Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo.

The peptidyl-prolyl isomerase, Pin1, is exploited in cancer to activate oncogenes and inactivate tumor suppressors. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to identify covalent inhibitors targeting Pin1's active site Cys113, leading to the development of Sulfopin, a nanomolar Pin1 inhibitor. Sulfopin is highly selective, as validated by two independent chemoproteomics methods, achieves potent cellular and in vivo target engagement and phenocopies Pin1 genetic knockout. Pin1 inhibition had only a modest effect on cancer cell line viability. Nevertheless, Sulfopin induced downregulation of c-Myc target genes, reduced tumor progression and conferred survival benefit in murine and zebrafish models of MYCN-driven neuroblastoma, and in a murine model of pancreatic cancer. Our results demonstrate that Sulfopin is a chemical probe suitable for assessment of Pin1-dependent pharmacology in cells and in vivo, and that Pin1 warrants further investigation as a potential cancer drug target.

Identification of a potent and selective covalent Pin1 inhibitor.

Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) is commonly overexpressed in human cancers, including pancreatic ductal adenocarcinoma (PDAC). While Pin1 is dispensable for viability in mice, it is required for activated Ras to induce tumorigenesis, suggesting a role for Pin1 inhibitors in Ras-driven tumors, such as PDAC. We report the development of rationally designed peptide inhibitors that covalently target Cys113, a highly conserved cysteine located in the Pin1 active site. The inhibitors were iteratively optimized for potency, selectivity and cell permeability to give BJP-06-005-3, a versatile tool compound with which to probe Pin1 biology and interrogate its role in cancer. In parallel to inhibitor development, we employed genetic and chemical-genetic strategies to assess the consequences of Pin1 loss in human PDAC cell lines. We demonstrate that Pin1 cooperates with mutant KRAS to promote transformation in PDAC, and that Pin1 inhibition impairs cell viability over time in PDAC cell lines.

Incidence of anastomotic stricture after hepaticojejunostomy with continuous sutures in patients who underwent laparoscopic pancreaticoduodenectomy.

PURPOSE: Laparoscopic hepatojejunostomy (HJ) with continuous sutures is commonly performed in laparoscopic pancreaticoduodenectomy (LPD). This study aimed to investigate the long-term surgical outcomes of HJ in LPD. METHODS: We retrospectively evaluated 103 consecutive patients who underwent pancreaticoduodenectomy via laparoscopic HJ with continuous suturing using multifilament (n = 48) or monofilament-absorbable sutures (n = 47). RESULTS: During follow-up, anastomotic stricture of HJ was identified in 8 (7.8%) patients via balloon enteroscopy-assisted cholangiography. The median time from surgery to confirmation of stricture formation was 7.6 months (range 3.6-19.4). The incidence of HJ stricture was significantly higher in patients with a thin bile duct (diameter < 6.0 mm) than in those with a thick bile duct (diameter ≥ 6.0 mm) [7/27 (25.9%) vs. 1/76 (1.3%), respectively, p < 0.01]. Similarly, it was significantly higher in the monofilament group than in the multifilament group [7/54 (13.0%) vs. 1/49 (2.0%), respectively, p = 0.04]. In the monofilament suture group, 37.5% of patients with thin bile ducts developed stricture after HJ. A multivariate analysis revealed that a thin bile duct was an independent risk factor for HJ stricture (hazard ratio: 25.3, p < 0.01). CONCLUSIONS: Stricture after laparoscopic HJ using continuous sutures frequently occurs in patients with thin bile ducts, particularly when monofilament-absorbable suture is used.

Causative bacteria associated with a clinically relevant postoperative pancreatic fistula infection after distal pancreatectomy.

