Faculty Bibliography

Bodies have continuous reticular networks, comprising collagens and other extracellular matrix components, through all tissues and organs. We recently validated fluid flow through human interstitium and demonstrated that they are filled with hyaluronic acid by staining with biotinylated hyaluronic acid binding protein. Their continuity across tissue boundaries (skin and subcutis), and between organs (colon and mesentery) and along vessels (within adventitia) and nerves (within perineurium) has been demonstrated in this manner. We aim to evaluate the continuity of interstitium within human pancreas and beyond into adjoining tissues. Tissue blocks of histologically normal pancreas from nine pancreatectomy specimens were sectioned in parallel for staining with hematoxylin and eosin, Picrosirius red, and biotinylated hyaluronic acid binding protein. Also, specimens of invasive pancreatic cancer were assessed for interstitial tumor invasion. Picrosirius red ensheathes all microscopic units of the endocrine and exocrine pancreas, including acini, islets, and ducts, adventitia of blood vessels and perineurium, and into adjacent duodenum. Interstitial spaces within the fibrous tissue are filled with hyaluronic acid by staining and are also continuous through all microscopic structures of the pancreas, into adjoining duodenum and along vessels (within adventitia) and nerves (within perineurium). Invasive carcinoma is seen spreading through pre-existing interstitial spaces. Interstitium of the human pancreas is continuous within and beyond the pancreas. This continuity suggests the capacity to be a route of molecular, microbiome, and cellular trafficking and communication. In particular, it is a route of cancer spread.

The aim of this study was to evaluate if the Ki-67 labeling index (LI) on immediate pre-ablation biopsies of colorectal liver metastases (CLM) is associated with the presence of viable tumor cells in subsequent ablation zone biopsies and/or local tumor progression-free survival (LTPFS). Biopsies of CLM were performed before and after microwave ablation (MWA), as part of a prospective clinical trial between October 2013 and May 2019. Pre-ablation biopsy slides were examined for the Ki-67 LI using light microscopy. Ablation zone biopsy specimens were evaluated for the presence of viable tumor using hematoxylin-eosin and immunohistochemistry. Differences in CLM Ki-67 LI between positive and negative for viable tumor ablation zone biopsies were assessed using the Mann-Whitney U test. Biopsy, tumor and margin data were evaluated as predictors of LTPFS using Kaplan-Meier/Cox methods. Thirty-four patients with 48 CLM underwent biopsy before and after MWA. Sufficient tissue for Ki-67 labeling was obtained in 43/48 (89.6%) CLM. Viable tumor cells were detected in 11 ablation zones (22.9%). There was no significant difference in the CLM Ki-67 LI between the positive and negative for viable tumor ablation zones (mean: 69.2% vs. 64.3% respectively, p = 0.4). Adequate ablation zone margins (> 5 mm; p = 0.029) and negative ablation zone biopsies (p = 0.009) were significant predictors of longer LTPFS. KRAS status, tumor size and Ki-67 LI were not significant predictors of LTPFS. Complete tumor ablation (with adequate margins and negative ablation zone biopsies) is the most important factor in achieving local control of CLM, even for tumors exhibiting aggressive tumor biology.

BACKGROUND:To improve outcomes for patients with pancreatic ductal adenocarcinoma, a complete resection is crucial. However, evidence regarding the impact of microscopically positive surgical margins (R1) on recurrence is conflicting due to varying definitions and limited populations of patients with borderline-resectable and locally advanced pancreatic cancer. Therefore, we aimed to determine the impact of the resection margin status on recurrence and survival in patients with pancreatic ductal adenocarcinoma stratified by local tumor stage. METHODS:We performed a retrospective cohort study on patients with nonmetastatic pancreatic ductal adenocarcinoma undergoing pancreatectomy at a high-volume academic center (2012-2022). R1 was subclassified into microscopic invasion of the margin (R1 direct) or carcinoma present within 1 mm but not directly involving the margin (R1 <1 mm). Overall survival and time to recurrence were assessed by log-rank test and multivariable Cox regression. RESULTS:Of 472 included patients, 154 (33%) had an R1 resection. Of those 50 (32%) had R1 <1 mm and 104 (68%) R1 direct. The most commonly involved margin was the uncinate (41%) followed by the pancreatic neck (16%) and vascular margins (9%). Overall, a stepwise shortening of time to recurrence and overall survival was observed with an increasing degree of margin involvement (median time to recurrence: R0 39.3 months, R1 <1 mm 16.0 months, and R1 direct 13.4 months, all comparisons P < .05). Multivariable analyses confirmed the independent prognostic value of R1 direct across all surgical stages. CONCLUSION/CONCLUSIONS:The resection margin status portends an independent prognostic value. Moreover, this association persists in patients with borderline-resectable and locally advanced pancreatic cancer. Increasing the R0-resection rate is the most important potentially influenceable prognostic factor for improving surgery-related outcomes.

Bodies have continuous reticular networks, comprising collagens, elastin, glycosaminoglycans, and other extracellular matrix components, through all tissues and organs. Fibrous coverings of nerves and blood vessels create structural continuity beyond organ boundaries. We recently validated fluid flow through human fibrous tissues, though whether these interstitial spaces are continuous through the body or discontinuous, confined within individual organs, remains unclear. Here we show evidence for continuity of interstitial spaces using two approaches. Non-biological particles (tattoo pigment, colloidal silver) were tracked within colon and skin interstitial spaces and into adjacent fascia. Hyaluronic acid, a macromolecular component of interstitial spaces, was also visualized. Both techniques demonstrate interstitial continuity within and between organs including within perineurium and vascular adventitia traversing organs and the spaces between them. We suggest that there is a body-wide network of fluid-filled interstitial spaces that has significant implications for molecular signaling, cell trafficking, and the spread of malignant and infectious disease.

BACKGROUND:Recent studies have suggested the important roles of CD47 and tumor-associated macrophages in the prognosis and immunotherapy of various human malignancies. However, the clinical significance of CD47 expression and CD163+ TAMs in pancreatic neuroendocrine tumor (PanNET) remains unclear. METHODS:In this study, 47 well-differentiated PanNET resection specimens were collected. CD47 expression and CD163+ macrophages were evaluated using immunohistochemistry and correlated with clinicopathologic properties. RESULTS:Positive CD47 staining was seen in all PanNETs as well as adjacent normal islets. Compared to normal islets, CD47 overexpressed in PanNETs (p = 0.0015). In the cohort, lymph node metastasis (LNM), lymphovascular invasion (LVI), and perineural invasion (PNI) were found in 36.2, 59.6, and 48.9% of the cases, respectively. Interestingly, PanNETs with LNM, LVI, or PNI had significantly lower H-score of CD47 than those without LNM (p = 0.035), LVI (p = 0.0005), or PNI (p = 0.0035). PanNETs in patients with disease progression (recurrence/death) also showed a significantly lower expression of CD47 than those without progression (p = 0.022). In contrast, CD163+ macrophage counts were significantly higher in cases with LNM, LVI, and PNI. CONCLUSIONS:Our data suggest relative low CD47 expression and high CD163+ TAMs may act as indicators for poor prognosis of PanNETs.