Outcome after neoadjuvant chemoradiation and correlation with nutritional status in patients with locally advanced pancreatic cancer.

BACKGROUND: Cancer patients commonly suffer from weight loss since rapid tumor growth can cause catabolic metabolism and depletion of energy stores such as abdominal fat. In locally advanced pancreatic cancer this is even more pronounced due to abdominal pain, fatigue, nausea or malnutrition. In the present article, we quantify this frequently observed weight loss and assess its impact on outcome and survival. METHODS: Data on demographics, biometrics, toxicity and survival were collected for the last 100 patients treated with neoadjuvant chemoradiation for locally advanced pancreatic cancer at our department (45.0 Gy and boost up to 54.0 Gy plus concurrent and subsequent gemcitabine), and the subcutaneous fat area at the umbilicus level was measured by computer tomography before and after chemoradiation. RESULTS: After chemoradiation, patients showed a highly statistically significant weight loss and reduction of the subcutaneous fat area. We could determine a very strong correlation of subcutaneous fat area to patient BMI. By categorizing patients according to their BMI based on the WHO classification as slender, normal, overweight and obese, we found improved but not statistically significant survival among obese patients. Accordingly, patients who showed less weight loss tended to survive longer. CONCLUSIONS: In this study, patients with pancreatic cancer lost weight during chemoradiation and their subcutaneous fat diminished. Changes in subcutaneous fat area were highly correlated with patients' BMI. Moreover, obese patients and patients who lost less weight had an improved outcome after treatment. Although the extent of weight loss was not significantly correlated with survival, the observed trend warrants greater attention to nutritional status in the future.

MR-guided adaptive versus ITV-based stereotactic body radiotherapy for hepatic metastases (MAESTRO): a randomized controlled phase II trial.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is an established local treatment method for patients with hepatic oligometastasis or oligoprogression. Liver metastases often occur in close proximity to radiosensitive organs at risk (OARs). This limits the possibility to apply sufficiently high doses needed for optimal local control. Online MR-guided radiotherapy (oMRgRT) is expected to hold potential to improve hepatic SBRT by offering superior soft-tissue contrast for enhanced target identification as well as the benefit of gating and daily real-time adaptive treatment. The MAESTRO trial therefore aims to assess the potential advantages of adaptive, gated MR-guided SBRT compared to conventional SBRT at a standard linac using an ITV (internal target volume) approach. METHODS: This trial is conducted as a prospective, randomized, three-armed phase II study in 82 patients with hepatic metastases (solid malignant tumor, 1-3 hepatic metastases confirmed by magnetic resonance imaging (MRI), maximum diameter of each metastasis ≤ 5 cm (in case of 3 metastases: sum of diameters ≤ 12 cm), age ≥ 18 years, Karnofsky Performance Score ≥ 60%). If a biologically effective dose (BED) ≥ 100 Gy (α/ß = 10 Gy) is feasible based on ITV-based planning, patients will be randomized to either MRgRT or ITV-based SBRT. If a lesion cannot be treated with a BED ≥ 100 Gy, the patient will be treated with MRgRT at the highest possible dose. Primary endpoint is the non-inferiority of MRgRT at the MRIdian Linac® system compared to ITV-based SBRT regarding hepatobiliary and gastrointestinal toxicity CTCAE III or higher. Secondary outcomes investigated are local, locoregional (intrahepatic) and distant tumor control, progression-free survival, overall survival, possible increase of BED using MRgRT if the BED is limited with ITV-based SBRT, treatment-related toxicity, quality of life, dosimetric parameters of radiotherapy plans as well as morphological and functional changes in MRI. Potential prognostic biomarkers will also be evaluated. DISCUSSION: MRgRT is known to be both highly cost- and labor-intensive. The MAESTRO trial aims to provide randomized, higher-level evidence for the dosimetric and possible consecutive clinical benefit of MR-guided, on-table adaptive and gated SBRT for dose escalation in critically located hepatic metastases adjacent to radiosensitive OARs. TRIAL REGISTRATION: The study has been prospectively registered on August 30th, 2021: Clinicaltrials.gov, "Magnetic Resonance-guided Adaptive Stereotactic Body Radiotherapy for Hepatic Metastases (MAESTRO)", NCT05027711.

