Liver specification of human iPSC-derived endothelial cells transplanted into mouse liver.

Background & Aims: Liver sinusoidal endothelial cells (LSECs) are important in liver development, regeneration, and pathophysiology, but the differentiation process underlying their tissue-specific phenotype is poorly understood and difficult to study because primary human cells are scarce. The aim of this study was to use human induced pluripotent stem cell (hiPSC)-derived LSEC-like cells to investigate the differentiation process of LSECs. Methods: hiPSC-derived endothelial cells (iECs) were transplanted into the livers of Fah-/-/Rag2-/-/Il2rg-/- mice and assessed over a 12-week period. Lineage tracing, immunofluorescence, flow cytometry, plasma human factor VIII measurement, and bulk and single cell transcriptomic analysis were used to assess the molecular and functional changes that occurred following transplantation. Results: Progressive and long-term repopulation of the liver vasculature occurred as iECs expanded along the sinusoids between hepatocytes and increasingly produced human factor VIII, indicating differentiation into LSEC-like cells. To chart the developmental profile associated with LSEC specification, the bulk transcriptomes of transplanted cells between 1 and 12 weeks after transplantation were compared against primary human adult LSECs. This demonstrated a chronological increase in LSEC markers, LSEC differentiation pathways, and zonation. Bulk transcriptome analysis suggested that the transcription factors NOTCH1, GATA4, and FOS have a central role in LSEC specification, interacting with a network of 27 transcription factors. Novel markers associated with this process included EMCN and CLEC14A. Additionally, single cell transcriptomic analysis demonstrated that transplanted iECs at 4 weeks contained zonal subpopulations with a region-specific phenotype. Conclusions: Collectively, this study confirms that hiPSCs can adopt LSEC-like features and provides insight into LSEC specification. This humanised xenograft system can be applied to further interrogate LSEC developmental biology and pathophysiology, bypassing current logistical obstacles associated with primary human LSECs. Impact and implications: Liver sinusoidal endothelial cells (LSECs) are important cells for liver biology, but better model systems are required to study them. We present a pluripotent stem cell xenografting model that produces human LSEC-like cells. A detailed and longitudinal transcriptomic analysis of the development of LSEC-like cells is included, which will guide future studies to interrogate LSEC biology and produce LSEC-like cells that could be used for regenerative medicine.

Neoadjuvant therapy and major arterial resection for potentially reconstructable arterial involvement by stage 3 adenocarcinoma of the pancreas.

BACKGROUND: Stage 3 pancreatic ductal adenocarcinoma (PDAC) is defined by arterial involvement. This study objective was to evaluate outcomes for patients with stage 3 PDAC with potentially reconstructable arterial involvement, considered for neoadjuvant therapy (NAT) and pancreatic resection, and to compare outcomes following arterial (AR) and non-arterial resection (NAR). METHODS: This study included patients from 2009 to 2016 with biopsy-proven stage 3 PDAC who were offered NAT before surgical exploration. AR was performed if required to achieve R0 resection. Time to event outcomes were analysed from diagnosis date. RESULTS: 87/89 patients (97.8%) received NAT (chemotherapy 41.6%, chemotherapy/radiotherapy 56.2%). 46/89 (51.7%) underwent exploration; 31 underwent resection (AR n = 20, NAR n = 11). AR patients had longer operative time (681 vs. 563 min, p = 0.006) and more blood loss (1600 vs. 575 mL, p = 0.0004), with no difference for blood transfusion, pancreatic fistula, length of stay, reoperation, or mortality. R0 rate was 30/31. Post-resection 90-day mortality was 3.2%. Median overall survival was statistically comparable between the AR and NAR groups (19.7 vs. 28.4 months, p = 0.41). CONCLUSIONS: AR had comparable clinical and oncologic outcomes to NAR. Following careful selection and non-progression after NAT, major AR may cautiously be considered if required to obtain a negative resection margin.

Comparison of outcomes and costs between laparoscopic distal pancreatectomy and open resection at a single center.

BACKGROUND: The cost implications of laparoscopic distal pancreatectomy (LDP) and a detailed breakdown of hospital expenditures has not been presented in the literature to date. This study aimed to compare hospital costs and short-term clinical outcomes between LDP and open distal pancreatectomy (ODP). METHODS: The authors evaluated all the distal pancreatic resections performed at their center between January 2004 and March 2010. Parametric and nonparametric statistical analysis was used to compare hospital departmental and total hospital costs as well as oncologic and surgical outcomes. RESULTS: A total of 118 cases (42 laparoscopic resections, including 5 conversions, and 76 open resections) were analyzed. The demographic characteristics were similar between the groups except for a predominance of females in the laparoscopic group (P = 0.036). The indications for surgery differed by a paucity of malignant tumors being approached laparoscopically (P < 0.001). Intraoperatively, there were no differences in estimated blood loss, operating room time, or transfusion requirement. The pathologic outcomes did not differ significantly. The median hospital length of stay (LOS) was 5 days (range 3-31 days) for the LDP cohort and 7 days (range 4-19 days) for the ODP cohort (P < 0.001). Postoperative pancreatic fistula occurred for 22 patients, with a higher proportion observed in the LDP group (28.57%; n = 12) than in the open group (13.16%; n = 10; P = 0.05). However, the rates for grade B and higher grade fistula were higher in the ODP group (0 LDP and 4 ODP). The median preadmission and operative costs did not differ significantly. The ODP cohort had significantly higher costs in all other hospital departments, including the total cost. CONCLUSION: LDP is both a cost-effective and safe approach for distal pancreatic lesions. This series showed a shorter LOS and lower total hospital costs for LDP than for ODP, accompanied by equivalent postoperative outcomes.

Influence of training on the family.

BACKGROUND: There is currently a shortage of surgeons working in rural Australia. This may be due to partner dissatisfaction with rural placements during training. METHODS: A questionnaire encompassing logistic, financial and emotional aspects of peripheral placements was distributed to trainees and their partners. A similar questionnaire was also distributed to 25 rural surgical consultants. RESULTS: Seventy-four per cent of trainees were either married or in long-term relationships. A further 24% had children. The average number of residential moves per year of training was 0.74. Respondents reported difficulties that included accommodation suitability, general practitioner availability, financial burden and finding amenities such as school and crèches. Many (66%) partners had experienced high levels of isolation or loneliness, whereas some reported the development of a stress-related disorder, depression or anxiety. Most respondents indicated that their partner would influence their decision to work in a given location. Furthermore, 20% of consultant surgeons had either moved town or had seriously considered moving town because of their spouse or children's dissatisfaction. CONCLUSION: Training in peripheral locations causes significant stress to the trainee and their families. These experiences dissuade trainees from working in rural locations as consultants.