Impact of treatment characteristics on response of different breast cancer phenotypes: pooled analysis of the German neo-adjuvant chemotherapy trials

Pathological complete response (pCR) to neoadjuvant treatment correlates with outcome in breast cancer. We determined whether characteristics of neoadjuvant therapy are associated with pCR. We used multi-level models, which accounted for heterogeneity in pCR across trials and trial arms, to analyze individual patient data from 3332 women included in 7 German neoadjuvant trials with uniform protocols. PCR was associated with an increase in number of chemotherapy cycles (odds ratio [OR] 1.2 for every two additional cycles; P = 0.009), with higher cumulative anthracycline doses (OR 1.6; P = 0.002), higher cumulative taxane doses (OR 1.6; P = 0.009), and with capecitabine containing regimens (OR 1.62; P = 0.022). Association of pCR with increase in number of cycles appeared more pronounced in hormone receptor (HR)-positive tumors (OR 1.35) than in HR-negative tumors (OR 1.04; P for interaction = 0.046). Effect of anthracycline dose was particularly pronounced in HER2-negative tumors (OR 1.61), compared to HER2-positive tumors (OR 0.83; P for interaction = 0.14). Simultaneous trastuzumab treatment in HER2-positive tumors increased odds of pCR 3.2-fold (P < 0.001). No association of pCR and number of trastuzumab cycles was found (OR 1.20, P = 0.39). Dosing characteristics appear important for successful treatment of breast cancer. Longer treatment, higher cumulative doses of anthracyclines and taxanes, and the addition of capecitabine and trastuzumab are associated with better response. Tailoring according to breast cancer phenotype might be possible: longer treatment in HR-positive tumors, higher cumulative anthracycline doses for HER2-negative tumors, shorter treatment at higher cumulative doses for triple-negative tumors, and limited number of preoperative trastuzumab cycles in HER2-positive tumors.     

Pregnancy after transplantation

The National Transplantation Pregnancy Registry (NTPR) was established in 1991 to study the outcomes of pregnancies in female transplant recipients and pregnancies fathered by male transplant recipients. Data from the NTPR have helped to endorse the reassurances from publications of smaller experiences that successful pregnancies are possible in the transplant population. In our last review for this journal (2000), we noted that important future issues would include the reassessment of prepregnancy guidelines, gestational and organ-specific problems, the role of new immunosuppressive drugs, and the long-term effects of pregnancy on both graft and child. Data collected by the NTPR over the last 7 years have addressed these issues, thus providing additional information for health care providers of transplant recipients of childbearing age. There has been some refinement of prepregnancy guidelines, but there is a need for additional data collection so that organ-specific outcomes and risks can further be identified. To date, the outcomes of the children followed have been encouraging, and specific remote effects have not been identified, but continued surveillance is still vital. Of special concern are the new immunosuppressive drugs, specifically for mycophenolate mofetil (CellCept, Roche Laboratories Inc., Nutley, New Jersey), where data reported to the NTPR and through postmarketing surveillance have shown an increased incidence of nonviable outcomes and a specific pattern and increased incidence of malformation in the newborn, which has resulted in a pregnancy category change. Newer information points to an increased need for vigilance among centers and continued monitoring of pregnancy outcomes in this population. As the first reported pregnancy after transplantation occurred in a kidney recipient 50 years ago, in March 1958, this review also highlights the first reported pregnancies in other solid organ recipients.     

Molecular biology and clinical manifestation of hereditary factor VII deficiency

Inherited factor VII (FVII) deficiency is a rare autosomal recessive disorder. Mutations and polymorphisms of the FVII gene were characterized in more than 40 unrelated patients with FVII deficiency. Among the 29 different mutations, the most frequent were Ala294 Val, Ala294Val;404delC, IVS7+7, and Val281 Phe. Four novel mutations (IVS2+1G>C, Arg247 Cys, Glu265 Lys, Asp343 His) were detected. The relationships between genotypes of mutations and polymorphisms of the FVII gene, FVII deficiency, and clinical phenotype were investigated. Homozygosity of the Phe4 Leu, IVS4+1G>A, Cys135 Arg, Ala244 Val, and Ala294 Val;404delC and the double heterozygosity of Tyr68 Cys / IVS3-1G>A, Val252 Met / IVS2+5G>T, Val281 Phe / Cys135 Arg, Ala294 Val / Val281 Phe, Ala294 Val;404delC / Val281Phe, Ala294 Val;404delC / Arg152 stop, Ala294Val;404delC / Gln(-35) stop, Ala294 Val / Val252 Met, Ala294 Val / Gly156 Asp, and Thr359 Met / Asp242 His were related to clinical symptoms. Double heterozygotes for Arg247 Cys / IVS2+1G>C, Ala206 Thr / Pro303 Arg, Leu(-20) Pro / Val252 Met as well as IVS7+7 /Ala294 Val, IVS7+7 /Ala206 Thr, and IVS7+7 / Met298 Ile were asymptomatic. The clinical symptomatology is rather poor in correlation with the FVII activity. Concerning the clinical phanotype, a correlation seems to exist between specific mutations and clinical symptoms.     

L-type calcium channels involvement in aortic smooth muscle contraction as revealed by membrane potential and active force dynamics

Membrane potential (MP) is essential in smooth muscle (SM) contractile activity, mainly by its effect upon L-type Ca2+ channels. We simultaneously recorded SM isometric tension and MP in de-endothelised rat aorta rings and examined their submaximal activation by K+, norepinephrine (NE) or phenylephrine (PHE) and the influence of methoxyverapamil (D600). K+ -induced contraction strictly correlated with depolarization, while faster contractions induced by NE or PHE started and peaked with a less depolarized membrane. D600 completely relaxed K+ or NE contracted rings, time-correlated with full repolarization, but partially relaxed PHE-contracted rings, with partial repolarization, which did not precede relaxation. The observed MP and force dynamics support known mechanisms of action of the drugs used. L-type channels participate in the depolarizing and contractile effect of NE, as opposite to their minor involvement in the effects of PHE.     

