Disease-free survival after pancreatectomy for pancreatic neuroendocrine tumours: a 17-year single-center experience of 223 patients.

BACKGROUND: Metastasis or recurrence of pancreatic neuroendocrine tumours (pNETs) after pancreatectomy presents an important source of post-surgical morbidity. Accordingly we aim to define disease-free survival (DFS) in this population. METHODS: Patients who underwent pancreatectomy for pNETs between Jan 2005 and Jan 2022, were included. Clinicopathologic and survival data were collected and the primary endpoint was DFS. Kaplan-Meier survival analysis and Cox proportional hazards regression modelling were performed. RESULTS: Of the 223 patients, 144 (65%) distal/subtotal/partial pancreatectomies, 71 (32%) pancreaticoduodectomies, 6 (3%) total pancreatectomies, and 2 (1%) enucleations were performed. Forty-five (20%) patients had disease recurrence or metastasis after index pancreatectomy during the 17 years of the study. Non-functional pNETs (n=162, 73%) were more common than hormonally functional sub-types. The 2-year and 5-year DFS were 82% and 76%, respectively. Kaplan-Meier analysis demonstrated node positivity, size ≥4cm, lymphovascular invasion, perineural invasion, Ki-67 ≥20% and non-functional pNETs to be significantly associated with lowered DFS (p<0.05). Univariate Cox analysis identified the following predictors to be significantly associated with poorer DFS: larger tumour size (HR: 1.16 [95% CI: 1.04-1.28]), Ki-67 index ≥20% (HR: 4.93 [95% CI: 2.00-11.44]), perineural invasion (HR: 3.23 [95% CI: 1.40-7.89]), open surgery (HR: 3.34 [95% CI: 1.03-1.33]), node-positive disease (HR: 5.27 [95% CI: 2.28-13.26]) and increased BMI (HR: 1.10 [95% CI: 1.03-1.17]) (p<0.05). CONCLUSIONS: One in every five resected patients developed recurrence or metastasis after pancreatectomy. Prognostic predictors of DFS in pNETs could help optimize treatment and enhance follow-up protocols to improve quality and reduce morbidity.

Therapeutic Effects of Mesenchymal Stromal Cells Require Mitochondrial Transfer and Quality Control.

Due to their beneficial effects in an array of diseases, Mesenchymal Stromal Cells (MSCs) have been the focus of intense preclinical research and clinical implementation for decades. MSCs have multilineage differentiation capacity, support hematopoiesis, secrete pro-regenerative factors and exert immunoregulatory functions promoting homeostasis and the resolution of injury/inflammation. The main effects of MSCs include modulation of immune cells (macrophages, neutrophils, and lymphocytes), secretion of antimicrobial peptides, and transfer of mitochondria (Mt) to injured cells. These actions can be enhanced by priming (i.e., licensing) MSCs prior to exposure to deleterious microenvironments. Preclinical evidence suggests that MSCs can exert therapeutic effects in a variety of pathological states, including cardiac, respiratory, hepatic, renal, and neurological diseases. One of the key emerging beneficial actions of MSCs is the improvement of mitochondrial functions in the injured tissues by enhancing mitochondrial quality control (MQC). Recent advances in the understanding of cellular MQC, including mitochondrial biogenesis, mitophagy, fission, and fusion, helped uncover how MSCs enhance these processes. Specifically, MSCs have been suggested to regulate peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α)-dependent biogenesis, Parkin-dependent mitophagy, and Mitofusins (Mfn1/2) or Dynamin Related Protein-1 (Drp1)-mediated fission/fusion. In addition, previous studies also verified mitochondrial transfer from MSCs through tunneling nanotubes and via microvesicular transport. Combined, these effects improve mitochondrial functions, thereby contributing to the resolution of injury and inflammation. Thus, uncovering how MSCs affect MQC opens new therapeutic avenues for organ injury, and the transplantation of MSC-derived mitochondria to injured tissues might represent an attractive new therapeutic approach.

Elevated baseline expression of seven virulence factor RNA transcripts in visceralizing species of Leishmania: a preliminary quantitative PCR study.

Introduction: Leishmaniasis is a neglected tropical disease that manifests as three major disease phenotypes: cutaneous, mucocutaneous, and visceral. In this preliminary study, we quantified virulence factor (VF) RNA transcript expression in Leishmania species, stratified by geographic origin and propensity for specific disease phenotypes. Methods: Cultured promastigotes of 19 Leishmania clinical and ATCC isolates were extracted for total cellular RNA, cDNA was reverse transcribed, and qPCR assays were performed to quantify VF RNA transcript expression for hsp23, hsp70, hsp83, hsp100, mpi, cpb, and gp63. Results: Comparison of visceralizing species (Leishmania donovani, Leishmania chagasi, and Leishmania infantum) versus non-visceralizing species [Leishmania (Viannia) spp., Leishmania tropica, Leishmania major, Leishmania mexicana, and Leishmania amazonensis] revealed a significantly greater pooled transcript expression for visceralizing species (p = 0.0032). Similarly, Old World species demonstrated significantly higher VF RNA transcript expression than New World species (p = 0.0015). On a per-gene basis, species with a propensity to visceralize ubiquitously expressed higher levels of gp63 (p = 0.005), cpb (p = 0.0032), mpi (p = 0.0032), hsp23 (p = 0.0039), hsp70 (p = 0.0032), hsp83 (p = 0.0032), and hsp100 (p = 0.0032). Conclusion: Here, we provide quantitative, preliminary evidence of elevated VF RNA transcript expression driven largely by the visceralizing causative species of Leishmania. This work highlights the extensive heterogeneity in pathogenicity mechanisms between Leishmania species, which may partly underpin the fatal progression of visceral leishmaniasis.