Challenges and Opportunities for Real-World Evidence in Metastatic Luminal Breast Cancer

BackgroundThe therapeutic armamentarium for patients with metastatic breast cancer is becoming more and more specific. Recommendations from clinical trials are not available for all treatment situations and patient subgroups, and it is therefore important to collect real-world data.SummaryTo develop recommendations for up-to-date treatments and participation in clinical trials for patients with metastatic breast cancer, the Prospective Academic Translational Research PRAEGNANT Network was established to optimize the quality of oncological care in the advanced therapeutic setting. The main aim of PRAEGNANT is to systematically record medical care for patients with metastatic breast cancer in the real-life setting, including the outcome and side effects of different treatment strategies, to monitor quality-of-life changes during therapy, to identify patients eligible for participation in clinical studies, and to allow targeted therapies based on the molecular structures of breast carcinomas.Key MessagesThis article describes the PRAEGNANT network and sheds light on the question of whether the various end points from clinical trials can be transferred to the real-world treatment situation.     

Impact of a preceding striatal excitotoxic lesion and treatment with ciliary neurotrophic factor on striatal graft survival

The survival of grafted embryonic striatal tissue, dissected from the lateral ganglionic eminence, depends on the status of the host striatum. We found significantly larger volumes of surviving graft tissue and of striatal-like tissue (P-zone) within the graft, when the host striatum had been subjected to an excitotoxic lesion prior to transplantation surgery. Concomitantly the numbers of surviving grafted cells, assessed in both cresyl violet-stained sections and in sections stained with an immunohistochemical marker for striatal neurons, increased as compared to when graft tissue was placed in an intact unlesioned striatum. Finally, we examined the impact of treatment of the donor tissue with ciliary neurotrophic factor (CNTF) on graft survival. CNTF has previously been shown to protect striatal neurons against excitotoxic insults both in vitro and in vivo, but it did not improve striatal graft survival when added to the cell suspension prior to implantation.     

Effects of ciliary neurotrophic factor on excitotoxicity and calcium-ionophore A23187-induced cell death in cultured embryonic striatal neurons

Ciliary neurotrophic factor (CNTF) has a protective effect on the striatum in animal models of Huntington's disease. However, the mechanism through which it exerts its effect is not clear. In this study, we show that there is a concentration-dependent direct protective effect of CNTF against N-methyl-D-aspartate-mediated excitotoxicity on striatal neurons in vitro. The CNTF has to be added more than half an hour before the insult for the effect to occur and its effect is eliminated by the presence of the protein synthesis inhibitor cycloheximide. This suggests that the protective mechanism of CNTF does not involve acute interference with the glutamate receptors, but probably requires gene/protein expression. We have also shown that the effect of CNTF against glutamate-induced excitotoxicity is dependent on the concentration of glutamate with a protective effect more evident at a low grade excitotoxic insult. Finally, we saw no effect of CNTF on calcium ionophore A23187-induced toxicity in striatal cultures, indicating that the growth factor does not promote survival by enhancing general defenses against raised intracellular levels of calcium.     

Developmentally Regulated Expression of HDNF/NT-3 mRNA in Rat Spinal Cord Motoneurons and Expression of BDNF mRNA in Embryonic Dorsal Root Ganglion

Northern blot analysis was used to demonstrate high levels of hippocampus-derived neurotrophic factor/neurotrophin-3 (HDNF/NT-3) mRNA in the embryonic day (E) 13 - 14 and 15 - 16 spinal cord. The level decreased at E18 - 19 and remained the same until postnatal day (P) 1, after which it decreased further to a level below the detection limit in the adult. In situ hybridization revealed that the NT-3 mRNA detected in the developing spinal cord was derived from motoneurons and the decrease seen at E18 - 19 was caused by a reduction in the number of motoneurons expressing NT-3 mRNA. The distribution of NT-3 mRNA-expressing cells in the E15 spinal cord was very similar to the distribution of cells expressing choline acetyltransferase or nerve growth factor receptor (NGFR) mRNA. Moreover, a striking similarity between the developmentally regulated expression of NT-3 and NGFR mRNA was noted in spinal cord motoneurons. A subpopulation of all neurons in the dorsal root ganglia expressed brain-derived neurotrophic factor (BDNF) mRNA from E13, the earliest time examined, to adulthood. These results are consistent with a trophic role of NT-3 for proprioceptive sensory neurons innervating the ventral horn, and imply a local action of BDNF for developing sensory neurons within the dorsal root ganglia.     