PURPOSE: Clinically relevant postoperative pancreatic fistulas (CR-POPF) occurring after distal pancreatectomy often cause intra-abdominal infections. We monitored the presence of bacterial contamination in the ascitic fluid after distal pancreatectomy to clarify the bacterial origin of intra-abdominal infections associated with CR-POPF. METHODS: In 176 patients who underwent distal pancreatectomy, ascitic fluid bacterial cultures were performed on postoperative days (POD) 1-4 and when the drainage fluid became turbid. The association between postoperative ascitic bacterial contamination and CR-POPF incidence was investigated. RESULTS: CR-POPF occurred in 18 cases (10.2%). Among the patients with CR-POPF, bacterial contamination was detected in 0% on POD 1, in 38.9% on POD 4, and in 72.2% on the day (median, day 9.5) when the drainage fluid became turbid. A univariate analysis revealed a significant difference in ascitic bacterial contamination on POD 4 (p < 0.001) and amylase level on POD 3-4 (p < 0.001). A multivariate analysis revealed the amylase level and ascitic bacterial contamination on POD 4 to be independent risk factors. CONCLUSIONS: In the CR-POPF group, ascitic bacterial contamination was not observed in the early postoperative stage, but the bacterial contamination rate increased after pancreatic juice leakage occurred. Therefore, CR-POPF-related infections in distal pancreatectomy may be caused by a retrograde infection of pancreatic juice.

Safe exposure of the left renal vein during laparoscopic distal pancreatectomy for pancreatic ductal adenocarcinoma: anatomical variations and pitfalls.

PURPOSE: The left renal vein is technically difficult to expose during laparoscopic distal pancreatectomy for pancreatic ductal adenocarcinoma despite being an important landmark for posterior dissection. We hereby propose a novel technique to safely expose the left renal vein while avoiding the associated anatomical pitfalls. METHODS: The anatomy of the left renal artery and vein was analyzed using multidetector computed tomography. We initially exposed the left renal vein on the left posterior side of the superior mesenteric artery followed by exposure toward the left kidney. We retrospectively examined the perioperative results of this technique in 33 patients who underwent laparoscopic distal pancreatectomy. RESULTS: 15.7% of the patients had an accessory left renal artery coursing cranial to the vein. In 43.1%, the left renal arterial branch ventrally traversed the vein at the renal hilum, thereby posing a risk for arterial injury. The location of the left renal vein varies cranial (17.6%) or caudal (82.4%) to the pancreas. The left renal vein was exposed without any vascular injury using this technique. The median operative time was 259 min, blood loss was 18 mL, and R0 resection rate was 97.0%. CONCLUSIONS: The initial exposure of the left renal vein should, therefore, be on the left posterior side of the superior mesenteric artery.

Two cases of pancreatic neuroendocrine tumors with ectopic ACTH syndrome during their disease course.

Pancreatic neuroendocrine tumors (PanNETs) are rare malignant tumors that occur in the pancreas. They are divided into functioning and non-functioning tumors based on the presence or absence of their specific hormonal hyper-expression symptoms. Adrenocorticotropic hormone (ACTH)-producing PanNETs are rare, functional tumors, and their clinical characteristics and outcomes have not been well reported.Here, we report the cases of two patients with PanNETs who presented with ectopic ACTH syndrome (EAS) during the course of their disease. Case 1 involved a non-functioning PanNET at the time of surgery. During treatment for recurrent liver metastases, the patient presented with EAS and tumor-associated hypercalcemia, probably due to ACTH and parathyroid hormone-related peptide (PTHrP) production from the liver tumor. Case 2 was a gastrinoma, and similar to Case 1, this patient presented with EAS during the treatment of recurrent liver metastases.It is not uncommon for patients with PanNETs to have multiple hormones and develop secondary hormone secretion during their disease course, although tumor phenotypes differ between primary and metastatic sites. In patients with functioning PanNETs, symptom control with anti-hormonal therapy is essential, in addition to anti-tumor therapy, especially for EAS, which is an endocrine emergency disease that requires prompt diagnosis and treatment.

Hypoxia enhances the interaction between pancreatic stellate cells and cancer cells via increased secretion of connective tissue growth factor.