Inhibition of hematopoietic tumor growth by combined treatment with deferoxamine and an IgG monoclonal antibody against the transferrin receptor: evidence for a threshold model of iron deprivation toxicity.

Recent studies have suggested that iron deprivation may represent a useful new approach in cancer therapy, and several strategies for producing such deprivation are now under investigation. Thus, for example, we recently provided evidence that combined treatment with the iron chelator deferoxamine and an IgG monoclonal antibody against the transferrin receptor (ATRA) produces synergistic inhibition of hematopoietic tumor cell growth in vitro (J. D. Kemp, K. M. Smith, L. J. Kanner, F. Gomez, J. A. Thorson, and P. W. Naumann, Blood, 76: 991-995, 1990). The current study is an attempt to analyze the mechanisms responsible for the synergistic interaction. The data show that a single IgG ATRA can produce up to 75% inhibition of iron uptake while having little effect on DNA synthesis; this suggests that tumor cells either take up or have stored amounts of iron well in excess of that required to support immediate metabolic needs. When deferoxamine and the IgG ATRA are used together, the effects on iron acquisition and receptor down-modulation are either additive or subadditive but are clearly not synergistic. Overall, the findings suggest that the IgG ATRA produces an injury to iron uptake that is just below a critical threshold and that the additional effect provided by the iron chelator is sufficient to exceed that threshold and produce a rapid depletion of iron pools that are vital for short-term DNA synthesis. IgG ATRAS thus seem to be of even greater interest as therapeutic reagents, and further study of their properties and of how they interact with deferoxamine appears to be warranted.

Inhibition of lymphoma growth in vivo by combined treatment with hydroxyethyl starch deferoxamine conjugate and IgG monoclonal antibodies against the transferrin receptor.

Synergistic inhibition of hematopoietic tumor growth can be observed in vitro when the iron chelator deferoxamine (DFO) is used in combination with an IgG mAb against the anti-transferrin receptor antibody (ATRA). Our goal was to ascertain whether similar findings could be seen in vivo. A high molecular weight conjugate of deferoxamine, known as hydroxyethyl starch (HES) DFO or HES-DFO, was tested in conjunction with C2, a well-defined rat antimouse transferrin receptor mAb, against the 38C13 tumor in C3H/HeN mice. It was shown that while neither HES-DFO alone nor C2 alone produced consistent, significant inhibition of tumor growth, the combination of HES-DFO and C2 produced virtually complete inhibition of initial tumor outgrowth. The latter combination failed, however, to inhibit the growth of established tumors. It was then found that when C2 was used in conjunction with RL34, another IgG ATRA, the two ATRAS were themselves capable of causing synergistic inhibition of the growth of 38C13 in vitro. When the two IgG ATRAS were used together in vivo, regressions of established tumors were observed. Moreover, the addition of HES-DFO to the IgG ATRA pair then caused more frequent regressions. Although there was never any obvious toxicity seen with a single IgG ATRA, the use of the IgG ATRA pair was associated with sporadic mortality. In addition, although HES-DFO by itself was also not associated with any obvious toxicity, combined treatment with HES-DFO and a single ATRA resulted in death due to bacterial infection in about half of the mice after 10-15 days. Combined treatment with HES-DFO and the ATRA pair resulted in death attributed to infection in nearly all of the mice after 6 days. Thus, an iron deprivation treatment protocol with HES-DFO and IgG ATRAS produced both a significant antitumor effect and an increased risk of infection in a murine model system.

Iron deprivation induces apoptosis independently of p53 in human and murine tumour cells.

