometry tests revealed no evidence of a hearing impairment in any patient following therapy. Mean body weight increased during the study period by 0.5 kg. Forced expiratory volume increased by approximately 5% of the predicted volume, forced vital capacity increased by 2% of predicted capacity, and forced mid expiratory flow rate increased by 7% (A) or 4% (B) of the predicted normal value, although these changes were not statistically significant. CONCLUSION: We conclude that tobramycin given in a daily single dose (with the advantage of being more practical in a home environment) has an efficacy equal to that of three daily doses in terms of elective antipseudomonal therapy in clinically stable patients with CF.

Continuous vs thrice-daily ceftazidime for elective intravenous antipseudomonal therapy in cystic fibrosis.

BACKGROUND/AIM: We hypothesized that a continuous 24-h infusion of 100 mg/kg per day ceftazidime (treatment C) would result in equivalent or even superior anti-infectious efficacy in chronic Pseudomonus aeruginosa (PA) infection in patients with cystic fibrosis (CF) in comparison to the usual application of 200 mg/kg per day ceftazidime in three doses (treatment T). METHODS: This was a randomized crossover study comparing outcome after 14 days and 35 days. Tobramycin administered once daily (10 mg/kg per day) was administered concomitantly in both groups. The primary end-point was a decrease in the leukocyte count, and the secondary endpoints were clinical and lung function parameters, Pseudomonas quantification in sputum, and inflammation markers (immunogloblulin [Ig] G, C-reactive protein [CRP]) in serum. All patients received antibiotics electively as 14-day courses on a regular basis, not for acute exacerbations. RESULTS: Fifty-six patients (29 females, mean patient age 14.4 years, age range 5-37) initially received treatments C or T, followed by the alternative treatment after a mean interval of 37 (+/- 21) weeks. After 2 weeks of antibiotic treatment, the overall study group showed significant improvements compared to baseline for body weight, leukocyte counts, CRP, forced expiratory volume in 1 s (FEV(1)), FVC (forced vital capacity), and bacterial load in the airways, with no significant differences between treatment groups. Both regimens were well tolerated. Three weeks after cessation of antimicrobial therapy, leukocytes and PA density had returned to pre-treatment values. CONCLUSION: We conclude that continuous or thrice-daily dosing of intravenous ceftazidime, both combined with once-daily tobramycin, are equally effective application regimens for elective antipseudomonal therapy in clinically stable patients with CF.

Clinical relevance of prevention of respiratory syncytial virus lower respiratory tract infection in preterm infants born between 33 and 35 weeks gestational age.

Premature infants are vulnerable to severe respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) resulting in hospitalisation and the potential for longer-term respiratory morbidity. Whilst the severity and consequence of RSV LRTI are generally accepted and recognised in infants born

Effect of comprehensive validation of the template isolation procedure on the reliability of bacteraemia detection by a 16S rRNA gene PCR.

The influence of the DNA extraction method on the sensitivity and specificity of bacteraemia detection by a 16S rRNA gene PCR assay was investigated. The detection limit of the assay was 5 fg with purified DNA from Escherichia coli or Staphylococcus aureus, corresponding to one bacterial cell. However, with spiked blood samples, the detection limits were 10(4) and 10(6) CFU/mL, respectively. The sensitivity of the S. aureus assay was improved to the level of the E. coli test with the addition of proteinase K to the commercial DNA extraction kit protocol. Ten (16.6%) of 60 amplification reactions were positive with templates isolated from sterile blood, while PCR reagent controls were negative, thereby indicating contamination during the DNA extraction process. Blood samples were spiked with serial dilutions of E. coli and S. aureus cells, and six PCR results were obtained from three extractions for each blood sample. A classification threshold system was devised, based on the number of positive reactions for each sample. Samples were deemed positive if at least four positive reactions were recorded, making it possible to avoid false-positive results caused by contamination. These results indicate that a comprehensive validation procedure covering all aspects of the assay, including DNA extraction, can improve considerably the validity of PCR assays for bacteraemia, and is a prerequisite for the meaningful detection of bacteraemia by PCR in the clinical setting.

Acid phosphatase during the life cycle of the nematode, panagrellus silusiae.