BACKGROUND: Pancreatic cancer (PC), a hypovascular tumor, thrives under hypoxic conditions. Pancreatic stellate cells (PSCs) promote PC progression by secreting soluble factors, but their functions in hypoxia are poorly understood. This study aimed to clarify the effects of hypoxic conditions on the interaction between PC cells and PSCs. METHODS: We isolated human PSCs from fresh pancreatic ductal adenocarcinomas and analyzed functional differences in PSCs between normoxia (21% O2) and hypoxia (1% O2), including expression of various factors related to tumor-stromal interactions. We particularly analyzed effects on PC invasiveness of an overexpressed molecule-connective tissue growth factor (CTGF)-in PSCs under hypoxic conditions, using RNA interference techniques. RESULTS: Conditioned media from hypoxic PSCs enhanced PC cell invasiveness more intensely than that from normoxic PSCs (P < 0.01). When co-cultured with PSCs, PC cell invasion was more enhanced under hypoxia than under normoxia (P < 0.05). Among various soluble factors, which were related to invasiveness, CTGF was one of the overexpressed molecules in hypoxic PSCs. A higher level of CTGF expression was also found in supernatant of hypoxic PSCs than in supernatant of normoxic PSCs. PC cell invasiveness was reduced by CTGF knockdown in hypoxic PSCs co-cultured with PC cells (P < 0.05). CONCLUSION: Hypoxia induces PSCs' secretion of CTGF, leading to enhancement of PC invasiveness. CTGF derived from hypoxia-stimulated PSCs may be a new therapeutic target for pancreatic cancer.

Clinical feasibility of endoscopic ultrasound-guided biliary drainage for preoperative management of malignant biliary obstruction (with videos).

BACKGROUND/PURPOSE: EUS-guided biliary drainage (EUS-BD) has recently been reported to be a useful salvage technique after ERCP fail. However, data on EUS-BD used for preoperative biliary drainage (PBD) are limited. The aim of this study was to verify the clinical feasibility of EUS-BD for PBD. METHODS: PBD was performed for malignant biliary obstruction in 318 patients at our institution between July 2014 and April 2022. Fifteen (4.7%) of these patients underwent surgical resection after preoperative EUS-BD (HGS 13; HDS 1; AGS with HGS 1) and were retrospectively analyzed. RESULTS: The stent was successfully placed in all 15 cases with a median procedure time of 15 min (technical success rate 100%). The median total bilirubin value decreased significantly from 3.7 before drainage to 0.9 after surgery (p < .001) and cholangitis was well managed (clinical success rate 100%). Surgery was performed at a median of 22 days after drainage, and there were no stent-related adverse events or recurrences of biliary obstruction. Severe surgery-related adverse events occurred in three cases, but none were associated with EUS-BD. The stent was removed during surgery in 12 cases. CONCLUSIONS: EUS-BD can be a feasible and safe alternative method of PBD for malignant biliary obstruction after ERCP fail.

Significance of combination therapy of zoledronic acid and gemcitabine on pancreatic cancer.

In the present study, we examined the cytotoxic effects of combination therapy with zoledronic acid (ZOL) and gemcitabine (GEM) on pancreatic cancer cells in vitro and in vivo. Four human pancreatic cancer cell lines were treated with ZOL, GEM or a combination of both, and the effects of the respective drug regimens on cell proliferation, invasion and matrix metalloproteinase (MMP) expression were examined. A pancreatic cancer cell line was also intrasplenically or orthotopically implanted into athymic mice and the effects of these drugs on tumor metastasis and growth in vivo were evaluated by histological and immunohistochemical analyses. Combination treatment with low doses of ZOL and GEM efficiently inhibited the proliferation (P < 0.001) and invasion (P < 0.001) of pancreatic cancer cells in vitro. Western blotting assay revealed that MMP-2 and MMP-9 expression levels were decreased after ZOL treatment. In vivo, combined treatment significantly inhibited tumor growth (P < 0.05) and the development of liver metastasis (P < 0.05). These data revealed that ZOL and GEM, when used in combination, have significant antitumor, anti-metastatic and anti-angiogenic effects on pancreatic cancer cells. The present study is the first to report the significance of the combination treatment of ZOL and GEM in pancreatic cancer using an in vivo model. These data are promising for the future application of this drug regimen in patients with pancreatic cancer.

Significance of Zinc Replacement Therapy After Pancreaticoduodenectomy.

