Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients with HIV-Associated Cryptococcal Meningitis

Amphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 μmol/liter (95% CI, 30 to 45 μmol/liter) by day 7 and by 49 μmol/liter (95% CI, 35 to 64μmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 μmol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3; P = 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11; P = 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility.     

Antitumor activity of an anti‐CD98 antibody

CD98 is expressed on several tissue types and specifically upregulated on fast‐cycling cells undergoing clonal expansion. Various solid (e.g., nonsmall cell lung carcinoma) as well as hematological malignancies (e.g., acute myeloid leukemia) overexpress CD98. We have identified a CD98‐specific mouse monoclonal antibody that exhibits potent preclinical antitumor activity against established lymphoma tumor xenografts. Additionally, the humanized antibody designated IGN523 demonstrated robust tumor growth inhibition in leukemic cell‐line derived xenograft models and was as efficacious as standard of care carboplatin in patient‐derived nonsmall lung cancer xenografts. In vitro studies revealed that IGN523 elicited strong ADCC activity, induced lysosomal membrane permeabilization and inhibited essential amino acid transport function, ultimately resulting in caspase‐3 and ‐7‐mediated apoptosis of tumor cells. IGN523 is currently being evaluated in a Phase I clinical trial for acute myeloid leukemia (NCT02040506). Furthermore, preclinical data support the therapeutic potential of IGN523 in solid tumors.     

Impact of tumour volume on prediction of progression-free survival in sinonasal cancer

Background

The present study aimed to analyse potential prognostic factors, with emphasis on tumour volume, in determining progression free survival (PFS) for malignancies of the nasal cavity and the paranasal sinuses.

Patients and methods

Retrospective analysis of 106 patients with primary sinonasal malignancies treated and followed-up between March 2006 and October 2012. Possible predictive parameters for PFS were entered into univariate and multivariate Cox regression analysis. Kaplan-Meier curve analysis included age, sex, baseline tumour volume (based on MR imaging), histology type, TNM stage and prognostic groups according to the American Joint Committee on Cancer (AJCC) classification. Receiver operating characteristic (ROC) curve analysis concerning the predictive value of tumour volume for recurrence was also conducted.

Results

The main histological subgroup consisted of epithelial tumours (77%). The majority of the patients (68%) showed advanced tumour burden (AJCC stage III–IV). Lymph node involvement was present in 18 cases. The mean tumour volume was 26.6 ± 21.2 cm³. The median PFS for all patients was 24.9 months (range: 2.5–84.5 months). The ROC curve analysis for the tumour volume showed 58.1% sensitivity and 75.4% specificity for predicting recurrence. Tumour volume, AJCC staging, T- and N- stage were significant predictors in the univariate analysis. Positive lymph node status and tumour volume remained significant and independent predictors in the multivariate analysis.

Conclusions

Radiological tumour volume proofed to be a statistically reliable predictor of PFS. In the multivariate analysis, T-, N- and overall AJCC staging did not show significant prognostic value.     

Nitrous oxide free low-flow anesthesia

The routine use of nitrous oxide as a component of the carrier gas has been unanimously called into question in recent surveys, in fact, its use is now recommended in indicated cases only. Whereas a lot of contraindications are listed in the surveys, precise definitions of justified indications are not given. In clinical routine practice, there are absolutely no problems in carrying out inhalational anaesthesia without nitrous oxide. The missing analgetic effect can be compensated for by moderately increasing the additively used amount of opioids, while the missing hypnotic effect can be achieved by raising the expired concentration of the inhalational anaesthetic by not more than 0.2-0.25 x MAC. Thus, when isoflurane is used, an expired concentration of 1.2 vol% is desired, in the case of sevoflurane of 2.2 vol% and with desflurane of 5.0 vol%. In addition, doing without nitrous oxide facilitates the performance of low flow anaesthetic techniques considerably. Since the patient only inhales oxygen and the volatile anaesthetic, the total gas uptake is reduced significantly. Washing out nitrogen is no longer necessary. This means that the initial phase of low flow anaesthesia, during which high fresh gas flows have to be used, can be kept short. Its duration is now determined by the wash-in of the volatile anaesthetic. Since there is no uptake of nitrous oxide, a considerably greater volume of gas is circulating within the breathing system, minimizing the possibility of accidental gas volume deficiency. Thus, if anaesthesia machines with highly gas-tight breathing systems are used, even the performance of non-quantitative closed system anaesthesia becomes possible in routine clinical practice. The carrier gas flow can be reduced to just that amount of oxygen which is really taken up by the patient. This oxygen volume can be roughly calculated by applying the Brody's formula. Using fresh gas flows as low as 0.25 l/min, however, will result in a significant decrease of the output of conventional vaporizers outside the circuit. Thus, it becomes nearly impossible to maintain an expired isoflurane concentration of 1.2 vol%. With respect to their pharmcokinetic properties, the newer low soluble volatile agents sevoflurane and desflurane are better suited for use with flows corresponding to the basal oxygen uptake. Our own clinical experience, gained in the last six months from a trial involving over 1,800 patients, shows that the increase in opioid consumption resulted in additional costs of about 0.25-0.50 DM per patient. The increased concentration of inhalational agents brought additional costs of 3.00 to 5.00 DM for a two-hour anaesthesia. On the other hand, doing without nitrous oxide saved 2.61 DM per one-hour anaesthesia, whereby our consumption of nitrous oxide is extremely low as minimal flow anaesthesia is performed consistently. Furthermore, these calculations disregard the cost of the technical maintenance fo the central gas piping system and of the regular measurement of workplace contamination with nitrous oxide by a certified institute, which in Germany, ad least, is obligatory. The additional costs of nitrous oxide-free inhalational anaesthesia seem to be balanced by the savings. Given the numerous justified arguments against the routine use of nitrous oxide, the lack of precisely-defined indications and the clinical experience showing that doing without nitrous oxide is uncomplicated, self-financing and ecologically beneficial, the use of nitrous oxide should be given up completely.     

Über den Kochsalzgehalt der Suppen als Maßstab der Geschmacksrichtung

Ohne ZusammenfassungMit 1 Textabbildung.     

Zur Nomenklatur in der sogenannten Salmonella-Gruppe

Zusammenfassung Gegen den vonKauffmann veröffentlichten Vorschlag einer neuen wissenschaftlichen Salmonella-Nomenklatur, nach dem in Zukunft die Typen gruppenmäßig mit großen Buchstaben und Zahlen zu kennzeichnen sind, werden Bedenken erhoben. Eine Nomenklatur, die mit der Klassifizierung in der vonKauffmann vorgeschlagenen Weise verknüpft ist, wird die Übersichtlichkeit, die sie zunächst zu besitzen scheint, verlieren, sobald neue Typen entdeckt werden. Der Name eines Typs ist von dem jeweiligen Stande der Forschung abhängig und daher Änderungen unterworfen. Die Benennung widerspricht daher den sachlichen Grundsätzen einer wissenschaftlichen Nomenklatur.Welche der serologischen Typen später als Arten anzusehen sein werden oder zu solchen zusammengefaßt werden können, kann heute noch nicht angegeben werden. Soll zur vorläufigen Verständigung über die einzelnen Salmonellastämme eine Kennzeichnung durch Zahlen erfolgen, so ist nur eine fortlaufende Numerierung zweckmäßig, die nicht mit einer Klassifikation verknüpft ist.