Rapid detection of Creutzfeldt-Jakob disease and scrapie prion proteins

Creutzfeldt-Jakob disease (CJD) and Gerstmann-Str?ussler syndrome (GSS) of humans as well as scrapie of animals are caused by prions. The scrapie prion protein isoform (PrPSc) is the only macromolecule identified to date which is a component of the infectious prion particle. PrPSc is converted to PrP 27-30 by limited proteolysis while the cellular isoform, designated PrPC, is completely digested under the same conditions. ELISA studies demonstrated that native PrP 27-30 bound to plastic surfaces resisted proteolysis and exhibited little or no immunoreactivity but after denaturation with guanidinium thiocyanate (GdnSCN), immunoreactivity was greatly enhanced. PrPSc bound to nitrocellulose also exhibited enhanced immunoreactivity after denaturation. PrPSc was readily detected in brain extracts from scrapie-infected hamsters, mice, and sheep by dot-blot immunoassays using limited proteolysis followed by GdnSCN denaturation. The high sensitivity and specificity of the immunoassay allowed detection of regional differences in PrPSc in sheep brain. CJD prion protein isoform (PrPCJD) was also detected in the brains of all 10 patients tested with neuropathologically confirmed CJD and in 1 patient with GSS. Enhanced immunoreactivity of PrPSc or PrPCJD after denaturation cannot only be used for immunodiagnosis of prion diseases but may also form the basis of new assays in experimental studies directed at the chemical structure of the prion particle.     

PCSK9 and neurocognitive function: Should it be still an issue after FOURIER and EBBINGHAUS results?

The serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) modulates the levels of low-density lipoprotein cholesterol and cardiovascular risk. Potential risks of adverse neurological effects of intensive lipid-lowering treatment have been hypothesized, as cholesterol is a component of the central nervous system. Moreover, several observations suggest that PCSK9 might play a role in neurogenesis, neuronal migration and apoptosis. In rodents, increased expression of PCSK9 has been detected in specific areas of the central nervous system during embryonic development; also, PCSK9 modulates low-density lipoprotein receptor levels in the ischemic brain areas. Despite a putative participation of PCSK9 in nervous system physiology, the absence of PCSK9 in knockout mice or in humans with loss-of-function mutations of PCSK9 gene has not been linked to neurological alterations. In recent years, some concerns have been raised about the potential neurological side effects of cholesterol-lowering treatments and, more specifically of PCSK9 inhibitors. In this review, the evidence regarding the function of PCSK9 in neuron differentiation, apoptosis, and migration and in nervous system development and latest clinical trials evaluating the effects of PCSK9 inhibitors on neurocognitive function will be described.     

Human primary auditory cortex: cytoarchitectonic subdivisions and mapping into a spatial reference system

The transverse temporal gyrus of Heschl contains the human auditory cortex. Several schematic maps of the cytoarchitectonic correlate of this functional entity are available, but they present partly conflicting data (number and position of borders of the primary auditory areas) and they do not enable reliable comparisons with functional imaging data in a common spatial reference system. In order to provide a 3-D data set of the precise position and extent of the human primary auditory cortex, its putative subdivisions, and its topographical intersubject variability, we performed a quantitative cytoarchitectonic analysis of 10 brains using a recently established technique for observer-independent definition of areal borders. Three areas, Te1.1, Te1.0, and Te1.2, with a well-developed layer IV, which represent the primary auditory cortex (Brodmann area 41), can be identified along the mediolateral axis of the Heschl gyrus. The cell density was significantly higher in Te1.1 compared to Te1.2 in the left but not in the right hemisphere. The cytoarchitectonically defined areal borders of the primary auditory cortex do not consistently match macroanatomic landmarks like gyral and sulcal borders. The three primary auditory areas of each postmortem brain were mapped to a spatial reference system which is based on a brain registered by in vivo magnetic resonance imaging. The integration of a sample of postmortem brains in a spatial reference system allows one to estimate the spatial variability of each cytoarchitectonically defined region with respect to this reference system. In future, the transfer of in vivo structural and functional data into the same spatial reference system will enable accurate comparisons of cytoarchitectonic maps of the primary auditory cortex with activation centers as established with functional imaging procedures.     

Effects of Hepatitis C-Induced Liver Fibrosis on Survival in Kidney Transplant Candidates

We sought to investigate survival among kidney transplant candidates with varying degrees of liver fibrosis. We studied 108 patients with hepatitis C+ who underwent pre-kidney transplant liver biopsy (1992–2004). Eighteen patients had advanced fibrosis (bridging fibrosis or cirrhosis), and 90 had lesser degrees of fibrosis. Advanced fibrosis patients were younger and had lower prevalence of diabetes. Survival was similar between those with and without advanced fibrosis among all 108 patients (P = 0.92) and among the 58 patients who underwent kidney transplantation (P = 0.83). Fibrosis stage was associated with a 1.1 (0.72, 1.7; P = 0.65) adjusted hazards ratio for mortality among all 108 patients and a 0.64 (0.24, 1.73; P = 0.38) adjusted hazards ratio among the 58 patients who underwent kidney transplantation. These data support the premise that non-liver disease comorbidities are more important outcome determinants in this population. Kidney transplantation alone may be considered in patients with hepatitis C with compensated cirrhosis or bridging fibrosis.