Iron deprivation induces apoptosis in some sensitive cultured tumour cells, while other cells are resistant. In order to elucidate the mechanisms involved in apoptosis induction by iron deprivation, we studied the expression of p53 and the expression of selected p53-regulated genes. To discriminate between changes coupled only with iron deprivation and changes involved in apoptosis induction by iron deprivation, we compared the expression of the genes in sensitive (human Raji, mouse 38C13) versus resistant (human HeLa, mouse EL4) cells under iron deprivation. Iron deprivation was achieved by incubation in a defined iron-free medium. The level of p53 mRNA decreased significantly under iron deprivation in sensitive cells, but it did not change in resistant cells. On the contrary, the level of the p53 protein under iron deprivation was slightly increased in sensitive cells while it was not changed in resistant cells. The activity of p53 was assessed by the expression of selected p53-regulated targets, i.e. p21(WAF1/CIP1) gene, mdm2, bcl-2 and bax. We did not detect any relevant change in mRNA levels as well as in protein levels of these genes under iron deprivation with the exception of p21(WAF1/CIP1). We detected a significant increase in the level of p21 mRNA in both (sensitive and resistant) mouse cell lines tested, however, we did not find any change in both (sensitive and resistant) human cell lines. Moreover, the p21(WAF1/CIP1) protein was accumulated in mouse-sensitive 38C13 cells under iron deprivation while all other cell lines tested, including human-sensitive cell line Raji, did not show any accumulation of p21(WAF1/CIP1) protein. It seems that the p21(WAF1/CIP1) mRNA, as well as protein accumulation, is not specifically coupled with apoptosis induction by iron deprivation and that it is rather cell-line specific. Taken together, we suggest that iron deprivation induces apoptosis at least in some cell types independently of the p53 pathway.

Clinical comparison of Gentle-Haler Actuator and Aerochamber Spacer for Metered Dose Inhaler (MDI) use by asthmatics.

UNLABELLED: Spacing devices such as the Aerochamber have been shown to improve delivery of medication from MDIs in patients who could not use proper technique with an MDI alone, but the Aerochamber may be inconvenient to carry & use because of its bulkiness. We therefore compared clinical responses of asthmatics using a new, smaller MDI actuator (Gentle-Haler) with no spacer to their responses using a standard MDI actuator & spacer (Aerochamber). METHODS: We treated 30 asthmatic patients in 2 sessions with the beta-agonist albuterol using the above-mentioned devices. Both devices were utilized in each treatment session, with one delivering albuterol & the other generating a placebo. During the second session on a different day, the albuterol & placebo were reversed with respect to the two devices. On each study day, physiologic measurements of FEV1, FVC, FEF25-75, blood pressure, & pulse were obtained at pretreatment (baseline) & after treatment at 15 & 30 minutes & 1, 2, 3, 4, 5 & 6 hours. Analysis of variance & Student's t test were used to compare the ratio of physiologic responses to albuterol delivered with the two devices. RESULTS: Both devices were equally effective in eliciting desirable increases in FEV1, FEF25-75, & FVC. No statistically significant differences (5% significance level) in effectiveness of the albuterol were associated with the use of either device. A very small (< 7%) but statistically significant reduction in diastolic blood pressure (3 of 8 time points) & systolic pressure (1 of 8 time points) was associated with the use of the Gentle-Haler.(ABSTRACT TRUNCATED AT 250 WORDS)

The technical competence of registered nurses in the administration of oral medications.

An individual who desires to become a registered nurse (RN) may choose from three types of education: associate degree, diploma, and baccalaureate degree programs. The dilemma of this decision is heightened by the strong disagreement within the nursing profession regarding which of the three modes best prepares a nurse to become a competent practitioner. The purpose of this study was to examine variables which might explain variance in the technical competence of RNs as evidenced by skill in administering oral medications. Six variables were investigated as possible predictors of the variance in oral medication administration procedure, i.e., basic nursing education, drug knowledge, age, previous RN experience, previous nursing experience, and highest nursing education completed. Sixty volunteer RNs in a Baltimore community hospital (252 beds) were observed twice each as they administered two oral medications to a patient. A Technical Competence Tool (TCT) was used to record performance of the 16 critical behaviors deemed essential for safe and accurate drug administration. The total scores from observation one and two were summed to obtain a total competence score. Each nurse also completed a 14-item Drug Knowledge Profile (DKP) and Demographic Data Sheet (DDS). Although there was a wide range of total competence scores, only three percent of the variance was explained by the six predictor variables. It was concluded that the selected variables were not significant predictors of the technical competence of RNs in the administration of oral medications.(ABSTRACT TRUNCATED AT 250 WORDS)

[Cephalosporin antibiotics from microbiologic viewpoint. A comparison of antibacterial and pharmacokinetic properties]. / Cephalosporin-Antibiotika aus der Sicht des Mikrobiologen. Ein Vergleich der antibakteriellen und pharmakokinetischen Eigenschaften

