Pharmacokinetics of low-dose isosorbide dinitrate and metabolites after buccal or oral administration]

The kinetics of isosorbide dinitrate (ISDN; CAS 87-33-2) and its metabolites isosorbide-5-mononitrate (IS-5-MN) and isosorbide-2-mononitrate (IS-2-MN) were examined after buccal and oral administration of 5 mg ISDN. Twelve healthy volunteers were included in a randomized cross-over study. The mean dose-corrected AUCs for total nitrate in serum after the two different preparations were in the same range. The relative bioavailability of ISDN applied buccally, however, was more than twice that after oral application. The metabolism of ISDN differed depending on the route of administration, where the AUC-ratios ISDN: IS-2-MN: IS-5-MN were 1:2.7:19.4 after buccal and 1:5.7:53.4 after oral application respectively. The absorption rate constants Ka for ISDN and the MRT after buccal and oral application did not differ significantly. The same holds for the mean residence time.     

Deterioration of detectable human immunodeficiency virus serum p24 antigen in samples stored for batch testing.

Virologic measurements are becoming important surrogate markers for therapeutic efficacy in clinical trials with human immunodeficiency virus (HIV)-infected subjects. One such marker which is inexpensive and easily evaluated is the HIV p-24 antigen. To determine the storage stability of p24 antigen assayed by enzyme-linked immunosorbent assay of serum collected during clinical trials, a retrospective analysis was performed. The p24 antigen results were available from four Adult or Pediatric AIDS Clinical Trials Group protocols: studies 047, 050, 128, and 213. Paired samples (n = 930) which were assayed by ELISA for p24 antigen both in real time and in batch were analyzed for agreement. Batch and real-time values were correlated; however, there was a lack of agreement which increased with prolonged storage time of batched samples and greater p24 antigen levels. The p24 antigen values were significantly lower in the batched samples, which had a maximum storage time of 1,548 days. The degradation rate of p24 antigen per year was 0.052 log10 for samples with less than 30 pg/ml, 0.197 log10 for those with 30 to 100 pg/ml, and 0.245 log10 for those with > 100 pg/ml. Due to degradation over time, use of p24 antigen values from batch assays with long-term storage could bias study results toward a lack of treatment effect. On the basis of these results we make the following recommendations. (i) Samples should be assayed either in real time by laboratories undergoing quality assurance or in batch with short-term storage (less than 1 year). (ii) When real-time assays are to be performed, the serum samples should not be stored at 4 degrees C, but should be frozen immediately after processing and stored frozen until tested.     

13th St. Gallen International Breast Cancer Conference 2013: Primary Therapy of Early Breast Cancer Evidence,Controversies, Consensus – Opinion of a German Team of Experts (Zurich 2013)

Zusammenfassung

Alle zwei Jahre findet in St. Gallen (Schweiz) die internationale Konsensuskonferenz zur Behandlung des primären Mammakarzinoms statt. Da sich das internationale Panel in St. Gallen aus Experten unterschiedlicher Länder zusammensetzt, spiegelt der Konsensus ein internationales Meinungsbild wider. Vor diesem Hintergrund erscheint es aus deutscher Sicht sinnvoll, die Abstimmungsergebnisse für den Therapiealltag in Deutschland zu konkretisieren. Eine deutsche Arbeitsgruppe mit acht Brustkrebsexperten, von denen zwei Mitglieder des internationalen St. Gallen-Panels sind, hat daher die Abstimmungsergebnisse der St. Gallen-Konsensuskonferenz (2013) für den Klinikalltag in Deutschland kommentiert. Inhaltliche Schwerpunkte der diesjährigen St. Gallen-Konferenz waren operative Fragestellungen der Brust und der Axilla, strahlentherapeutische und systemische Therapieoptionen sowie die klinische Relevanz der Tumorbiologie. Intensiv diskutiert wurde der klinische Einsatz von Multigen-Assays, inkl. ihrer Bedeutung für die individuelle Therapieentscheidung.     

A cross-sectional investigation of fatigue in advanced renal cell carcinoma treatment: Results from the FAMOUS study

ObjectiveWith an increasing choice of new treatment options, the management of side effects to maintain a chosen treatment if likely to be effective on the tumor remains important. The perception of side effects however varies between the physician and the patient, leading to possible wrong assumptions on tolerability that result in dose modifications, which may ultimately affect effectiveness. The aim was to assess fatigue in patients with advanced or metastatic renal cell carcinoma (RCC) by comparing the evaluation of the physician to the one provided by their respective patient. In addition, we aimed to assess possible influences of fatigue on parameters of quality of life.MethodsPatients receiving systemic treatment for advanced RCC and their physicians were questioned independently regarding incidence and severity of fatigue and its effect on quality of life.ResultsBoth physicians and patients completed 98 matching questionnaires. Patients were treated with sunitinib, sorafenib, bevacizumab combined with interferon alpha, temsirolimus, everolimus, or interferon alpha alone. Incidence and severity of fatigue was differently assessed by patients and physicians, with fatigue being more severe when reported by the patient. The severity of fatigue increased with progressing treatment lines. Quality of life was significantly lower in patients experiencing fatigue compared with patients without fatigue. Emotional, functional, and physical well-being were all affected by fatigue, the latter being the most affected subscale. Social well-being was least affected.ConclusionFatigue is a complex and cumulative condition of patients treated for advanced RCC, and it considerably affects patient's quality of life. As many of its underlying causes may be treated, the divergent perception of occurrence and severity of fatigue should be integrated in treatment concepts. The active role of the patient in helping to manage ailments through assessment should be implemented when optimizing treatment of RCC.     

Rare patients in routine care: Treatment and outcome in advanced papillary renal cell carcinoma in the prospective German clinical RCC-Registry

Non-clear cell renal cell carcinoma is a very rare malignancy that includes several histological subtypes. Each subtype may need to be addressed separately regarding prognosis and treatment; however, no Phase III clinical trial data exist. Thus, treatment recommendations for patients with non-clear cell metastatic RCC (mRCC) remain unclear. We present first prospective data on choice of first- and second-line treatment in routine practice and outcome of patients with papillary mRCC. From the prospective German clinical cohort study (RCC-Registry), 99 patients with papillary mRCC treated with systemic first-line therapy between December 2007 and May 2017 were included. Prospectively enrolled patients who had started first-line treatment until May 15, 2016, were included into the outcome analyses (n = 82). Treatment was similar to therapies used for clear cell mRCC and consisted of tyrosine kinase inhibitors, mechanistic target of rapamycin inhibitors and recently checkpoint inhibitors. Median progression-free survival from start of first-line treatment was 5.4 months (95% confidence interval [CI], 4.1–9.2) and median overall survival was 12.0 months (95% CI, 8.1–20.0). At data cutoff, 73% of the patients died, 6% were still observed, 12% were lost to follow-up, and 9% were alive at the end of the individual 3-year observation period. Despite the lack of prospective Phase III evidence in patients with papillary mRCC, our real-world data reveal effectiveness of systemic clear cell mRCC therapy in papillary mRCC. The prognosis seems to be inferior for papillary compared to clear cell mRCC. Further studies are needed to identify drivers of effectiveness of systemic therapy for papillary mRCC.