BACKGROUND/AIM: Recently, a decrease in serum zinc levels and the need for zinc preparations have been reported in the perioperative period of gastrointestinal surgery. In this study, we examined treatment outcomes among patients supplemented with zinc after pancreaticoduodenectomy (PD) and evaluated the significance of zinc replacement therapy. PATIENTS AND METHODS: From June 2020 to April 2021, 56 patients who received zinc acetate hydrate (50 mg/day) from postoperative day 3 after PD in our department were retrospectively reviewed. Patients' characteristics and preoperative as well as postoperative data, including serum zinc levels and surgical results at 1 month were reviewed. RESULTS: Preoperative zinc deficiency was present in 86.1% (46/56) of the patients. Moreover, despite zinc supplementation, 17.8% (10/56) of patients had postoperative zinc deficiency. A comparison between the low zinc level group (Zn <80 µg/dl) and the normal zinc level group (Zn ≥80 µg/dl) after surgery showed siginificant differences among patients with malignant diseases (vs. benign diseases, p=0.044), those undergoing open surgery (vs. minimally invasive surgery, p=0.036), and those with intraoperative blood loss ≥346 ml (vs. <346 ml: p=0.041) in the univariate analysis. Multivariate analysis revealed that zinc deficiency was significantly associated with open surgery [odds ratio (OR)=15.885, 95% confidence interval (CI)=1.77-142.01, p=0.013] and intraoperative blood loss (OR=9.329, 95% CI=1.50-57.74, p=0.016). CONCLUSION: In patients undergoing open PD for pancreatic cancer, zinc preparations of 50 mg may not be sufficient and further supplementation may be necessary.

Surgical approaches to the superior mesenteric artery during minimally invasive pancreaticoduodenectomy: A systematic review.

BACKGROUND: Minimally invasive pancreaticoduodenectomy (MIPD) has recently been safely performed by experts, and various methods for resection have been reported. This review summarizes the literature describing surgical approaches for MIPD. METHODS: A systematic literature search of PubMed (MEDLINE) was conducted for studies reporting robotic and laparoscopic pancreaticoduodenectomy; the reference lists of review articles were searched. Of 444 articles yielded, 23 manuscripts describing the surgical approach to dissect around the superior mesenteric artery (SMA), including hand-searched articles, were assessed. RESULTS: Various approaches to dissect around the SMA have been reported. These approaches were categorized according to the direction toward the SMA when initiating dissection around the SMA: anterior approach (two articles), posterior approach (four articles), right approach (16 articles), and left approach (three articles). Thus, many reports used the right approach. Most articles provided a technical description. Some articles showed the advantage of their method in a comparison study. However, these were single-center retrospective studies with a small sample size. CONCLUSIONS: Various approaches for MIPD have been reported; however, few authors have reported the advantage of their methods compared to other methods. Further discussion is needed to clarify the appropriate surgical approach to the SMA during MIPD.

Minimally invasive anatomic liver resection: Results of a survey of world experts.

BACKGROUND: Although the number of minimally invasive liver resections (MILRs) has been steadily increasing in many institutions, minimally invasive anatomic liver resection (MIALR) remains a complicated procedure that has not been standardized. We present the results of a survey among expert liver surgeons as a benchmark for standardizing MIALR. METHOD: We administered this survey to 34 expert liver surgeons who routinely perform MIALR. The survey contained questions on personal experience with liver resection, inflow/outflow control methods, and identification techniques of intersegmental/sectional planes (IPs). RESULTS: All 34 participants completed the survey; 24 experts (70%) had more than 11 years of experience with MILR, and over 80% of experts had performed over 100 open resections and MILRs each. Regarding the methods used for laparoscopic or robotic anatomic resection, the Glissonean approach (GA) was a more frequent procedure than the hilar approach (HA). Although hepatic veins were considered essential landmarks, the exposure methods varied. The top three techniques that the experts recommended for identifying IPs were creating a demarcation line, indocyanine green negative staining method, and intraoperative ultrasound. CONCLUSION: Minimally invasive anatomic liver resection remains a challenging procedure; however, a certain degree of consensus exists among expert liver surgeons.