This study showed that there is a relationship between acid phosphatase levels and life cycle stages in the nematode, Panagrellus silusiae. Ten different isozymes of acid phosphatase were separated electrophoretically. Relative activity peaked at different stages in the life cycle for the different isozymes. Later in the life cycle, there is a general decrease in the relative activity of acid phosphatase itself, while there is a concurrent increase in the number of isozymes present. At least 97% of the acid phosphatase in P. silusiac is soluble (unbound). Acid phosphatase appears to be present in large quantities in the entire gastrointestinal tract, the excretory canals, and the reproductive system of mature Panagrellus silusiae.

Customer care. Patient satisfaction in the prehospital setting.

The focus of the study was to prioritize six emergency medical service treatment factors in terms of their impact upon patient satisfaction in the prehospital setting. The six treatment areas analyzed were: EMS response time; medical care provided on scene; explanation of care by the provider; the provider's ability to reduce patient anxiety; the provider's ability to meet the patient's non-medical needs; and the level of courtesy/politeness shown by the EMS provider toward the patient. Telephone interviews were conducted with both patients and bystanders to obtain their perception of how well the system met their needs. The study analyzed how the six issues were rated and then evaluated the impact an individual's low score in a category had on that person's overall rating of the service provided. The overall satisfaction rating is not a calculated score, but an overall score specified by the respondent. The effect each issue had on the respondent's overall rating was determined by averaging the overall ratings for a category's low scorers, averaging the overall ratings for high scorers and then measuring the difference. Results of the study indicate that the factor with the greatest negative impact on patient satisfaction came from a perceived lack of crew courtesy and politeness. Respondents who indicated a fair to poor score in this category decreased their overall score by 60.2%. Ratings in other categories yielded the following results: When respondents rated the response time as fair to poor, their average overall rating showed an 18.4% decrease. When respondents rated the quality of medical care as fair to poor, their average overall rating showed a decrease of 22.6%. When the crew's ability to explain what was happening to the patient was rated as fair to poor, the average overall score dropped 33.6%. When the EMT's and medic's ability to reduce the patient's anxiety was rated fair to poor, average overall score declined by 32.6%. Finally, when the crew's ability to satisfy a patient's non-medical needs was rated as fair to poor, the average overall score diminished by 37.4%.

Morphogenetic studies of a genetically controlled tumor-like condition in Lycopersicon hybrids.

A dominant tumor-like condition recently isolated in a tomato hybrid is described from the viewpoint of morphogenesis. Tumors, consisting of masses of enlarged parenchymatous cells, generally appear on the ventral surface of the third leaf and the subsequently formed leaves of the hybrid derivatives. These outgrowths do not differentiate into teratomas. Abortive floral buds develop under greenhouse conditions and the tumorous plants are much dwarfed compared to the normal segregants of the same population. the same tumor genotype behaves differently under the field conditions: it grows and blossoms like the normal plants, setting fruits with viable seeds, and tumors fail to develop. Thus, tumor expression and general morphology of the tumor plants are greatly modified by environmental conditions.Tissue culture studies employing a variety of media have shown that tissues excised from tumor-producing plants are not autonomous with respect to growth hormones, nor are tissues from the non-tumorous segregants. Nevertheless, tissues from tumor and non-tumor genotypes show different growth requirements. Tumor and non-tumor tomatoes can thus be distinguished on the basis of in vitro growth responses, a result consistent with their different genetic constitution. Differentiation of buds or roots was not observed in either type of tissue.

Out-of-hospital cardiac arrests: an 8-year New York City experience.

A retrospective study was conducted to determine the outcome of out-of-hospital cardiac arrests by one prehospital system in New York City from January, 1986, through December, 1993. The results were recorded consistent with the Utstein Style. Of 481 attempted patient resuscitations 406 were of cardiac etiology, with 382 patients having arrested prior to EMS arrival; their overall survival rate was 2.1% (8/382). Cardiac arrests were witnessed in 246 patients. Of the witnessed arrest patients found in ventricular fibrillation (96/246), the overall survival rate was 7.3% (7/96). Of the 7 survivors who were discharged from the hospital, 71.4% (5/7) had a good cerebral performance/good overall performance. Of 24 patients who arrested in the presence of EMS, the survival rate was 12.5% (3/24). This study confirms a poor survival rate for patients suffering out-of-hospital cardiac arrests in New York City.

Effect of dietary ingestion of oxalic acid on growth and reproduction in male and female Long-Evans rats.

Male and female Long-Evans rats placed on a diet of Purina laboratory chow supplemented with 2.5 and 5.0% oxalic acid for a period of 70 days revealed decreased body weights and restricted growth rates. Ingestion of 5.0% oxalic acid depressed absolute organ weights of several visceral and endocrine tissues but enhanced the organ/body weight ratios of both male and female rats. Vaginal smears indicated disrupted estrous cycles.

