Telomeres promote genome integrity by protecting chromosome ends from the activation of the DNA damage response and protecting chromosomes from the loss of coding sequences due to the end replication problem. Telomere length (TL) is progressively shortened as age progresses, thus resulting in cellular senescence. Therefore, TL is in strong adverse linear correlation with aging. Mounting evidence supports the notion that telomeres and male/female infertility are in a close relationship, posing the biology of telomeres as a hot topic in the era of human-assisted reproduction. Specifically, the length of sperm telomeres is gradually increasing as men get older, while the telomere length of the oocytes seems not to follow similar patterns with that of sperm. Nonetheless, the telomere length of the embryos during the cleavage stages seems to have a paternal origin, but the telomere length can be further extended by telomerase activity during the blastocyst stage. The latter has been proposed as a new molecular biomarker with strong predictive value regarding male infertility. As far as the role of telomeres in assisted reproduction, the data is limited but the length of telomeres in both gametes seems to be affected mainly by the cause of infertility rather than the assisted reproductive therapy (ART) procedure itself. The present review aims to shed more light into the role of telomeres in human embryological parameters, including gametes and embryos and also presents opinions regarding the association between telomeres and in vitro fertilization (IVF).

Background. Somatotroph adenomas (SAs) exhibit a variable responsiveness to somatostatin analogue (SS-a) treatment, a process that is not well understood. We investigated established and novel histological markers as predictors of SS-a responsiveness. Methods. We retrospectively investigated pathology samples from 36 acromegalic patients that underwent transsphenoidal surgery. Clinical, hormonal, and imaging data were available in 24/36 patients, before and after SS-a treatment. Specimens were semiquantitatively analyzed with immunocytochemistry for Ki-67, KER, SSTR-2, SSTR-5, ZAC-1, E-cadherin, and AIP. Results. Collectively, 18 (50) adenomas were each classified as densely/sparsely granulated somatotroph adenomas (DGSAs/SGSAs), respectively. Patients that received preoperative SS-a had lower expression of SSTR-2 compared to those that did not (2.0 (1.0, 3.0) vs. 3.0 (3.0, 3.0), p=0.042). Compared with DGSAs, SGSAs had higher Ki-67 labeling index (LI) (1.0 (0.5, 1.0) vs. 2.0 (1.0, 3.5), p=0.013), and a higher proportion of high MR T2 signal (1 (6) vs. 6 (33), p=0.035), and tended to express less ZAC-1 (p=0.061) and E-cadherin (p=0.067). In linear regression corrected for baseline growth hormone (GH), ZAC-1 immunostaining was significantly associated with a decrease in GH levels after SS-a treatment (beta (95 confidence interval): 1.53 (2.80, 0.26), p=0.021). No markers were associated with changes in circulating insulin-like growth factor-I (IGF-I) after treatment with SS-a. Conclusion. The novel marker ZAC-1 was associated with GH response to medical treatment with SS-a. The SGSA cases were characterized by higher Ki-67 values and MR T2 signals indicative of an inferior response to SS-a. These findings improve our understanding of the mechanisms underlying SA response to medical treatment.

Background: Hypoxia is recognized as a key feature of cancer growth and is involved in various cellular processes, including proliferation, angiogenesis, and immune surveillance. Besides hypoxia-inducible factor 1-alpha (HIF-1α), which is the main mediator of hypoxia effects and can also be activated under normoxic conditions, little is known about its counterpart, HIF-2. This study focused on investigating the clinical and molecular landscape of HIF-2-altered urothelial carcinoma (UC). Methods: Publicly available next-generation sequencing (NGS) data from muscle-invasive UC cell lines and patient tumor samples from the MSK/TCGA 2020 cohort (n = 476) were interrogated for the level of expression (mRNA, protein) and presence of mutations, copy number variations, structural variants in the EPAS1 gene encoding HIF-2, and findings among various clinical (stage, grade, progression-free and overall survival) and molecular (tumor mutational burden, enriched gene expression) parameters were compared between altered and unaltered tumors. Results: 19% (7/37) of UC cell lines and 7% (27/380) of patients with muscle-invasive UC display high EPAS1 mRNA and protein expression or/and EPAS1 alterations. EPAS1-altered tumors are associated with higher stage, grade, and lymph node metastasis as well as with shorter PFS (14 vs. 51 months, q = 0.01) and OS (15 vs. 55 months, q = 0.01). EPAS1 mRNA expression is directly correlated with that of its target-genes, including VEGF, FLT1, KDR, DLL4, CDH5, ANGPT1 (q < 0.001). While there is a slightly higher tumor mutational burden in EPAS1-altered tumors (9.9 vs. 4.9 mut/Mb), they are enriched in and associated with genes promoting immune evasion, including ARID5B, SPINT1, AAK1, CLIC3, SORT1, SASH1, and FGFR3, respectively (q < 0.001). Conclusions: HIF-2-altered UC has an aggressive clinical and a distinct genomic and immunogenomic profile enriched in angiogenesis- and immune evasion-promoting genes.

Extranodal Hodgkin lymphoma involving the breast is infrequent. Most cases reported in the literature were diagnosed by histology after lumpectomy. We present a Hodgkin lymphoma mimicking inflammatory breast carcinoma in a 57-year-old woman. The diagnosis was performed by fine-needle aspiration (FNA) of the breast lesion and the axillary lymph nodes with rapid on-site evaluation followed by immunocytochemistry, and it was confirmed by histology. The patient after first-line chemotherapy developed relapse/refractory disease. Salvage chemotherapy regimens were applied with poor results and severe toxicity. Total remission was achieved with monotherapy of brentuximab vedotin, a novel anti-CD30-targeted antibody drug conjugate. This is a unique case of breast HL with misleading clinical presentation initially diagnosed by cytology. FNA as a minimally invasive diagnostic tool was crucial in avoiding unnecessary breast surgery and further delay of chemotherapy. It is also the first report highlighting the importance of this novel immunotherapy in the management of refractory Hodgkin lymphoma with breast involvement.

Head and neck paragangliomas (PGLs) most commonly derive from the carotid body, jugulotympanic, vagal, and laryngeal paraganglia. Thyroid PGLs originate in the inferior laryngeal paraganglion, which may lie inside the thyroid parenchyma. Intrathyroid PGLs are rare with approximately 75 cases reported to date, mostly as solitary lesions. The coexistence of thyroid PGL with medullary thyroid carcinoma (MTC) has not been reported. Here, we report a unique case of intrathyroid PGL concomitant with MTC in the context of multiple endocrine neoplasia type 2B syndrome. Interestingly, the patient showed a prolonged survival with good clinical response to tyrosine kinase inhibitors, despite her advanced metastatic MTC. We discuss the challenges in pathology, differential diagnosis, and genetic background for the development of these thyroid lesions.