The Prognosis of Skip Metastasis in Papillary Thyroid Microcarcinoma Is Better Than That of Continuous Metastasis.

CONTEXT: A few papillary thyroid microcarcinomas (PTMCs) may have skip metastasis (SLNM), but the risk factors remain controversial and the prognosis is unclear. OBJECTIVES: To investigate the incidence, lymph node metastasis (LNM) patterns, risk factors, and prognosis of SLNM in PTMCs. METHODS: We reviewed the medical records of PTMC patients who underwent thyroid surgery in our institution. Analyses of risk factors were performed for SLNM. Recurrence-free survival (RFS) of SLNM, central lymph node metastasis (CLNM), and continuous metastasis (CLNM and lateral lymph node metastasis [CLNM + LLNM]) were compared after propensity score matching (PSM). RESULTS: SLNM was detected in 1.7% (50/3923) and frequently involved level III (66.7%). Compared with CLNM + LLNM, SLNM had more LNM at a single level (P < 0.01) and less LNM at 2 levels (P < 0.05). A tumor size of 0.5 to 1 cm (odds ratio [OR], 2.26; 95% CI, 1.27-4.00) and location in the upper pole (OR, 3.30; 95% CI, 2.02-5.40) were independent risk factors for SLNM. A total of 910 (23.2%) PTMCs with LNM were included in the prognostic analysis. At a median follow-up of 60 months, the RFS of SLNM did not differ from that of CLNM (P = 0.10) but was significantly higher than that of CLNM + LLNM (P < 0.01) after using PSM. CONCLUSIONS: When the tumor size is 0.5 to 1 cm or its location is in the upper pole, we must remain vigilant to SLNM in PTMC. Because its prognosis is comparable to that of only CLNM and better than that of CLNM + LLNM, less intensive treatment should be considered.

Long-term outcomes and prognostic factors in papillary thyroid microcarcinoma patients with distant metastases.

PURPOSES: Distant metastasis from papillary thyroid microcarcinoma (PTMC) is extremely rare and the long-term outcomes and independent prognostic factors remain unclear. The present study aimed to investigate clinicopathological characteristics and evaluate the long-term outcomes and prognostic factors of PTMC patients with distant metastases (DM) who underwent surgery and radioactive iodine (131I) treatment. METHODS: We retrospectively reviewed the medical records of 13,441 patients with thyroid cancer (including 1697 cases with PTMC) who underwent 131I treatment at our institution between January 2008 and December 2019. PTMC patients with distant metastases with sufficient clinical follow-up data were enrolled in this cohort study. The overall survival (OS) and progression-free survival (PFS) were analyzed by the Kaplan-Meier method and the prognostic factors were assessed by Cox proportional hazards. RESULTS: Thirty-three PTMC patients with DM were enrolled in this study. The median follow-up was 75 months (range: 5-151 months). The 5-year and 10-year OS rates were 96.97 and 81.41%, respectively, and the 5-year and 10-year PFS rates were 90.46 and 69.68%, respectively. Multivariate analysis showed that male sex (P = 0.005), radioactive iodine refractory PTMC (P = 0.033), and symptomatic DM (P = 0.022) were significantly associated with worse 10-year PFS in PTMC patients with DM. No independent predictor related to poor 10-year OS was found in the present study. CONCLUSIONS: The prognosis of PTMC patients becomes worse after the development of DM. Male sex, radioactive iodine refractory PTMC, and symptomatic DM were identified as independent factors associated with PFS.

Single-Cell Transcriptomic Analysis of Ecosystems in Papillary Thyroid Carcinoma Progression.