International Expert Consensus on Precision Anatomy for minimally invasive distal pancreatectomy: PAM-HBP Surgery Project.

BACKGROUND: Surgical views with high resolution and magnification have enabled us to recognize the precise anatomical structures that can be used as landmarks during minimally invasive distal pancreatectomy (MIDP). This study aimed to validate the usefulness of anatomy-based approaches for MIDP before and during the Expert Consensus Meeting: Precision Anatomy for Minimally Invasive HBP Surgery (February 24, 2021). METHODS: Twenty-five international MIDP experts developed clinical questions regarding surgical anatomy and approaches for MIDP. Studies identified via a comprehensive literature search were classified using Scottish Intercollegiate Guidelines Network methodology. Online Delphi voting was conducted after experts had drafted the recommendations, with the goal of obtaining >75% consensus. Experts discussed the revised recommendations in front of the validation committee and an international audience of 384 attendees. Finalized recommendations were made after a second round of online Delphi voting. RESULTS: Four clinical questions were addressed, resulting in 10 recommendations. All recommendations reached at least a 75% consensus among experts. CONCLUSIONS: The expert consensus on precision anatomy for MIDP has been presented as a set of recommendations based on available evidence and expert opinions. These recommendations should guide experts and trainees in performing safe MIDP and foster its appropriate dissemination worldwide.

International expert consensus on precision anatomy for minimally invasive pancreatoduodenectomy: PAM-HBP surgery project.

BACKGROUND: The anatomical structure around the pancreatic head is very complex and it is important to understand its precise anatomy and corresponding anatomical approach to safely perform minimally invasive pancreatoduodenectomy (MIPD). This consensus statement aimed to develop recommendations for elucidating the anatomy and surgical approaches to MIPD. METHODS: Studies identified via a comprehensive literature search were classified using the Scottish Intercollegiate Guidelines Network method. Delphi voting was conducted after experts had drafted recommendations, with a goal of obtaining >75% consensus. Experts discussed the revised recommendations with the validation committee and an international audience of 384 attendees. Finalized recommendations were made after a second round of online Delphi voting. RESULTS: Three clinical questions were addressed, providing six recommendations. All recommendations reached at least a consensus of 75%. Preoperatively evaluating the presence of anatomical variations and superior mesenteric artery (SMA) and superior mesenteric vein (SMV) branching patterns was recommended. Moreover, it was recommended to fully understand the anatomical approach to SMA and intraoperatively confirm the SMA course based on each anatomical landmark before initiating dissection. CONCLUSIONS: MIPD experts suggest that surgical trainees perform resection based on precise anatomical landmarks for safe and reliable MIPD.

Reconsideration of the Appropriate Dissection Range Based on Japanese Anatomical Classification for Resectable Pancreatic Head Cancer in the Era of Multimodal Treatment.

Patients with resectable pancreatic cancer are considered to already have micro-distant metastasis, because most of the recurrence patterns postoperatively are distant metastases. Multimodal treatment dramatically improves prognosis; thus, micro-distant metastasis is considered to be controlled by chemotherapy. The survival benefit of "regional lymph node dissection" for pancreatic head cancer remains unclear. We reviewed the literature that could be helpful in determining the appropriate resection range. Regional lymph nodes with no suspected metastases on preoperative imaging may become areas treated with preoperative and postoperative adjuvant chemotherapy. Many studies have reported that the R0 resection rate is associated with prognosis. Thus, "dissection to achieve R0 resection" is required. The recent development of high-quality computed tomography has made it possible to evaluate the extent of cancer infiltration. Therefore, it is possible to simulate the dissection range to achieve R0 resection preoperatively. However, it is often difficult to distinguish between areas of inflammatory changes and cancer infiltration during resection. Even if the "dissection to achieve R0 resection" range is simulated based on the computed tomography evaluation, it is difficult to identify the range intraoperatively. It is necessary to be aware of anatomical landmarks to determine the appropriate dissection range during surgery.