With the necessity not only of differentiating between effectiveness and non-effectiveness, as in the earlier phases of chemotherapy, but also of detecting graduated differences in effect quantitatively, animal experiment and clinical trial have been shown to be no longer adequate. In a correlating comparison of antibacterial activity with the drug level in vivo as the two decisive basic elements of chemotherapeutic effect, new and interesting possibilities arise for the evaluation of antibiotics. In a comparative evaluation of nine different cephalosporin antibiotics, not only the objective antibacterial and pharmacokinetic properties are taken into consideration, but also the dosage recommendations of the manufacturers as subjective factors. The result is that the cephalosporins in the treatment of gram-positive infections (except enterococci) are almost equivalent. In the gram-negative field, there are marked differences which produce a different species-dependent therapeutic value for the various preparations. A fundamentally superior "universal" cephalosporin for all bacterial infections does not exist.

[Development of resistance in imipenem therapy in Pseudomonas aeruginosa]. / Resistenzentwicklung unter Imipenem-Therapie bei Pseudomonas aeruginosa.

8.4% of the isolated Pseudomonas aeruginosa strains were resistant against imipenem in this study. 3.7% of them became resistant as a result of the antibiotic therapy. In some patients on intensive care units, the resistance of Pseudomonas aeruginosa against imipenem emerged within a few days. In two of these cases a simultaneous loss of activity of the other pseudomonas-beta-lactams was observed.

[Diphtheria immunity in school beginners and after reimmunization with d-vaccine]. / Diphtherie-Immunität bei Schulanfängern und nach Wiederimpfung mit d-Impfstoff.

The antitoxin immune status against diphtheria was determined in 814 children, aged 6-7 years, 5-6 years after first immunization. All children were then re-immunized with d-vaccine. 4-8 weeks later antitoxin was again measured to assess the immunogenic effect of the booster injection (reduced toxoid dosage of 5 IU/0.5 ml). Although all children had been completely immunized as infants, 149 of them (18.3%) presented inadequate or no immunity to diphtheria. The booster injection resulted in a reliably protective antibody concentration of 0.1 IU/ml serum even in children with low or no longer demonstrable residual immunity. The high proportion of inadequately protected children and the further continual loss of antitoxin antibodies makes booster injection mandatory at the time of beginning school as well as in juveniles and adults. The Standing Immunization Commission of the Federal German Health Office recommends this re-immunization every 10 years in the form of combined tetanus-diphtheria immunization with Td vaccine.

[Present-day serological diagnosis of syphilis: comparison of TPHA and FTA-ABS tests with classical flocculation and complement-fixation reaction (author's transl)]. / Moderne Serodiagnostik der Syphilis. Ein Vergleich von TPHA- und FTA-ABS-Test mit den klassischen Flockungs- und Komplementbindungs-Reaktionen.

Twelve laboratories in the north Rhine-Westphalia participated in comparing TPHA and FTA-ABS tests with the so-called classical syphilis reactions (VDRL test, cardiolipin and pallida complement-fixation reaction, as well as Meinicke clearing reaction II). TPHA and FTA-ABS tests proved to be superior to the conventional methods both as regards specificity and sensitivity. Present-day serological tests of syphilis can thus be limited to the TPHA test to exclude syphilis, the FTA-ABS test as a confirmatory reaction and the VDRL test to judge the need or effectiveness of antisyphilitic treatment. These reactions which supersede the conventional syphilis tests serve for rational, reliable and cheap serological diagnosis of syphilis.

[In vitro activity of ciprofloxacin and ofloxacin against Mycobacterium tuberculosis, M. avium, M. africanum, M. kansasii and BCG strains]. / In-vitro-Aktivität von Ciprofloxacin und Ofloxacin gegen Mycobacterium tuberculosis, M. avium, M. africanum, M. kansasii und BCG-Stämme.

The in vitro activity of ciprofloxacin and ofloxacin against 33 strains of mycobacteria was investigated in a comparative study. The resulting MIC values were compared with serum levels, measured in a cross-over study. Possible therapeutic application of these substances in mycobacterial infections are being discussed. We found the antimycobacterial activity of ciprofloxacin to be insufficient for its clinical application, whereas the corresponding MIC values for ofloxacin could be achieved in vivo. Further animal and clinical studies appear justified.