[Poststenotic systolic pressure and blood flow measurements during intra-arterial and vasoactive therapy]. / Poststenotische systolische Druck- und Blutflussmessungen unter intraarterieller und vasoaktiver Therapie.

In 34 male patients with peripheral arterial occlusive disease of the lower extremities the individual responsibility to an intraarterial adenosine triphosphate infusion was tested with the help of Doppler-sonographic poststenotic measurements of the systolic blood pressure as well as comparatively to this by determination of the arterial blood-flow in rest in the region of the calf. While the greater part of the patients with occlusive disease reacted with a significant increase of the blood supply, nearly with the same frequency a decrease of pressure or no change could be established concerning the behaviour of the peripheral pressure. For the judgment of the efficacy of an intraarterial infusion treatment in the acute experiment plethysmographic measurements of the blood-flow are, therefore, more suitable and should be preferred to Doppler-sonographic pressure parameters. As to the controls of long-term therapy under conservative treatment as well as for the judgment of the success in the reconstructive surgery of vessels, however, the post-stenotic measurements of the pressure stood the test apart from further methods in clinical practice.

[Extracardiac hemodynamic effects of the calcium antagonist nifedipine]. / Extrakardiale hämodynamische Wirkungen des Kalziumantagonisten Nifedipin.

For the purpose of testing extracardial haemodynamic effects of the calcium antagonist nifedipine (corinfar) in 15 patients with arterial obstructive disease and in a control group plethysmographic and doppler-sonographic measurements before and after oral application of the substance were performed. In these cases after the application of nifedipine a significant increase of the blood flow in the crural region developed. At the same time a slight decrease of the systolic pressure could be established at the upper and lower extremity. In patients with arterial obstructive disease these haemodynamic reactions had a less significant result. They correspond to an arterial vasodilatation with decrease of the peripheral resistance and simultaneously they explain a part of the antianginous effect of the calcium antagonist. The increase of the blood flow which is to be objectified after the application of nifedipine also in poststenotic areas might be of clinical importance particularly in the combined occurrence of atherosclerotically conditioned disturbances of the blood supply of the coronary and peripheral vascular system.

Binding of Staphylococcus aureus to fibronectin and glycolipids on corneal surfaces.

Staphylococcus aureus is one of the most common pathogens of bacterial corneal ulcers. It is generally believed that the first step necessary in the development of an infection involves adherence of bacteria to host tissue. The mechanisms by which staphylococci adhere to ocular epithelium have not yet been defined. An in vitro assay was used to measure binding of S. aureus and Streptococcus pyogenes to a cornea epithelial cell line. Reduction of the amount of cell-surface fibronectin by proteinase treatment decreased the adherence of S. pyogenes to a greater degree than that of S. aureus. The significantly higher number of staphylococci adhering to the cells as compared with S. pyogenes (P < 0.001) suggests the presence of additional binding sites for S. aureus. Using a thin-layer chromatogram overlay assay, we showed binding of S. aureus to various glycolipids extracted from corneal epithelial cells and corneal tissue. S. aureus was found to bind to gangliosides and asialo-GM1, whereas S. pyogenes did not bind to any of these complex lipids. The increased adherence potential of S. aureus due to the ability to bind to glycolipids may provide a selective advantage for S. aureus and explain the prevalence of this organism in bacterial corneal ulcers.

[Clinical aspects and prognosis of highly malignant non-Hodgkin's lymphomas]. / Klinik und Prognose der Non-Hodgkin-Lymphome hoher Malignität.

Clinical data and courses of the disease of 56 patients with non-Hodgkin-lymphomas of high malignancy were demonstrated. The age-depending summit of the frequency was between the 51st and 60th year of age, the age median was about 48 years. The initial remission rate three months after the beginning of the therapy was 66%. Out of the responders in 44% relapsed, in which cases 70% of the relapses developed in the first year after the beginning of treatment. After twelve months the survival rate was 0.52 and after 48 months 0.32. Patients with initial remission, with localized stages I and II (Ann Arbor) as well as with primarily extranodal manifestation and with histology of centroblastoma had a clear prognostic advantage. Initial B-symptomas, an advanced stage of the disease and a histology of immunoblastoma and lymphoblastoma as well were negatively correlated to the prognosis.