Morphological and Immunohistochemical Characterization of Human Intrinsic Gastric Neurons.

Our knowledge about human gastric enteric neuron types is even more limited than that of human intestinal types. Here, we immunohistochemically stained wholemounts and sections of gastric specimens obtained from 18 tumor-resected patients. Myenteric wholemounts were labeled for choline acetyl transferase (ChAT), neuronal nitric oxide synthase (NOS), and the human neuronal protein HuC/D (as pan-neuronal marker for quantitative analysis) or alternatively for neurofilament (for morphological evaluation). ChAT-positive neurons outnumbered NOS-positive neurons (56 vs. 27%), and neurons negative for both markers accounted for 17%. Two larger groups of neurons (each between 12 and 14%) costained for ChAT and vasoactive intestinal peptide (VIP) or for NOS and VIP, respectively. Clear morphochemical correlation was found for uniaxonal stubby type I neurons (ChAT+; putative excitatory inter- or motor neurons), for uniaxonal spiny type I neurons (NOS+/VIP+; putative inhibitory motor or interneurons), and for multiaxonal type II neurons (ChAT+; putative afferent neurons; immunostaining of additional wholemounts revealed their coreactivity for somatostatin). Whereas these latter neuron types were already known from the human intestine, the morphology of gastric myenteric neurons coreactive for ChAT and VIP was newly described: they had numerous short, extremely thin dendrites and resembled, together with their cell bodies, a "hairy" head. In our sections, nerve fibers coreactive for ChAT and VIP were commonly found only in the mucosa. We suggest these myenteric ChAT+/VIP+/hairy neurons to be mucosal effector neurons. In contrast to myenteric neurons, the much less common submucosal neurons were not embedded in a continuous plexus and did not display any clear morphochemical phenotypes.

CDK4/6 Inhibition - Therapy Sequences and the Quest to Find the Best Biomarkers - an Overview of Current Programs.

In recent years, new targeted therapies have been developed to treat patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer. Some of these therapies have not just become the new therapy standard but also led to significantly longer overall survival rates. The cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have become the therapeutic standard for first-line therapy. Around 70 - 80% of patients are treated with a CDK4/6i. In recent years, a number of biomarkers associated with progression, clonal selection or evolution have been reported for CDK4/6i and their endocrine combination partners. Understanding the mechanisms behind treatment efficacy and resistance is important. A better understanding could contribute to planning the most effective therapeutic sequences and utilizing basic molecular information to overcome endocrine resistance. One study with large numbers of patients which aims to elucidate these mechanisms is the Comprehensive Analysis of sPatial, TempORal and molecular patterns of ribociclib efficacy and resistance in advanced Breast Cancer patients (CAPTOR BC) trial. This overview summarizes the latest clinical research on resistance to endocrine therapies, focusing on CDK4/6 inhibitors and discussing current study concepts.

Susceptibility gene mutations in germline and tumors of patients with HER2-negative advanced breast cancer.

Germline mutations in BRCA1 and BRCA2 (gBRCA1/2) are required for a PARP inhibitor therapy in patients with HER2-negative (HER2-) advanced breast cancer (aBC). However, little is known about the prognostic impact of gBRCA1/2 mutations in aBC patients treated with chemotherapy. This study aimed to investigate the frequencies and prognosis of germline and somatic BRCA1/2 mutations in HER2- aBC patients receiving the first chemotherapy in the advanced setting. Patients receiving their first chemotherapy for HER2- aBC were retrospectively selected from the prospective PRAEGNANT registry (NCT02338167). Genotyping of 26 cancer predisposition genes was performed with germline DNA of 471 patients and somatic tumor DNA of 94 patients. Mutation frequencies, progression-free and overall survival (PFS, OS) according to germline mutation status were assessed. gBRCA1/2 mutations were present in 23 patients (4.9%), and 33 patients (7.0%) had mutations in other cancer risk genes. Patients with a gBRCA1/2 mutation had a better OS compared to non-mutation carriers (HR: 0.38; 95%CI: 0.17-0.86). PFS comparison was not statistically significant. Mutations in other risk genes did not affect prognosis. Two somatic BRCA2 mutations were found in 94 patients without gBRCA1/2 mutations. Most frequently somatic mutated genes were TP53 (44.7%), CDH1 (10.6%) and PTEN (6.4%). In conclusion, aBC patients with gBRCA1/2 mutations had a more favorable prognosis under chemotherapy compared to non-mutation carriers. The mutation frequency of ~5% with gBRCA1/2 mutations together with improved outcome indicates that germline genotyping of all metastatic patients for whom a PARP inhibitor therapy is indicated should be considered.