[Usefulness of commercial culture media for gonococcal diagnosis in general practice. Comparative study of various test systems]. / Zur Brauchbarkeit handelsüblicher Kulturmedien für die Gonokokkendiagnose in der Praxis. Vergleichende Untersuchung verschiedener Testsysteme.

In comparative investigations under standardized conditions, the gonococcus culture systems distributed by Miles GmbH, Orion Diagnostica GmbH, and Röhm Pharma GmbH were examined with regard to their usefulness for cultural diagnosis of gonorrhea in general practice. It was shown that because of substantial imperfections Microcult GC (Miles) is not suitable for the diagnosis of gonorrhea. Since microorganisms were grown on Biocult (Orion) and Gono-Nährböden (Röhm) which may cause a false-positive diagnosis, as well as microorganisms that may cause a false-negative diagnosis, these products are only of limited value for the venerologist in practice.

[Incidence of bacteremia following extractions--a double blind study on local disinfection using chlorhexidine]. / Bakteriämie-Häufigkeit bei Extraktionen. Doppelblindstudie zur lokalen Desinfektion mit Chlorhexidin.

In a randomised double-blind study the incidence of bacteremia after two minutes mouth rinsing with chlorhexidine 0.1% followed by tooth extractions was registered. A significant reduction of bacteremia could not be observed in comparison with mouth rinsing with physiological saline solution. Tooth extractions always require the preventive administration of antibiotics to patients known with high risk of endocarditis.

[Sisomicin versus gentamicin. A comparison of antibacterial and pharmacokinetic properties (author's transl)]. / Sisomicin versus gentamicin. Ein Vergleich der antibakteriellen und pharmakokinetischen Eigenschaften

In a comparison of the antibacterial in-vitro activity of sisomicin, gentamicin, and tobramycine, sisomicin showed a higher activity against E. coli, indole-positive Proteus spp. and organisms of the Klebsiella-Enterobacter-Serratia group, whereas tobramycine was superior against Pseudomonas spp. However, the differences in activity between sisomicin and gentamicin were only within one step of dilution which is hardly sufficient to guarantee a basic superiority of one or the other preparation for clinical purposes. In 12 healthy probands serum levels and renal elimination of sisomicin and gentamicin after a single intramuscular injection of 1 mg/kg body weight were investigated in a randomised change-over trial. With corresponding serum levels, almost identical elimination half-lives of 109 and 111 minutes, and recovery values of 84 and 88.4%, respectively, there were no significant differences in the pharmacokinetics of sisomicin and gentamicin. Thus in the antibacterial treatment of gentamicin-sensitive gram-negative organisms sisomicin presents an equally good alternative. With organisms only moderately sensitive or resistant to gentamicin, sisomicin, tobramycine and amikacin should be additionally tested.

In vitro susceptibility of clinically important bacteria to amikacin: correlation of results of broth dilution and disk sensitivity tests and effect of medium composition.

Minimal inhibitory concentrations of amikacin for 296 strains of gram-positive and gram-negative bacteria determined in Mueller-Hinton broth by the method recommended by the International Collaborative Study Group confirmed previous observations that amikacin is effective against current clinical isolates sensitive to gentamicin and that strains moderatly sensitive or resistant to gentamicin are often inhibited by clinically achievable concentrations. A simple linear regression analysis was used for comparison of zone sizes obtained with 10-mug disks of amikacin with minimal inhibitory concentrations obtained by the tube dilution technique. For 152 strains, including seven species of Enterobacteriaceae, the correleation coefficient (r) was -0.79 on Oxoid diagnostic senstivity test agar (which yields zone sizes similar to those obtained on Mueller-Hinton medium) and -0.78 on Oxoid isotonic sensitest agar (which contains cations in isotonic concentrations); the figures were -0.74 and -0.66, respectively, for 80 strains of Pseudomonas aeruginosa. Zone sizes for enteric gram-negative bacilli were on the average 2-3 mm smaller on isotonic sensitest agar than on diagnostic sensitivity test agar, and about 6 mm smaller for strains of P. aeruginosa and Providencia. Minimal inhibitory concentrations of amikacin can be estimated satisfactorily by extrapolation of results of agar diffusion tests, but the composition of the medium, particularly its calcium and magnesium content, should be defined precisely.