Absorption/metabolism of sulforaphane and quercetin, and regulation of phase II enzymes, in human jejunum in vivo.

For the first time the human intestinal effective permeability, estimated from the luminal disappearance and intestinal metabolism of phytochemicals, sulforaphane and quercetin-3,4'-glucoside, as well as the simultaneous changes in gene expression in vivo in enterocytes, has been studied in the human jejunum in vivo (Loc-I-Gut). Both compounds as components of an onion and broccoli extract could readily permeate the enterocytes in the perfused jejunal segment. At the physiologically relevant, dietary concentration tested, the average effective jejunal permeability (Peff) and percentage absorbed (+/- S.D.) were 18.7 +/- 12.6 x 10-4 cm/s and 74 +/- 29% for sulforaphane and 8.9 +/- 7.1 x 10-4 cm/s and 60 +/- 31% for quercetin-3,4'-diglucoside, respectively. Furthermore, a proportion of each compound was conjugated and excreted back into the lumen as sulforaphane-glutathione and quercetin-3'-glucuronide. The capacity of the isolated segment to deconjugate quercetin from quercetin-3,4'-diglucoside during the perfusion was much higher than the beta-glucosidase activity of the preperfusion jejunal contents, indicating that the majority (79-100%) of the beta-glucosidase capacity derives from the enterocytes in situ. Simultaneously, we determined short-term changes in gene expression in exfoliated enterocytes, which showed 2.0 +/- 0.4-fold induction of glutathione transferase A1 (GSTA1) mRNA (p < 0.002) and 2.4 +/- 1.2-fold induction of UDP-glucuronosyl transferase 1A1 (UGT1A1) mRNA (p < 0.02). The changes in gene expression were also seen in differentiated Caco-2 cells, where sulforaphane was responsible for induction of GSTA1 and quercetin for induction of UGT1A1. These results show that food components have the potential to modify drug metabolism in the human enterocyte in vivo very rapidly.     

Observations on the mode of action of an intratubal device, the P-block

A hydrogelic intratubal device, called P-block, Mark 9, was inserted hysteroscopically with local anesthesia in the intramural part of the fallopian tube of 25 women referred for the procedure as an alternative to abdominal sterilization. Hysterosalpingography revealing bilateral oviductal patency was followed by hysteroscopic checkup verifying bilateral presence of P-blocks, except in three patients who had expulsion of the P-blocks on one side. All of the 22 patients had retention of the P-blocks 6 to 7 months after insertion. None became pregnant. Thus it is suggested that an intratubal device in the isthmic part of the human fallopian tube acts as an intrauterine contraceptive device, preventing intratubal and intrauterine pregnancies. Endeavors to explain the contraceptive effect of a nonocclusive intratubal device are discussed on the basis of our present knowledge of tubal physiology. Distension of part of the human isthmus is likely to disturb normal gamete transport through the isthmus.     

Surgery for Pituitary Tumor Apoplexy Is Associated with Rapid Headache and Cranial Nerve Improvement

Pituitary tumor apoplexy (PTA) classically comprises sudden-onset headache, loss of vision, ophthalmoparesis, and decreased consciousness. It typically results from hemorrhage and/or infarction within a pituitary adenoma. Presentation is heterologous, and optimal management is debated. The time course of recovery of cranial nerve deficits (CNDs) and headaches is not well established. In this study, a retrospective series of consecutive patients with PTA managed at a single academic institution over a 22-year period is presented. Headaches at the time of surgery were more severe in the early and subacute surgical cohort and improved significantly within 72 h postoperatively (p < 0.01). At one year, 90% of CNDs affecting cranial nerves (CNs) 3, 4, and 6 had recovered, with no differences between early (<4 d), subacute (4–14 d), and delayed (>14 d) time-to-surgery cohorts. Remarkably, half recovered within three days. In total, 56% of CN2 deficits recovered, with the early surgery cohort including more severe deficits and recovering at a lower rate (p = 0.01). No correlation of time-to-surgery and rapidity of recovery of CNDs was observed (p = 0.65, 0.72). Surgery for PTA is associated with rapid recovery of CNDs in the early, subacute, and delayed time frames, and with rapid headache improvement in the early and subacute time frames in 50% or more of patients.