Cis P-tau underlies vascular contribution to cognitive impairment and dementia and can be effectively targeted by immunotherapy in mice.

Compelling evidence supports vascular contributions to cognitive impairment and dementia (VCID) including Alzheimer's disease (AD), but the underlying pathogenic mechanisms and treatments are not fully understood. Cis P-tau is an early driver of neurodegeneration resulting from traumatic brain injury, but its role in VCID remains unclear. Here, we found robust cis P-tau despite no tau tangles in patients with VCID and in mice modeling key aspects of clinical VCID, likely because of the inhibition of its isomerase Pin1 by DAPK1. Elimination of cis P-tau in VCID mice using cis-targeted immunotherapy, brain-specific Pin1 overexpression, or DAPK1 knockout effectively rescues VCID-like neurodegeneration and cognitive impairment in executive function. Cis mAb also prevents and ameliorates progression of AD-like neurodegeneration and memory loss in mice. Furthermore, single-cell RNA sequencing revealed that young VCID mice display diverse cortical cell type-specific transcriptomic changes resembling old patients with AD, and the vast majority of these global changes were recovered by cis-targeted immunotherapy. Moreover, purified soluble cis P-tau was sufficient to induce progressive neurodegeneration and brain dysfunction by causing axonopathy and conserved transcriptomic signature found in VCID mice and patients with AD with early pathology. Thus, cis P-tau might play a major role in mediating VCID and AD, and antibody targeting it may be useful for early diagnosis, prevention, and treatment of cognitive impairment and dementia after neurovascular insults and in AD.

Correction to: Intramural metastasis to the appendix from ascending colon cancer: a case report.

In the original publication of this article [1], an author's name should be changed from Shin Takasue to Shin Takesue.

Intramural metastasis to the appendix from ascending colon cancer: a case report.

BACKGROUND: Intramural metastasis is rare in colorectal cancer, especially metastasis of ascending colon cancer to the appendix. CASE PRESENTATION: A 64-year-old man was admitted to our hospital for surgery for ascending colon cancer detected by medical examination. Colonoscopy identified a type-2 tumor in the ascending colon, which was diagnosed as adenocarcinoma. Abdominal computed tomography revealed focal thickening of the ascending colon and middle of the appendix and swelling of the lymph nodes around the ileocolic artery. The patient underwent laparoscopic right hemi-colectomy with D3 lymph node dissection. Histopathological findings revealed that the ascending colon cancer was moderately differentiated adenocarcinoma with lymphatic and vascular invasion (stage IIIB; pT3N2M0). Additionally, moderately differentiated adenocarcinoma was observed mainly in the submucosa and muscularis propria of the appendix, which was approximately 10 cm proximal to the ascending colon cancer. These findings indicated intramural metastasis to the appendix from the ascending colon cancer. The patient experienced recurrence with lung metastasis 2.5 years after the first surgery. CONCLUSIONS: Intramural metastasis of ascending colon cancer to the appendix is extremely rare. Because the risk of recurrence and the prognosis for intramural metastasis has not been clarified, careful follow-up is recommended.

Endoscopic Transpapillary Pancreatic Duct Stent Placement for Symptomatic Peripancreatic Fluid Collection Caused by Clinically Relevant Postoperative Pancreatic Fistula After Distal Pancreatectomy.

This study aimed to evaluate the safety and efficacy of endoscopic transpapillary pancreatic duct stent placement (ETPS) for symptomatic peripancreatic fluid collection caused by postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP). ETPS was also compared with percutaneous drainage (PTD). Retrospectively 38 patients were studied who developed clinically relevant POPF. Of 38 patients, 4 underwent PTD and 11 underwent ETPS. Technical and clinical success rates of ETPS (100% and 91%, respectively) were comparable with PTD (100% and 75%, respectively). The tip of a pancreatic stent was placed over the pancreatic stump in 4 patients and draining of pus through the pancreatic stent was observed. The hospital stay after DP and the interval from intervention to discharge were significantly shorter in the ETPS group than in the PTD group. ETPS is safe and successful for managing peripancreatic fluid collection caused by POPF after DP and should be considered as a therapeutic option.