Background: Despite extensive research, the papillary thyroid carcinoma (PTC) ecosystem is poorly characterized and, in particular, locoregional progression. Available evidence supports that single-cell transcriptome sequencing (Sc-RNA seq) can dissect tumor ecosystems. Methods: Tissue samples from one PTC patient, including matched primary tumor (Ca), lymph node (LN) metastasis, and paracancerous tissue (PCa), were subjected to Sc-RNA seq with 10×Genomics. Dual-label immunofluorescence and immunohistochemistry were used to confirm the existence of cell subtypes in a separate cohort. Results: 11,805 cell transcriptomes were profiled, cell landscapes of PTC were composed of malignant follicular epithelial cells (MFECs), CD8+ and CD4+ T cells, B cells, vascular endothelial cells, fibroblasts and cancer-associated fibroblasts (CAFs). Between Ca and LN ecosystems, the proportions of MFEC and interstitial cells were similar, less than 1/25(229/6,694, 361/3,895), while the proportion of normal follicular epithelial cells (NFECs) and interstitial cells was > 2 in PCa (455/171). NFECs in PCa formed a separate cluster, while MFECs in Ca and LN exhibited a profound transcriptional overlap, and the interstitial cells among these samples had an overall concordance in their identity and representation, albeit with some distinctions in terms of the cell percentage per subset. A fraction of the B cell subpopulation in Ca expressed inhibitory receptors, while their respective ligand genes were clearly transcribed in T cell and malignant epithelial cell clusters, while some CD8+ T cells in both Ca and LN produced high levels of inhibitory receptors whose respective ligands were overexpressed in some CD4+ T cells. Three CAF subtypes in Ca and LN were identified, which may be due to mutual transitions. Conclusions: Our data provide new insights into the PTC ecosystem and highlight the differences in ecosystems in PTC progression, which updates our understanding of PTC biology and will improve individualized patient treatment.

GnRHa protects the ovarian reserve by reducing endoplasmic reticulum stress during cyclophosphamide-based chemotherapy.

Chemotherapy-induced ovarian dysfunction is a serious adverse effect in premenopausal patients with cancer. Gonadotrophin-releasing hormone analogs (GnRHa) protect ovarian function, but its molecular mechanisms have not yet been determined. In this study, we attempted to determine the previously unknown molecular mechanism by which such protection occurs. Serum anti-Müllerian hormone (AMH) levels were tested in tumor-bearing nude mice, a series of exploratory experiments were conducted. We discovered that GnRHa protects granulosa cells from chemotherapeutic toxicity in vivo and in vitro. We also showed that CTX-induced endoplasmic reticulum stress inhibits the secretion of AMH, and treatment with GnRHa relieves ER stress and the subsequent unfolded-protein response by modulating mTOR signaling to induce autophagy. The results of mechanistic studies indicated that GnRHa-modulated mTOR signaling to induce autophagy, which alleviated CTX-induced ER stress and promoted the secretion of AMH.

Can Anti-Müllerian Hormone Be a Reliable Biomarker for Assessing Ovarian Function in Women Postchemotherapy?

PURPOSE: The predictive value of anti-Müllerian hormone (AMH) for ovarian dysfunction postchemotherapy is controversial. This study aimed to evaluate the value of serum AMH levels clinically and theoretically. PATIENTS ANIMALS AND METHODS: We detected the serum estradiol, follicular stimulating hormone (FSH), luteinizing hormone (LH), and AMH levels in 144 premenopausal women with breast cancer receiving cyclophosphamide-based chemotherapy. The hormone levels before and postchemotherapy were compared; the correlations among the hormones and amenorrhea and menstrual recovery were analyzed. In addition, the serum AMH levels were detected randomly in 177 normal healthy women and 36 normal female C57BL/6J mice of different ages; meanwhile, the status of ovarian follicles was also examined. Furthermore, 72 Balb/c nude mice with breast cancer were randomly assigned to three groups that received different doses of cyclophosphamide (CTX) (control, 100 mg/kg, and 200 mg/kg), and the alterations in serum AMH levels and ovarian follicles were recorded and analyzed. RESULTS: Chemotherapy-induced amenorrhea was associated with prechemotherapy AMH levels, E2 levels, and FSH levels (P < 0.0001). The recovery of menstruation was associated with prechemotherapy AMH levels (P < 0.0001), but not with E2 and FSH levels (P > 0.05). In patients with breast cancer treated with chemotherapy, the serum AMH levels did not differ significantly between the pre- and post-chemotherapy periods in patients aged <35 years (P > 0.05), whereas a dramatic reduction was detected in patients aged >35 years (P < 0.0001). In healthy women, the serum AMH levels declined sharply after 35 years of age (P < 0.0001) and remained relatively stable at a younger age. Similar results were obtained in experiments using normal mice. The cancer-bearing mice exposed to 200 mg/kg CTX exhibited a significant decline in AMH levels and a remarkable decrease in the number of primordial and growing follicles (P < 0.0001). CONCLUSION: Our results indicate that AMH is an efficient marker for predicting postchemotherapy ovarian function exclusively in premenopausal female patients with breast cancer aged >35 years.