Annette Ramaswamy

Although growth differentiation factor-15 (GDF-15) is highly expressed in PCa, its role in the development and progression of PCa is unclear. The present study aims to determine the density of GDF-15+ cells and immune cells (M1-/M2 macrophages [MΦ], lymphocytes) in PCa of different Gleason scores (GS) compared to BPH. Immunohistochemistry and double immunofluorescence were performed on paraffin-embedded human PCa and BPH biopsies with antibodies directed against GDF-15, CD68 (M1 MΦ), CD163 (M2 MΦ), CD4, CD8, CD19 (T /B lymphocytes), or PD-L1. PGP9.5 served as a marker for innervation and neuroendocrine cells. GDF-15+ cell density was higher in all GS than in BPH. CD68+ MΦ density in GS9 and CD163+ MΦ exceeded that in BPH. GDF-15+ cell density correlated significantly positively with CD68+ or CD163+ MΦ density in extratumoral areas. Double immunoreactive GDF-15+/CD68+ cells were found as transepithelial migrating MΦ. Stromal CD68+ MΦ lacked GDF-15+. The area of PGP9.5+ innervation was higher in GS9 than in BPH. PGP9.5+ cells, occasionally copositive for GDF-15+, also occurred in the glandular epithelium. In GS6, but not in BPH, GDF-15+, PD-L1+, and CD68+ cells were found in epithelium within luminal excrescences. The degree of extra-/intra-tumoral GDF-15 increases in M1/M2Φ is proposed to be useful to stratify progredient malignancy of PCa. GDF-15 is a potential target for anti-tumor therapy.

Background: A recent study found that multifocal jejunoileal neuroendocrine tumors (SI-NETs) are genetically unrelated synchronous neoplasms. So far, it is unclear if this finding of synchronous independent neoplasms is mirrored by heterogeneity of key morphological parameters of SI-NETs and how it affects patient survival. Methods: We separately assessed WHO grade (based on the Ki-67 index), expression of basal diagnostic markers (synaptophysin/chromogranin A/CDX2/serotonin), SSTR2a, and the contexture of the immunogenic microenvironment in 146 separate tumors from 28 patients with multifocal SI-NETs and correlated the results with clinicopathological factors and survival. Results: Synaptophysin and chromogranin A were strongly expressed in all tumors. WHO grade was concordant within all multifocal lesions in more than 80% of cases and the highest grade was usually found in the most advanced primary. Intertumoral expression of serotonin, SSTR2, and CDX2 was discrepant in 32%, 43%, and 50% of all patients, respectively. Neither heterogeneity of any of the aforementioned markers nor multifocality itself had any impact on patient survival (p = n.s.). Discussion: Multifocal SI-NET show considerable variability in some of the central diagnostic parameters. However, neither intertumoral heterogeneity of those parameters nor multifocality itself had any impact on patient survival, showing that extensive testing of all multifocal lesions is not necessarily required.

The most common spinal disorder in elderly is lumbar spinal stenosis (LSS), resulting partly from ligamentum flavum (LF) hypertrophy. Its pathophysiology is not completely understood. The present study wants to elucidate the role of estrogen receptor α (ER α) in fibroblasts of hypertrophied LF. LF samples of 38 patients with LSS were obtained during spinal decompression. Twelve LF samples from patients with disk herniation served as controls. Hematoxylin & Eosin (H&E) and Elastica stains and immunohistochemistry for ER α were performed. The proportions of fibrosis, loss and/or degeneration of elastic fibers and proliferation of collagen fibers were assessed according to the scores of Sairyo and Okuda. Group differences in the ER α and Sairyo and Okuda scores between patients and controls, male and female sex and absence and presence of additional orthopedic diagnoses were assessed with the Mann–Whitney U test. There was a tendency towards higher expression of ER α in LF fibroblasts in the hypertrophy group (p = 0.065). The Sairyo and Okuda scores were more severe for the hypertrophy group but, in general, not statistically relevant. There was no statistically relevant correlation between the expression of ER α and sex (p = 0.326). ER α expression was higher in patients with osteochondrosis but not statistically significant (p = 0.113). In patients with scoliosis, ER α expression was significantly lower (p = 0.044). LF hypertrophy may be accompanied by a higher expression of ER α in fibroblasts. No difference in ER α expression was observed regarding sex. Further studies are needed to clarify the biological and clinical significance of these findings.

Current evidence suggests that patients with Luminal A early breast cancer can skip chemotherapy or extended endocrine therapy, but immunohistochemistry-based biomarker analysis for St Gallen subtyping may not be reproducible. We asked whether RT-qPCR can be used instead to address this clinical question. RNA was extracted from tumor material derived from ER+/HER2- patients receiving adjuvant endocrine treatment for low-risk cancers and was semi-quantified by RT-qPCR with the MammaTyper®. St Gallen subtypes were based on the mRNA expression of ERBB2/HER2, ESR1/ER, PGR/PR and MKI67/Ki67 after dichotomizing at predefined cut-offs. Differences in distant disease-free survival (DDFS) were assessed by Kaplan Meier analysis and Cox regression. With a median follow up of 7.8 years, there were ten events in the group of 195 Luminal A-like tumors (5.1%) and 18 events in the remaining 127 tumors (14.1%), consisting mostly of Luminal B-like cases (N = 119). Luminal A-like had significantly better DDFS over the entire follow-up period (HR 0.35, 95% CIs 0.16–0.76, p = 0.0078) with a trend towards reduced probability of recurrences also in the late phase (> 5 years) (HR 0.20, p = 0.052). The survival advantage spanning the entire follow-up period persisted in the pN0 or pN0-N1 subgroups or after correcting for clinicopathological parameters. MKI67 alone significantly predicted for worse DDFS (HR 2.62, 95% CIs 1.24–5.56, p = 0.0088). St Gallen Luminal A-like tumors identified by RT-qPCR display markedly low rates of distant recurrence at ten years follow-up. Patients with such tumors could be spared chemotherapy due to the obviously unfavourable benefit/toxicity ratio.